Abraxis BioScience Abraxane • Nanoparticle albumin-bound (nab) paclitaxel, paclitaxel albumin bound (PAB) • ABI-007

PRODUCT DESIGNATION

Generic Name

Nanoparticle albumin-bound (nab) paclitaxel, paclitaxel albumin bound (PAB)

Brand Name

Abraxane

Other Designation

ABI-007

Description

Abraxane is a cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.

Structure Link

Click for Structure   (Link will open in new window.)

Special Report

In March 2010, Abraxis BioScience reported that the phase III clinical trial (protocol ID: CA031; NCT00540514) comparing Abraxane (protein-bound paclitaxel) with paclitaxel (Taxol; Bristol-Myers Squibb), both in combination with carboplatin, met its primary endpoint by demonstrating that Abraxane showed a significant improvement in overall response rate (ORR) compared to Taxol, in the first line treatment of patients with advanced non-small cell lung cancer (nsclc), as assessed by independent radiologist review. This trial is the subject of a special protocol assessment (SPA) with the FDA, which means that the FDA has previously agreed upon the design, clinical endpoints, and statistical analyses of the trial. Specifically, the FDA agreed that the demonstration of a statistically superior response rate of the Abraxane and carboplatin combination over the paclitaxel and carboplatin combination would be sufficient to submit a supplemental new drug application (sNDA), as a 505(b)(2) submission, for approval of Abraxane in combination with carboplatin for first line treatment of nsclc. See Combination Trials module.

PRODUCT SOURCE

Primary Developer

Abraxis BioScience

Affiliations

APP Pharmaceuticals
Abraxis Oncology, a division of APP created in November 2003, will be responsible for the commercialization of Abraxane in the USA.

In November 2001, American BioScience licensed exclusive North American manufacturing and marketing rights to ABI-007 to American Pharmaceutical Partners, its majority-owned subsidiary, for a period of 3 years for $45 million. American Pharmaceutical Partners also gained nonexclusive rights to manufacture ABI-007 for sales outside North America and in North America when the 3-year exclusive rights expire.

AstraZeneca (terminated 1/09)
In November 2008, Abraxis BioScience entered into an agreement with AstraZeneca, under which, subject to approval by the board of directors of Abraxis, the company would re-acquire the exclusive rights to market Abraxane (paclitaxel protein-bound particles for injectable suspension) in the USA. The collaboration was subsequently terminated in January 2009.

April 2006, Abraxis BioScience entered into an agreement with AstraZeneca for the co-promotion of Abraxane in the USA for a term of 5 1/2 years. Under the terms of the agreement, AstraZeneca will pay Abraxis an upfront fee of $200 million and equally share in the costs associated with advertising, promotions in the USA and certain clinical trials that are part of the overall clinical development program. Further milestone payments will be made to Abraxis upon the achievement of new indication approvals within prespecified timelines. The co-promotion agreement, beginning July 1, 2006, will run for five and a half years. AstraZeneca will receive a 22% commission on net sales of Abraxane during the term of the agreement, with a trailing commission of 10% for the first year and 5% for the second year following the 5-year term. Abraxis will retain all responsibility for clinical and regulatory development, manufacture and distribution of the product. In addition to the sales force already established at Abraxis, AstraZeneca will add an experienced sales force who will now solely co-promote Abraxane in the USA market. This commercial collaboration will provide significantly greater reach and is expected to accelerate the market penetration of Abraxane in the USA. Abraxis BioScience will grant AstraZeneca a right of first offer to license or co-promote Abraxane outside the USA, other than selected countries, should a partner be sought.

Other
As of December 2008, Abraxane was launched in Australia in collaboration with Specialised Therapeutics Australia, and in the United Arab Emirates with partner Neobiocon

PRODUCT SPECIFICATIONS

Therapeutic Indication

Malignancy

Therapeutic Category

Cytotoxic

Drug Class

Taxane

Drug Type

Spindle poison • Tubulin polymerization inhibitor • Antimitotic

Mechanism

Cytotoxicity

Mechanism Details

Preclinical animal data show that large-sized (up to 600 mm3) orthotopic tumors and lymphatic and systemic metastases can be eradicated using repetitive cycles of Abraxane administered concurrently with Avastin. The dose of Abraxane and the timing of Avastin administration were modified to achieve sustainable regressions of large-sized primary tumors as well as lymphatic and lung metastases. Luciferase-tagged MDA-MB-231-Luc+ human breast carcinoma cells were implanted orthotopically and allowed to grow to 350-600 mm3 in size. Animals were then treated with Abraxane. In combination groups, Avastin was administered either concurrently with Abraxane or post-Abraxane treatment; and either continued for the duration of the experiment or discontinued after cessation of Abraxane therapy. Tumor growth was monitored for about 100 days post-implantation, and organs were analyzed for luciferase activity representing metastatic spread. After two cycles of Abraxane and Avastin administered concurrently all preclinical models were free of metastasis in lymph nodes and lungs and there was complete regression of the large orthotopic primary MDA-MB-231-Luc+ tumors. Three cycles of combined therapy with Abraxane reduced average metastatic burden by 98% and regressed primary tumors by 80%. Optimal effect of Avastin was observed when administered concurrently with Abraxane and continued for the duration of the experiment. No benefits of the combined therapy were observed when Avastin was administered sequentially after Abraxane. No toxicity was observed in any of the treated preclinical models (Volk L, etal, AACR08, Abs. 4021).

C3H mice were injected with mouse ovarian carcinoma (OCa-1) cells and treated with a single dose of 10 Gy radiation, IV Abraxane 90 mg/kg, or both. No drug-related toxicity was observed at the 90 mg/kg dose. Treatment endpoint was absolute tumor growth delay (AGD), defined as the difference (in days) between treated and untreated tumors to grow from 7-12 mm in diameter. In mice treated with ABI-007 and radiation combined, enhancement factor (EF) was calculated as the ratio of the difference in days to grow from 7-12 mm in diameter between the combination-treated tumors and those treated with Abraxane alone, to the AGD of tumors treated with radiation only. Abraxane as a single agent significantly prolonged the growth delay of OCa-1 tumors by about 2 weeks, with untreated tumors growing to 12 mm diameter in 16 days and those treated with Abraxane in 31 days. Abraxane was slightly more effective as a single agent than a single dose of 10 Gy radiation. When administered up to 5 days pre-radiation, Abraxane produced a supra-additive antitumor effect. At short inter-treatment intervals of 9-24 hours, EF was 1.3, increased to 2.5 at inter-treatment intervals of 2-3 days, and then decreased to 1.8 at 4 days, and 1.5 at 5 days. When Abraxane was administered after radiation, combined antitumor treatment effect was less than additive. Thus, Abraxane possesses single agent anti-tumor activity against this ovarian tumor and greatly augments the effect of radiotherapy in a time-dependent manner. Enhanced treatment effects are likely the result of multiple mechanisms with a cell cycle related mechanism (G2/M arrest) controlling the short inter-treatment intervals and tumor reoxygenation being the dominate mechanism when treatment intervals take several days (Mason KA, etal, AACR06, Abs. 5439).

A preclinical study compared the antitumor activity of docetaxel (Taxotere; sanofi aventis) and Abraxane in MX-1 breast carcinoma xenograft (both docetaxel and Abraxane at 15 mg/kg), and in LX-1 lung, PC3 prostate, HT29 colon, and MDA-MB-231 breast (docetaxel at 15 mg/kg, Abraxane at 50 mg/kg and 120 mg/kg). MTD of Abraxane was between 120-240 mg/kg, and MTD of docetaxel was 15mg/kg. In MX-1 breast carcinoma cells, Abraxane at 15 mg/kg was more effective than docetaxel at 15 mg/kg (p<0.0001), with tumor growth inhibition (TGI) of 79.8% and 29.1%, respectively. In LX-1 lung tumor cells, Abraxane at 120 mg/kg (TGI=98%) and at 50 mg/kg (TGI=84%) were superior to docetaxel at 15 mg/kg (TGI=61%; p<0.0001 and p=0.0001, respectively) (Trieu V, etal, AACR06, Abs. 5437). In HEr2-positive xenografts (HT29, PC3, and MDA-MB-231), the efficacy of Abraxane increased with increasing SPARC expression, compared to docetaxel. In HT29 colon tumor cells (high SPARC expressor), Abraxane at 120 mg/kg (TGI=65%) and 50 mg/kg (TGI=50%) were superior to docetaxel 15 mg/kg (TGI=36%; p<0.0001 and p=0.006, respectively). In PC3 prostate cancer cells (medium SPARC expressor), Abraxane at 120 mg/kg (TGI=99%) was equivalent to docetaxel 15 mg/kg (TGI=97%), and Abraxane 50 mg/kg (TGI=94%) was less effective than docetaxel 15 mg/kg (p<0.0001). In MDA-MB-231 breast tumor cells (low SPARC expressor), both Abraxane 120 mg/kg (TGI=99%) and 50 mg/kg (TGI=94%) were less effective than docetaxel 15 mg/kg (TGI=97%; p<0.0001 for each) (Desai N, etal, EORTC-NCI-AACR06, Abs. 505).

Ongoing mechanistic studies suggest that the increased antitumor activity of Abraxane and its increased intratumoral concentration may be attributed, in part, to albumin-mediated receptor transport of the drug across the blood vessel wall into the tumor. Targeting endothelial cell transport is a novel approach to increasing drug concentration in tumors, exploiting a natural biological pathway the malignant cell inherently uses to supply itself nutrients and energy for rapid growth. Using this mechanism, the target would be shifted from tumor cells themselves to the specific albumin receptor on the blood vessel wall of the tumor neovasculature. Abraxane represents the first example of the albumin-bound nanoparticle technology platform which may have the potential to exploit this natural biological pathway.

A preclinical study examined the role of SPARC, a matricellular protein, in albumin uptake/accumulation and tumor distribution of nanoparticle albumin-bound paclitaxel (ABI-007) compared to Taxol in breast tumors. Overexpression of SPARC was examined by antibody immunostaining of primary breast tumor (n=141), normal human breast tissue (n=115), other normal human tissues, human MX-1 tumor xenografts, and normal mouse tissues (scored 0-4). SPARC overexpression by cultured mammary carcinoma (MX-1) relative to cultured primary human endothelial cells from umbilical veins (HUVEC) or lung microvasculature (HMVEC), human mammary epithelial cells (HMEC), was examined by fluorescence immunohistochemistry. Cellular albumin uptake was examined by visualizing MX-1 cells exposed to FITC-labeled albumin by fluorescent microscopy. Human primary breast tumors exhibited strong SPARC staning of 46% (score >/=2) compared to 1% for normal breast tissue. SPARC expression was absent in normal human tissue (stomach, colon, rectum, liver, spleen, lung, kidney, brain, prostate, heart) (n=3 donors). Strong focal SPARC staining (score 4) was detected in MX-1 xenografts, which colocalized with albumin staining. SPARC was absent in normal mouse tissue (liver, lung, muscle, brain, heart, stomach, spleen) (n=20 mice), except for variable expression in the kidney. SPARC expression was strong in cultured MX-1 cells relative to HUVEC, HMVEC, or HMEC. Significant surface SPARC was observed on MX-1. FITC-labeled albumin was rapidly internalized by MX-1 by a lysosome-independent mechanism (determined in conjunction with lysotracker) and colocalized with intracellular SPARC. These results indicate that SPARC was overexpressed in human breast tumor and absent in normal tissue. Colocalization of albumin and SPARC in MX-1 tumor suggested that SPARC, by its albumin-binding activity, may behave as an intratumoral target for albumin-bound paclitaxel in Abraxane. MX-1 cells rapidly internalized albumin, which colocalized with SPARC intracellularly. These observations may partly explain the greater tumor accumulation of Abraxane compared to Taxol. SPARC screening may identify patients more responsive to Abraxane (Trieu V, etal, AACR05, Abs. 5584).

Human MX-1 tumor xenografts, human primary breast tumor tissues (n=141), and normal human breast tissue (n=115) were immunostained and scored (0-4) for albumin, SPARC, and caveolin-1 staining. Cultured MX-1 cells were also immunostained for SPARC. Abraxane and paclitaxel (Taxol; Amgen) prepared with radioactive paclitaxel (20 mg/kg IV) were used to determine the biodistribution of paclitaxel in normal tissues of athymic mice. Albumin staining in the MX-1 tumor was focal and colocalized with SPARC. Based on caveolin-1 staining, blood vessel density in albumin-containing areas was no different from albumin-free areas. SPARC expression by MX-1 cultured cells was confirmed by positive staining with anti-SPARC antibody. Paclitaxel accumulation in normal tissues (SPARC- negative) was significantly lower for Abraxane versus Taxol (p<0.004) in 7/10 tissues. Strong SPARC staining (score >2) was observed in 46% of human primary breast tumors versus 1% for normal tissues (p<0.0001). In a subset of 50 tumor tissues, SPARC expression did not correlate with staging, estrogen receptor status, or progesterone receptor status; however, there was trend for high SPARC expression among p53-negative tumors. By its albumin binding activity, SPARC may act an intratumoral target for albumin binding in breast tumors. Improved tumor accumulation of Abraxane versus Taxol may be partly explained by the albumin dependence of paclitaxel transport in Abraxane. Abraxane accumulation in normal tissues was lower than for Taxol, consistent with lack of SPARC expression in normal tissues. Screening of patients for SPARC may identify those more responsive to Abraxane (Desai N, etal, SABCS04, Abs. 206).

Target

Microtubules

Administration Route

intravenous (IV) • intra-arterial

Delivery Technology

Nanoparticle formulation

Delivery Details

ABI-007 is a novel protein (albumin) stabilized, cremophor-free, nanoparticle formulation of paclitaxel that may be used without premedication, and may allow the administration of paclitaxel safely at doses higher than 175 mg/m².

Abraxane, having eliminated the risks of toxic solvents, requires no premedication and can deliver a 50% higher dose of chemotherapy than possible with paclitaxel. Inadvertent substitution of solvent-based paclitaxel at 260 mg/m² without steroid premedication over 30 minutes could pose significant risks to patients potentially resulting in fatal hypersensitivity reactions, a high incidence of severe neutropenia and a possibility for severe, prolonged peripheral neuropathy.

