Generic Name

Bortezomib

Brand Name

Velcade

Other Designation

MLN341 (formerly LDP-341, PS-341 & MG-341)

PRODUCT SOURCE

Primary Developer

Millennium Pharmaceuticals

Affiliations

Pharsight • Johnson and Johnson • Janssen-Cilag

CLINICAL STATUS

Indication in Development

breast cancer, advanced or metastatic

Latest Status

Phase II (begin 8/01, closed 12/03, completed 4/05) USA, phase II (begin 1/02, closed 11/03) USA

Clinical History

A phase II clinical trial (protocol ID: CDR0000069114, NU-NCI00B11, NCI-1862, NCT00028639) of bortezomib in patients with metastatic breast cancer was performed at Northwestern University (Chicago, IL) to determine the safety and efficacy for this treatment. Patients must have been administered >/= 1 previous chemotherapy regimen for metastatic breast cancer. Bortezomib (1.5 mg/m²) was administered IV on days 1, 4, 8, 11 of a 21 day cycle. Dose escalation to 1.7 mg/m² may be considered in the absence of significant adverse events. Re-evaluation was performed every 3 cycles. A total of 12 patients were enrolled for stage-one interim analysis and all patients were evaluable for response. There were no Grade 4 toxicities. Grade 3 toxicities included pulmonary toxicities (n=2) and Grade 2 toxicities included thrombocytopenia (n=1), diarrhea (n=1), nausea (n=3), vomiting (n=1), pulmonary (n=4), pain (n=2), depression (n=1) and fatigue (n=2). Dose escalation to 1.7 mg/m² was performed for 1 patient in 1 cycle. Only 3/12 patients completed 3 cycles of therapy (median cycles/patient = 1) and 8/12 patients PD following </= 1 cycle of therapy. No objective responses were observed. All 12 patients initially progressed while on therapy and the median time to disease progression was 25 days (range=10-62). To date, 6 patients have died with a median time to death of 136 days. Results indicate that bortezomib is not active in patients with metastatic breast cancer. This 2-stage trial was terminated following the first stage as a result of the absence of any objective response (Brown J, etal, ASCO04, Abs. 546).

A phase II clinical trial (protocol ID: CDR0000068976, MDA-ID-00308, NCI-1855, NCT00025584) of bortezomib in minimally pretreated (1 previous regimen) patients with metastatic breast cancer was performed at the M. D. Anderson Cancer Center (Houston, TX) to determine safety and efficacy for this treatment. Patients were administered bortezomib (1.5 mg/m²) IV biweekly for 2 consecutive weeks in a 21-day cycle. Patients were evaluated clinically every 3 weeks to assess toxicity. A total of 12 patients were enrolled. Of these patients, 10 are evaluable for response, 1 died early from disease complications and 1 is still on treatment. 9 patients had predominant visceral disease. 20-S proteasome inhibition compared to the pre-dose administration was observed in all cases. The median number of cycles of bortezomib was 2 cycles (range=1-5 cycles). Of 10 evaluable patients, 1 (10%) had SD and 9 (90%) had PD. Median TTP was 47 days (range=17-110 days). The most frequently observed Grade 3-4 toxicities included fatigue 70% (n=7) and skin rash 40% (n=4). Median time of onset of the skin rash was 11 days (range=10-27 days). Results indicate that bortezomib inhibits 20S-proteasome and is tolerable, but is not significantly active in patients with metastatic breast cancer at this schedule (Cristofanilli M, etal, ASCO04, Abs. 3102).

A phase II clinical trial (protocol ID: CDR0000069114, NU-NCI00B11, NCI-1862, NCT00028639) of PS-341 in metastatic breast cancer, initiated in January 2002, will enroll approximately 12-35 patients within 6-24 months. The trial is conducted at the Robert H. Lurie Cancer Center (Northwestern University) with William John Gradishar aTrial Chair. IV PS-341 is administered over 3-5 seconds twice weekly, for 2 weeks. Treatment is repeated every 3 weeks in the absence of disease progression or unacceptable toxicity. This trial was closed in November 2003.

A phase II clinical trial (protocol ID: CDR0000068976, MDA-ID-00308, NCI-1855, NCT00025584) initiated in August 2001 at M. D. Anderson Cancer Center with Massimo Cristofanilli ( tel: 713-792-2817) as Trial Chair is investigating IV PS-341 administered over 3-5 seconds, twice weekly, on weeks 1 and 2 in MBC patients. Treatment is repeated every 3 weeks in the absence of disease progression or unacceptable toxicity. A maximum of 12-35 patients will be accrued within 9-12 months. This trial was temporarily closed in December 2003. As of April 2005, this trial is completed.

A second phase I clinical trial was initiated in March 1999. An IND to begin a phase I clinical trial at M. D. Anderson Cancer Center at the laboratory of Dr. Logothetis is to be filed in July 1998; Christos Papandreou, MD, is the PI.

Indication in Development

genitourinary malignancies

Latest Status

Phase I (closed 00) USA

Clinical History

A phase I clinical trial of weekly IV LDP-341, at a starting dose of 0.13 mg/m², administered for 4 weeks, with 2 weeks off, was initiated at MDACC in patients with genitourinary malignancies. Endpoints include determination of DLT, MTD ,and PK of LDP-341, and a parallel examinination of its predictive value on proteasome activity and its association with tumor response and toxicity (Elliott PJ, etal. ASCO99, Abs. 804:209a).

Indication in Development

sarcoma, bone and soft tissue, advanced or metastatic

Latest Status

Phase II (begin 10/01, closed 5/04) USA

Clinical History

Results were published from a multicenter phase II clinical trial (protocol ID: CDR0000069060, MSKCC-01073, NCI-1757, NCT00027716) of bortezomib in patients with recurrent or metastatic sarcomas that was performed at the Memorial Sloan-Kettering Cancer Center (New York, NY) to determine safety and efficacy for this treatment. Up to 2 arms were opened, each using a Simon 2-stage design. Stratum I included patients with osteogenic sarcoma, Ewing sarcoma, and rhabdomyosarcoma. Stratus II included patients with other types of soft tissue sarcomas. Patients were not allowed to have been administered previous chemotherapy for metastatic disease. The initial dose of bortezomib was a 1.5 mg/m² IV push twice weekly followed by a rest week. The dose was escalated to 1.7 mg/m² if patients tolerated cycle 1 well. The dose escalation was eliminated as a result of toxicity observed in the first 6 patients. The most serious adverse effects observed included painful neuropathy, myalgias, and asthenia. The most frequently observed toxicities included fatigue, diarrhea, constipation, and nausea. Pharmacodynamic results for 18 patients with complete data collection did not exhibit consistent differences between patients with or without Grade 2 or Grade 3 neuropathy. Stratum I had low accrual and was closed. Among 21 evaluable patients in stratum II, 1 patient with leiomyosarcoma had a PR. As a result of inactivity of this agent, the trial was closed after the first stage of accrual. Results indicate that bortezomib has minimal activity in soft tissue sarcoma as a single agent. If studied further in sarcomas, bortezomib should be investigated in combination with agents with demonstrated preclinical synergy (Maki R, etal, Cancer, 1 Apr 2005;103(7):1431-8).

A multicenter, phase II clinical trial (protocol ID: CDR0000069060, MSKCC-01073, NCI-1757, NCT00027716) to determine effectiveness of PS-341 in treating patients with advanced or metastatic sarcoma was initiated in October 2001. Patients are stratified according to disease with stratum I, including soft tissue sarcoma not specified in stratum II and osteogenic sarcoma arising from soft tissues versus stratum II involving Ewing's sarcoma of soft tissue or bone, rhabdomyosarcoma, and osteogenic sarcoma of bone. A total of 21-41 patients will be accrued for stratum I within 5-11 months, and 21-41 patients will be accrued for stratum II within 10.5-22 months. IV PS-341 is administered over 3-5 seconds on days 1, 4, 8, and 11. Courses are repeated every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year. Robert Maki (Ph: 212-639-5720) of the Memorial Sloan-Kettering Cancer Center is the PI. Stratum I was closed to accrual as of 10/17/03. As of May 2004, this trial is temporarily closed.

Indication in Development

solid tumors, advanced or refractory • solid tumor, pediatric

Latest Status

Phase I (completed 6/00) USA, phase I (begin 11/01, closed 3/03) USA (pediatric), phase I (begin 9/99, completed 9/01) USA, phase I (closed 01) USA, phase I (begin 1/03, closed 10/04) USA, Australia, phase I (completed 6/04) USA, phase I (begin 8/04, ongoing 12/05) USA

Clinical History

A dose escalation, phase I clinical trial (protocol ID: CDR0000383782, WSU-C-2802, NCI-6432, NCT00091117) of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction was initiated in August 2004 at multiple locations in the USA and Australia (n=11) to determine the MTD, safety, and tolerability for this treatment. Patients are stratified according to hepatic function (normal versus mild dysfunction versus moderate dysfunction versus severe dysfunction). Patients are adminstered bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients per stratum are administered escalating doses of bortezomib until the MTD is determined. Patients with normal hepatic function are not administered escalating doses of bortezomib. A total of approximately 12-69 patients will be accrued for this trial. Patricia LoRusso, DO, of the Barbara Ann Karmanos Cancer Institute (tel: 313-745-1238; 800-527-6266) is the protocol chair.

A phase I clinical trial of bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer was performed at the M. D. Anderson Cancer Center (Houston, TX) to determine the DLT, MTD, and efficacy for this treatment. Bortezomib was administered IV weekly for 4 weeks, every 5 weeks. A total of 53 patients (androgen-independent prostate cancer=48) were administered 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m²/dose, using an escalation scheme with a continuous reassessment method. Dose-related 20S proteasome inhibition was observed, with DLT at 2.0 mg/m² (diarrhea, hypotension) occurring at an average 1-hour post-dose of >/= 75% 20S proteasome inhibition. Additional observed side effects included fatigue, hypertension, constipation, nausea, and vomiting. No relationship was observed between body-surface area and bortezomib clearance over the narrow dose range examined. Evidence of biologic activity (decrease in serum prostate-specific antigen and IL-6 levels) was observed at >/= 50% 20S proteasome inhibition. Prostate-specific antigen response was observed in 2 patients with androgen-independent prostate cancer. Partial response in the lymph nodes was observed in 2 patients. The MTD and recommended phase II dose of bortezomib using this schedule is 1.6 mg/m². Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity was observed in androgen-independent prostate cancer at tolerated doses of bortezomib (Papandreou C, etal, J Clin Oncol, 1 Jun 2004;22(11):2108-21).

In a dose escalation, multicenter phase I clinical trial (protocol ID: CDR0000270687, WCCC-CO-02903, CWRU-040315, CWRU-1Y03, NCI-5874, NCT00054483) patients with advanced malignancies are stratified according to most recent creatinine clearance and are treated with IV bortezomib over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients are treated with escalating doses of bortezomib until MTD is determined. Once the MTD is determined, an additional cohort of up to 6 patients is treated at the MTD. Beginning January 2003, a total of 60-69 patients are to be enrolled in the USA and Australia. Daniel Mulkerin, MD, at University of Wisconsin Comprehensive Cancer Center is the Protocol Chair. As of October 2004, this trial is closed.

Phase I dose escalation clinical trial to determine the MTD, DLT, and antitumor activity of PS-341 in treating pediatric patients with advanced solid tumors was started in November 2001 (protocol ID: CDR0000068760, COG-ADVL0015, NCT00021216). IV PS-341 is administered on days 1, 4, 8, and 11. Treatment is repeated every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients are administered escalating doses of PS-341 until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT. If DLT in the form of myelosuppression occurs in stratum I, dose escalation is continued with patients meeting the qualifications for stratum II. Approximately 24-36 patients will be accrued. Susan Blaney of the Children's Oncology Group is the Trial Chair. This trial was closed in March 2003.

Phase I dose escalation, multicenter clinical trial of PS-341 in patients with advanced solid tumors or lymphomas was completed in September 2001 (protocol ID: CDR0000067212, NYU-9909, NCI-T99-0047, NCT00004002). IV PS-341 was administered on days 1 and 4. Treatment was repeated every 14 days for at least 2 courses in the absence of unacceptable toxicity or disease progression. Patients with stable or responding disease underwent additional courses at the discretion of the treating physician. Cohorts of 3-6 patients were administered escalating doses of PS-341 until the MTD was determined. Patients were followed at 4 weeks. A maximum of 27 patients were to be accrued. Franco M. Muggia (tel: 212-263-6485) of the NYU School of Medicine's Kaplan Comprehensive Cancer Center was the PI.