ABI's proprietary nanoparticle albumin-bound (nab) technology binds water-insoluble compounds with albumin in a nanoparticle state (130 nanometers or 100th the size of a single red blood cell) via a novel manufacturing process that retains the full biological properties of albumin. Albumin is the most ubiquitous protein in the human body and is a natural carrier for hydrophobic (water-insoluble) nutrients, vitamins, steroids and other compounds. Molecules bound to albumin in the body are readily available for delivery to cells. Albumin regulates the delivery of essential molecules across the blood vessel wall into tissues by activating recently discovered albumin receptors on blood vessels. Albumin has been shown to accumulate in areas of inflammation and in some tumors. Because the albumin binding is very similar to the binding that naturally occurs in the body, the resulting product is readily bioavailable once administered to patients.

According to the proposed mechanism of delivery of this nab-driven chemotherapy, a nanoshell of the human blood protein albumin targets a previously unrecognized tumor-activated, albumin-specific biologic pathway within tumors. This nano-shuttle system is believed to activate Gp60, an albumin-specific receptor-mediated transcytosis path through the cell wall of proliferating tumor cells, using caveolin-1 activated caveolar transport. Once in the stromal microenvironment, the albumin-bound drug may be preferentially localized by SPARC, a second albumin-specific binding protein secreted into the stroma by tumor cells. The resulting collapse of the stroma surrounding the tumor cell may thus enhance the delivery of the nab-chemotherapeutic to the intracellular core of the tumor cell itself.

In animal models, ABI's nab technology resulted in increased delivery of chemotherapeutic drugs to the tumor compared with solvent-based drugs. The mechanism for this advantage is being actively studied and may be related to albumin-activated transport of molecules into tissues by binding to the gp60 albumin receptor on blood vessels with subsequent accumulation of albumin in tumors. By tapping into these natural pathways it is possible that the increased uptake of albumin by rapidly growing tumors results in increased delivery of chemotherapeutic drugs to the tumor. The clinical relevance of these findings is unknown at this time.

Research has shown that ABI-007, which is approximately 1/100th the size of a single red blood cell (RBC), acts as a novel biologic nanotransporter for hydrophobic drugs such as paclitaxel, by making use of the properties of albumin, resulting in an increased and prolonged intracellular availability of the chemotherapeutic agent. The efficient penetration of RBC by ABI-007 suggests that the RBC may also serve as a secondary storage depot for paclitaxel, and that the RBC deliver paclitaxel to cells through a sustained-release mechanism, with prolonged activity of the parent molecule.

The Protosphere Nanoparticle technology, on which ABI-007 is based, integrates biocompatible proteins with drugs to create the nanoparticle form of the drug having a size of about 100-200 nanometers (approximately 1/100th the size of a single red blood cell). This technology, developed by American Bioscience (ABI), has been tested for administration of drugs by intravenous, intra-arterial, inhalational, oral, and topical use. These protein-engineered nanoparticles avoid the use of toxic solvents and emulsifiers commonly used for administration of insoluble drugs e.g., paclitaxel and docetaxel, the active ingredients in Taxol and Taxotere, respectively. It is believed that this nanotechnology may allow the particle containing drug to pass through leaky vessels associated with tumors, potentially resulting in higher local concentration of the anticancer drug at the tumor site.

Toxicities

In the pivotal phase III trial, neutropenia (all grades) was experienced by 80% of patients treated with Abraxane and 82% of patients treated with paclitaxel; the rate of Grade 4 neutropenia experienced by Abraxane-treated patients despite the 50% higher dose administered was 9% compared to 22% for the paclitaxel-treated patients. No patients treated with Abraxane experienced severe hypersensitivity reactions. Sensory neuropathy (all grades) occurred in 71% of patients treated with Abraxane and 56% of those treated with paclitaxel. Grade 3 sensory neuropathy symptoms were observed in 10% of patients on Abraxane versus 2% of those on paclitaxel. There were no episodes of Grade 4 neuropathy in this trial. Among patients who developed Grade 3 peripheral sensory neuropathy while on Abraxane, 58% (14/24) had documented rapid improvement in symptoms after a median of 22 days, and 42% of patients (10/24) were able to resume treatment at a reduced dose. Only 3% of patients on Abraxane discontinued treatment because of peripheral neuropathy. No severe edema was observed, and nail changes were uncommon in both treatment arms. There was no increased toxicity in elderly patients treated with Abraxane compared to younger patients.

The most important adverse events include neutropenia (all cases=80%; severe=9%), anemia (all=33%; severe=1%), infections (24%), sensory neuropathy (any symptoms=71%; severe=10%), nausea (any=30%; severe=3%), vomiting (any=18%; severe=4%), diarrhea (any=26%; severe=<1%), myalgia/arthralgia (any=44%; severe=8%), and mucositis (any=7%; severe=<1%). Other adverse reactions included asthenia (any=47%; severe=8%), ocular/visual disturbances (any=13%; severe=1%), fluid retention (any=10%; severe=0%), alopecia (90%), hepatic dysfunction (elevations in bilirubin=7%, alkaline phosphatase=36%, AST [SGOT]=39%), and renal dysfunction (any=11%; severe=1%). Thrombocytopenia (any=2%; severe=<1%), hypersensitivity reactions (any=4%; severe=0%), cardiovascular reactions (severe=3%), and injection site reactions (1%) were uncommon.

Cancer Indications

solid tumor • breast cancer • ovarian cancer • lung cancer • Kaposi's sarcoma (KS) • colorectal cancer • head and neck cancer • melanoma, malignant • hematologic malignancy • prostate cancer • cervical cancer

Approved Indications

breast cancer after failure of combination chemotherapy for metastatic disease (Stage IV), or disease relapsed within 6 months of adjuvant chemotherapy that included an anthracycline unless clinically contraindicated • breast cancer, metastatic, first line or refractory  

Indications in Development

solid tumors, advanced, refractory • solid tumors, advanced, metastatic • head and neck cancer, metastatic, refractory • non-small-cell lung cancer (nsclc), advanced, chemotherapy-naive • melanoma, malignant, metastatic • melanoma, malignant, cutaneous, metastatic, chemotherapy-naive • breast cancer, inoperable or metastatic, first line, previously treated • breast cancer, metastatic • breast cancer, advanced, relapsed or refractory • ovarian cancer • prostate cancer • breast cancer, node positive • cervical cancer, persistent or recurrent, refractory • pancreatic cancer, locally advanced, inoperable, or metastatic • bladder cancer, transitional cell, refractory

Preclinical History

Immunohistochemistry staining showed that 72/119 head and neck tumor tissue and 0/24 normal tissue samples were SPARC-positive (p<0.0001). Among all head and neck tumor samples, SPARC was expressed in 22/27 (81%) tongue tumors, 12/18 (68%) cheek tumors, 2/3 (67%) ethmoid sinus tumors, 17/33 (52%) larynx tumors, 3/6 (50%) jaw tumors, 3/6 (50%) lip tumors, 9/20 (45%) nose tumors, 0/3 (0%) gingival tumors, and 0/3 (0%) nasopharyngeal tumors. Out of 16 patients treated with Abraxane (CR/PR, n=11; SD/PD, n=5), 10/11 (91%) of responders demonstrated SPARC expression, versus 2/5 (40%) non-responders (p=0.06). Abraxane response was significantly higher in SPARC-positive patients (10/12, 83%) versus SPARC-negative patients (1/4, 25%; p=0.06). SPARC-negative patients exhibited significantly lower response rate (1/4, 25%) versus the ORR of 78% (p<0.05) in the phase I clinical trial of Abraxane in patients with squamous cell carcinoma of the tongue (Damascelli B, etal, AJR Am J Roentgenol July 2003; 181[1]:253-60). SPARC expression in head and neck tumors may account for the enhanced response noted with Abraxane (Trieu V, etal, AACR06, Abs. 4477).

A preclinical study determined the effects of Abraxane and bevacizumab (Avastin; Genentech) as single or combined therapy on the growth of orthotopically implanted MDA-MB-231 breast tumors, and on lymph node and lung metastasis. Human breast carcinoma cells were implanted into the mammary fatpad of female nu/nu mice and allowed to reach an average size of 230 mm³ before treatment. A total of 10 mice were treated with 1 or 2 cycles of Abraxane (10 mg/kg, QD x 5), followed by Avastin (4 mg/kg) twice a week for 6 weeks. Additional groups were treated with Abraxane alone, Avastin alone, or saline. No toxicity was observed in any of the groups. Tumors reached an average size of 1000 mm³ per group on days 25, 30, 45, and 80 after treatment with saline, Avastin, and 1 and 2 cycles of Abraxane, respectively. Combined Avastin and Abraxane therapy, particularly with 2 cycles of Abraxane, yielded significantly better outcomes than either therapy alone. Complete regression was observed in 30% of mice; tumors in the remaining mice were reduced by 90%, compared to controls. Combined therapy reduced lymph node and lung metastasis, with 6/20 mice in combination therapy having no metastasis (p=0.03 versus controls). Total metastatic burden to lymph nodes was reduced in a dose-dependent manner, with 42%, 85%, and 82% suppression of lymph node metastasis burden at Avastin doses of 2, 4, and 8 mg/kg, respectively. Avastin alone suppressed node metastasis by only 8%. Metastatic burden to the lungs was not sufficient for statistical analysis, although the same trend was observed. Avastin alone did not significantly inhibit primary tumors or metastasis. The efficacy of Abraxane was much higher than that of Avastin and was substantially improved by adding a second cycle of the drug. The combination of Abraxane and Avastin eradicated primary tumors in 30% of mice and completely eliminated regional and distant metastases in 70% of treated animals (Ran S, etal, SABCS06, Abs. 1094).

ABI-007 and Taxol were administered IV to Harlan Sprague-Dawley male rats to determine PK and drug disposition. Paclitaxel PK properties also were assessed in 27 patients with advanced solid tumors who were randomly assigned to treatment with ABI-007 (260 mg/m²) for 30 minutes (n=14) or Taxol (175 mg/m²) for 3 hours (n = 13), with cycles repeated every 3 weeks. The volume of distribution at steady state and clearance for paclitaxel formulated as Cremophor-free nanoparticle ABI-007 were significantly greater than those for paclitaxel formulated with Cremophor (Taxol) in rats. Fecal excretion was the main elimination pathway with both formulations. Consistent with the preclinical data, paclitaxel clearance and volume of distribution were significantly higher for ABI-007 than for Taxol in humans (21.13 compared to 14.76 L/h/m² and 663.8 compared to 433.4 L/h/m²). Paclitaxel formulated as ABI-007 differs from paclitaxel formulated as Taxol, with a higher plasma clearance and a larger volume of distribution. This finding is consistent with the absence of paclitaxel-sequestering Cremophor micelles after administration of ABI-007. This unique property of ABI-007 could be important for its therapeutic effectiveness (Sparreboom A, etal, Clin Cancer Res, 1 Jun 2005;11(11):4136-43).

A preclinical study examined the safety and efficacy of Abraxane compared to docetaxel in preclinical models. In this dose-escalation trial, Abraxane and docetaxel were administered to nude mice on an every 4 days for 3 cycles schedule. The dose levels examined were docetaxel at 7, 15, 22, 33, and 50 mg/kg and Abraxane at 15, 30, 60, 120, and 240 mg/kg. Antitumor activity of Abraxane and docetaxel was compared in nude mice with human MX-1 mammary xenografts at a dose of 15 mg/kg weekly for 3 weeks. In the dose-escalation study in mice, the docetaxel maximum tolerated dose (MTD) was 15 mg/kg and lethal dose (LD100) was 50 mg/kg. In contrast, the Abraxane MTD was between 120 and 240 mg/kg and LD100 was 240 mg/kg. In the tumor study, Abraxane was more effective than equal doses of docetaxel in tumor growth inhibition (79.8% compared to 29.1%). These results indicate that nanoparticle abumin-bound paclitaxel (Abraxane) is superior to docetaxel in the MX-1 tumor model when tested at equal doses. Additionally, the toxicity of Abraxane was significantly lower than that of Taxotere, which would allow dosing of Abraxane at substantially higher levels. These results are comparable to the enhanced therapeutic index observed with Abraxane compared to Taxol and indicate that the presence of surfactants may impair the transport, antitumor activity and enhance the toxicity of taxanes. Studies in additional tumor models comparing Abraxane and Taxotere are ongoing (Desai N, etal, AACR05, Abs. 1437).

A preclinical study examined the antiangiogenic and antitumor activity of ABI-007. The antiangiogenic activity of ABI-007 was examined by the rat aortic ring, human umbilical vein endothelial cell (HUVEC) proliferation and tube formation assays. Optimal dose of ABI-007 for metronomic therapy was determined by measuring the levels of circulating endothelial progenitors in peripheral blood of Bal/c non-tumor bearing mice (n=5 per group; dosing: 1-30 mg/kg, IP, once a day for 7 days) with flow cytometry. Subsequently, the antitumor effects of metronomic (once a day; IP) and MTD (once a day for 5 days; 1 cycle; IV) ABI-007 and Taxol were examined and compared in SCID mice bearing human MDA-MD-231 breast and PC3 prostate cancer xenografts. ABI-007 at 5 nM significantly inhibited rat aortic microvessel outgrowth by 53%, human endothelial cell proliferation by 24% and tube formation by 75%. The optimal dose of ABI-007 for metronomic therapy was determined to be 6-10 mg/kg based on circulating endothelial progenitors measurements. Metronomic ABI-007 (6 mg/kg) but not Taxol (1.3 mg/kg) significantly inhibited tumor growth in both xenograft models. Neither ABI-007 nor Taxol administered metronomically caused any weight loss. Although MTD ABI-007 (30 mg/kg) inhibited tumor growth more effectively than MTD Taxol (13 mg/kg), significant weight loss was observed with the former. Interestingly, the antitumor effect of metronomic ABI-007 approximated that of MTD Taxol. These results indicate that ABI-007 exhibits potent antiangiogenic and antitumor activity when used in a metronomic regimen (Ng S, etal, AACR05, Abs. 2988).