In a phase I clinical trial of PS-341, 22 patients with advanced cancer completed 34 courses of treatment at doses of 0.5, 0.9, 1.25, 1.5, and 1.7 mg/m². PS341 was administered twice a week for 4 out of every 6 weeks. Toxicities were graded by NCI CTC and recorded as maximum grade per patient for all treatment cycles. Common toxicities were fatigue (8 Grade 1, 3 Grade 2, 1 Grade 3), anorexia (4 Grade 1, 2 Grade 2), diarrhea (4 Grade 1, 1 Grade 2), nausea (13 Grade 1, 4 Grade 2), vomiting (5 Grade 1, 1 Grade 2) fever (4 Grade 1, 2 Grade 2), and thrombocytopenia (5 Grade 1, 2 Grade 2, and 3 Grade 3). Dose dependent decreases in 20S proteasome activity in peripheral mononuclear cells (PBMNC) were observed with 38[%] inhibition at 0.5 mg/m², 48[%] at 0.9 mg/m², and 72[%] at 1.25 mg/m². Increases in levels of p53 after treatment with PS-341 were detected as well as increases in PBMNC ubiquitinated proteins. No objective responses were documented in 18 evaluable patients to date (Erlichman C, etal, ASCO01, Abs.337:85a).

A phase I trial of PS341 administered as an IV bolus twice weekly for 2 consecutive weeks with a one week recovery period was evaluated in 43 patients with advanced solid tumor malignancies, at 9 dose levels ( 0.13, 0.25, 0.40, 0.60, 0.75, 0.90, 1.08, 1.30, 1.56 mg/m²). Patients were heavily pretreated [median number of prior chemotherapy regimens - 4 (range=1-16)]. In addition, 12 patients were treated with prior definitive radiation therapy. There was no hematologic DLT. At the 1.3 mg/m²/dose level, 1 patient developed Grade 3 painful neurosensory toxicity after 4 cycles of therapy. All other DLT was seen in the 12 patients treated at the 1.56 mg/m²/dose level and consisted of: 1 episode of Grade 3 fatigue, 1 episode of Grade 3 orthostatic dehydration, 3 episodes of Grade 3 diarrhea, and 2 episodes of Grade 3 painful neurosensory toxicity. The recommended phase II dose in this patient population at this schedule is 1.3 mg/m²/dose. Inhibition of the 20S proteasome in whole blood of treated patients was consistent from patient to patient treated at each dose level and increased with dose. There was 65% inhibition at the MTD. A major response was seen in the trial involving a patient with nsclc (bronchioloalveolar-type) treated with 5 prior regimens who experienced a PR at the 1.56 mg/m²/dose level (Aghajanian C, etal, ASCO01, Abs. 338:85a)

A phase I clinical trial in 28 heavily pretreated patients with advanced solid tumors (melanoma=4, renal cell=4, nsclc=3, prostate cancer=3, colon cancer=3, adenocarcinoma of unknown primary=2, endometrial=2, head & neck=2, and 1 each gastric, ovary, breast, bladder and cervical) was performed at Memorial Sloan-Kettering Cancer Center, to determine the MTD, as well as to correlate determination of 20S proteasome activity in whole blood with outcome. According to the protocol, 53 courses of therapy were administered at a twice weekly schedule of IV bolus infusions at dose levels ranging from 0.13 mg/m² to 1.08 mg/m² per dose, for 2 consecutive weeks with a one week rest period. There were no drug-related toxicities. At 1-hour postdrug infusion (the anticipated point of maximal inhibition of 20S proteasome activity), the level of 20S proteasome inhibition, as measured in whole blood, correlated with the dose delivered ranging from no significant inhibition at 0.13 to 0.25 mg/m², to 30% at 0.40 mg/m², to 40% at 0.60 mg/m², to 50% at 0.75 mg/m², to 60% at 0.90 mg/m²) with the percentage of 20S proteasome inhibition being remarkably consistent from patient to patient (Aghajanian C, etal, ASCO00, Abs. 736:189a).

Indication in Development

acute myeloid leukemia (AML), refractory or relapsed • acute lymphoblastic leukemia (ALL) • myelodysplastic syndrome (MDS) • chronic myeloid leukemia (CML), blast phase • chronic lymphocytic leukemia (CLL), relapsed • hematological malignancies • Waldenstrom's macroglobulinemia

Latest Status

Phase I (begin 2/00, closed 5/02) USA, phase I (completed 12/01) USA, phase I (completed 5/02) USA, phase I (begin 1/04, ongoing 12/05), phase II (begin 6/01, closed 5/04) USA, phase II (begin 7/01, closed 4/05) USA, phase II (begin 10/02, closed 4/05) USA, Canada

Clinical History

In June 2005, results were presented from a phase II clinical trial (protocol ID: CDR0000257042, CAN-NCIC-IND152, NCI-58443, ECOG-JI152, NCI-NCIC-152, NCT00045695) of single agent Velcade in patients with relapsed or refractory Waldenstrom's Macroglobulemia, a form of indolent lymphoma, at the 9th International Conference of Malignant Lymphoma. Patients were administered a median of 2 previous lines of therapy. A total of 25 patients were evaluable. An ORR of 80% was observed including 36% PR and 44% MR. Decreases in serum IgM were observed in 24 out of 25 patients with a median 44% reduction. Observed adverse events included neutropenia, leukopenia, gastrointestinal symptoms and sensory neuropathy.

A dose escalation, open label, multicenter, phase I clinical trial (protocol ID: CDR0000350340, COG-ADVL0317, NCT00077467) of bortezomib in children with refractory or recurrent leukemia was initiated in January 2004 at multiple locations in USA and Canada, to determine MTD, recommended phase II dose, toxicity, efficacy and PK. Patients are stratified according to disease stage (relapsed compared to refractory) to be administered bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients are administered escalating doses of bortezomib until the MTD is determined. A total of 3-36 patients will be accrued for this trial within 1.5-36 months. Terzah Horton, MD, PhD (tel: 832-824-4269), and Lisa Bomgaars, MD (tel: 832-824-4588), of the Texas Children's Cancer Center are Protocol Chairs.

A phase II clinical trial (protocol ID: CDR0000068872, MDA-ID-00274, NCI-1756, MDA-DM-00274, NCT00023881) of bortezomib, designed to determine the activity and safety, was initiated in July 2001, at M. D. Anderson Cancer Center, in patients with imatinib-refractory, chromosome-positive, CML in chronic (CP) or accelerated phase (AP). Patients are administered bortezomib (1.5 mg/m²), over 3 to 5 seconds, twice weekly on weeks 1-2 and 4-5, in 3-week cycles. Doses are adjusted according to toxicity. Hydroxyurea and/or anagrelide administration was allowed for the first 6 weeks of therapy. Treatment is repeated every 6 weeks, for up to 12 months, in the absence of disease progression or unacceptable toxicity. A total of 5-30 patients will be accrued within 15-30 months. Jorge Cortes, MD (tel: 713-794-5783 or 800-392-1611; jcortes@mdanderson.org), is Protocol Chair. To date, 7 patients (CP=2, AP=5) have been administered a median of 6 doses of bortezomib. A significant decline in basophils (from 19% to 2%, 28% to 3%, and 51% to 3%) was observed in the 3 patients with the highest basophil counts, who re-entered CP. These responses were transient with basophils increasing while off therapy. No cytogenetic responses were observed. Observed Grade 3 toxicities included diarrhea, fatigue, dizziness, and hypotension. An allergic reaction was observed in 1 patient after the second dose of bortezomib. During therapy, mononuclear cells were collected to observe apoptosis. The observed apoptosis pattern varied from patient to patient, with 3 patients clearly being sensitive to bortezomib after incubating cells in vitro, and 2 demonstrating evidence of apoptosis after in vivo exposure to bortezomib. Bortezomib has antileukemicactivity in vitro and in vivo in CML and may have particular targeted effect on basophilic CML progression (Cortes J, etal, ASH03, Abs. 4971). As of April 2005, this trial is closed.

In a multicenter, phase II clinical trial (protocol ID: CDR0000257042, CAN-NCIC-IND152, NCI-58443, ECOG-JI152, NCI-NCIC-152, NCT00045695) IV bortezomib is administered over 3-5 seconds on days 1, 4, 8, and 11 to treat untreated or relapsed Waldenstrom's macroglobulinemia. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed at 4 weeks. Those with CR, PR, or SD are followed every 3 months thereafter. Beginning October 2002, a total of 15-25 patients will be accrued at several cancer centers in Canada and the USA. Christine I. Chen of Princess Margaret Hospital is Trial Chair. As of April 2005, this trial is closed.

In a phase I clinical trial at The University of Texas, M.D. Anderson Cancer Center, PS-341 was administered at dose levels: 0.75, 0.9, 1.25, and 1.5 mg/m² IV bolus (3-5 second push) twice weekly for 4 weeks every 6 weeks to 15 patients (AML, n=11), (ALL, n=3), (MDS, n=1). A total of 12 patients were evaluable: 0.75 mg/m² (3 treated/2 evaluable), 0.9 mg/m² (skipped per CRM model), 1.25 mg/m² (7 treated/6 evaluable), 1.5 mg/m² (5 treated/4 evaluable). No Grade 3 toxicity was observed at 0.75 or 1.25 mg/m²; 3 patients at 1.5 mg/m² had Grade 3 toxicity (DLT) (syncope with orthostatic hypotension, n=2; peripheral edema, n=1; non-cardiogenic chest pain, n=1)). A single patient was treated 8 doses at 1.25 mg/m² and a second course at 1.5 mg/m²; this patient experienced orthostatic hypotension after 3 doses at 1.5 mg/m². There was no clinical evidence of sustained antileukemia activity. Up to 2 patients exhibited a transient decrease in peripheral blood blasts (65% to 5% and 26% to 2%, treated at 1.25 and 1.5 mg/m² respectively), and 1 in BM blasts (20% to 4%, at 1.25 mg/m²). Median proteasome inhibition at 1 hour was 44% at 0.75 mg/m² (n=3), 54% at 1.25 mg/m² (n=4) and 63% at 1.5 mg/m² (n=3). Activity was restored after 24 hours, with median 16% residual inhibition and by the time of subsequent doses, inhibition was only 6% to 8%. Significant apoptosis was observed in cells obtained from a patient 24 hours after the first dose. The MTD of PS-341 on this schedule is 1.25 mg/m², a dose that induces significant although transient proteasome inhibition (Cortes JE, etal, ASH02, Abs. 2201:560a; Cortes J, etal, Clin Cancer Res, 15 May 2004;10(10):3371-6).

An NCI-sponsored phase I clinical trial (protocol ID: CDR0000067668, MDA-DM-99245, NCI-94, NCT00005064) was initiated in February 2000 to enroll 30 patients with refractory or relapsed AML, ALL, MDS, or CML in blast phase at M. D. Anderson Cancer Center under PI Jorge Cortes, MD, to determine MTD of LDP-341, assess plasma pharmacology of this drug, its ability to inhibit proteasome function and accelerate apoptosis in circulating blasts, and assess its antileukemic effects. In this dose escalation trial, patients are administered IV bolus LDP-341, twice-weekly, for 4 weeks, followed by 2 weeks of rest, with treatment continuing for a maximum of 12 courses in the absence of unacceptable toxicity or disease progression. This trial was closed in May 2002.

A phase II, open label, dose finding clinical trial of LDP-341 as a single agent in the treatment of patients with with B- or T-cell CLL who have relapsed during or within 6 months after treatment with a purine analog, was initiated in June 2001 to assess the safety and response rate associated with two doses of LDP-341. The 64-patient trial was initially developed as a single center trial, with Dr. Stefan Faderl as lead investigator and Dr. Michael Keating as co-investigator, both of The University of Texas M. D. Anderson Cancer Center. Once underway, Millennium plans to expand the trial by adding 4 or 5 additional sites.