A preclinical study examined the effects of Abraxane in combination with antiangiogenic Hunter Killer Peptide (HKP) in MDA-MB-435 human breast tumor xenografts. MDA-MB-435 human tumor xenografts were established at an average tumor volume of 100 mm3, mice were randomized into groups of 12-13 animals and administered HKP, Abraxane, or HKP and Abraxane. HKP (250 ug) was administered IV once a week for 16 weeks. Abraxane was administered IV daily for 5 days at 10 mg/kg/day only for the first week of treatment. The Abraxane dose used was substantially below its MTD (30mg/kg/day, once a day for 5 days) to prevent the tumor from complete regression so the effect of HKP could be observed. After 19 weeks of treatment, tumor volume was significantly reduced between control group (10,298 mm3 ± 2,570) and HKP (4,372 mm3 ± 2,470) or ABI-007 (3,909 mm3 ± 506). The combination of ABI-007 and HKP significantly decreased the tumor volume compared to either monotherapy (411 mm3 ± 386). The treatments were well tolerated. The combination of Abraxane (ABI-007), a nanoparticle albumin-bound paclitaxel, with the vascular targeting anti-angiogenic dimeric peptide HKP (CNGRC-GG-(KLAKLAK)2) against the MDA-MB-435 xenograft breast tumor demonstrated a significant decrease in tumor volume compared to monotherapy with either agent alone. These results indicate that the combination of Abraxane with antiangiogenic agents such as HKPs or perhaps bevacizumab (Avastin) may be beneficial (Riley R, etal, AACR05, Abs. 3007).

When the efficacy of ABI-007 was compared with Taxol at their respective MTD in 5 different human tumor xenografts (NCI-H522 lung, MX-1 mammary, SKOV-3 ovarian, PC-3 prostate, HT29 colon) in athymic nude mice, in all 5 studies, MTD of ABI-007 were 1.5–2.2 fold higher than Taxol. At the MTD, ABI-007 demonstrated superior efficacy than Taxol especially in the breast, colon and ovarian models (Desai N, etal, ASCO02, Abs. 462:116a).

MARKET STATUS

Approved/Filed Indication

breast cancer after failure of combination chemotherapy for metastatic disease (Stage IV), or disease relapsed within 6 months of adjuvant chemotherapy that included an anthracycline unless clinically contraindicated

Clinical Aspects

In April 2010, the Scottish Medicines Consortium (SMC) accepted Abraxane for restricted use within the National Health Service (NHS) for Scotland in patients who would otherwise be treated with docetaxel or 3-weekly solvent-based paclitaxel as second line treatment for metastatic breast cancer.

In Jume 2009, Abraxis launched Abraxane in China.

In February 2009, Abraxane was launched in Germany.

As of January 2009, Abraxane has been approved for marketing in 36 countries. In addition to Europe, Abraxane was recently launched in Australia in collaboration with Specialised Therapeutics Australia; in the United Arab Emirates with partner Neobiocon; and, in India with Biocon. The Korean FDA has granted marketing approval for Abraxane and the launch in that country is expected in 2009 with Abraxis’ partner Green Cross. Additionally, approval has been received in China. Abraxane is currently under active review in Japan and Russia.

In December 2008, Abraxis BioScience launched Abraxane in the European Union (EU), beginning with an introduction to the UK market. In the EU, Abraxane is indicated for the treatment of patients with metastatic breast cancer refractory to first line treatment for metastatic disease and not eligible for standard, anthracycline-containing therapy. The UK Department of Health approved a price of £246 per 100 mg vial of Abraxane. Following the current launch in the UK, Abraxane will be launched in Germany in the first quarter of 2009, followed by additional nations in Europe on a country by country basis. Innovex, a unit of Quintiles Transnational, is providing the sales force and commercial services for Abraxis BioScience in the EU. In the phase III clinical trial upon which European marketing approval was based, Abraxane nearly doubled the overall target lesion response rate versus solvent-based paclitaxel, resulting in a 28% improvement in progression-free survival (PFS) when compared to solvent-based paclitaxel. In addition, time-to-tumor progression (TTP) versus solvent-based paclitaxel was significantly prolonged in patients treated with Abraxane. The tolerability with Abraxane and solvent-based paclitaxel was comparable, despite the 50% greater dose of paclitaxel administered as Abraxane. Neutropenia was lower with Abraxane compared to solvent-based paclitaxel. Although there was an increase in incidence of Grade 3 peripheral neuropathy, time to improvement was improved compared to that reported for solvent-based paclitaxel. No adverse events were reported that were not already known for paclitaxel.

In October 2008, the Therapeutic Goods Administration (TGA) in Australia approved Abraxane (100 mg) for the treatment of metastatic carcinoma of the breast after failure of anthracycline therapy. Abraxis will market Abraxane in Australia through a strategic relationship with Specialised Therapeutics Australia, based in Melbourne.

In July 2008, Biocon and Abraxis BioScience launched of Abraxane in India for the treatment of breast cancer after failure of combination therapy for metastatic disease or relapse within six months of adjuvant chemotherapy. Abraxane is now available in India as a single-use 100 mg vial as a lyophilized powder, to be reconstituted for IV administration.

In July 2008, Abraxis received approval from the China State Food and Drug Administration to market Abraxane Paclitaxel for Injection (Albumin Bound) for the treatment of breast cancer after failure of standard chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. This approval was based on phase III clinical trials in the USA and China in which Abraxane doubled the response rate and significantly prolonged time to tumor progression. In the USA trial, Abraxane also significantly improved OS versus Taxol (paclitaxel) in the approved indication. According to data from the USA pivotal head-to-head trial, Abraxane nearly doubled the overall response rate versus Taxol (33% versus 19%; p=.001) and achieved a 25% improvement in time-to-tumor progression (TTP) when compared to Taxol. Furthermore, survival of patients treated with Abraxane in the second line setting was significantly prolonged by an additional 27% compared to solvent-based Taxol. The tolerability of the two agents was comparable, despite the 50% greater dose of paclitaxel administered as Abraxane. A multicenter, randomized, open label, phase II clinical trial, conducted in China between June 20, 2005 and August 1, 2006, enrolled 210 patients with metastatic breast cancer assigned to either IV paclitaxel (175 mg/m²) over 3 hours every 3 weeks (n=106) with standard premedication (steroids and antihistamines) or IV Abraxane (260 mg/m²) over 30 minutes every 3 weeks (n=104) without premedication for 1-6 cycles. [The MTD of nab-paclitaxel was 300 mg/m² infused over 30 minutes without premedication in Chinese patients with solid tumors (Teng XY, Ai Zheng, Nov 2004;23(11 Suppl):1431-6)]. In this randomized phase II clinical trial comparing nab-paclitaxel with solvent-based paclitaxel in Chinese patients with metastatic breast cancer, treatment with Abraxane produced a significantly higher overall response rate than solvent-based paclitaxel, consistent with the results seen in the global phase III clinical trial in Caucasian patients. The primary endpoint was investigator-assessed overall response rate (ORR) and assessment of safety and tolerability. Secondary endpoints included TTP, survival and PK. Abraxane significantly improved the investigator assessed ORR versus solvent-based paclitaxel (54% versus 29%; p=0.001). In an unplanned analysis, the response rate of 61% was greater in the nab-paclitaxel treatment arm for first line therapy (no prior anthracycline-containing therapy) compared to 21%, p=0.001) in the paclitaxel arm. Median TTP was also longer for Abraxane than for solvent-based paclitaxel, but the difference was not significant (7.6 months versus 6.2 months p=0.078) . Abraxane treatment was also associated with 26% improvement in PFS when compared to solvent-based paclitaxel (7.6 months versus 6.2 months; p=0.118). The aim of this randomized trial is to compare the response rates and to evaluate the safety of nab-paclitaxel with those of solvent-based paclitaxel in Chinese patients with metastatic breast cancer. The primary endpoints were overall response rate (CR+PR) and toxicity. Stable disease (SD) lasting >/=16 weeks was also noted. All patients treated with at least 1 dose of trial drug were evaluable for trial endpoints. The ORR was 54% (54/104) in the Abraxane arm versus 27% (29/106) in the paclitaxel arm; SD was 17% (18/104) and 25% (27/206), respectively. CBR was 69% (72/104) in the Abraxane arm versus 53% (56/106) in the paclitaxel arm; TTP was 7.8 months and 5.7 months, respectively. Common toxicities occurring at >/=20% of patients were alopecia (78%), peripheral neuropathy (75%, Grade 3=7%), neutropenia (65%), leucopenia (60%), myalgia (39%), arthralgia (23%), and nausea (21%) and were similar between groups. Grade 3/4 neutropenia, measured on days 1 and 8, was also similar between groups. Compared to solvent- based paclitaxel, treatment with nab-paclitaxel was associated with a higher response rate and longer TTP without increased toxicity. These comparative data in Chinese patients are almost identical to results previously reported in Caucasian patients (Gradishar WJ, etal, J Clin Oncol, 1 Nov 2005;23(31):7794-803). Abraxane significantly improved overall response rate versus solvent-based paclitaxel (54% versus 29%; p=<.001) and achieved a 26% improvement in PFS when compared to solvent-based paclitaxel (7.6 months versus 6.2 months; p=0.118). Both therapies had similar toxicity profiles (Guan Z, etal, ASCO07, Abs. 1038) .

As of July 2008, Abraxane was under regulatory review by the Federal Authority for Healthcare and Social Development Regulation in Russia for the treatment of breast cancer.

In April 2008, the Korean FDA (KFDA) granted marketing approval for Abraxane for the treatment of metastatic breast cancer after failure of standard chemotherapy. In the phase III clinical trial on which this approval was based Abraxane doubled the response rate and significantly prolonged PFS and OS compared to paclitaxel (Taxol; Bristol-Myers Squibb) in the approved indication. Green Cross currently expects to launch Abraxane in Korea in the first quarter of 2009 following pricing approval. Green Cross plans to establish a dedicated sales force for Abraxane and implement various marketing campaigns to support a successful launch. Abraxis has two additional global partnerships for the commercialization of Abraxane with Taiho Pharmaceuticals in Japan and Biocon in India.

As of March 2008, Abraxane was approved in 33 countries, including the USA, the Europe Union, India and Canada, and is also is under active regulatory review in Australia, Russia, Korea and China. Abraxane was approved in Europe earlier this year, in India in 2007 and in Canada in 2006 for the treatment of metastatic breast cancer including first line disease. Abraxane is the fastest growing taxane in its indication in the USA, used in approximately 5,000 patients with metastatic breast cancer per month in North America.

In January 2008, the European Commission granted Abraxane marketing approval for the treatment of patients with metastatic breast cancer refractory to first line treatment and for whom standard, anthracycline-containing therapy is not indicated. According to results from the phase III clinical trial (protocol ID: CA012-0; NCT00046527), on which this approval was based, Abraxane doubled the response rate and significantly prolonged PFS and OS compared to paclitaxel (Taxol; Bristol-Myers Squibb) in the approved indication. The trial’s PI was William J. Gradishar, MD, Professor of Medicine, Northwestern University, Feinberg School of Medicine, and Division of Hematology and Medical Oncology and Co-Director, Lynn Sage Breast Cancer Program at Northwestern Memorial Hospital. Abraxane nearly doubled the overall target lesion response rate versus Taxol and achieved a 37% improvement in PFS when compared to paclitaxel. In addition, time-to-tumor progression versus Taxol was significantly prolonged in patients treated with Abraxane. The tolerability with Abraxane and Taxol was comparable, despite the 50% greater dose of paclitaxel administered compared to Abraxane. Neutropenia was lower with Abraxane compared to Taxol. Although there was an increase in incidence of Grade 3 peripheral neuropathy with Abraxane, time-to-improvement was improved compared to that reported for Taxol. No adverse events were reported that were not already known to be associated with paclitaxel.

In October 2007, Abraxane received a positive opinion in favor of approval from the European CHMP for the treatment of metastatic breast cancer refractory to first line chemotherapy. The CHMP positive opinion was based on the clinical trial data that supported the approval of Abraxane in the USA and Canada (see below). In that trial, Abraxane was significantly superior in the clinical endpoints of response rate, progression free survival (PFS) and survival when compared with paclitaxel (Taxol; Bristol-Myers Squibb) in metastatic breast cancer. The positive opinion from the full scientific panel was based on the review of a marketing authorization application (MAA) using the centralized registration procedure. Abraxis BioScience has now begun the process of establishing a European infrastructure for the commercialization of Abraxane across Europe. The launch of Abraxane in Europe by Abraxis will initially focus on the UK, France, Spain, Italy and Germany.

In October 2007, Abraxane Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) was approved for marketing in India for the treatment of breast cancer by the country’s Drug Controller General.

In January 2007, the Therapeutic Goods Administration (TGA) in Australia accepted for review the company's marketing application for Abraxane for the treatment of metastatic breast cancer.

As of January 2007, Abraxis plannned to file for regulatory approval of Abraxane in China, Japan, Korea, and Taiwan, among other countries.

In July 2007, Abraxis submitted to India’s Ministry of Health and Family Welfare an application to market Abraxane in India for the treatment of breast cancer.

In September 2006, the European Medicines Agency (EMEA) accepted for review Abraxis BioScience's, application for Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) for the treatment of breast cancer. The typical EMEA review period for this centralized procedure is approximately 12 months. The European submission is based on a multicenter, randomized, pivotal phase III clinical trial of 454 women with metastatic breast cancer conducted by the company that compared Abraxane at a dose of 260 mg/m² administered as a 30-minute infusion without premedication (n=229) with solvent-based paclitaxel injection (Taxol; Bristol-Myers Squibb) at 175 mg/m² as a 3-hour infusion with standard steroid and antihistamine premedication (n=225). As reported in the European submission, overall response rate was 33.2% in the Abraxane arm compared to 18.7% (p=0.001) in the paclitaxel injection treatment arm. TTP was significantly prolonged in the Abraxane compared to the paclitaxel injection group for all patients (23.0 weeks versus 16.6 weeks, or 5.3 months versus 3.8 months). Median PFS was significantly longer for the Abraxane group compared to the paclitaxel injection group for all patients (22.7 weeks versus 16.6 weeks, or 5.2 months versus 3.8 months). Incidence of Grade 4 neutropenia was significantly lower for Abraxane compared with standard paclitaxel (9% versus 22%), despite a 49% higher paclitaxel dose. Febrile neutropenia was uncommon (<2%), and the incidence did not differ between the two arms. Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard paclitaxel arm (10% versus 2%) but was easily managed and improved rapidly (median=22 days). No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time (Gradishar WJ, etal, J Clin Oncol, 1 Nov 2005;23(31):7794-803). The most important adverse events included lower white and red blood cell counts, infections, tingling and numbness in the extremities, nausea, vomiting, diarrhea, muscle and joint aches, and mouth sores.