As of December 2000, patients with hematologic malignancies are being enrolled in a phase I trial of LDP-341, being conducted at the University of North Carolina (Chapel Hill, NC). LDP-341 is administered as a twice weekly bolus injection for four consecutive weeks, followed by a two week rest period, with responses being measured after each six week cycle. As of December 2000, three patients have been enrolled at each of the first three dose levels of 0.40, 1.04, and 1.20 mg/m²/dose, have completed at least one cycle of treatment, and are evaluable for response. The majority of these patients were heavily pretreated, and included 1 with myelodysplasia and excess blasts, 2 with Hodgkin’s disease, 3 with NHL, and 3 with multiple myeloma. A total of 84 chemotherapy administrations were completed without reaching MTD. Up to 2 of the 3 patients with multiple myeloma had clinically significant responses. The first patient had a decrease in IgG levels from 3,111 to 1,215 mg/dl, and a decline in marrow plasmacytosis from 41% to normal, while the second had an IgG decrease from 3,878 to 3,819 mg/dl, and marrow plasmacytosis from 28% to 5%. While the second of these patients developed Grade 3 dermatological toxicity and arthritis requiring discontinuation of therapy during cycle 2, the first patient is currently receiving cycle 4 of PS-341, and after the third cycle a monoclonal serum protein was no longer detectable by immunofixation (Stinchcombe T, etal, ASH00, Abs. 2219:516a). In updated results, 27 patients were administered 293 doses of bortezomib including 24 complete cycles. At doses above 1.04 mg/m², DLT included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In 3 out of 10 patients being administered additional therapy, serious reversible adverse events were observed during cycle 2, including postural hypotension (n=1), systemic hypersensitivity reaction (n=1), and Grade 4 transaminitis (n=1; patient with hepatitis C and a substantial acetaminophen ingestion). Pharmacodynamic trials indicate that bortezomib induced 20S proteasome inhibition in a time-dependent and dose-related manner. Of 9 evaluable patients with pretreated plasma cell dyscrasias who completed one cycle of therapy, CR was observed in 1 (11%) and a decrease in paraprotein levels and/or marrow plasmacytosis in 8 (89%) others. Shrinkage of nodal disease was also observed in 1 patient with mantel cell lymphoma and 1 with follicular lymphoma. Bortezomib was well tolerated at a dose of 1.04 mg/m² using this dosing schedule in multiple myeloma and possibly NHL, although patients should be monitored for electrolyte abnormalities and late toxicities (Orlowski R, etal, J Clin Oncol, 15 Nov 2002;20(22):4420-7).

A phase I multicenter, dose escalation trial to determine the effectiveness of PS-341 treatment in patients with hematologic malignancies (protocol ID: CDR0000068105, MSKCC-00031, NCI-G00-1827, NCT00006098) was completed in May 2002. IV PS-341 was administered over 30 minutes on days 1, 4, 8, 11, 15, 18, 22, and 25 followed by 2- week rest. Treatment was repeated every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients were treated with escalating doses of PS-341 until the MTD was determined. A total of 3-30 patients were to be accrued. PI was Steven Soignet (Ph: 212-639-8984) of Memorial Sloan-Kettering Cancer Center.

Indication in Development

glioma, recurrent

Latest Status

Phase I (begin 1/01, ongoing 12/05) USA

Clinical History

An NCI-sponsored phase I clinical trial (protocol ID: JHOC-NABTT-9910, NABTT-9910, CDR0000068326, NCT00006773) was initiated in January 2001 to determine MTD with or without anticonvulsant drugs known to be metabolized by the P450 hepatic enzyme complex in 42 patients with recurrent glioma and determine the drug's biologic activity in these patients by measuring proteasome 20S activity. Patients stratified according to concurrent anticonvulsant drug use (phenytoin, carbamazepine, phenobarbital, primidone, or felbamate versus gabapentin, lamotrigine, valproic acid or no anticonvulsant drugs), are treated with IV LDP-341 over 3-5 seconds twice-weekly for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Once the MTD is determined, 10 additional patients are treated at the MTD. Patients are followed every 2 months. Jeffrey Olson, MD, at New Approaches to Brain Tumor Therapy is Trial Chair.

Indication in Development

neuroendocrine tumors

Latest Status

Phase II (begin 4/01, completed 9/02) USA

Clinical History

A total of 14 patients with measurable, metastatic, well differentiated neuroendocrine carcinomas were enrolled in this clinical trial. Primary sites included small bowel (n=7), pancreas (n=3), stomach (n=1), lung (n=1), and unknown (n=2). PS-341 was administered for 6 months as an IV bolus at 1.5 mg/m² twice a week, for 2 weeks, followed by 1-week rest. Among 8 assessable patients at 12 weeks, 62% exhibited SD, while 38% exhibited progressive disease. Grade 3 toxicity included reversible ileus (n=3), peripheral neuropathy (n=3), transient thrombocytopenia (n=2), neutropenia (n=2), fatigue (n=1), conjunctivitis (n=1), and hypertension/atrial flutter (n=1). While most of these adverse events were expected, ileus was not. Ileus resolved in all 3 patients within 24 hours without surgery, and of note, all patients had prior laparotomies for bowel carcinoid. Up to 4 patients went off trial within 3-12 weeks of therapy because of Grade 3 toxicity of hypertension/atrial flutter (n=1), peripheral neuropathy (n=2), and ileus (n=1). Accrual is ongoing (Shah MH, etal, ASCO02, Abs. 111:29a). In updated results, a total of 16 patients were enrolled. None of the patients experienced a PR or CR. Patients were administered a total of 264 doses of therapy, with a median of 15 doses per patient. No Grade 4 toxicities were observed. The most frequently observed Grade 3 adverse events included peripheral sensory neuropathy (37%), diarrhea (25%), vomiting (18%), and ileus (18%). Of 10 patients who experienced Grade 2 to 3 peripheral sensory neuropathy, 6 also exhibited Grade 2 to 3 dizziness (n=2), orthostatic hypotension (n=2), syncope (n=1), ileus (n=2), or abdominal cramps (n=1). Variations in tumor marker levels did not correspond with tumor response. The mean percentage of 20S proteasome inhibition attained in whole blood at 1 and 24 hours following bortezomib administration was 68 and 30%, respectively. Despite attaining the surrogate biologic end point, single agent bortezomib did not result in any objective responses in patients with metastatic carcinoid or islet cell tumors. Additional investigation should be performed to clarify the possible association of autonomic neuropathy with bortezomib (Shah MH, etal, Clin Cancer Res, 15 Sep 2004;10(18 Pt 1):6111-8).

A phase II multicenter clinical trial of PS-341 in treating patients with metastatic neuroendocrine tumors (miscellaneous islet cell cancer, gastrinoma, insulinoma, somatostatinoma, glucagonama, gastrointestinal cacinoid tumor) was initiated in April 2001 (protocol ID: CDR0000068660, OSU-00H0328, NCI-1856, NCT00017199). IV PS-341 is administered over 3-5 seconds on days 1, 4, 8, and 11. Treatment is repeated every 21 days for at least 8 courses in the absence of disease progression or unacceptable toxicity. Patients who have achieved CR are treated with 2 additional courses beyond CR. A total of 16-25 patients will be accrued within 6 months. Manisha H. Shah (Ph: 614-293-8629) of the Arthur G. James Cancer Hospital - Ohio State University is the principal investigator.

Indication in Development

non-small cell lung cancer (NSCLC), advanced, relapsed or refractory • bronchioloalveolar carcinoma (BAC) • bronchioloalveolar carcinoma (BAC), Stage IIIb with malignant pleural effusion or Stage IV, refractory, previously treated • adenocarcinoma with bronchioloalveolar carcinoma (BAC) features • adenocarcinoma with bronchioloalveolar carcinoma (BAC) features, Stage IIIb with malignant pleural effusion or Stage IV, refractory, previously treated

Latest Status

Phase II (begin 12/02, closed 6/04) USA, phase II (begin 7/02, ongoing 12/05) USA, phase II (begin 4/05, ongoing 10/05) USA, phase II (begin 7/05, terminated 10/06) USA, Canada, Europe

Clinical History

Refer to the Combination Trials module for ongoing or completed combination trials with bortezomib.

A multicenter (n=50), nonrandomized, open label, uncontrolled, single group assignment, phase II clinical trial (protocol ID: C05002; NCT00117351) was first reported in July 2005, in the USA, Canada, and Europe, to evaluate the safety and efficacy of Velcade in treating patients with previously treated, refractory, Stage IIIb (with malignant pleural effusion) or IV bronchioloalveolar carcinoma and adenocarcinoma with bronchioloalveolar features. Patients must have progressed on or after treatment with of 1 to 2 prior lines of chemotherapy, one of which must be an EGFr tyrosine kinase inhibitor, must not undergo prior treatment with Velcade, and must not have history of allergic reaction attributable to compounds containing boron or mannitol or hypersensitivity reactions to drugs formulated with polysorbate 80. The trial’s primary objective is to determine the efficacy of the investigational agent in terms of tumor response rate. According to the protocol, patients are administered Velcade by injection twice per week for two weeks followed by a week of rest. These three-week treatment cycles will be repeated as long as the patients' doctor determines the injections may continue. The length of participation in the clinical trial will depend upon a patients' response to the investigational medication. The overall duration of this clinical trial is expected to be a maximum of 26 months. This trial is to enroll about 150 patients and was terminated in October 2006.

In April 2005, a phase II clinical trial of Velcade in patients with either advanced bronchioloalveolar carcinoma (BAC) or adenocarcinoma with BAC features that have progressed on or after being administered 1 to 2 lines of chemotherapy, one of which must have been an epidermal growth factor receptor tyrosine kinase inhibitor (EGrF TKI), was initiated in the USA. This clinical trial, called the PEAK (Prospective Evaluation of bortezomib in Adenocarcinoma with bronchioalveolar features as a Keystone of therapy) trial, was designed to examine the safety and efficacy for this treatment.

In December 2002, a multicenter, randomized, open label, phase II clinical trial (protocol ID: CDR0000305974, UCLA-0301037, M34102-048, WCCC-M34102-048, MILLENNIUM-M34102-048, NCT00064012) of Velcade was initiated in patients with Stage IIIb (locally advanced) or Stage IV (metastatic) nsclc. The trial will assess response rates of patients with previously treated nsclc to Velcade monotherapy, or in combination with docetaxel. Approximately 155 patients with Stage IIIb or IV, relapsed or refractory nsclc. Up to 75 patients will be randomized to a treatment arm of Velcade monotherapy, and up to 80 patients to a combination arm consisting of Velcade and docetaxel. The primary endpoint of the trial is tumor response as assessed by the RECIST guidelines. QoL is assessed on day 1 of each treatment course (before drug administration) and at the completion of trial therapy. Patients are followed every 3 months. Robert Figlin, MD, FACP of Jonsson Comprehensive Cancer Center, UCLA is Protocol Chair. As of June 2004, this trial is closed.

A phase II clinical trial (protocol ID: UPCC-06501, NCI-5763, CDR0000069405, NCT00040768) with Velcade to determine response rate, TTP, and survival of patients with advanced nsclc treated with PS-341 was initiated in July 2002 at University of Pennsylvania Cancer Center under Protocol Chair, James Stevenson. IV PS-341 is administered over 3-5 seconds on days 1, 4, 8, and 11. Courses are repeated every 21 days in the absence of disease progression or unacceptable toxicity. This trial was reported temporarily closed in January 2004. As of April 2004, recruitment for this trial was again ongoing.

Indication in Development

non-Hodgkin's lymphoma (NHL), B-cell • non-Hodgkin's lymphoma (NHL), low grade, B cell • mantle cell lymphoma (MCL), relapsed or refractory • lymphoproliferative disorder • non-Hodgkin's lymphoma (NHL), follicular • Hodgkin's disease

Latest Status

Phase I (begin 11/99, closed 3/03) USA; phase II (begin 6/01, ongoing 12/05) USA, phase II (begin 2/02, closed 7/04) Canada, phase II (begin 5/02, closed 6/04) USA, phase II (begin 6/03, closed 9/05) USA, Canada, Europe (UK), phase II (begin 7/03, closed 9/05) USA, phase II (begin 4/04, closed 3/05) USA, phase II (begin 6/03, closed 11/04) USA, Europe (UK), phase II (closed 12/04) Europe (UK)

Clinical History

Refer to the Combination Trials module for ongoing or completed combination trials with bortezomib.

In November 2005, at its annual Analyst Day in New York City, Millenium Pharmaceuticals announced its intention to file a supplemental new drug application (sNDA) for Velcade in mantle cell lymphoma (MCL) in the second half of 2006.

A phase II clinical trial of bortezomib in patients with relapsed or refractory NHL and Hodgkin’s Disease was performed at St Bartholomew's Hospital (London, UK) to determine safety and efficacy for this treatment. Patients were administered bortezomib (1.3 mg/m²) twice weekly for 2 of 3 weeks. Patients were assessed for toxicity at each cycle, re-staged after 4 cycles and were administered up to 8 cycles of treatment. A total of 32 patients (mantle cell lymphoma=11, follicular lymphoma=10, Waldenstrom’s macroglobulinaemia=4, lymphoplasmacytic lymphoma=1, Hodgkin’s Disease=3, diffuse large B-cell lymphoma=1, ATL=1, diffuse follicle centre lymphoma=1) were administered a total of 119 cycles of treatment. Patients were heavily pretreated with a median of 3.5 previous therapies (range=1-8) and 12 patients (38%) had been administered prior Hodgkin’s Diesease therapy. The most frequently observed Grade III-IV toxicities in patients, who were administered a median of 4 cycles of treatment (range=1-8), were thrombocytopenia (n=14, 45%), fatigue (n=8, 26%), anaemia (n=5, 16%) and peripheral neuropathy (n=2, 6%). Of 11 patients with mantle cell lymphoma, 4 responded to treatment with 1 PR and 1 CR corresponding to an ORR of 36% and 1 patient progressed at the end of 8 cycles, having required 2 dose reductions. No patients with follicular lymphoma had an objective response at the outcome assessment following a median of 4 cycles (range=1-8) and within a month of completing therapy, however 4 had stable disease and 2 achieved a "late response" with decreases in tumor volumes of 76.7% and 56.1% when assessed 3 months later. A total of 2 patients with Waldenstrom’s macroglobulinaemia experienced a PR on the basis of >50% decrease in paraprotein, but with no change in the bone marrow. No patients with Hodgkin’s Disease or other diagnoses responded to treatment. These results indicate that bortezomib demonstrates encouraging activity in mantle cell lymphoma, evidence of activity in Waldenstrom’s macroglobulinaemia, and a suggestion of "late responses" in follicular lymphoma (Strauss S, etal, ASH04, Abs. 1386). In updated results, 39 patients were evaluable. Of the 18 mantle cell lymphoma patients, there were 1 CR and 6 PR corresponding to overall response rate of 39%. Of the 12 follicular lymphoma patients there were two late responses three months post-treatment (decrease in tumor volumes of 76.7% and 56.1%) corresponding to an ORR of 17%. Observed adverse events included thrombocytopenia, fatigue, anemia, and peripheral neuropathy. In further updated results presented at the 9th International Conference of Malignant Lymphoma (6/05), a total of 48 patients were evaluable for response. Of the 24 mantle cell lymphoma patients, there was 1 CR and 6 PR corresponding to an ORR of 29%. Of the 11 follicular lymphoma patients, there were 2 late responses observed three months post-treatment resulting in an ORR of 18%. Adverse events were manageable and included thrombocytopenia, anemia, fatigue, gastrointestinal symptoms and peripheral neuropathy.

In November 2004, the FDA granted Velcade 'fast track' designation for relapsed and refractory mantle cell lymphoma.

An international multicenter (US=28, UK=1), open label, phase II clinical trial (protocol ID: CDR0000365659, MILLENNIUM-M34103-053, MILLENNIUM-20030973, UCLA-0306037-01, NCT00084851; NCT00063713) of bortezomib, dubbed PINNACLE, in patients with relapsed or refractory MCL was initiated in June 2003 to determine median TTP, rates of response, MST, and duration of response for this treatment. with relapsed or refractory mantle cell lymphoma (MCL), treated with a with a maximum of 2 prior regimens, were treated with IV bolus Velcade (1.3 mg/m2) on days 1, 4, 8, and 11 of a 21-day cycle for 4 cycles beyond CR or up to 1 year unless there was disease progression or toxicity. QoL and work missed are assessed at baseline, on day 1 of course 4, and then at 28 days after the last dose of trial drug. Patients are followed every 6 weeks for 18 weeks, and then every 3 months thereafter. Richard Fisher, MD (tel: 585-275-0842), of the James P. Wilmot Cancer Center (Rochester, NY) is the PI. Between June 2003 and November 2004, 102 patients enrolled in this 3-stage, phase 2 trial at 29 sites . Response was assessed by the investigators using International Workshop criteria, while final results are based on central radiology review. Among 48 patients evaluable for response at the second stage, 57% had been treated with 2 prior regimens. Median time from diagnosis was 2.3 (range=0.2-9.0) years. A median of 4 cycles was administered. Median follow-up was 6.2 months. Response rate including CR + unconfirmed CR (CRu) + PR was 40% (19/48) with CR + CRu being 6% (3/48). Velcade was well tolerated. Although 34% of 102 evaluable patients experienced a serious adverse event, only 21 of 46 events were considered related to Velcade by the investigator. The most common Velcade-related serious adverse events included vomiting, abdominal pain, dehydration, and asthenia. Mean platelet counts followed a cyclical pattern, decreasing during treatment and recovering to baseline by the next cycle, as seen in multiple myeloma. In only 9.3% of patients the nadir platelet count was <25,000 cells/µl. These data confirm the activity of Velcade in MCL and support the rapid development of Velcade as a new treatment option for MCL (Goy A, etal, ASCO05, Abs. 6563).

A phase II clinical trial (protocol ID: CDR0000361745, CALGB-50206, NCT00082966) of bortezomib in patients with relapsed or refractory classical Hodgkin’s lymphoma was initiated in April 2004 at multiple locations in the USA to determine the efficacy, TTP, 2-year OS, safety, and tolerability for this treatment. Patients are administered bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 21 days, for up to 8 courses, in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year, and then every 6 months for 2 years. A total of 18-43 patients will be accrued for this trial within 9-24 months. Nancy Bartlett, MD (tel: 314-362-4843), of the Cancer and Leukemia Group B is the protocol chair. As of March 2005, this trial is closed.

A phase II clinical trial (protocol ID: CAN-NCIC-150, CDR0000069207, CAN-NCIC-IND150, NCT00030875) of bortezomib, designed to determine its safety and efficacy, in patients with MCL, was performed by the National Cancer Institute of Canada (Kingston, ON, Canada), Cross Cancer Institute (Edmonton, AB, Canada), British Columbia Cancer Agency (Vancouver, BC, Canada), and Hamilton Regional Cancer Centre (Hamilton, ON, Canada). Bortezomib (1.3 mg/m²) was administered IV twice weekly for 2 week,s in 3-week cycles, to patients with measurable mantle cell lymphoma who have been administered 0 to 2 prior treatment regimens. Bortezomib treatment was continued until disease progression or unacceptable toxicity. Patients with no response or disease progression are administered 4 courses of therapy. A total of 14 patients have been enrolled, all evaluable for toxicity and 12 evaluable for response. Prior number of chemotherapy regimens range from 0-2 (0=6 patients, 1=6, 2=2). The median number of cycles of bortezomib administered is 4 (range=1-7). Among 12 patients evaluable for response, there were 4 (33%) PR, and disease stabilized in 5 (42%), and progressed in 3 (25%). Serious adverse events associated with fluid retention were experienced by 5 patients, and 2 of these patients died while on therapy. Up to 1 of these deaths was a result of Grade 4 acute vascular leak syndrome, and the other a result of progressive mantle cell lymphoma in the context of severe edema. Other serious adverse events included 2 cases of dyspnea/peripheral edema (1 with documented congestive heart failure) and 1 case of hypoxia/peripheral edema. The 5 patients with serious adverse events had baseline dyspnea (n=3), fluid retention (n=1), or both (n=1). Bortezomib demonstrated evidence of antitumor activity in mantle cell lymphoma with acceptable toxicity in patients without fluid retention and/or dyspnea at baseline. Accrual of patients continues (Assouline S, etal, ASH03, Abs. 3358). In updated results, accrual was closed in July 2004 after 30 patients were enrolled. A median of 4 treatment cycles has been administered (range=1-7) and 25 patients are evaluable for toxicity. Observed >/= Grade 2 adverse effects thought to be related to trial drug included anorexia (8%), nausea (16%), vomiting (4%), diarrhea (20%), fatigue (60%), dizziness (4%), sensory neuropathy (12%), edema (8%), hypotension (4%), vascular leak syndrome (4%), arthralgia (12%), myalgia (12%), neuropathic pain (12%), dyspnea (12%), and rash (12%). Discontinuation of therapy was required for 9 patients because of toxic effects, 6 of whom exhibitred neuropathy or myalgia. During accrual of the first 14 patients, 5 serious adverse events were experienced by patients with pre-existing edema, dyspnea, and/or effusion. Therefore, the eligibility criteria were amended to exclude such patients thereafter and no further serious adverse events have been exhibited. To date, 24 patients are evaluable for response. Of the 10 patients having no prior chemotherapy, 3 exhibited PR, 6 exhibited SD, and 1 exhibited PD corresponding to a response rate of 30%. Of the 14 previously treated patients, 1 exhibited CRu, 4 exhibited PR, 7 exhibited SD and 2 exhibited PD. The overall response rate is 33%, but interestingly it is comparable in both previously untreated and treated groups. These results indicate that bortezomib is an active agent in mantle cell lymphoma, but at this dose and schedule complete remission is rare. Since higher doses will not be possible given the frequency of neuropathy and myalgia, alternative schedules, or novel combinations with other active agents will be of interest to pursue (Belch A, etal, ASH04, Abs. 608). In updated results, 28 patients were evaluable for response. The overall response rate was 46.4%, including 1 unconfirmed CR and 12 PR. Patients who had not previously been administered chemotherapy achieved an overall response rate 46.2%, while patients who had been administered previous therapy achieved an overall response rate of 46.7%. Observed adverse events observed were fatigue, diarrhea, neuropathy, myalgia, as well as peripheral edema in newly diagnosed patients presenting with edema. The protocol was amended to exclude patients with preexisting dypsnea, edema, or effusion.