In November 2005, American BioScience (ABI) licensed Abraxane to Taiho Pharmaceutical (Taiho) and established a Joint Steering Committee which will oversee the development of Abraxane in Japan for treatment of breast, lung, gastric, and other solid tumors. Abraxane is being commercialized in North America by Abraxis Oncology, a division of American Pharmaceutical Partners. Under the terms of the license agreement, ABI will receive upfront and milestone payments in excess of $50 million, in addition to substantial royalties. ABI also will supply Abraxane for the Japanese market.

A unique reimbursement Code J9264 (paclitaxel protein-bound particles) was awarded to Abraxane, which will become effective on January 1, 2006 and facilitate reimbursement from Medicare, Medicaid as well as private payors.

In June 2005, American Pharmaceutical Partners filed a New Drug Submission (NDS) for Abraxane with the Therapeutic Products Directorate (TPD) of Health Canada. The submission seeks Health Canada’s approval to market Abraxane in Canada for the treatment of metastatic breast cancer.

In February 2005, American Pharmaceutical Partners launched Abraxane for Injectable Suspension as a treatment for patients with breast cancer that failed combination chemotherapy for metastatic disease (Stage IV) or relapsed within 6 months of adjuvant chemotherapy that included an anthracycline unless clinically contraindicated. Abraxane will be marketed by the national sales force of Abraxis Oncology, APP's proprietary sales and marketing division. APP plans to expand the Abraxane program to a wide variety of oncology settings. ABB has more than 40 planned or ongoing clinical trials in various indications including prostate cancer, head and neck cancer, ovarian cancer, melanoma, and lung cancer. Survival data for Abraxane will be presented at the Miami Breast Cancer Conference on February 25. APP is currently in the process of meeting with decision makers to clarify reimbursement policies for Abraxane. APP plans to distribute Abraxane through local and national specialty distributors, and is also working with oncology purchasing organizations. The first commercial patients for Abraxane were treated on February 9th, 2005. APP plans regulatory filings for Abraxane in Canada and Mexico for mid 2005. The next market that APP plans to seek approval of Abraxane in is Europe.

In January 2005, the FDA approved Abraxane for Injectable Suspension [paclitaxel protein (albumin)-bound particles for injectable suspension] in metastatic breast cancer. Abraxane is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

The New Drug Application (NDA) reviewed by the FDA included data from 106 patients in 2 single-arm, open label trials and from one randomized, comparative phase III clinical trial of 460 women with metastatic breast cancer. This randomized trial was designed to compare Abraxane (260 mg/m²), administered as a 30-minute infusion without premedication versus paclitaxel injection (175 mg/m²) as a 3-hour infusion with standard steroid and antihistamine premedication. Among all patients, 14% were chemotherapy naive, 27% had been treated with chemotherapy in the adjuvant setting, 40% in the metastatic setting, and 19% in both metastatic and adjuvant settings. Therefore, 41% were treated with Abraxane in a first line setting and 59% were treated in a second or greater than second line setting; 77% of patients had been previously exposed to anthracyclines. The prospectively defined endpoint for this trial was a protocol specific target lesion response rate based on data from the first 6 cycles of therapy using an independent radiologic review reconciled with investigator-assessed response. It is well established that independent radiologically reviewed response rates are lower than the investigator reported response rates typically reported in the scientific literature. This reconciled target lesion response rate for the 233 patients in the Abraxane treatment arm of the trial was superior at 21.5% compared to 11.1% for the 227 patients in the paclitaxel-treatment arm. In this trial, investigator response rates for Abraxane and paclitaxel were 33% and 19%, respectively (as reported at the San Antonio Breast Cancer Symposium in December 2003). Despite a 50% higher dose of chemotherapy infused over 30 minutes without premedication for hypersensitivity, Abraxane was well tolerated in the pivotal phase III trial.

As of January 2005, plans were underway to test Abraxane in combination with other chemotherapeutic agents in the treatment of front-line metastatic breast cancer.

In May 2004, the NDA for Abraxane was accepted for filing with standard review by the FDA, indicating that the application is sufficiently complete to permit a substantive review.

In March 2004, American BioScience (ABI) completed the filing of an NDA to the FDA for Abraxane for the treatment of metastatic breast cancer. The NDA was submitted under the FDA's 'fast track designation obtained in January 2003. As part of the NDA filing, ABI has requested the FDA to consider the application for priority review designation, which is intended potentially accelerate drug approval. The filing of the NDA is based upon supportive phase I and II clinical trials of Abraxane and a pivotal randomized controlled phase III trial that compared the safety and efficacy of Abraxane (260 mg/m²) to that of Taxol (175 mg/m²) administered every three weeks in 460 patients with metastatic breast cancer. The phase III trial demonstrated that Abraxane resulted in almost doubling of the response rate and a prolongation of TTP in patients with metastatic breast cancer, treated in the first and second line setting. In addition, the trial confirmed that Abraxane could be administered safely over 30 minutes without the need for steroid premedication.

In November 2003, Patrick Soon-Shiong, Chairman and CEO of American Pharmaceutical Partners (APP) discussed at the CIBC World Markets Fourteenth Annual Health Care Conference, results from a randomized, open label, double blind, phase III clinical trial (protocol ID: CA012-0; NCT00046527) of IV Abraxane (260 mg/m²) infused over 30 minutes versus solvent-based paclitaxel (175 mg/m²) infused over 3 hours in metastatic breast cancer completed in December 2002. Results were reviewed independently by 3 radiologists blinded to treatment procedures, drug used, and investigator responses. In each review, Abraxane demonstrated significant superiority to paclitaxel, particularly in TTP. There were no severe hypersensitivity reactions and over 90% of the patients in the Abraxane arm were administered treatment without steroids. Conversely, over 98% of patients in the Taxol arm were also administered steroids. More than 95% of patients in both arms tolerated the full dose and did not require dose reductions. Furthermore, less neutropenia was observed in the Abraxane arm, but 11% of patients did experience sensory neuropathy, although symptoms resolved rapidly. In July 2004, updated results were presented at the American Society of Clinical Oncology annual meeting. The overall tumor response rate for patients treated with Abraxane was 33%, compared to 19% for those treated with cremophor-based paclitaxel. Patients in the Abraxane arm also experienced a longer time to tumor progression (21.9 weeks versus 16.1 weeks). In addition, Abraxane was less costly than paclitaxel, yielding a dominant cost effectiveness strategy. A participating center for this trial includes Northwestern University School of Medicine (Chicago, IL) (Gradishar W, etal, ASCO04, Abs. 635). In updated results, in the overall patient population, median survival for those patients being administered Abraxane was 10 weeks longer (65.0 weeks versus 55.7 weeks) than for patients being administered Taxol, but this difference did not reach statistical significance. However there was a significant prolongation in survival in patients being administered Abraxane in the second line or greater setting as compared to those being administered Taxol (56.4 weeks versus 46.7 weeks). In this group, there was a 29% decrease in the risk of death (hazard ratio=0.71) for patients who were administered Abraxane compared to those who were administered Taxol.

A phase II clinical trial (protocol ID: CA013-0; NCT00046514) of ABI-007 in metastatic breast cancer was initiated in June 2001 at Baylor-Sammons Cancer Center (Dallas, TX), and US Oncology, under Joanne Blum, MD, as the PI. Patients were eligible to enter this trial if they had metastatic breast cancer refractory to either paclitaxel and/or docetaxel. All 55 patients with taxane-refractory, measurable metastatic breast cancer, were treated with ABI-007 (100mg/m²), weekly, over 30 minutes on day 1, 8, and 15 on a 28-day cycle without premedication. In all 55 patients disease had progressed while on a taxane regimen or relapsed within 12 months of adjuvant taxane; the median number of prior chemotherapy regimens (metastatic setting) was 3 (range=1-6) with 5 (29%) patients having been treated with docetaxel and 12 (71%) with paclitaxel for metastatic disease, and 4 (24%) patients treated with adjuvant taxane. According to this interim report involving 55 treated patients, 17 who completed 4 cycles of therapy or progressed, were evaluable for toxicity and response. There were only 2 cases of Grade 4 toxicity, one thrombocytopenia and one neutropenia. Grade 3 toxicities were mainly pain (n=3) neutropenia (n=2), nausea and vomiting (n=2), and one case each of anemia, thrombocytopenia, and shortness of breath. Among the 17 evaluable patients, there were 4 (24%) PR (3 unconfirmed). This agent was well tolerated with positive evidence of antitumor activity (Blum JL etal, ASCO03, Abs. 64).

Subsequently 100 patients were enrolled in this phase II clinical trial (protocol ID: CA013-0; NCT00046514). Following weekly ABI-007 administration, a reduction of tumor size by at least 50% (PR) was confirmed in 5/28 (18%) of the patients evaluated to date with duration of response ranging from 6 months to over 10 months. Furthermore, 6/28 (21%) of these patients remained progression-free for over 8 months, with 2 over 10 months; all six patients remain in the trial being treated with weekly dosing of ABI-007. At the 100 mg/m² weekly dose, ABI-007 was well tolerated with no incidence of Grade 3 or 4 neuropathy; Grade 4 neutropenia (without growth factor support) was seen in only 4% of patients. There was no evidence of allergic reactions at any grade despite the fact that no steroid premedication was administered. The most common adverse events reported were mild in nature and included those typical of taxane therapy including alopecia, nausea, and fatigue. Because of the low incidence of toxicity the trial is being extended to explore an increased dose of ABI-007 in light of the low incidence of toxicity at the 100 mg/m² weekly dose. The weekly MTD of ABI-007 has not yet been established and a trial to determine MTD is ongoing at the Arizona Cancer Center. As of July 2004, 106 patients have been enrolled and 66 patients are evaluable for toxicity and response. Grade 4 neutropenia occurred in 5 patients, Grade 3 nausea and infection in 3, Grade 2 fatigue and vomiting in 2, and Grade 1 constipation, dehydration, diarrhea, edema, mucositis and sensory neuropathy in 1 each. There was also an isolated case of febrile neutropenia. A PR occurred in 13 (20%) patients, with disease stabilization in 3. Responding patients have continued on ABI-007 without progression for greater than or equal to 24 weeks, with 5 of these patients still on treatment for more than 1 year. Based upon these results, this trial has been amended to treat additional patients using this schedule at an increased dose of 125 mg/m². As of October 2004, this trial is no longer recruiting patients (Blum JL, etal, ASCO04, Abs. 543).

Further statistical analysis reveals a 15% ORR with a 38% probability of survival at 12 months. Furthermore, 40% of patients on treatment with Abraxane were free of disease progression for as long as 4 months; and almost 30% for as long as 6 months. Of those patients who progressed while on Taxotere alone in the metastatic setting (n=33), a 24% response rate was noted after administration of weekly Abraxane. Of those patients who progressed while on Taxol alone in the metastatic setting (n=31), a 16% response rate was noted after administration of weekly Abraxane. In updated results, 74 patients were administered Abraxane (125 mg/m²) weekly IV over 30 minutes on days 1, 8, and 15 on a 28-day cycle without premedication. Dose reductions were required for 19 patients (26%), most because of sensory neuropathy and neutropenia. Observed treatment-related Grade 4 toxicities included neutropenia (n=2), anemia (n=1), thrombocytopenia (n=1), infection (n=1), stomatitis/pharyngitis (n=1), hypokalemia (n=1), and thrombosis/embolism (n=1). Observed treatment related Grade 3 toxicities affecting >1 patient included neutropenia (n=21), sensory neuropathy (n=8), fatigue (n=6), nausea (n=2), diarrhea (n=2), anorexia (n=2), anemia (n=2), thrombocytopenia (n=2), febrile neutropenia (n=2), and muscle weakness (n=2). These results indicate that abraxane administered weekly at 125 mg/m² is well tolerated for this poor prognosis patient population with taxane-refractory metastatic breast cancer. Administration of Abraxane at 100 mg/m² has previously been shown to be extremely well tolerated and active in this patient population, and the potential risk-benefit of the higher dose (125 mg/m²) awaits efficacy analysis as the data matures (OShaughnessy JA, etal, SABCS04, Abs. 1070). In further updated results, only 3 of 75 patients had to discontinue Abraxane as a result of peripheral neuropathy. Of those patients who experienced Grade 3 peripheral neuropathy, 80% were able to resume treatment following a delay of only 1 or 2 weeks and continued to be administered Abraxane at a decreased dose for an average of 4 additional months. These results and previous phase III results indicate that the peripheral neuropathy from Abraxane is not comparable to the peripheral neuropathy from Taxol or Taxotere with respect to duration and impact on the patient. The results showed Abraxane to be active in this poor-prognosis population, including 87% of patients with visceral disease, 69% of patients with >3 metastatic sites=69%, and 88% of patients with tumor growth on taxanes. The disease control rate was 55% in Taxotere-refractory patients and 39% in Taxol-refractory patients. Of those patients whose disease progressed while on Taxotere alone in the metastatic setting (n=27), a 19% response rate was observed after being administered weekly Abraxane. Of those patients whose disease progressed while on Taxol alone in the metastatic setting (n=23) a 13% response rate was observed after being administered weekly Abraxane. Abraxane was observed to be well tolerated when administered weekly over 30 minutes without steroids or G-CSF prophylaxis, with a 3% frequency of Grade 4 neutropenia (without G-CSF), a 1% frequency of Grade 4 anemia = 1%, and no severe hypersensitivity reactions (despite absence of premedication). In this heavily pretreated patient population, 75% of patients were treated at the full high dose of 125 mg/m² weekly Abraxane, with no dose decreases as a result of toxicities. Of the patients who developed Grade 3 sensory neuropathy, 77% were able to restart Abraxabe at a decreased dose (75-100 mg/m²) and were administered a mean of 12.2 additional doses of Abraxane.

In January 2003, ABI-007 was granted "fast track" status by the FDA for treatment of metastatic breast cancer.

In December 2002, patient enrollment was completed in the pivotal, randomized, controlled, phase III clinical trial of ABI-007, that is comparing the safety and efficacy of ABI-007 (260 mg/m²) to Taxol (175 mg/m²) administered every three weeks in patients with metastatic breast cancer. ABI-007 is infused over 30 minutes without steroid pretreatment at a higher dose than Taxol, which requires steroid therapy and infusion over 3 hours. A total of 460 patients with first- and second-line metastatic breast cancer were enrolled in this multicenter trial. In October 2002 the independent Data Monitoring Committee concluded that the approved clinical trial sample size, which provides for 460 patients, would not need to be augmented to achieve the endpoints in this phase III trial.