In a phase II clinical trial (protocol ID: CDR0000068860, MSKCC-01049, NCI-2795, CWRU-MSKCC-1Y02, UNMC-03903, NCT00023764), being conducted by Memorial Sloan-Kettering Cancer Center, under PI Owen A. O'Connor, MD, PhD, over 77 cycles of bortezomib (average=2.5 per patient) were administered to 21 patients with relapsed or refractory indolent lymphomas (small lymphocytic lymphoma-CLL type=3, follicular lymphoma=9, MCL=8, and nodeal marginal zone lymphoma=1). All patients had been previously treated with various regimens, including CHOP, CVP, cyclophosphamide/fludarabine, rituximab (n=5), radioimmunotherapy, and interferon; one patient had been treated with a complex combination chemotherapy regimen that included alkylating agents, tubulin inhibitors, anthracyclines and antimetabolites. Patients were treated with bortezomib (1.5 mg/m²), twice weekly, for two consecutive weeks with a one week rest period. There were no Grade 3/4 toxicities, except for 1 patient who developed Grade 3 sensory and motor neutopathy. Restaging was routinely performed after two complete cycles of therapy. Disease stabilized in all patients with small lymphocytic lymphoma after 2 and 4 cycles. A major response was achieved by 6/8 evaluable patients with follicular lymphoma, including 1 durable CR, and a PR by 1 patient with marginal zone lymphoma after 2 cycles of therapy. Major responses were also seen in 3 patients with refractory MCL. Up to 1 of these patients, who experienced a 7 month duration of remission from his preceding CHOP/rituximab, achieved a durable PR lasting 17 months following 4 cycles of bortezomib. According to the protocol, he is presently being retreated, and to date has achieved a 30% disease reduction of. He continues on active treatment. These data continue to support the biological activity of bortezomib in patients with indolent lymphomas, and suggests that analysis of this drugs activity may well be very sub-type dependent [O'Connor O, etal, ASH03, Abs. 2346, and Blood, 16 Nov 2003;102(11); O’Connor O, etal, ECCO03, Abs. 1009]. More mature data were presented at ASH03, involving 24 patients with indolent NHL, including 9 patients with follicular lymphoma, 10 with MCL, 3 with small cell lymphocytic lymphoma, and two with nodal marginal zone lymphoma. Among 8 evaluable patients with follicular lymphoma, 6 experienced major responses, 1 durable CR, and 5 PR. Median duration of response was 6 months. Among 9/10 evaluable patients with MCL, there were 5 PR, and disease stabilized in 5 patients. Duration of response ranged from one to 19 months. In one patient who relapsed 19 months after treatment with Velcade, a second PR occurred 3 months after retreatment, which is still durable. Both patients with nodal marginal zone lymphoma achieved a PR lasting for >5 months. Disease stabilized in all 3 patients with small lymphocytic lymphoma, lasting between 4 and 6 months. Side effects, including thrombocytopenia, sensory neuropathy, small vessel necrotizing vasculitis, and lymphopenia, were generally manageable. In updated results, a total of 25 patients (small lymphocytic lymphoma=3, FL=9, MCL=11, marginal zone lymphoma=2) were enrolled. All but 1 patient had been administered some form of treatment prior to being administered bortezomib, including CHOP +/- R (60%), CVP +/- R (20%), or some other purine analog based treatment program (15%), with some patients having been administered prior high dose chemotherapy with peripheral blood stem cell transplant (12%) or radioimmunotherapy (8%). No Grade III or IV toxicities were observed, except for 1 patient that developed a Grade 3 sensory and motor neuropathy. Restaging trials were routinely performed following 2 complete cycles of therapy. All patients with small lymphocytic lymphoma were determined to have SD following 2 and 4 cycles. Of 9 evaluable patients with follicular lymphoma, 6 (67%) exhibited a major response, with 1 patient exhibiting a durable CR. To date, these responses have lasted 3, 4, 6, 9, 9+, and 12+ plus months. The 2 patients with marginal zone lymphoma had PRs following 2 cycles of therapy, lasting 3+ and 6+ months each. Of 10 evaluable patients with mantle cell lymphoma, 5 (50%) had PRs with this response lasting 1+, 1+, 3+ 6 and 19 months, corresponding to a response rate of 50%. A single patient who had a PR lasting 19 months was retreated with 4 cycles of bortezomib, and had a second PR now lasting 4+ months. To date, none of the patients with small lymphocytic lymphoma/CLL have responded (n=3). These results indicate that bortezomib is active in patients with select subtypes of indolent non-Hodgkin’s lymphoma (O’Connor O, etal, ASCO04, Abs. 6582). In updated results, a total of 26 patients (follicular lymphoma=10, mantle cell lymphoma=11, small lymphocytic lymphoma or chronic lymphocytic leukemia=3, marginal zone lymphoma=2) were enrolled, and 24 are evaluable. Patients were administered a median of four cycles of therapy. For 25 evaluable patients, the ORR was 58%. For patients with follicular non-Hodgkin's lymphoma, 1/9 had CR, 1/9 had unconfirmed CR, and 5/9 had PR. All responses were durable, lasting from 3 to 24+ months. For mantle cell lymphoma patients, 1/10 had an unconfirmed CR, 4/10 had PR and 4/10 had SD. All responses were durable and ranged from 6 to 19 months with the median duration of response not reached. Both patients with marginal zone lymphoma had PR, lasting 8+ and 11+ months. Patients with small lymphocytic lymphoma or chronic lymphocytic leukemia have yet to respond. The drug was well tolerated overall, with only one Grade 4 toxicity (hyponatremia). The most frequently observed Grade 3 toxicities were lymphopenia (n = 14) and thrombocytopenia (n = 7). Other observed adverse events included neuropathy, hypoatremia, hypokalemia, and prothrombin time. These results indicate that Velcade was well tolerated, and has significant single-agent activity in patients with certain subtypes of NHL (O’Connor O, etal, JCO, 1 Feb 2005, 23(4):676-684). In updated results, a total of 51 (follicular lymphoma=19, mantle cell lymphoma =23, small lymphocytic lymphoma-CLL type=5, marginal zone lymphoma (MZL)=4) patients were enrolled. The average number of cycles administered per patient was four. All but 1 patient had been administered some form of treatment prior to being administered bortezomib, including CHOP +/- R (60%), CVP +/- R (20%); or some other purine analog based treatment program (15%). No Grade IV toxicities were observed and the most frequently observed Grade 3 toxicity was lymphopenia. Grade 3 sensory neuropathy was experienced by 3 patients. Restaging trials were routinely performed every two cycles. The overall response rate was 55%, though there is considerable variability among the subtypes both in the response rate, and time to response. Of 5 patients with small lymphocytic lymphoma, 1 exhibited a PR, in comparison to all 4 patients with marginal zone lymphoma who experienced a PR. In most of these latter cases, patients had tumor shrinkage following 2 to 4 doses. While all patients are in active follow-up, one has sustained the response > 10 months and another > 18 months. Of 23 patients with mantle cell lymphoma, the response rate was 56%. The shortest duration of remission was 6 months, and the longest was 19 months. Patients typically responded by the second cycle, or did not respond. An additional 3 courses have been administered to 2 patients, who achieved PR on each retreatment. For follicular lymphoma patients, the response rate was 60%, including 1 CR and 1 Cru. These patients responded later in treatment, typically after the third cycle and later. The median duration of response has not been attained. Results support the activity of bortezomib in patients with select subtypes of NHL, and raise the merits of potential retreatment in responding patients (O’Connor O, etal, ASH04, Abs. 607). In updated results, 52 patients were evaluable including 15 patients with follicular lymphoma, and 26 patients with mantle cell lymphoma. For follicular lymphoma patients the overall response rate was 60%, with 2 CR or unconfirmed CR. For mantle cell lymphoma, the overall response rate was 54% with 5 CR or near CR. Adverse events were generally manageable and included thrombocytopenia, sensory neuropathy, and weakness. n further updated results presented at the 9th International Conference of Malignant Lymphoma (6/05), a total of 65 patients were evaluable for response. For patients with follicular lymphoma, the ORR was 58% including 1 CR and 1 unconfirmed CR. For patients with marginal zone lymphoma, the ORR was 43%. Median PFS for all responding patients with indolent lymphomas was 12.5 months compared to 12 months for the patients' prior line of therapy. For patients with mantle cell lymphoma, the ORR was 40% including 3 CR and 2 unconfirmed CR. Median PFS for responding patients with MCL was 10 months compared to only 4.6 months for the patients' prior line of therapy. Adverse events observed were generally manageable and included thrombocytopenia, lymphopenia, sensory neuropathy and rash. These results indicate that in patients with relapsed or refractory mantle cell or indolent lymphomas, Velcade provides meaningful clinical activity with promising event-free survival where conventional chemotherapy has failed.

In this phase II clinical trial (protocol ID: CDR0000068860, MSKCC-01049, NCI-2795, CWRU-MSKCC-1Y02, UNMC-03903, NCT00023764) conducted at Memorial Sloan-Kettering Cancer Center, more than 22 cycles of PS-341 (average of 3.1 per patient) were administered to 7 previously treated patients with relapsed or refractory indolent lymphomas. Patients were treated at a dose of 1.5 mg/m² twice weekly, for 2 consecutive weeks, with a 1 week rest period. No Grade 3 or 4 toxicities were observed. Restaging trials were routinely performed after 2 complete cycles of therapy. Disease stabilized in 2 patients with small lymphocytic lymphoma, after 2 and 4 cycles. Of the 2 evaluable patients with follicular lymphoma, both were found to have a PR after at least 2 cycles of therapy. Major responses were also seen in 2 patients with mantle cell lymphoma, both of whom exhibited a PR after only 2 cycles of treatment, with 1 patient exhibiting over an 80% reduction in tumor volume. Accrual to this trial is ongoing (O'Connor OA, etal, ASH02, Abs. 3063:774a).

In a phase II clinical trial (protocol ID: ID01-596, NCT00038571), conducted at M. D. Anderson Cancer Center, bortezomib (1.5 mg/m²) was administered as an IV push on days 1, 4, 8 and 11, every 21 days. Restaging was done every 2 cycles. Patients were treated for up to a total of 6 cycles unless removed from trial for failure to respond or because of toxicity. Among 30 patients enrolled to date (MCL=18, other B-cell lymphoma= 12, including diffuse large cell lymphoma (DLCL)=8, follicular lymphoma=2, transformed folicular lymphoma=1, small lymphocytic lymphoma (SLL=1). Regarding prior therapies, there were 3.8 (range=1 to 8) regimens for the entire group, 2.1 (range=1 to 5) in the MCL group and 4.3 (range=1 to 8) among the other patients; 7 patients (MCL=3 and DLCL=4) had been previously treated with autologous stem cell transplant (ASCT). A total of 63 cycles were delivered with an average of 2.1 cycles per patient (range=1 to 6). Main toxicities were Grade 3/4 GI toxicity, such as nausea and /or vomiting or diarrhea (n=5) and hypotension/fatigue/dehydration (n=4). In terms of hematologic toxicity, 6 patients exhibited ANC < 1000, but only one exhibited <500 ANC. There were 2 infectious episodes, 1 pneumonia without neutropenia, and 1 episode of generalized herpes zoster in a patient who died of encephalitis. Platelets < 20K were seen in 8 patients but only 1 exhibited <10K; there was no bleeding. Grade 3 neuropathy (prior vincristine and taxanes) was seen in 1 patient, and 4 patients developed transient rash with biopsied small vessel necrotizing vasculitis in 2. Dose adjustment (dose minus 1) was required in only 3/29 patients. In the MCL subgroup, among 15 evaluable patients, 8/15 responded with 3 CR, and 5 PR for a RR of 53%. In terms of duration of response, 1 patient with a CR exhibited an ASCT 2 months later without evidence of disease, the 2 other CR are free of disease at 3 and 7 months out. The 5 patients with PR exhibited a median response duration of 3 (range=1-11) months. Among 6/8 evaluable patients with DLCL, there was 1/6 (16%) PR, and disease progressed in 5; 1 patient with transformed folicular lymphoma was inevaluable, and the other patients did not respond. Bortezomib showed promising activity particularly in MCL (RR=53%). In other subtypes of B-cell lymphomas, the RR was not as high but this was a more heavily pretreated population. Despite the fact that most DLCL was primary refractory; there was 1 PR in a patient with relapsed DLCL who had failed 4 prior regimens including an upfront autologous stem cell transplant. The main toxicity (fatigue, dehydration, hypotension) with bortezomib was manageable and improved with prophylactic routine IV hydration. Future directions will explore combinations with other chemotherapeutic and/or biologic agents [Goy A, etal, ASH03, Abs. 627, and Blood, 16 Nov 2003;102(11); Goy A, etal, ASCO03, Abs. 2291]. Andre Goy, MD, of the University of Texas M. D. Anderson Cancer Center, presented more mature data at ASH03, involving 40 patients with various types of NHL were treated with Velcade. There was an overall response rate of 50% among 20/22 evaluable patients with MCL. Specifically, there were 4 CR, 6 PR (including 2 with major PR), and disease stabilized in 2 patients. These patients are still being followed to determine the duration of response. To date, the median duration of response has been 5.6 (range=1-14) months. This patient population was heavily pre-treated, having been exposed to an average of 4 prior therapies (range=1-12). In 6/9 evaluable patients with diffuse large cell lymphoma, there was 1 PR. These patients all had relapsed lymphoma unsuccessfully treated with multiple prior therapies. One patient who had also failed four prior therapies for Waldenstrom's macroglobulinemia, a B-cell malignancy, achieved a PR after two cycles. The most common side effects observed in this trial were fatigue, dehydration, and hypotension, which were generally manageable. In updated results, a total of 45 patients [group A=25, group B=20 (diffuse large cell lymphoma=10, follicular lymphoma=4, transformed follicular lymphoma=3, small lymphocytic lymphoma=1, Waldenstrom’s macroglobulinemia=1] were enrolled. Group A had 3 median previous therapies (range=1-6) and Group B had 4 (range=1-12). Of 21 patients in Group A evaluable for response, 3 (14%) exhibited a CR, 1 (5%) exhibited an unconfirmed CR, 7 (33%) exhibited a PR, 2 (10%) exhibited a MR, 2 (10%) exhibited SD, and 6 (29%) exhibited PD, corresponding to a response rate of 52%. Mean duration of response was 5.7 months. For group B, there were 8 patients with diffuse large cell lymphoma evaluable for response with 1 (13%) PR lasting 4 months, 1 (13%) SD, and 6 (75%) PD. For group B, there were 4 patients with follicular lymphoma evaluable for response with 2 (50%) MR, 1 (25%) SD, and 1(25%) PD. For group B, there was 1 patient with transformed follicular lymphoma evaluable for response with 1 (100%) PD. For group B, there were 2 patients with small lymphocytic lymphoma evaluable for response with 1 (50%) SD and 1 (50%) PD. For group B, there was 1 patient with Waldenstrom’s macroglobulinemia evaluable for response with 1 PR. Observed Grade 3/4 toxicities included gastrointestinal toxicities (n=5), hypotension/fatigue (n=6), neuropathy (n=1, patient with prior vinca/taxanes), and pneumonia (n=2). Observed hematologic toxicities included neutropenia (n=8, only 1 patients with ANC < 500) and thrombocytopenia (n=14, only 1 patient with platelets<10, most entered with platelets < 30-50). A total of 2 patients have died while on this trial, 1 as a result of Cryptococcus meningitis and 1 as a result of generalized zoster with encephalitis. These results indicate that bortezomib is active in patients with mantle cell lymphoma and demonstrates promising activity in other B-cell lymphomas (Goy A, etal, ASCO04, Abs. 6581). In updated results, a total of 60 patients (Arm A=33. Arm B=27; diffuse large B-cell lymphoma=12, follicular lymphoma=5, transformed follicular lymphoma=3, small lymphocytic lymphoma=4, Waldenstrom’s macroglobulinemias=2, marginal zone lymphoma=1) were enrolled with a median number of 3.5 previous therapies. In Arm A, 12 of 29 evaluable patients responded with 6 CR and 6 PR corresponding to an ORR of 41%. Approximately 80% of patients retained their response at 6 months. The median TTP for arm A has not been reached, with a median follow-up of 9.3 months. In arm B, 4 of 21 evaluable patients responded including 1 CR (small lymphocytic lymphoma=1), 1 unconfirmed CR (follicular lymphoma=1), and 2 PR (diffuse large B-cell lymphoma=1, Waldenstrom’s mactoglobulinemias=1), corresponding to an ORR of 19%. Observed Grade 3 toxicities included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Observed Grade 4 toxicities were experienced by nine patients (15%), and 3 deaths from progression of disease occurred within 30 days of withdrawal from the trial. Bortezomib demonstrated promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas (Goy A, etal, JCO, 1 Feb 2005, 23(4):667-675).

An open label, multicenter, phase II clinical trial (protocol ID: CDR0000316254, UCLA-0301090, NCT00066508) was initiated in July 2003, at Jonsson Comprehensive Cancer Center, UCLA under Protocol Chair Sven De Vos, MD, to determine the overall response rate in patients with chemotherapy-refractory diffuse large B-cell lymphoma treated with bortezomib. A total of 22-40 patients are administered IV bortezomib over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 21 days, for up to 8 courses, in the absence of disease progression or unacceptable toxicity. Patients are followed at 20 days, and then every 3 months thereafter.

In June 2003, a multicenter, single arm, open label, 3-stage, phase II clinical trial (protocol ID: M34103-053, NCT00063713) of Velcade was initiated in patients with relapsed or refractory MCL. The trial will assess TTP, response rate, duration of response, and OS of patients with relapsed or progressive MCL following 1 or 2 prior chemotherapeutic regimens. This trial, being conducted at multiple sites in North America and the UK, will enroll approximately 152 patients with relapsed or refractory mantle cell lymphoma who have had been treated with 1 or 2 prior lines of therapy. Response rates will be analyzed at two interim points to evaluate the progress of the trial. This trial was closed in Novemebr 2004.

A nonrandomized, open label, uncontrolled, phase II clinical trial (protocol ID: ID01-596, NCT00038571) of PS-341 in patients with relapsed or refractory B cell lymphomas previously treated with chemotherapy was initiated at the M. D. Anderson Cancer Center (Houston, TX) in May 2002 to determine the safety and efficacy for this treatment. Andre Goy, MD (tel: 713-792-2860), of the M. D. Anderson Cancer Center is the protocol chair. As of June 2004, this trial is no longer recruiting patients.

A phase II multicenter clinical trial (protocol ID: CAN-NCIC-150, CDR0000069207, CAN-NCIC-IND150, NCT00030875) is to determine effectiveness of PS-341 in treating patients with previously untreated or relapsed MCL. Beginning February 2002, 14-30 patients is to be accrued within 18-24 months for treatment with IV PS-341 over 3-5 seconds on days 1, 4, 8, and 11. Treatment is repeated every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients with CR are administered 2 courses beyond documentation of CR. Patients with SD are treated a maximum of 4 courses. Patients with PR continue therapy until disease progression or for 2 courses beyond documentation of stable PR. Patients are followed at 4 weeks, and then every 3 months thereafter. Andrew R. Belch of NCIC-Clinical Trials Group is Trial Chair. As of April 2003, this trial was temporarily closed. In June 2003, according to preliminary results from this phase II clinical trial of Velcade as a single-agent therapy in 12 patients with MCL, there were 3 CR, 4 PR, and SD in another 2 patients. As of July 2004, this trial is closed.

Phase I dose escalation, multicenter clinical trial of PS-341 in patients with advanced malignancies or B-cell lymphoproliferative disorders (protocol ID: CDR0000068233, MAYO-980111, NCI-T99-0071, WCCC-CO-99904, NCT00006362) was initiated in November 1999 at the Mayo Clinic Cancer Center, chaired by Alex A. Adjei (Ph: 507-284-2511). In regimen A, IV PS-341 is administered twice weekly for 4 weeks. Treatment is repeated every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients are given escalating doses of PS-341 until the MTD is determined. Once MTD is determined in regimen A, in regimen B, patients are administered IV PS-341 twice weekly, for 2 weeks. Treatment is repeated every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients are followed for 3 months. A maximum of 78 patients were to be accrued within 14 months. This trial was closed in March 2003.

A phase II clinical trial of PS-341 in treating patients with low-grade lymphoproliferative disorders (protocol ID: CDR0000068860, MSKCC-01049, NCI-2795, CWRU-MSKCC-1Y02, UNMC-03903, NCT00023764) started in June 2001 at the Memorial Sloan-Kettering Cancer Center, chaired by Owen A. O'Connor (Ph: 212-639-8889). Patients are stratified according to disease type (follicular lymphoma versus other). IV PS-341 is administered twice weekly for 2 weeks. Treatment is repeated every 3 weeks in the absence of disease progression or unacceptable toxicity. Approximately 36-70 patients (18-35 per stratum) will be accrued within 9-18 months.

Indication in Development

ovarian cancer, recurrent

Latest Status

Phase II (begin 11/01, suspended 10/05) USA

Clinical History

A phase II multicenter clinical trial was initiated in November 2001 to determine antitumor activity and toxicity of PS-341 in treating patients with recurrent platinum-sensitive ovarian epithelial or primary peritoneal carcinoma (protocol ID: CDR0000068853, GOG-0146N, NCT00023712). IV PS-341 is administered twice weekly for 2 weeks. Treatment is repeated every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years, and then every 6 months for 3 years. Approximately 22-60 patients will be accrued within 6-12 months. Carol Aghajanian (Ph: 212-639-2252) of the Gynecologic Oncology Group is the principal investigator. This trial was temporarily closed in January 2003, and recommenced recruiting in May 2004. As of October 2005, this trial has been suspended.

Indication in Development

kidney cancer, metastatic • bladder cancer, transitional cell • hepatocellular carcinoma

Latest Status

Phase I (begin 1/03, closed 10/04) USA; phase I/II (ongoing 6/04) Europe; phase II (begin 10/01, closed 12/02, completed 1/04) USA, phase II (begin 4/01, closed 1/03) USA, phase II (begin 7/03, ongoing 11/05) USA, Canada, phase II (begin 10/03, closed 4/05) USA, Canada, phase II (begin 1/04, ongoing 12/05) USA, phase II (begin 5/04, ongoing 12/05) USA

Clinical History

A phase II clinical trial (protocol ID: CDR0000068678, MSKCC-01032, NCI-3031, NCT00017329) of bortezomib in patients with advanced, metastatic, renal cell carcinoma was performed at the Memorial Sloan-Kettering Cancer Center to determine efficacy and toxicity for this treatment. A total of 37 patients were enrolled. The first 25 patients enrolled into the trial were administered a dose of 1.5 mg/m². The dose was reduced to 1.3 mg/m² for the subsequent 12 patients, because more than 50% of the patients administered the higher dose required dose reductions. Bortezomib was administered by IV administration on a twice-weekly schedule for 2 weeks, followed by 1 week without treatment until progression or unacceptable toxicity occurred. Of the enrolled patients, 23 (62%) previously had undergone nephrectomy, and 19 (51%) had previously been administered a cytokine therapy. Of 37 evaluable patients, 4 (11%) exhibited PR and 14 (38%) exhibited SD. The 4 patients with PR exhibited response durations of 8, 8+, 15+, and 20+ months. Grade 2 or 3 sensory neuropathy was experienced by 10 (53%) patients overall. In the 1.5 mg/m² group, 1 patient exhibited Grade 3 sensory neuropathy, while none of the patients in the 1.3 mg/m² group exhibited Grade 3 sensory neuropathy. These results indicate that bortezomib has an antitumor effect in individual patients with metastatic renal cell cancer. The small proportion of patients who experienced a PR does not support routine use in metastatic renal cell cancer (Kondagunta G, etal, J Clin Oncol, 15 Sept 2004;22(18):3720-5).

A phase I/II clinical trial of bortezomib in patients with unresectable hepatocellular carcinoma was performed at the Medical University Clinic (Hamburg, Germany) and Institute of Molecular Biology (Erlangen, Germany) to determine DLT, MTD, safety, response, and pharmacodynamics for this treatment. Bortezomib was administered as an IV bolus on days 1, 4, 8, and 11 of a 3 week cycle. To date, 18 patients have been accrued. A previous history of hepatitis B and/or C or alcoholic cirrhosis was present in 39% and 17% of the patients. A mean of 4.5 cycles (range=1-12) has been administered to each patient with 28 cycles being administered at dose level 1 (1 mg/m², n=6) and 54 cycles being administered at dose level 2 (1.3 mg/m², n=12). No Grade 3/4 DLT were observed in cycle 1. Observed Grade 2/3 toxicities per patient included thrombocytopenia (Grade 2=7, Grade 3=3), fatigue (Grade 2=5, Grade 3=3), neuropathy (Grade 2=2, Grade 3=1), loss of appetite (Grade 2=6, Grade 3=2), hypotension (Grade 2=0, Grade 3=2), and abdominal cramps (Grade 2=2, Grade 3=1). Grade IV thrombocytopenia was experienced by 1 patient. Dose reduction was required for 5 patients. Based on the observed toxicities for all cycles, 1.3 mg/m² was designated the MTD. Of 15 evaluable patients, 7 (47%) exhibited SD lasting for 21, 14, 36+, 22+, 16+, 12+, and 9+ weeks, and 8 (53%) exhibited PD. The pharmacodynamics for bortezomib were comparable to findings in patients without compromised liver function. These results indicate that bortezomib is well tolerated in patients with unresectable hepatocellular carcinoma (Hegewisch-Becker S, etal, ASCO04, Abs. 4089).

An open label, phase II clinical trial (protocol ID: CDR0000369715, FCCC-03042, NCI-6135, NCT00085410) of bortezomib as a first line systemic therapy in patients with unresectable locally advanced or metastatic adenocarcinoma of the bile duct or gallbladder was initiated in May 2004 at the Abramson Cancer Center (Philadelphia, PA), Fox Chase - Temple Cancer Center (Philadelphia, PA), and Fox Chase Cancer Center (Philadelphia, PA) to determine the objective response rate, TTP, and OS for this treatment. Patients are administered bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year. A total of 20-35 patients will be accrued for this trial within 12-15 months. Steven Cohen, MD (Tel: 215-728-2450; 888-369-2571), of the Fox Chase Cancer Center is the protocol chair.

A phase II clinical trial (protocol ID: UCCRC-11049A, NCI-3291) of bortezomib in patients with Stage IV RCC was completed in January 2004. Performed at the University of Chicago Medical Center, it was designed to determine the response rate, TTP, and toxicity of this treatment. Bortezomib (1.5 mg/m²) was administered IV twice weekly for 2 weeks of a 3-week cycle. Dose escalation of bortezomib to 1.7 mg/m² followed as a result of the absence of Grade 3 or 4 toxicities. Re-evaluation was performed after 3 cycles. Among 23 patients enrolled, 21 were evaluable for response; 2 were never treated (1 refused treatment and 1 had insufficient tumor for biopsy). Among evaluable patients, 18 completed at least 3 cycles of therapy; disase progressed in 3 patients after 2 treatment cycles. Observed Grade 4 nonhematologic toxicities included arthralgia, diarrhea, and vomiting. Grade 4 hematologic toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia], gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Other observed toxicities included neuropathy (Grade 1/2; n=7), thrombosis (n=1), and pleural effusion (n=1). There was 1 objective response. Based on these results, bortezomib does not seem to be active in metastatic RCC. Insufficient biopsy and whole blood samples prevented any conclusions in regards to proteasome inhibition within the tumor (Davis N, etal, J Clin Oncol, 1 Jan 2004;22(1):115-9).

A multicenter, phase II clinical trial (protocol ID: CDR0000350328, MAYO-MC0255, NCI-6139, NCT00077441) of bortezomib in patients with hepatocellular carcinoma, was initiated in January 2004 at the Mayo Clinic Scottsdale (Scottsdale, AZ), Howard University College of Medicine (Washington, DC), Mayo Clinic (Jacksonville, FL), Sidney Kimmel Comprehensive Cancer Center (Baltimore, MD), Barbara Ann Karmanos Cancer Institute (Detroit, MI), Mayo Clinic Cancer Center (Rochester, MN), Washington University School of Medicine (Saint Louis, MO), and University of Wisconsin Comprehensive Cancer Center (Madison, WI), to determine the response rate, duration of response, time-to-disease progression, survival, and adverse event rate. Patients are administered bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression, and then every 6 months for up to 3 years from trial entry. A total of 22-55 patients will be accrued for this trial within 9-19 months. George Kim, MD (tel: 904-953-6153), of the Mayo Clinic Cancer Center is Protocol Chair. As of March 2005, this trial is suspended. Patient recruitment for this trial re-started in April 2005.

In a multicenter, phase II clinical trial (protocol ID: CDR0000335517, CALGB-90207, NCT00072150, NCT00072150) initiated in October 2003, a total of 15-40 patients with transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis are treated with IV bortezomib over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Endpoints are response rate, survival, safety, and toxicity. Patients with a solitary site of disease (i.e., lung or nodal metastases) and who exhibit a PR may be considered for surgical resection. Patients with PR and residual disease after salvage surgery are eligible to continue trial therapy. Patients who achieve a CR are treated with 2 additional courses of trial therapy. Patients are followed every 6 months. This trial began in October 2003, and is being conducted in the USA and Canada under protocol chairs Jonathan Rosenberg, MD, and Eric Small, MD, of Cancer and Leukemia Group B. As of April 2005, this trial is closed.