As of May 2002, 2 multicenter phase II clinical trials were conducted to evaluate 2 dose levels of ABI-007. Patients were recruited between November 1999 and May 2001. A total of 63 patients, enrolled in the first trial, were administered 300 mg/m² ABI-007, while 43 patients in the second trial were treated with 175 mg/m². In the first trial, toxicities include absolute neutrophil count (ANC) under 2000/mm3 (65%), ANC under 500/mm3 (23%), thrombocytopenia under 100,000/mm3 (7%), thrombocytopenia under 50,000/mm3 (5%), and febrile neutropenia (3 patients, 2 hospitalized). Toxicities in the second trial inlcude ANC under 2000 mm3 (16%), ANC under 500 mm3 (5%), thrombocytopenia under 100,000 mm3 (2%), thrombocytopenia under 50,000/mm3 (2%), and febrile neutropenia (1 patient hospitalized). For both trials, Grade 3-4 nonhematologic toxicities include peripheral neuropathy, myalgia, vomiting, diarrhea, rash, and amblyopia. Among 59 evaluable patients in the first trial, ORR was 61% with 2 CR (3%) and 34 PR (58%). Disease stabilized in 11 (19%) and progressed in 12 (20%). In 41 evaluable patients in the second trial, ORR was 51% with 3 CR (7%), and 18 PR (44%). Disease stabilized in 15 (37%) and progressed in 5 (12%). ABI-001 appears to be well tolerated and efficacious for the treatment of metastatic breast cancer (Ibrahim NK, etal, ASCO02, Abs. 209:53a).

In February 2002, at a Goldman Sachs' Oncology Conference held in New York City, ABI reported that since initiation of clinical trials in 1998, over 250 patients had been treated with ABI-007 in phase I and phase II clinical trials. A total of two multicenter phase II trials, undertaken to examine the safety and efficacy profile of ABI-007, administered at the current FDA-approved dose of paclitaxel (175 mg/m²) and at a much higher dose of 300 mg/m² over 30 minutes, every 21 days, as monotherapy, without steroid pretreatment, in patients with metastatic breast cancer, were completed in 2001.

Market Status

Approved (1/05) and launched (2/05) USA, launched (11/05) Japan; approved (10/07) and launched (7/08) India; approved (1/08) and launched (09) EU; approved (4/08) Korea; approved (7/08) and launched (6/09) China; approved (10/08) Australia; as of March 2010, Abraxane was approved in 39 countries worldwide.

Approved/Filed Indication

breast cancer, metastatic, first line or refractory

Clinical Aspects

In March 2008, Abraxis BioScience’s partner, Taiho Pharmaceutical filed a Japanese New Drug Application (J-NDA) with the Ministry of Health, Labour and Welfare in Japan to market Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) for the treatment of metastatic breast cancer. The submission in Japan includes 4 clinical trials that were part of the original NDA in the USA, including the randomized, pivotal phase III multicenter, comparative trial involving 460 women with metastatic breast cancer conducted by Abraxis and published in the Journal of Clinical Oncology. This randomized trial compared Abraxane (260 mg/m²) administered as a 30-minute infusion without premedication versus solvent-based paclitaxel injection (175 mg/m²), administered as a 3-hour infusion with standard steroid and antihistamine premedication. In this trial Abraxane doubled the response rate and significantly prolonged progression-free survival (PFS) and overall survival (OS) in the approved indication, and showed comparable tolerability versus paclitaxel. Additionally, the submission in Japan included several subsequent phase I and phase II trials, including two conducted by Taiho in Japan.

In January 2007, the Therapeutic Goods Administration (TGA) in Australia accepted for review Abraxis BioScience's marketing application for Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) for the treatment of metastatic breast cancer. The review period in Australia typically is 12 to 18 months from the date that the application is accepted. The Australian submission is based on clinical studies, including a multicenter, randomized, pivotal phase III trial involving 460 women with metastatic breast cancer comparing Abraxane (260 mg/m²) administered as a 30-minute infusion without premedication versus Taxol (175 mg/m²), administered as a 3-hour infusion with standard steroid and antihistamine premedication. In the randomized trial, the overall response rate of patients treated with Abraxane was 33.2%, compared to 18.7% (p=0.001) in patients in the paclitaxel injection treatment arm. Time-to-progression (TTP) was significantly prolonged at 23.0 weeks (5.3 months) in the Abraxane group versus 16.6 weeks (3.8 months) in the paclitaxel injection group for all patients (p=0.002). Median progression-free survival (PFS) was significantly longer at 22.7 weeks (5.2 months) for the Abraxane group compared to 16.6 weeks (3.8 months) for the paclitaxel injection group for all patients (p=0.003). No severe hypersensitivity reactions were reported in patients treated with Abraxane despite the absence of standard premedication, and peripheral neuropathies, while more frequent in the Abraxane-treated patients, improved at a faster rate with Abraxane compared with Taxol. The most important adverse events included lower white and red blood cell counts, infections, tingling and numbness in the extremities, nausea, vomiting, diarrhea, muscle and joint aches, and mouth sores.

In June 2006, Abraxis BioScience received approval for Abraxane for Injectable Suspension (paclitaxel powder for injectable suspension) (nanoparticle, albumin-bound (nab) paclitaxel) from the Therapeutic Products Directorate of Health Canada under a Notice of Compliance for the treatment of metastatic breast cancer in Canada. Canada is the first major commercial market to grant an approval for Abraxane that includes first line treatment of metastatic breast cancer. The company, through its Canadian affiliate of Abraxis Oncology, anticipates launching Abraxane late in the third quarter of 2006. In the pivotal head-to-head trial Abraxane nearly doubled the overall response rate versus paclitaxel (Taxol; Bristol-Myers Squibb) resulting in a 37% improvement in PFS when compared to Taxol. In addition, TTP versus Taxol was significantly prolonged in patients treated with Abraxane. This first line approval for Abraxane is based on results from the pivotal, multicenter, randomized, comparative, phase III clinical trial involving 460 women with metastatic breast cancer. This randomized trial was designed to compare Abraxane (260 mg/m²), administered as a 30-minute infusion without pre-medication versus paclitaxel (175 mg/m²) administered as a 3-hour infusion with standard steroid and antihistamine pre-medication. Of the patient population, 41% were being treated in the first line setting, and 59% for refractory disease; 77% of these patients had been previously exposed to anthracyclines. Despite a 50% higher dose of chemotherapy infused over 30 minutes without premedication for hypersensitivity, Abraxane was well tolerated in the pivotal phase III trial. Overall target lesion response rate was 33.2% in the Abraxane treatment arm compared to 18.7% in the paclitaxel treatment arm. TTP was significantly prolonged in the Abraxane group than in the paclitaxel injection group for all patients (5.3 versus 3.8 months). Median PFS was significantly longer for the Abraxane group than for the paclitaxel injection group for all patients (5.2 versus 3.8 months). Survival for patients treated with Abraxane was prolonged by 10 weeks; median time-to-death for Abraxane and paclitaxel injection groups for all patients was 14.9 and 12.7 months, respectively.

Market Status

Approved (6/06) Canada; approved and launched (08) Australia

Sales History

USA sales of Abraxane were $34.8 million in 1Q05; more than 2,700 patients have been treated since launch. USA sales of Abraxane were $19.4 million in 2Q05, and $54.2 million in 1H05. USA sales of Abraxane were $32.1 million in 3Q05. USA sales of Abraxane were $86.3 million in 9M05. USA sales of Abraxane were $47.5 million in 4Q05, and $133.7 million in FY05 (11 months).

Abraxane experienced a 52% unit volume increase for the period of February 2006 to December 2006 versus the same period in the prior year, which compares favorably to Taxotere and Taxol with growth rates for that same period of -2% and +9%, respectively. In the second line and second line plus metastatic breast cancer settings, the market share for Abraxane was 28% and 43%, respectively. Abraxane sales were $56.1 million in 4Q06, which includes $9.1 million in deferred revenue related to the AstraZeneca co-promotion agreement in the USA; net sales were $47.4 million. USA Abraxane sales were $36.3 million in 2Q06, up 87% from 2Q05, and sales and $66.4 million in 1H06, up 23% from 1H05. Growth in the 1H06 compared to the second half of 2005 was up 19%, while the overall growth of the taxane market for the same period was 10%. Abraxane sales were $174.9 million in FY06, which includes $156.7 million of net sales, compared to $133.7 million in FY05.

Abraxane sales were $150 million in 1H07. Abraxane sales were $324.7 million in FY07.

WW sales of Abraxane were $79.9 million in 1Q08, up 12.8% from $70.9 million in 1Q07, $73.8 million in 2Q08, compared with $78.7 million in 2Q07, and $153.8 million in 1H08 compared with $149.6 million in 1H07. As of April 2008, Abraxane was the fastest growing taxane in its indication in the USA, being used in approximately 5,000 patients with metastatic breast cancer per month in North America. WW sales of Abraxane were $92 million in 3Q08, up 7% from $86 million in 3Q07. Abraxane's share of the taxane market in the second line metastatic breast cancer setting was 42%. Sales of Abraxane were $245.8 million in 9M08 , up 4.2% from $235.9 million in 9M07. WW sales of Abraxane were $89.8 million in 4Q08, compared with $88.8 million for the same period in 2007. WW sales of Abraxane were $335.6 million in FY08, up 3.4% compared with $324.7 million in 2007.

WW sales Abraxane were $70.6 million in 1Q09 compared with $79.9 million in 1Q08, which included recognition of deferred revenue of $9.1 million. Excluding the recognition of deferred revenue, total Abraxane revenue in 1Q09 was $70.6 million compared with $70.8 million in 1Q08. WW sales of Abraxane were $82.9 million in 3Q09 compared with $92.0 million in 3Q08, which included recognition of deferred revenue of $9.1 million related to the co-promotion agreement. Excluding the recognition of deferred revenue, total revenue from sales of Abraxane remained steady at $82.9 million for both the 3Q09 and 3Q10. In 9M09, excluding the recognition of deferred revenue, total revenue from the sales of Abraxane were $228.6 million up 5% ($10.1 million) compared with $218.5 million for 9M08. Incremental revenue from the continued global expansion into China, Australia, and European markets, as well as a higher average net selling price in the USA, contributed to the increase in revenue compared to the prior year. WW sales of Abraxane were $314.5 million in FY09, down 6.3% form FY08 levels.

Pricing

In March 2008, the AWP of 100 mg was $1,047.04. In 2005, the designated wholesale acquisition cost (WAC) for Abraxane is $795.96 per 100 mg vial and the AWP will be $994.95.

Year

2009

Total Sales

$314,545,000.00

CLINICAL STATUS

Indication in Development

solid tumors, advanced, refractory • solid tumors, advanced, metastatic

Latest Status

Phase I (completed 3/01) USA, phase I (begin 4/00, closed 10/04) USA, phase I (begin 10/04, ongoing 11/05) USA, phase I (closed 5/05) Asia (China), phase I (begin 6/08, ongoing 12/08) USA; Clinical trial (begin 9/06, withdrawn 9/08)

Clinical History

An open label, single group assignment, phase I clinical trial (protocol ID: 2007-0857; NCT00732836) was initiated in June 2008, in the USA, to evaluate the safety and efficacy of arterial infusion of paclitaxel in treating patients with advanced solid cancer with predominant hepatic metastases. Patients must not have clinically significant ascites, must not have hypersensitivity to Abraxane, and must not have history of CNS metastasis unless the patients are neurologically stable after treatment with surgery and/or radiation therapy. The trial’s primary objective is to find the highest tolerated dose of Abraxane that can be administered directly into the liver. According to protocol, up to 4 groups of 6 patients will be enrolled in part 1 of the clinical trial, and up to 18 patients will be enrolled in part 2. During part 1, the dose of the trial drug will depend on when the patient was enrolled. The first group of patients is treated at the lowest dose level of the study drug. Each new group will be treated at a higher dose of the trial drug than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of the trial drug is found. In part 2, patients are treated at the highest dose that was tolerated in the part 1 portion. The trial drug will be administered on day 1 of cycles that are 21 days long. In cycle 1 only, patients are administered the trial drug by a vein. The infusion will last 60 minutes. In cycles 2 and later, patients are administered the trial drug through a catheter. Once a week, including before each dose of the trial drug, blood (about 2 teaspoons) will be drawn for routine tests. These blood draws can be done at M. D. Anderson or somewhere else, if there is a place that is more convenient. Once during each cycle (on a day when patients are already in clinic), a physical exam, including measurement of height, weight, and vital signs will be taken. Urine will be collected for routine tests. At the end of every 3 cycles, scans will be performed (the same type of scans as at screening) to check the status of the disease. In cycles 1 and 2, additional blood will be drawn for PK testing. The trial, to enroll about 42 patients, is being conducted under PI, Razelle Kurzrock, MD, U.T. M.D. Anderson Cancer Center (Houston, TX).

An open label, interventional, clinical trial (protocol ID: CDR0000554709; ECOG-E1Y06; NCT00499291) was initiated in September 2006, to determine the efficacy of nab-paclitaxel in treating patients with advanced or refractory solid tumors. The trial’s primary objective is to develop a population PK model and to characterize the inter-individual PK variability of nab-paclitaxel. Secondary objectives are to explore nab-paclitaxel PK parameters, to explore the association between exposure to total and unbound paclitaxel after administration of nab-paclitaxel and neutropenia, to explore the association between the CYP2C8*3 variant and paclitaxel clearance, and to explore the association between other variants of CYP2C8 and other genes involved in paclitaxel disposition including CYP3A4, CYP3A5, SLCO1B3, and ABCB1 and paclitaxel PK parameters and toxicity after one course of treatment. According to the protocol, patients are administered IV nab-paclitaxel over 30 minutes on days 1, 8, 15, 22, 29, 36, 43, and 50. Treatment may repeat every 9 weeks in the absence of disease progression or unacceptable toxicity. Serial blood samplings are obtained at specified time points during course 1 including baseline and days 1 and 8 of course 1 for PK evaluations. Samples are also examined for genotype by PCR including variant genotypes in 2C8, CYP3A4, CYP3A5, ABCB1, ABCC2, ABCC10 and OATP1B3 genes. This trial, to enroll about 129 patients, is being conducted under Study Chair, Sridhar Mani, MD, Albert Einstein College of Medicine of Yeshiva University (Bronx, NY) and was withdrawn in September 2008.