In a nonrandomized, open label, multicenter phase II clinical trial (protocol ID: CDR0000315537, PMH-PHL-018, NCI-6150, NCT00066352), patients with transitional cell cancer of the urothelium, including the bladder, renal pelvis, or ureter are treated with IV bortezomib over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Those in CR may be treated up to 2 courses after confirmation of CR. Patients are followed within 3 weeks, and then every 3 months thereafter. Beginning July 2003, a total of 20-35 patients are to be enrolled at University of Chicago Cancer Research Center, Ottawa Regional Cancer Centre, Cancer Care Ontario, and Princess Margaret Hospital at University Health Network. Eric Winquist, MD, at Princess Margaret Hospital at University Health Network is Protocol Chair.

A dose escalation, multicenter, phase I clinical trial (protocol ID: CDR0000270687, WCCC-CO-02903, NCI-5874, CWRU-040315, CWRU-1Y03, NCT00054483) of bortezomib in treating advanced malignancies and renal insufficiency was initiated in January 2003 with Trial Chair Daniel Mulkerin, MD, of the University of Wisconsin Comprehensive Cancer Center. A total of 60-69 patients will be enrolled at participating cancer centers in California, Maryland, Michigan, New York, Ohio, Pennsylvania, Texas, and Wisconsin. Cohorts of 3-6 patients undergo escalating doses of bortezomib until the MTD is determined, with an additional cohort of up to 6 treated at the MTD. IV bortezomib is administered over 3-5 seconds on days 1, 4, 8, and 11. Courses are repeated every 21 days in the absence of disease progression or unacceptable toxicity. As of October 2004, this trial is closed.

A phase II randomized, multicenter, clinical trial to determine the effectiveness of PS-341 in treating metastatic renal cell cancer was initiated in October 2001 (protocol ID: CDR0000068955, UCCRC-11049A, NCI-3291, NCT00025376). Patients are randomized to 1 of 2 treatment arms. IV PS-341 is administered to arm I patients, over 3-5 seconds twice weekly on weeks 1 and 2. Treatment is repeated every 3 weeks, for 3 courses, in the absence of disease progression or unacceptable toxicity. Patients then undergo core biopsy. In arm II, patients undergo core biopsy, and then IV PS-341 is administered as in arm I. Patients undergo radiologic re-evaluation of measurable lesions. Those with SD or PR or CR continue to be treated with PS-341 in the absence of disease progression or unacceptable toxicity. Patients are followed for 2 years. Walter M. Stadler (Ph: 773-702-4400) of the University of Chicago Cancer Research Center is the principal investigator. This trial was closed in December 2002.

A phase II clinical trial (protocol ID: CDR0000068678, MSKCC-01032, NCI-3031, NCT00017329) to determine effectiveness of PS-341 in treating patients with metastatic renal cell carcinoma was initiated in April 2001 at Memorial Sloan-Kettering Cancer Center with Beverly Drucker (Ph: 212-639-7216) as the PI. IV PS-341 is administered over 3-5 seconds, twice weekly, for 2 weeks. Treatment is repeated every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients are then followed at 2 weeks. A total of 12-37 patients will be accrued within 6-19 months. This trial was closed in January 2003.

Indication in Development

melanoma, malignant, metastatic

Latest Status

Phase II (begin 7/01, closed 7/02) USA

Clinical History

A multicenter, phase II clinical trial of PS-341 in treating patients with metastatic malignant melanoma (protocol ID: CDR0000068883, MAYO-MC007A, NCI-3293, NCT00024011) was initiated in July 2001at the Mayo Clinic Cancer Center chaired by Svetomir Markovic (tel: 507-284-3903). IV PS-341 is administered over 3-5 seconds on days 1, 4, 8, and 11. Treatment is repeated every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression, and then every 6 months until 2 years after registration. A total of 22-50 patients will be accrued within 12 months. This trial was closed in July 2002.

Indication in Development

colorectal cancer, metastatic, refractory • gastric cancer, unresectable or metastatic • stomach cancer

Latest Status

Phase II (begin 12/02, closed 12/03) Canada, phase II (begin 11/03, closed 12/04) USA, phase II (closed 6/04) USA, Canada

Clinical History

A phase II clinical trial of bortezomib, designed to determine the activity, response rates, safety, and tolerability, in patients with metastatic or recurrent colorectal cancer who have been administered no more than 1 prior line of chemotherapy with irinotecan/5-FU or oxaliplatin/5-FU for metastatic disease, was performed by the Princess Margaret Hospital (Toronto, Canada) and NCI (Bethesda, MD). Bortezomib (1.3 mg/m²/day) was administered as an IV bolus on days 1, 4, 8, and 11 of a 21-day cycle. Tumor biopsies were performed before treatment and on day 8 of the first treatment cycle. To date, a total of 15 patients have been administered a median of 2 (range=2-4) cycles of bortezomib treatment. Disease stabilized in 4 (27%) patients, and progressed in 9 (60%);2 (14 %) patients (1 of these patients remains on trial after 1 cycle of treatment) could not be evaluated. Of the patients with SD, 1 progressed after 49 days, 2 remain on trial, and 1 withdrew as a result of a rash. The most frequently observed adverse events of any grade include constipation (n=5), lymphopenia (n=4) nausea (n=2) and vomiting (n=3). Observed Grade 3 adverse events included abdominal/back pain which resulted in 1 patient withdrawal from the trial and elevated alkaline phosphatase (n=1). Recruitment to this trial is ongoing (Mackay H, etal, AACR-NCI-EORTC03, Abs. B263). In updated results, a total of 19 patients were administered 41 (range=1-4/patient) cycles of treatment. Of 17 evaluable patients, 3 (18%) exhibited SD and 14 (82%) exhibited PD. Of the 2 patients with SD in cycle 2, 2 patients discontinued treatment during cycle 4 as a result of Grade 3 abdominal pain and Grade 3 peripheral neuropathy. After 3 cycles, 1 patient exhibited SD, but was withdrawn as a result of a cerebrovascular accident. The most frequently observed adverse events of any grade included lymphopenia (80% of cycles), fatigue (77%), anemia (66%), constipation (61%), nausea (51%), and headache (42%). Discontinuation of treatment was required as a result of the following adverse events, Grade 3 peripheral neuropathy (n=2), cerebrovascular accident, and Grade 3 abdominal pain, myalgia, and rash. These results indicate that bortezomib has insufficient activity in patients with metastatic colorectal cancer, and this trial was closed to accrual (Mackay H, etal, ASCO04, Abs. 3109).

An open label, nonrandomized, multicenter phase II clinical trial (protocol ID: CDR0000341565, MSKCC-03101, NCI-6003, NCT00074009) of bortezomib in patients with unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma began in November 2003 at University of Chicago Cancer Research Center, Memorial Sloan-Kettering Cancer Center, and University of Wisconsin Comprehensive Cancer Center. PI are Manish Shah, MD, and Gary K. Schwartz, MD. A total of 15-33 patients are administered IV bortezomib over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year. As of December 2004, this trial is closed.

In December 2002, Millennium initiated a multicenter (n=20) randomized, open label, phase II clinical trial (protocol ID: CDR0000258488, PMH-PHL-012, NCI-5890, NCT00052507) in Canada, in patients with metastatic or recurrent colorectal cancer to evaluate response to treatment with Velcade monotherapy. A total of 21-41 patients will be accrued for this trial to be treated with IV bortezomib on days 1, 4, 8, and 11. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Trial objectives are to determine the efficacy of bortezomib, in terms of response rate and SD rate, the drug's toxicity, TTP, and response duration, and whether there is a relationship between levels of transcription factors NF kappa B and HIF-1 alpha and clinical outcome in patients treated with this drug. The primary endpoint of the trial is tumor response. Amit M. Oza, MD (tel: 416-946-2818), of Princess Margaret Hospital (Toronto, Canada) is Protocol Chair.

Indication in Development

multiple myeloma, refractory or relapsed • multiple myeloma, newly diagnosed, high-risk Stage III

Latest Status

Phase I (begin 3/04, closed 10/05) USA; phase I/II (begin 5/04, ongoing 12/05) USA; phase II (begin 2/04, closed 4/05) USA, phase II (ongoing 6/04) USA; phase III (begin 10/02, closed 1/04) USA, Europe, phase III (begin 10/02, closed 5/03) USA, phase III (begin 1/05, ongoing 10/05) USA, Europe (combination); phase IV (begin 3/05, ongoing 10/05) USA, Canada

Clinical History

Several combination trials with velcade are ongoing. Refer to the combination trials module.

In March 2005, a multicenter, phase IV clinical trial (EVEREST - Evaluation of Velcade Employed as Retreatment for Efficacy, Safety, and Tolerability) of Velcade in patients with multiple myeloma who have previously responded to Velcade and relapsed following a treatment-free remission was initiated to determine the efficacy, safety and tolerability for this treatment. In previous trials, Velcade has been proven to be effective in patients with relapsed and refractory myeloma, with responses lasting about a year. When these responding patients relapse, there are few treatment options. There is also no known mechanism of resistance to Velcade and no new cumulative toxicity with extended therapy, so retreatment of these patients with Velcade could be a viable treatment option. This open label, clinical trial will be performed at approximately 80 sites in North America and will enroll up to approximately 120 patients. Eligible patients need to have tolerated 1.0 or 1.3 mg/m² doses of Velcade alone or in combination with dexamethasone, have had a decrease of M-protein of 50% or more that has lasted at least 6 months with a treatment-free interval of at least 4 months. In the EVEREST trial, the maximum number of cycles will be dependent on patient response and investigator discretion.

In January 2005, Millenium Pharmaceuticals and Johnson & Johnson Pharmaceutical Research & Development initiated a multicenter, international, randomized, phase III clinical trial (protocol ID: VISTA) of Velcade for injection in combination with melphalan and prednisone, compared to melphalan and prednisone alone in patients with newly diagnosed multiple myeloma who are not transplant candidates. This trial was designed to determine efficacy, safety, and tolerability of these regimens. Refer to the combination trial database for more information about this trial. The VISTA trial was examined by the FDA through the SPA process. An SPA is a binding agreement between the FDA and the sponsor of a clinical trial requiring that the trial design meets the scientific and regulatory requirements of the FDA to support a NDA or sNDA. Millennium and Johnson & Johnson are also planning to support 2 additional large, multinational phase III frontline muliple myeloma trials planned to commence in the first half of this year. These trials will be performed with patients who plan to undergo stem cell transplantation. In these trials, which will be conducted by major European hematology cooperative groups, Velcade will be integrated into the induction regimen.

A dose escalation, multicenter, phase I/II clinical trial (protocol ID: CDR0000365583, UCLA-0306106, MILLENNIUM-MM2003, NCT00084747) of adjuvant bortezomib as maintenance therapy after autologous peripheral blood stem cell transplantation in patients with intermediate or advanced MM was initiated in May 2004 at the Jonsson Comprehensive Cancer Center (Los Angeles, CA) to determine the response rate, progression-free survival, and toxicity for this treatment. Patients are administered bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients are administered escalating doses of bortezomib until the MTD is determined. Patients are followed every 3 months. A total of 3-30 patients will be accrued for this trial within 2 years. Gary Schiller, MD (tel: 310-825-5513), of the Jonsson Comprehensive Cancer Center is the principal investigator.

A randomized, open label, dose comparison, multicenter, phase I clinical trial (protocol ID: M34103-058, NCT00080405) of bortezomib in patients with relapsed multiple myeloma was initiated at the University of Pittsburgh Medical Center (Pittsburgh, PA), Sarah Cannon Cancer Center (Nashville, TN), Princess Margaret Hospital/Toronto Research Institute (Toronto, Canada), and Royal Victoria Hospital (Montreal, Canada) in March 2004 to characterize the clinical PK and pharmacodynamic profiles for 2 doses of bortezomib. Patients will be randomized to 1 of 2 bortezomib doses, 1.0 mg/m² for arm A or 1.3 mg/m² for arm B. Bortezomib will be administered on days 1, 4, 8, and 11 of a 21-day cycle. Patients randomized to arm A, but not responding to therapy after 3 cycles may have the dose of bortezomib increased to 1.3 mg/m² if no prohibitive toxicity was experienced at the lower dose. The duration of treatment in this trial is a maximum of 8 cycles. The expected enrollment for this trial is 40. Elizabel Trehu, MD (tel: 1-866-VELCADE), of Velcade is the protocol chair. The estimated completion date for this trial is September 2004. As of October 2005, this trial is closed.

A multicenter, phase II clinical trial (protocol ID: ECOG-E2A02, CDR0000349450, NCT00075881) of bortezomib in patients with newly diagnosed high risk Stage III MM was initiated in February 2004, and will be conducted by the ECOG under direction of Angela Dispenzieri, MD, and David Vesole MD, PhD. A total of 44 patients will be accrued. During induction therapy, IV bortezomib is administered over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 3 weeks, for 8 courses, in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression must complete at least 2 courses of induction therapy. Those who achieve complete remission are administered 2 additional courses, but no more than 8 courses total, and then proceed to maintenance therapy comprising IV bortezomib over 3-5 seconds on days 1 and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression may return to induction therapy (reinduction therapy). Courses repeat every 3 weeks until second disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years, and then every 6 months for 4 years from trial entry. As of April 2005, this trial is closed.

In December 2003, at ASH03, Millennium reported encouraging preliminary results from a multicenter, investigator initiated, phase II clinical trial, examining use of Velcade for treatment of patients with previously untreated multiple myeloma. This ongoing trial is being conducted by Dr. Jagannath, MD, and Brian Durie, MD, of Salick Health Care (Los Angeles, CA), and Jeffrey Wolf, MD, of Alta Bates Cancer Center (Berkeley, CA). Primary objectives of the trial are to determine in patients with newly diagnosed MM administered Velcade alone or in combination with dexamethasone, the response rate, tolerability and toxicity, and TTP in patients achieving a CR. According to the protocol, patients were treated with 1.3 mg/m² bortezomib twice weekly, for two weeks, and a week of rest for a maximum of 6 cycles. Dexamethasone (40 mg) was permitted on the day of and after each Velcade dose for patients not achieving at least a PR after cycle two and for all patients who achieved less than a CR following 4 cycles. Responses were determined based on a modification of the European Bone Marrow Transplantation (EBMT) registry criteria (Blade J, etal, Br J Haematol, Sep 1998;102(5):1115-23), with the addition of a near CR category, describing a 100% disappearance of M protein by electrophoresis but positive immunofixation. Stem cells are harvested from transplant candidates at the discretion of their physician. Nerve conduction and other neurologic testing are carried out pre and post-bortezomib treatment. As of August 13, 2003, 13 patients had been accrued, consisting of 6 males and 7 females, with a median age of 67 (range=45-83) years, Karnofsky performance score of 90 (range=60-100), 2-microglobulin of 6.1 (range=1.9-8.9), hemoglobin of 10.5 (range=7.9-11.7), and platelet count of 277 (range=138-840). The myeloma make-up of the population consisted of IgG (64%), IgA (36%) and light chain disease (0%), and were Durie Salmon symptomatic Stage I (23%), Stage II (31%), and Stage III (46%). Among 13 patients, 9 completed >= 2 cycles of bortezomib treatment and were hence evaluable, 3 completed 4 cycles and 1 completed all cycles. After the first two treatment cycles, 7/9 (77%) patients responded with 1 (11%) near CR, 4 (44%) with PR and 2 (22%) with MR. An additional PR and near CR were seen in the 3 patients completing 4 treatment cycles. Among 10 patients evaluated for adverse events, the most common >= Grade 1 toxicities were nausea (40%), diarrhea (50%), fatigue (40%), and peripheral neuropathy (30%). Grade 3 events included abdominal pain, diarrhea, dizziness, neutropenia, syncope, and vomiting. There was no Grade 4 toxicity and no dose modification was required. Initial results through only 2 cycles of bortezomib indicate a response rate (CR+PR+MR) of 77%, including 1 nearCR; no patients progressed. This suggests that bortezomib has encouraging activity in previously untreated patients with manageable toxicities. Rapid recruitment is ongoing, to enroll the projected 42 patients [Jagannath S, etal, ASH03, Abs. 1650 and Blood, 16 Nov 2003;102(11]. According to more mature results, reported during ASH03, among 16 patients enrolled in the trial, 12 were evaluable for response after being treated with at least two cycles of therapy. Among the 12 evaluable patients, the overall response rate (combined near CR and PR) in patients treated with up to 6 cycles of therapy was 75% (n=9); 4/12 (33%) achieved a near CR, and 5/12 (42%) a PR. By cycle two, 6 (50%) patients achieved a PR on Velcade alone. Adverse events were similar to those observed in other clinical trials with Velcade and included gastrointestinal events, fatigue and sensory neuropathy. In further updated results, a total of 19 patients (IgG=58%, IgA=32%, light chain=10%, median KPS=90; Durie-Salmon Stage III=55%) have been enrolled. As of 11/03, 12 patients have completed 6 cycles. Of the 12 evaluable patients, 4 (33%) exhibited near CR, 5 (42%) exhibited PR, 1 (8%) exhibited MR, and 2 (17%) exhibited PD. Stem cell transplant was undergone for 1 patient resulting in complete hematologic recovery. The most frequently observed adverse events (Grades 1 – 3) were fatigue (67%), diarrhea (58%), constipation (42%), nausea (42%), peripheral neuropathy (33%), and vomiting (33%). Additional Grade 3 events experienced by 1 patient each included abdominal pain, diarrhea, dizziness, dyspnea, fever, neuropathic pain, neutropenia, syncope, and vomiting. Dose modification was required for 1 patient. No Grade 4 toxicities were observed. Results indicate that bortezomib is a promising initial therapy for patients with newly diagnosed multiple myeloma, with manageable toxicities. Major responses (near CR and PR) were observed in 75% of patients by 6 cycles. Trial enrollment is ongoing and the full complement of 42 patients is expected to be recruited quickly (Jagannath S, etal, ASCO04, Abs. 6551). In additional updated results, 28 patients were enrolled and 24 were evaluable for response, having been administered at least 2 cycles of Velcade treatment. After being administered up to 6 cycles of therapy (n=24), the response rate in patients being administered Velcade alone or with added dexamethasone was 79%, which included combined CR, near CR and PR. All of the 6 CR or near CR were achieved with Velcade alone. Of the 13 PR, 7 were achieved with Velcade alone. The addition of dexamethasone resulted in additional benefit for 33% (8/14) patients, including 4 patients who improved from a MR to PR and 2 who improved from SD to PR. Adverse effects were comparable to those observed in other clinical trials with Velcade and included gastrointestinal events, fatigue, and sensory neuropathy.

A set of phase II clinical trials of bortezomib, designed to determine if patients multiple myeloma and renal insufficiency can be treated with bortezomib with manageable toxicities, were performed by the St Vincent’s Comprehensive Cancer Center (New York, NY), University of Arkansas Medical Science (Little Rock, AR), Cedars-Sinai Medical Center (Los Angeles, CA), Robert H. Lurie Cancer Center (Chicago, IL), M. D. Anderson Cancer Center (Houston, TX), Cleveland Clinical Foundation (Cleveland, OH), University of North Carolina Chapel Hill (Chapel Hill, NC), and Dana-Farber Cancer Institute (Boston, MA). The database for the SUMMIT and CREST phase II clinical trials (N=256) was studied to determine the number of patients with impaired renal function. Of the enrolled patients, 52 had calculated creatinine clearances </= 50 mL/minute, 99 were in the range of 51-80 mL/minute, and 105 were >80 mL/minute. In these 3 groups, similar rates of occurrence of Grade 3 and 4 adverse events (85%, 79%, 81%) and discontinuations (38%, 22%, 28%) were observed. Among the 256 patients enrolled in these trials, 10 were enrolled with calculated creatinine clearances of </=30 mL/minute with none requiring dialysis. Of these, 6 started therapy at full dose, 1.3 mg/m², administered biweekly for two weeks, followed by a ten-day rest period and 4 started at 1 mg/m² on the same schedule. There were 2 (20%) PR and 1 (10%) MR. The majority of patients were able to tolerate this therapy, with 7/10 patients being administered 30 or more doses of a possible 32. Of 10 patients, 3 discontinued therapy early as a result of neuropathy, failure to thrive, and pain. Limited pharmacokinetic data was available for 8 less severely affected patients with calculated creating clearances ranging from 31-169 mL/minute. The kinetic distribution and half-life of bortezomib was not affected by renal status, while bortezomib systemic exposure matched that obtained in the overall population. As previously reported in phase I trials, no correlation was observed between the maximum 20S proteasome inhibition and varying calculated creatinine clearance levels. In this trial, patients with multiple myeloma with severe renal impairment had similar response and discontinuation rates and were administered comparable numbers of borezomib doses as patients with less severe renal imparment. Therefore, although patients with impaired renal function may experience more complications and adverse prognostic factors, a significant number may be treated with benefit if closely monitored. Trials of bortezomib in severely impaired patients, including dialysis patients, are ongoing (Jagannath S, etal, ASH03, Abs. 828).

In October 2002, Millennium Pharmaceuticals sponsored an international, randomized, open label, multicenter phase III clinical trial (protocol ID: CDR0000258111, MILLENNIUM-M34101-039, FHCRC-1746.00, NCI-G02-2130, NCT00052260) of bortezomib versus high dose dexamethasone in treating relapsed or refractory multiple myeloma, under the direction of Denise Collins, Protocol Chair. Patients are randomized to 1 of 2 treatment arms. Arm I treatment consists of IV bortezomib on days 1, 4, 8, and 11, every 21 days, for 8 courses, and then again on days 1, 8, 15, and 22, every 35 days, for 3 courses. Arm II treatment consists of oral dexamethasone on days 1-4, 9-12, and 17-20 every 35 days, for 4 courses, and then again on days 1-4 every 28 days, for 3 courses. Objectives are to compare OS, response rates, and QoL of patients treated with these drugs. The trial is to enroll 612 patients. This trial was closed in January 2004.

Millennium is conducting APEX, an international, multicenter, phase III clinical trial (protocol ID: CDR0000258110, FHCRC-1747.00, MILLENNIUM-M34101-040, NCI-G02-2128, NCT00049478) of Velcade in patients with either relapsed or refractory multiple myeloma. During induction therapy IV PS-341 is administered on days 1, 4, 8, and 11. Treatment is repeated every 3 weeks, for up to 8 courses. For maintenance therapy, IV PS-341 is administered on days 1, 8, 15, and 22. Treatment is repeated every 5 weeks for up to 3 courses. Patients who experience PD after at least 2 courses or no change after at least 4 courses may also undergo oral dexamethasone on the day of and the day after PS-341 administration. Patients who experience PD after at least 2 courses of this combined therapy go off trial. Patients are followed at 30 days, every 6 weeks until disease progression, and then every 3 months thereafter. Approximately 400 patients were to be enrolled in this trial, which was closed in May 2003.

Indication in Development

small-cell lung cancer (SCLC), recurrent or refractory

Latest Status

Phase II (begin 8/03, closed 8/04) USA

Clinical History

Southwest Oncology Group under the direction of Primo Lara MD and Angela Davies, MD, is conducting a phase II clinical trial (protocol ID: CDR0000320527, SWOG-S0327, NCT00068289) of bortezomib in patients with recurrent or refractory extensive stage sclc previously treated with platinum-based therapy. Beginning August 2003, a total of 40-80 patients (20-40 per stratum) are to be enrolled and stratified according to platinum-sensitivity status (platinum sensitive versus platinum refractory). IV bortezomib is administered over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 6 months for 2 years. As of August 2004, this trial is closed.

Indication in Development

thyroid cancer

Latest Status

Phase II (begin 12/04 ongoing 6/09) USA

Clinical History

A multicenter (n=11), open label phase II clinical trial (protocol ID: CDR0000415376, MDA-2004-0059, NCI-6132; NCT00104871) was initiated in December 2004, in the USA and Canada, under Study Chair Steven I. Sherman, MD, MD Anderson Cancer Center (Houston, TX), to evaluate the safety and efficacy of bortezomib in patients with metastatic papillary or follicular thyroid cancer unresponsive to previous radioiodine therapy. The trial's primary objectives are determine the efficacy, response rate, and PFS. According to the protocol, patients are administered bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 21 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. After completion of trial treatment, patients are followed periodically. The trial is to enroll about 45 patients.

Approved Indications

multiple myeloma, relapsed or refractory, third line • multiple myeloma, second line • mantle cell lymphoma (MCL), relapsed or refractory, second line • multiple myeloma, combination therapy with Doxil for treatment of patients with multiple myeloma, not previously treated with bortezomib, second line • multiple myeloma, newly diagnosed, in combination with melphalan and prednisone, first line • multiple myeloma, newly diagnosed, in combination with melphalan and prednisone for the treatment of patients with previously untreated multiple myeloma who are not eligible for high dose chemotherapy with bone marrow transplant

Current as of

August 10, 2010