A phase I tolerability trial of ABI-007 in Chinese patients with advanced solid tumors was performed at multiple locations in China to determine MTD, DLT, and recommended dose for this treatment. ABI-007 was administered at dose levels from 135 up to 350 mg/m² every 3-weeks IV over 30 minutes without premedication. A total of 22 patients (breast=6, nsclc=5, nasopharyngeal carcinoma=5, rectum/colon=3, esophageal=1, stomach=1, synovial sarcoma=1) were enrolled. Patients were treated with a total of 94 cycles of ABI-007. No acute hypersensitivity reactions were exhibeted during the infusion or on the 1st day post dosing. The treatment was well tolerated. Observed adverse events were mostly grade 1/2 (95%). The most frequently observed toxicities were mild leucopenia and peripheral sensory neuropathy. Observed DLT, which occurred at dose level of 350 mg/m², were Grade 4 neutropenia (1 of 3 patients) and Grade 3 diplopia (1 of 3 patients). MTD was determined to be 300 mg/m². Of 21 evaluable patients, 1 (5%) had CR and 7 had PR (33%) corresponding to an ORR of 38%. Of 5 patients with nasopharyngeal carcinoma, 3 had responses lasting 25, 18 and 13+ weeks. As in the USA phase I trial, the MTD of ABI-007 in Chinese patients was 300 mg/m² administered without premedication over 30 minutes. Additional trials of ABI-007 are planned in Chinese patients with breast cancer and NSCLC (Teng X, etal, ASCO05, Abs. 5571).

A randomized, pilot, phase I clinical trial (protocol ID: NCI-04-C-0280, ABI-CA019) of paclitaxel versus ABI-007 in patients with incurable, locally advanced or metastatic solid tumors was initiated in October 2004 at the Warren Grant Magnuson Clinical Center (Bethesda, ML) to determine the PK for these treatments. In courses 1 and 2, patients are randomized to 1 of 2 treatment arms. In arm I, patients are administered paclitaxel IV over 3 hours on day 1, and ABI-007 IV over 30 minutes on day 22. In arm II, patients are administered ABI-007 IV over 30 minutes on day 1, and paclitaxel IV over 3 hours on day 22. In courses 3 and beyond, all patients are administered ABI-007 IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. A total of 17 patients will be accrued for this trial within 6 months. William Figg, MD (tel: 301-402-3622), of the NCI is the protocol chair.

In November 2005, additional results for a phase I clinical trial (protocol ID: CA-005-0) were published in the Journal of Clinical Oncology. A total of 39 patients were enrolled with melanoma (36%), breast cancer (23%), nsclc (13%), ovarian cancer (8%) and other malignancies. Among the patients enrolled, 92% had previous chemotherapy including approximately 40% of patients who were taxane-refractory. Maximum paclitaxel concentration and AUC increased linearly with dose. Dose-dependent changes in plasma clearance did not occur. PR was observed in 5 patients with breast, lung, and ovarian cancers, all of whom had previously been treated with paclitaxel containing polyoxyethylated castor oil in the formulation (Nyman D, etal, Journal of Clinical Oncology, 1 Nov 2005;23:(31):7785-7793).

A phase I clinical trial (protocol ID: CA-005-0) of ABI-007 administered weekly for 3 doses every 4 weeks in patients with advanced nonhematologic malignancies, under the direction of Michael J Hawkins, MD, is closed as of October 2004. ABI-007 is administered as an outpatient infusion for 3 weeks followed by a week of rest. The treatment course is repeated every 28 days if the patient improves on the therapy, and if there are no adverse events that require withdrawal of medication. The trial investigated the safety and MTD of ABI-007 in 17 patients with advanced nonhematologic malignancies. The three dose levels examined include 3 patients at 80 mg/m², 7 at 100 mg/m², 2 at 125 mg/m²-heavily pretreated, and 5 at 125mg/m²-lightly pretreated. Heavily (HP) and lightly (LP) pretreated patients were assigned based on prior therapies with radiation or highly suppressive bone marrow agents. More than 60 courses of ABI-007 have been administered. A total of 5 patients have received >18 doses over a 6 month period. Toxicities requiring dose reductions included neutropenia and neuropathy in 2 patients. Other mild toxicities included fatigue, nausea, and alopecia. To date, 3 patients have exhibited partial responses (PR) including 1 with melanoma, 1 with lung cancer, and 1 with breast cancer. The breast cancer patient and lung cancer patient both had prior therapy with a taxane. Up to 5 patients have exhibited stable disease (SD). Preliminary results indicate ABI-007 can be safely administered on a weekly schedule without premedication (Campbell KJ, etal, ASCO02, Abs. 403:101a). As of July 2004, 39 patients have been enrolled and treated with doses of ABI-007 ranging from 80 to 200 mg/m^2/day as a 30 minute IV infusion; with over 169 courses having been administered. The DLT in this trial for HP patients was Grade 4 neutropenia, with Grade 3 peripheral neuropathy identified as the DLT for LP patients. The MTD for HP patients is 100 mg/m², while the MTD for LP patients is 150 mg/m^2. Other toxicities reported included fatigue, nausea and vomiting, mild anemia, and alopecia, but there were no hypersensitivity reactions to this formulation. A PR has lasted 4 months for a patient with lung cancer, 7 months for a patient with breast cancer, and 4, 10, and 13 months for 3 patients with ovarian cancer. All 5 responding patients had prior therapy with paclitaxel. A participating center for this trial includes the University of Arizona (Tucson, AZ) (Nyman DW, etal, ASCO04, Abs. 2027).

In a phase I clinical trial, conducted at M. D. Anderson Cancer Center, 19 patients with advanced solid tumors (metastatic breast cancer=13 and melanoma=6) were treated with ABI-007 without premedication in a 30-minute infusion every 21 days, at the starting dose was 135 mg/m²; 85 courses were delivered with the median number delivered being 5 (range=1-11). The MTD was 300 mg/m². Hematologic toxicity manifested in 1 cycle as neutropenic fever caused by skin infection; otherwise, no Grade 3/4 hematologic toxicity was seen. The number of cycles with Grade 3/4 nonhematologic toxicity involved nausea/vomiting (n=1), stomatitis (n=2), diarrhea (n=2), constipation (n=1), myalgia (n=1), peripheral neuropathy (n=5), perioral numbness (n=5), fatigue (n=5), skin blisters (n=2), and polyuria/ polydypsia (n=3). Visual toxicities included Grade 3 keratitis (n=3), Grade 2 blurred vision (n=3), and eye flashes (n=1), and Grade I dry-eye syndrome (n=2). No hypersensitivity reactions were seen. DLT toxicity was peripheral neuropathy and superficial keratitis (Ibrahim NK, ASCO00, Abs. 609F:155a). In this phase I clinical trial, MTD of ABI-007 was determined to be 300 mg/m², by a 30-minute infusion, every 3 weeks, without premedication or G-CSF support.

Indication in Development

head and neck cancer, metastatic, refractory

Latest Status

Phase I (completed 00) Europe (Italy), phase I (completed 11/03) Europe (Italy), phase I/II (ongoing 5/05) USA, phase II (planned 5/05) USA (combination)

Clinical History

As of May 2005, a phase II clinical trial of Abraxane in combination with chemoradiation in patients with head and neck cancer is planned.

A phase I/II clinical trial of IV Abraxane in patients with head and neck cancer was ongoing as of May 2005 in the USA to determine the safety, tolerability, and efficacy for this treatment.

In November 2003, updated results of the phase I clinical trial of Abraxane in advanced squamous cell carcinoma of the tongue were published in the American Journal of Roentgenology. A total of 23 previously untreated patients were treated with intraarterial paclitaxel incorporated into albumin nanoparticles administered by transfemoral catheterization into the external carotid artery (n=10), selectively into the lingual artery (n=12), or into a faciolingual trunk (n=1). Doses administered were 230 mg/m² (n=8), 180 mg/m² (n=6), and 150 mg/m² (n=9). Out of 16 patients who had surgery, 8 had radiotherapy and 3 were treated with combined chemotherapy and radiotherapy. Of the 7 remaining patients, 1 was treated with chemotherapy alone, 4 with radiotherapy alone, 1 with chemotherapy plus radiotherapy, and 1 refused further treatment. A total of 67 successful infusions were performed. Clinical and radiologic OR was observed in 18 patients (78%; CR=26%, PR=52%). Disease stabilized in 3 patients (13%), and progressed in 2 patients (9%). Out of 4 patients with complete clinical response who had surgery, microscopic residual carcinoma < 1 mm was observed in 2 patients, < 5 mm in 1 patient, and < 1 mm in 1 patient. Toxicities include Grade 3 hematologic symptoms (n=2, 8.6%) and Grade 4 neurologic symptoms in 2 patients (reversible paralysis of the facial nerve, 8.6%). Catheter-related complications include reversible brachiofacial paralysis (n=1) and asymptomatic occlusion of the external carotid artery (n=1) (Damascelli B, etal, AJR Am J Roentgenol July 2003; 181[1]:253-60).

A phase I clinical trial of intra-arterial injection of ABI-007 was completed in 2000, in 28 patients with head and neck (n=18) and anal cancer (n=10), on the premise that increased accumulation of nanoparticles (< 200nm) of paclitaxel at the tumor site would increase efficacy, especially in these tumors characterized by overexpression of EGF receptors. Among the 18 patients with head and neck cancer 6 had newly diagnosed Stage IV disease and 12 recurrent disease after surgery, RT, and/or chemotherapy. All of the 10 patients with anal canal cancer had been previously treated with surgery, RT and/or chemotherapy. ABI-007 was injected by percutaneous superselective arterial catheterization every 4 weeks for 3 cycles. MTD was determined at 270 mg/m² and treatment dose was 250 mg/m². Among the 18 head and neck cancer patients toxicities included Grade I/II alopecia (24%), flu syndrome (22%), neurological (12%), gastrointestinal (12%), cutaneous (8%), ocular (7%); 15% experienced bone marrow toxicity(Grade I=9, Grade II=3, Grade IV=1). Responses, noted in 17 evaluable patients, included PR (52%), MR (12%), and disease atabilized in 24%, and progressed in 12%. Among anal canal cancer patients, toxicities included Grade I/II alopecia (29%), flu syndrome (25%), gastrointestinal (12% ), Grade I , neurological (10%) and cutaneous (7%); 17% experienced bone marrow toxicities ( Grade II=2, Grade III=1 and Grade IV=2). Responses, seen in 10 patients were pathological CR (10%) , PR (27%), MR (13%), and disease stabilized in 37%, and progressed in 13%. Carotid catheterization related complications (fully recovered) involved 3 previously treated patients >70 years-of-age (Damascelli B, etal, ASCO00, Abs. 816:209a).

Indication in Development

non-small-cell lung cancer (nsclc), advanced, chemotherapy-naive

Latest Status

Phase I/II (begin 12/03, closed 11/05) USA, phase I/II (begin 9/03, closed 8/07) USA; phase II (begin 9/05, ongoing 11/05) USA (combination)

Clinical History

In October 2007, Abraxis BioScience, an integrated, global biopharmaceutical company, reached a definitive agreement with the FDA under the Special Protocol Assessment (SPA) process on the phase III clinical trial design of the company’s pivotal study with Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin bound) for the treatment of non-small cell lung cancer (nsclc) in the first line setting. In the agreement, the FDA has determined that the design and planned analysis of the trial addresses the objectives necessary to support a regulatory submission (see Combination Trials module for details).

In November 2005, interim results from a single center, dose escalation, phase I/II clinical trial (protocol IDs: CA015-0, MSKCC-03111, ABI-CA015) with Abraxane were presented at the Chemotherapy Foundation Symposium XXIII in New York City. Abraxane was administered as a weekly, first-line therapy in chemotherapy-naive patients with stage IV nsclc and showed a high degree of antitumor activity. Of the 41 patients treated with Abraxane (125 mg/m²) on days 1, 8 and 15 every 28 days, a total of 34 have been evaluated for response. Patient responses included 1 confirmed CR, 7 confirmed PR, and 4 PR awaiting confirmation (response rate 35%).

As of May 2005, 11 clinical trials of Abraxane in patients with nsclc are ongoing or planned. Planned trials include several trials of Abraxane in combination with carboplatin and a trial of Abraxane in combination with carboplatin and bevacizumab (Avastin).

A single center, dose escalation, phase I/II clinical trial (protocol IDs: CA015-0, MSKCC-03111, ABI-CA015) was initiated in December 2003, at Memorial Sloan-Kettering Cancer Center under PI Naiyer Rizvi, MD, to administer Abraxane to patients with chemotherapy naive, advanced or metastatic (Stage IV) nsclc. This trial is designed to determine MTD and DLT of Abraxane, administered IV weekly, and evaluate its safety and antitumor activity. The trial is expected to be expanded into a phase II efficacy trial at the MTD to evaluate that safety and antitumor activity of Abraxane. Approximately 64 patients are to enroll in this trial.

An open label, dose escalation, phase I/II clinical trial (protocol ID: CDR0000350076; MSKCC-03111; ABI-CA015; NCT00077246) was initiated in September 2003, in the USA, to evaluate the safety and efficacy of paclitaxel in treating patients with chemotherapy-naïve, locally advanced or metastatic non-small cell lung cancer (nsclc). Patients must not have evidence of active brain metastases or leptomeningeal involvement, must not have prior allergy or hypersensitivity to study drug, and must not be treated with concurrent doxorubicin, taxanes, anthracyclines, or anticonvulsants. The trial’s primary objectives are to determine the MTD, DLT, antitumor activity, safety, and tolerability. Secondary objective is to assess the TTP, duration of response, and survival. According to the protocol, during phase I, patients are administered IV paclitaxel on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients are treated with escalating doses of ABI-007 until the MTD is determined. During phase II, patients are administered paclitaxel as in phase I at the MTD. Patients are followed monthly for 6 months and then every 3 months for 1.5 years. The trial, to enroll about 64 patients, is being conducted under Study Chair, Naiyer Rizvi, MD, Memorial Sloan-Kettering Cancer Center (New York, NY) and was closed in August 2007.

Indication in Development

melanoma, malignant, metastatic • melanoma, malignant, cutaneous, metastatic, chemotherapy-naive

Latest Status

Phase II (begin 2/04, closed 9/05) USA; phase III (begin 4/09, ongoing 8/09) USA, Australia

Clinical History

A multicenter (n=15), randomized, open label, parallel assignment, phase III clinical trial (protocol ID: CA033; NCT00864253) was initiated in April 2009, in the USA and Australia, to compare the safety, tolerability, and antitumor activity of ABI-007 versus dacarbazine in treating patients with metastatic, cutaneous, malignant melanoma who have not previously received chemotherapy. Patients must not have evidence of brain metastases, including leptomeningeal involvement, pre-existing peripheral neuropathy of Grade 2 or greater, or clinically significant concurrent illness. The trial’s primary outcome measure is to determine the PFS. Secondary outcome measures are to determine the survival, number of patients who achieve an objective confirmed CR or PR, number of patients with SD for more than 16 weeks or confirmed CR or PR, duration of response, to correlate SPARC and other molecular biomarkers with efficacy outcomes, to assess the incidence of treatment-emergent and treatment related AE and serious AE, laboratory abnormalities, nadir of myelosuppression during drug dosing, incidence of patients experiencing dose modifications, dose interruptions, and/or premature discontinuation of trial drug, PK parameters, Cmax, AUC, half-life of the apparent terminal portion of the concentration versus time curve, total body clearance, and the volume of distribution. According to the protocol, patients are randomized to one of two treatment arms. Patients in arm I are administered IV ABI-007 (150 mg/m²) over 30 minutes, on days 1, 8, and 15, every 4 weeks. Patients in arm II are administered IV dacarbazine (1000 mg/m²) on day 1 with steroid and antiemetic pre-medication. Treatment will be repeated every 21 days. The trial, to enroll about 514 patients, is being conducted under PI, Evan Hersh, MD, Arizona Cancer Center (Tucson, AZ), and Michael Millward, MD, Sir Charles Gairdner Hospital (Nedlands, Australia).

In November 2005, updated results were presented from a phase II clinical trial (protocol ID: UCLA-0309060, 03-09-060, ABI-CA014, NCT00081042) of ABI-007 in previously treated and previously untreated patients with metastatic malignant melanoma at the Chemotherapy Foundation Symposium XXIII in New York City. A total of 74 patients enrolled. Antitumor activity was greatest in 10/37 (27%) chemotherapy-naive patients. These patients responded and an additional 8 had SD for at least 16 weeks (disease control rate 49%). Median time to tumor progression (TTP) was more than 5 months, approximately 3 times longer than what has commonly been reported for DTIC (a chemotherapy drug approved for the treatment of malignant melanoma). The activity of Abraxane was less in previously-treated patients. Even in this group, the disease control rate was greater than 38% and TTP was 3.5 months.

Results were presented from an open label, multicenter phase II clinical trial (protocol ID: UCLA-0309060, 03-09-060, ABI-CA014, NCT00081042) of ABI-007 in previously treated and previously untreated patients with metastatic malignant melanoma that was performed to determine the safety and efficacy for this treatment. ABI-007 was administered weekly for 3 weeks every 4 weeks without premedication to chemotherapy naive (150 mg/m²) and previously treated (100 mg/m²) patients. A total of 49 (chemotherapy naïve=13, previously treated=36) patients were enrolled, of which 11 chemotherapy naïve and 13 previously treated patients are currently evaluable for toxicity and response. The median number of monthly cycles administered was 4 (range=2-6) for chemotherapy naïve patients and 4 (range=1-6) for previously treated patients. Treatment is continuing for 9 chemotherapy naïve and 25 previously treated patients. The percentage of cycles administered without dose modification was 84% for chemotherapy naïve patients and 92% for previously treated patients. No treatment-related deaths or treatment related Grade 4 toxicities occurred. No cases of febrile neutropenia were reported. Observed treatment related Grade 3 toxicities included fatigue (13%), neutropenia (13%), leukopenia (8%), rash (8%), alopecia (4%), anemia (4%), infection (4%), lymphedema (4%), motor neuropathy (4%), and tumor pain (4%). Progressive disease was experienced by 3 chemotherapy naïve and 9 previously treated patients. Partial response was experienced by 2 chemotherapy naïve patients. Disease stabilization was experienced by 1 chemotherapy naïve and 4 previously treated patients who have continued on ABI-007 for >/=24 weeks. These results indicate that ABI-007 is well tolerated and results in long-term disease control in patients with metastatic malignant melanoma, some of whom had rapidly progressive disease while on previous therapy (Hersh E, etal, ASCO05, Abs. 7558).

An open label, multicenter, phase II clinical trial (protocol ID: UCLA-0309060, 03-09-060, ABI-CA014, NCT00081042) of ABI-007 in patients with inoperable locally recurrent or metastatic melanoma was initiated in February 2004 at the Jonsson Comprehensive Cancer Center (Los Angeles, CA) to determine the activity, safety, tolerability, TTP, response rate, duration of response, and survival for this treatment. Patients are assigned to 1 of 2 treatment cohorts according to prior cytotoxic chemotherapy (previously treated versus chemotherapy-naïve). In Cohort I (previously treated), patients are administered ABI-007 (100 mg/m²) IV over 30 minutes on days 1, 8, and 15. In Cohort II (chemotherapy-naïve), patients are administered a higher dose of ABI-007 (150 mg/m²) as in cohort I. In both cohorts, courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients are followed monthly for 6 months and then every 3 months thereafter. A total of 24-70 patients (12-35 per cohort) will be accrued for this trial. Antoni Ribas MD (tel: 310-206-3928) of the Jonsson Comprehensive Cancer Center is the protocol chair. This trial is based on the observation from a phase I clinical trial of weekly administration of Abraxane in which PR were seen in patients with pretreated metastatic melanoma.

Indication in Development

breast cancer, inoperable or metastatic, first line, previously treated • breast cancer, metastatic • breast cancer, advanced, relapsed or refractory

Latest Status

Phase I (begin 3/09, ongoing 6/09) India; phase II (begin 3/05, ongoing 1/07) USA, phase II (begin 11/05, closed 6/06) USA, Europe (Russia), phase II (begin 03/05, ongoing 12/06) USA, phase II (begin 1/08, ongoing 6/09) USA

Clinical History

A multicenter (n=3), open label, placebo control, phase I clinical trial (protocol ID: DO/NDR/02/2008/01; NCT00915369) was initiated in March 2009, in India, to determine the safety and efficacy of nab-paclitaxel in treating patients with relapsed or refractory, advanced breast cancer. Patients must not have Her2-positive disease, must not have hypersensitivity to paclitaxel or any other taxane or compounds related to paclitaxel or excipients, and must not undergo concurrent chemotherapy, hormonal therapy immunotherapy, therapy with biologicals or radiotherapy. The trial’s primary outcome measure is to determine the PK data for all four dose levels. Secondary outcome measure is to evaluate the effect of nab-paclitaxel on QTc. According to the protocol, patients are administered nab-paclitaxel (220, 260, 310, or 375 mg/m²) for up to 6 cycles. This trial, to enroll about 24 patients, is being conducted under PI, D Raghunadharao, DM, Nizam's Institute of Medical Sciences (Hyderabaad, India), Govind Babu, DM, Kidwai Memorial Institute of Oncology (Bangalore, India), and Anish Maru, DM, SEAROC Cancer Center, S K Soni Hospital (Jaipur, India).

A 2-center, observational, phase II clinical trial (protocol ID: CDR0000586461; CHNMC-07157; ABRAXIS-ABX206-BC07US; NCT00609791) was initiated in January 2008, in the USA, to determine the safety and efficacy of paclitaxel albumin-stabilized nanoparticle formulation in treating patients with metastatic breast cancer. Patients must have first or second line chemotherapy planned, must not have untreated or symptomatic CNS metastases, and must not be treated with concurrent investigational agents or anticancer therapy. The trial’s primary objective is to determine age-related changes in the PK and age-related changes in the pharmacodynamics of nab-paclitaxel. Secondary objectives are to determine response and TTP, to explore predictors of PK parameters, and to explore predictors of the need for dose reduction, dose delays, or Grade 3 or 4 toxicity. According to the protocol, patients are stratified by age in years (<50 versus 50-60 versus 60-70 versus >70). Patients are then administered IV nab-paclitaxel over 30 minutes once daily on days 1, 8, and 15 as planned. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Blood is drawn for PK evaluations periodically during course 1. Patients complete questionnaires regarding risk factors that would predict for PK parameters at baseline, prior to the third course of treatment, and at end of the clinical trial. Data collected include medical characteristics, demographics, functional status, comorbidity, psychological status, social functioning and support, nutritional status, and cognition. This trial is to enroll about 40 patients.

Updated results from the open-label, non-randomized phase II clinical trial (protocol ID: I-04-012; NCT00251472) of weekly Abraxane (125 mg/m²) as first-line treatment for locally advanced or metastatic breast cancer, were presented at the 2006 San Antonio Breast Cancer Symposium. Out of 55 patients enrolled to date, 23 are evaluable for response. Median patient age was 59 years, ECOG performance status was 0 in 11 and 1 in 12 patients, and HEr2 status was positive in 5, negative in 17, and missing in 1 patient. Median number of cycles administered is 3, with a median dose of 125 mg/m². Dose level modifications due to toxicity occurred in 10 patients, and 32 patients remain on study. CR/PR response rate was 56.5%, with a 95% Clopper-Pearson confidence interval of 34.5-76.8. Median time to OR (CR or PR of measurable disease) was 3.6 months. Most common Grade 3/4 toxicities were Grade 3 neutropenia (9.8%), Grade 3 lower and upper limb muscle weakness (3.9%), Grade 3 neuropathy (3.9%), Grade 3 joint pain (3.9%), and Grade 4 vascular disorder (2.0%). Preliminary results suggest that Abraxane has an acceptable efficacy and safety profile as a single agent for the first-line treatment of locally advanced or metastatic breast cancer (Mirtsching BC, etal, SABCS06, Abs. 6073).

Several phase I and II combination clinical trials of Abraxane are being performed. Refer to the Combination Trial Module to see these trials.

In December 2006, according to interim results from a randomized, head-to-head phase II trial of Abraxis BioScience’s Abraxane versus docetaxel (Taxotere; sanofi-aventis), in the first line treatment of metastatic breast cancer, treatment with weekly Abraxane (100 mg/m² and 150 mg/m²) increased tumor response rate by >60% with less toxicity compared to treatment with Taxotere (100 mg/m²) every three weeks. The interim analysis also showed that weekly Abraxane nearly doubled the response rate with less toxicity compared to Abraxane (300 mg/m²) dosed every three weeks. Although the data are not fully mature, the interim analysis showed that all three Abraxane regimens result in longer progression-free survival (PFS) than Taxotere dosed every three weeks. A blinded, independent radiologic review of the response data is in process. Final analysis will be submitted to the American Society of Clinical Oncology (ASCO) meeting in 2007. In this randomized phase II trial, conducted in the USA and the Russian Federation between November 2005 and June 2006, more than 300 chemotherapy-naïve patients (postmenopausal=73%) with Stage IV metastatic breast cancer were treated with one of four treatment regimens; 76 patients were treated with Abraxane (300 mg/m²) dosed every three weeks, 76 with Abraxane (100 mg/m²) and 74 with Abraxane (150 mg/m²) dosed weekly for three weeks out of four, and 76 with Taxotere (100 mg/m²) dosed every three weeks. The purpose of the trial was to obtain comparative toxicity and preliminary antitumor response data addressing three issues, Abraxane versus Taxotere; weekly versus every three week dosing of Abraxane; and high and low dose of Abraxane. The secondary endpoint of the trial was PFS. Data from this trial were intended to provide direction for the design of future trials with Abraxane. The prospectively planned interim analysis demonstrated that first line weekly treatment with Abraxane (100 mg/m² or 150 mg/m²) compared to Taxotere resulted in a statistically significant increase in response rates of 61% (58% versus 36%, p=0.004), and 72% (62% versus 36%, p=0.0016), respectively. Both weekly dose regimens of Abraxane E also increased the response rate compared to every three week Abraxane (58% and 62% versus 33%; p <0.001). Although these data are not mature with only 33% of potential events having occurred, in the current analysis, all three Abraxane treatment arms resulted in longer PFS compared to Taxotere (by log rank). Compared to Taxotere, all three Abraxane treatment arms demonstrated less frequent adverse events with regard to Grade 4 neutropenia (74% for Taxotere versus 4%, 3%, 7% for Abraxane, respectively); febrile neutropenia (7% versus. 1%, 1%, 1%, respectively); and Grade 1/2 mucositis/stomatitis (20% versus 3%, 1%, 0%, respectively). There was no Grade 4 peripheral neuropathy reported in any of the treatment arms. There were no statistical differences in peripheral neuropathy between the Abraxane regimens compared to Taxotere. In this trial, the therapeutic index of weekly Abraxane (100 mg/m²) was superior to the other two regimens of Abraxane and to the Taxotere regimen, with a response rate of 58% versus 36% for Taxotere with improvement in the adverse event profile. There was no statistical difference in arthralgias between the 100 mg/m² dose of Abraxane, compared to Taxotere. Fatigue was significantly lower in Abraxane (100 mg/m²) compared to Taxotere (21% versus 46). Abraxane (100 mg/m²) weekly compared to the other two Abraxane treatment arms of 300 mg/m² every 3 weeks, or 150 mg/m² weekly resulted in less peripheral neuropathy (37% versus 51% and 47%, respectively), arthralgias (16% versus 33% and 35%, respectively), and fatigue (21% versus 33% and 39%, respectively). The only adverse event occurring at a greater frequency with Abraxane at 300 mg/m² every 3 weeks or 150 mg/m² weekly, compared to Taxotere, was arthralgia (33% and 35% versus 16%, respectively) [Gradishar W, etal, San Antonio Breast Cancer Symposium (SABCS06), Abs. 46] Based on these encouraging data, Abraxis plans to initiate a worldwide head-to-head phase III registration trial comparing weekly Abraxane to every three week Taxotere for the treatment of first line metastatic breast cancer. The phase III registration trial is expected to begin in the first half of 2007 in multiple sites throughout North America, Eastern and Western Europe, and Asia-Pacific.

An open-label, non-randomized, phase II clinical trial (protocol ID: I-04-012; NCT00251472) was sponsored by the International Oncology Network under PI Barry Mirtsching, MD, Center for Oncology Research and Treatment, Medical City (Dallas, TX), to evaluate the efficacy and safety of Abraxane (125 mg/m²) by 30-minute IV infusion weekly as first line treatment to patients (target n=75) with locally advanced inoperable breast cancer or metastatic breast cancer. Primary endpoint was response rates to Abraxane and secondary endpoints were TTP, OS, and drug toxicities. Adult patients with histologically confirmed cancer were treated with Abraxane on days 1, 8, and 15 for the first 3 weeks of each 4-week cycle. Patients with HEr2-positive disease were concurrently administered Herceptin, at a dose of 4 mg/kg on week 1, and 2 mg/kg on subsequent weeks, throughout therapy. A total of 28 patients were enrolled and 27 were treated from March 2005 to January 2006. Patient characteristics include gender (M/F) 0/27, median age 60.5 years, ECOG performance status (0-1) 13/14, and HEr2 status (+/=/missing) 6/18/3. A total of 285 cycles have been administered with a median dose of 125 mg/m² and 6 dose modifications have occurred due to toxicity. To date, 18 patients are still on study. CTC hematologic toxicities were Grade 3 leukopenia (3.7%) and Grade 3 neutropenia (7.4%). Grade 3 nonhematologic toxicities were gastritis (3.7%), peripheral sensory neuropathy (7.4%), arthralgia (3.7%), and bone pain (3.7%). No Grade 4 nonhematologic toxicities occurred. Preliminary data show that weekly Abraxane at a dose of 125 mg/m², with or without trastuzumab (Herceptin; Genentech) for first line treatment of metastatic breast cancer is well tolerated (Mirtsching B, etal, ASCO06, Abs. 10707).

As of May 2005, a total of 22 clinical trials with Abraxane, in patients with breast cancer, are ongoing or planned.

Final results from a phase II clinical trial that begin in November 1999 and ended in May 2001 in 63 woman with histologically confirmed and measurable MBC were reported in the September 2005 issue of the Journal of Clinical Oncology. Patients were administered 300 mg/m² ABI-007 IV over 30 minutes every 3 weeks without premedication. A total of 48 patients were administered prior chemotherapy and 39 patients were not administered prior treatment for metastatic disease. ORR were 48% for all patients. For patients who were treated with ABI-007 as first-line and greater than first-line therapy for their metastatic disease, the respective response rates were 64% and 21%. Median TTP was 26.6 weeks, and OS was 63.6 weeks. No severe hypersensitivity reactions were reported despite the lack of premedication. Toxicities observed were typical of paclitaxel and included Grade 4 neutropenia (24%), Grade 3 sensory neuropathy (11%), and Grade 4 febrile neutropenia (5%). Patients were administered a median of 6 treatment cycles, 16 patients had 25% dose reductions because of toxicities, and 2 of these patients had subsequent dose reductions. ABI-007 uses the natural carrier albumin rather than synthetic solvents to deliver paclitaxel and allows for safe administration of high paclitaxel doses without premedication, resulting in significant antitumor activity in patients with MBC, including patients treated as first-line therapy (Ibrahim NK, etal, J Clin Oncol, 1 Sep 2005;23(25):6019-26).

Indication in Development

ovarian cancer

Latest Status

Phase II (planned 5/05) USA (combination), phase II (planned 5/05) USA (combination)

Clinical History

As of May 2005, 2 phase II clinical trials of Abraxane in patients with ovarian cancer are planned, including a trial of Abraxane in combination with carboplatin as a first line treatment and a trial of Abraxane in combination with bevacizumab (Avastin).

Indication in Development

prostate cancer

Latest Status

Phase II (planned 5/05) USA (combination), phase II (planned 5/05) USA

Clinical History

As of May 2005, 2 phase II clinical trials of Abraxane in patients with prostate cancer are planned, including a trial of Abraxane in combination with bevacizumab (Avastin) and a trial of Abraxane in patients with advanced prostate cancer.

Indication in Development

breast cancer, node positive

Latest Status

Phase III (planned 9/06) USA

Clinical History

In September 2006, Abraxis BioScience met with the FDA's Oncologic Drugs Advisory Committee (ODAC) to discuss the need for a randomized trial to support the approval of Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) for use in the adjuvant treatment of node-positive breast cancer. ODAC panel members recommended that Abraxis and the FDA work together to identify selected patient populations for a 'reasonably sized', randomized trial to confirm safety and efficacy of Abraxane leading to approval as adjuvant treatment. The FDA generally follows the advice of the panel, however, they are not bound by the Committee's recommendations.

Indication in Development

cervical cancer, persistent or recurrent, refractory

Latest Status

Phase II (begin 5/06, suspended 3/08) USA

Clinical History

A multicenter (n=27), open label, phase II clinical trial (protocol ID: CDR0000463520; GOG-0127V; NCT00309959) was initiated in May 2006, in the USA, to evaluate the safety and efficacy of paclitaxel in treating patients with persistent or recurrent carcinoma of the cervix. Patients must have undergone 1 prior systemic chemotherapeutic regimen, must not undergo prior treatment with radiotherapy to any portion of the abdominal cavity or pelvis, chemotherapy for any abdominal or pelvic tumor, ABI-007 or any other taxane, and must not be treated with concurrent amifostine, ritonavir, saquinavir, indinavir, nelfinavir, or anticonvulsants. The trial’s primary objectives are to determine antitumor activity and toxicity. According to protocol, patients are administered IV paclitaxel over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of treatment, patients are followed periodically for up to 5 years. The trial, to enroll about 60 patients, is being conducted under Study Chair, David S. Alberts, MD, University of Arizona (Tucson, AZ) and was suspended in March 2008.

Indication in Development

pancreatic cancer, locally advanced, inoperable, or metastatic

Latest Status

Phase II (begin 6/08, closed 1/10) USA, Singapore

Clinical History

In the phase II clinical trial (protocol ID: CDR0000597455; EPROST-20080055; SCCC-2007096; SCCC-EPROST-20080055; NCT00691054), patients with advanced pancreatic cancer that progressed on gemcitabine-based therapy, were treated with Abraxane (100 mg/m²) over 30 minutes on days 1, 8, and 15 of a 28- day cycle. The primary endpoint was 6-month OS. Secondary endpoints were response rate by RECIST, PFS, safety and toxicity profile. Out of 20 patients accrued, 19 patients were evaluable for response; 18 (95%) had metastatic disease (Stage IV). The 6-month OS was 58% and the median OS was 7.3 months. The median PFS was 1.6 months. There was 1 confirmed PR and disease stabilized in 6 (32%) patients as best response. The remaining 12 patients (63%) had progressive disease (PD) on or before the first response assessment; 5 patients are alive with a median follow-up of 12.7 months (range 9.6-16.3), including one with SD on cycle 15 of therapy. After 2 cycles, the median CA 19-9 level decreased by 52% in patients with SD or PR, versus an 18% drop in the patients with progressive disease. Correlative studies with SPARC expression are ongoing. Nonhematologic toxicities were generally mild with Grade 1 or 2 nausea, anorexia, hypocalcemia and vomiting occurring in 63%, 47%, 37% and 26% of patients, respectively. Grade 3 or 4 neutropenia, neutropenic fever and anemia occurred in 32%, 11% and 11% of patients, respectively. There were no cases of Grade 3 or 4 neuropathy. Abraxane was well tolerated and provided clinical benefit in 37% of patients with disease refractory ti gemcitabine (Hosein PJ, etal, ASCO10, Abs. 4120).

A 2-center, open label, interventional, phase II clinical trial (protocol ID: CDR0000597455; EPROST-20080055; SCCC-2007096; SCCC-EPROST-20080055; NCT00691054) was initiated in June 2008, in the USA and Singapore, to determine the safety and efficacy of nab-paclitaxel in treating patients with locally advanced or metastatic pancreatic cancer trefractory to first line therapy with gemcitabine. The trial’s primary objective is to establish preliminary evidence of efficacy. Secondary objective is to determine the safety, toxicity profile, CR, PR, ORR, CA 19-9 response, and PFS. According to the protocol, patients are administered IV nab-paclitaxel over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of treatment, patients are followed every 3 months for 1 year and then annually thereafter. This trial, to enroll about 20 patients, is being conducted under Study Chair, Caio Max S. Rocha Lima, MD, University of Miami Sylvester Comprehensive Cancer Center (Miami, FL) and Investigator, Gilberto Lopes, MD, Johns Hopkins Singapore International Medical Centre. This trial was closed in January 2010.

Indication in Development

bladder cancer, transitional cell, refractory

Latest Status

Phase I/II (begin 12/07, ongoing 2/09) USA

Clinical History

An open label, uncontrolled, single group assignment, phase I/II clinical trial (protocol ID: AAAC1114; NCT00583349) was initiated in December 2007, in the USA, to evaluate the safety and efficacy of paclitaxel in treating patients with treatment-refractory transitional cell carcinoma of the bladder. Patients must have all grossly visible disease surgically removed, must not undergo prior treatment with docetaxel, paclitaxel, or radiation to the pelvis, and must not have history of vesicoureteral reflux, indwelling urinary stent, or neuropathy of any cause. The trial’s primary objectives are to determine safety, toxicity, efficacy, and evaluate the utility of paclitaxel. Other objectives are to further evaluate the safety and toxicity profile. According to protocol, the phase I trial is designed as a dose-escalation study with cohorts of three patients each. Each successive group is administered an increased concentration of Abraxane intravesically. No dose increase will occur until each member of the previous cohort has undergone the first instillation of the medication without experiencing a DLT. Any patient who experiences a DLT will be removed from the trial and treated appropriately. If 1 patient in the cohort experiences a DLT an additional 3 patients will be enrolled and treated at that dose-level. If none of the additional 3 patients experience a DLT, the next group of patients will be started on the next higher dose level. If at any dose level, 2 or more patients experience a DLT, the previous dose level will be considered as the MTD. An additional 3 patients (for a total of 6 patients) will then be treated at the MTD. If less than 2 patients experience a DLT this dose level will be established as the MTD. The phase II aspect is designed in a Simon II stage format, with 10 patients enrolled in the first stage. If there are 2 or more successful treatments in that group (negative urine cytology and bladder biopsy after 6 months), then the first stage will pass the rejection rule, and up to another 19 patients will be enrolled. If at any point in the trial there are a total of 6 or more successes, then the phase II aspect will be considered a successful trial and will be completed at that point. The trial, to enroll about 47 patients, is being conducted under PI, James M McKiernan, MD, Columbia University Medical Center, Urology (New York, NY).

Market Opportunities

Breast cancer is the most common cancer in women in Australia being diagnosed in 13,000 Australian women annually.

From 2000 to 2005, the incidence of breast cancer in China has increased 25% to 25 out of every 100,000 women. There are approximately 400,000 women with breast cancer in China, with approximately 168,000 new cases of breast cancer reported in China each year. In the commercial center of Shanghai, in 2007, 55 out of every 100,000 women had breast cancer, a 31%increase since 1997, and about 45 out of every 100,000 women in Beijing had the disease, representing a 23% increase during the past 10 years. There were approximately 1.5 million vials (30 mg/vial) of paclitaxel injection sold in China in 2007, representing total market value of $83 million. This represents a 30% increase over 2006, when the total market value of paclitaxel injection was approximately $64 million. The total taxane market in China was approximately $167 million in 2007.

In Korea, there are approximately 20,000 cases of metastatic breast cancer. The Korean oncology market for 2007 is estimated at $533 million of which the chemotherapy market and its taxane component are estimated at $400 million and $77 million, respectively.

According to the National Breast Cancer Centre of Australia, breast cancer is one of the most common cancers affecting women in Australia. In 2006 alone, an estimated 13,000 Australian women were diagnosed with breast cancer. Within five years, the number of women diagnosed with breast cancer each year is expected to reach almost 15,000. According to the National Breast Cancer Centre of Australia, breast cancer is one of the most common cancers affecting women in Australia. In 2006 alone, an estimated 13,000 Australian women were diagnosed with breast cancer. Within five years, the number of women diagnosed with breast cancer each year is expected to reach almost 15,000.

Available for licensing; as of September 2006, Abraxis intents to seek a global commercialization partner for Abraxane.

According to the American Cancer Society (ACS), while early detection efforts have decreased mortality rates, in 2004 an estimated 215,990 women are expected to be diagnosed with advanced breast cancer. Breast cancer is still the leading overall cause of death in women between the ages of 20 and 59, with 40,110 deaths estimated in 2004. One of every three malignancies diagnosed in the USA is breast cancer; excluding skin cancer, it's the most common cancer among women.

The Japanese market for chemotherapy agents was approximately $2.6 billion in 2005.

Patent/Legal Issues

In November 2009 the Office of Orphan Products Development of the FDA granted orphan drug designation to Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) for the treatment of pancreatic cancer as well as Stage IIb/IV melanoma.

In June 2008, a jury in federal court in Wilmington, DE awarded Elan $55.2 million in damages against Abraxis BioScience for infringement of a USA patent # 5,399,363 that covers coated nanoparticles used intravenously to deliver paclitaxel for the treatment of metastatic breast cancer. The jury also decided another patent # 5,834,025, held by Elan, on a similar technology to deliver such particles, is valid and enforceable. The award, which covers infringement beginning January 7, 2005, represents 17% Abraxis' 2007 sales. According to court papers, more than 30,000 patients had been treated with Abraxane. Abraxis will appeal the verdict. The case was originally filed in 2006.

As of July 2008, Abraxis had 3 issued Chinese patents covering Abraxane, as well as five additional pending patent applications in China.

In July 2006, Elan filed a lawsuit against Abraxis alleging patent infringement in relation to Abraxane, asserting that it uses technology protected by two Elan-owned patents.

In September 2003, the USPTO issued to American BioScience (ABI), and its inventors, Patrick Soon-Shiong, MD, and Neil Desai, PhD, patent #6,506,405 covering compositions of matter and methods of use for cremophor-free taxanes. American Pharmaceutical Partners (APP), under its license agreement for ABI-007, has exclusive rights in the USA to this patent, which has 89 claims covering compositions and unit dosage forms of cremophor-free taxanes, as well as methods of use of such taxanes, without the need for pretreatment with steroid therapy or growth factor support.

The Protosphere Nanoparticle technology is covered by 19 issued USA patents.

Current as of

June 30, 2010