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AST-VAC1, GRNVAC1 (May-11-2017)
Based on the finding that telomerase activity in leukemic blasts is frequently increased in patients with high risk acute myeloid leukemia (AML), investigators evaluated the feasibility, safety, immunogenicity, and therapeutic potential of human telomerase reverse transcriptase (hTERT)-expressing autologous dendritic cells (hTERT-DC) in patients with AML. hTERT-DC were produced from patient-specific leukapheresis, electroporated with an mRNA-encoding hTERT and a lysosomal-targeting sequence, and cryopreserved. A total of 22 patients with intermediate or high risk AML in first or second CR were enrolled in this phase II clinical trial (protocol ID: GRNVAC1 CP06-151; NCT00510133; http://clinicaltrials.gov/ct2/results?term=NCT00510133 ). A median of 17 intradermal vaccinations (range=6-32) containing 1×10^7 cells were administered as 6 weekly injections followed by 6 biweekly injections. A total of 21 patients (16 in first CR, 3 in second CR, and 2 with early disease recurrence) were treated with hTERT-DC. Treatment was well tolerated; no severe toxicities were reported, with the exception of 1 patient who developed idiopathic thrombocytopenic purpura. Among the 19 patients treated with hTERT-DC in CR, 11 (58%) patients developed hTERT-specific T-cell responses primarily targeted toward hTERT peptides with predicted low human leukocyte antigen (HLA)-binding affinities. With a median follow-up of 52 months, disease had not recurred in 11/19 (58%) patients in CR at the time of their last follow-up visit as well as 4/7 (57%) of patients aged =60 years. Findings indicate that the generation of hTERT-DC is feasible and vaccination with hTERT-DC appears to be safe and may be associated with favorable recurrence-free survival Khoury HJ, etal, Cancer, 14 Apr 2017; epub ahead of print; https://www.ncbi.nlm.nih.gov/pubmed/28411378 ).
PelareorepReolysin, Reovirus type 3 Dearing (RT3D) (May-9-2017)
In May 2017, the FDA granted Reolysin fast track designation for the treatment of metastatic breast cancer. In April 2017, data from the phase II clinical trial (protocol ID: I213; NCT01656538; http://clinicaltrials.gov/show/NCT01656538 ) assessing the combination of IV Reolysin and IV paclitaxel versus paclitaxel alone in patients with advanced or metastatic breast cancer indicated a statistically significant increase in median OS. Based on Reolysin's mechanism of action, along with the positive OS data generated to date, Oncolytics Biotech is pursuing metastatic breast cancer as its primary focus for late stage clinical testing.
REGN2810, SAR439684 (May-8-2017)
In May 2017, Regeneron Pharmaceuticals and Inovio Pharmaceuticals signed a clinical trial agreement to initiate a multicenter (n=30) open label, phase Ib/IIa clinical trial in the USA, to be conducted by Inovio in patients with newly diagnosed glioblastoma multiforme (GBM). The trial will evaluate REGN2810 in combination with Inovio's INO-5401 T cell activating immunotherapy encoding multiple antigens and INO-9012, an immune activator encoding IL-12. The trial is designed to evaluate the safety and efficacy of the combination therapy in ~ 50 patients. The trial’s primary endpoints are safety and tolerability. The trial will also evaluate immunological impact, PFS and OS. Under the terms of the agreement, the trial will be solely conducted and funded by Inovio, based upon a mutually agreed upon design, and Regeneron will supply REGN2810. Inovio and Regeneron will jointly conduct immunological analyses in support of the trial.
Sacituzumab govitecanIMMU-132 (May-5-2017)
In May 2017, Seattle Genetics terminated its license agreement with Immunomedics for sacituzumab govitecan (IMMU-132) and agreed to settle the related litigation. The license agreement had not yet closed due to legal action brought by an Immunomedics stockholder challenging the transaction. Effective upon the termination of the license, the parties have agreed to fully settle, resolve and release each other from all disputes, claims and liabilities. As part of the termination, Seattle Genetics will continue to hold 3.0 million shares of Immunomedics common stock, as well as a warrant to purchase an additional 8.7 million shares at $4.90 per share exercisable until December 31, 2017.
Plitidepsin, dehydrodidemnin B (May-4-2017)
In May 2017, Aplidin was granted orphan drug status by the Swiss Agency for Therapeutic Products (Swissmedic) for the treatment of patients with multiple myeloma.
In April 2017, the EPO notified Cel-Sci that it would be granted a new patent on Multikine (Leukocyte Interleukin, Injection) titled "A Method for Modulating HLA Class II Tumor Cell Surface Expression with a Cytokine Mixture". The patent relates to a method for altering the composition of tumor infiltrating mononuclear cells, increasing CD4+/CD8+ ratio, increasing tumor stroma/epithelial ratio, and modulating HLA class II expression on a tumor cell surface with Multikine resulting in the tumor becoming 'visible' to the immune system, culminating in a more robust and sustainable antitumor immune response.
As of April 2017, the phase III clinical trial (protocol ID: NCT01265849; http://clinicaltrials.gov/ct2/results?term=NCT01265849 ) with Multikine (leukocyte interleukin injection) in patients with advanced primary head and neck cancer remains on partial clinical hold. Pursuant to this action by the FDA, patients currently being treated in this trial may continue treatment, and patients already enrolled in the trial will continue to be followed. To date, the trial has enrolled 928 patients.
(Additional New Drugs Updates available in the Archives)
In May 2017, the FDA granted accelerated approval to pembrolizumab (Keytruda) in combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic non-squamous non-small cell lung cancer (nsclc) regardless of PD-L1 expression and with no EGFr or ALK genomic tumor aberrations. Merck must confirm the use of pembrolizumab in this indication with additional data. To date, Keytruda is the only PD-1 or PD-L1 checkpoint inhibitor approved to treat first line lung cancer either as monotherapy or as part of a combination therapy. Approval was based on a cohort (G1) of patients enrolled in a multicenter, open label, multi-cohort clinical trial phase I/II clinical trial (protocol ID: 3475-021; P22067; KEYNOTE-021; NCT02039674; http://clinicaltrials.gov/show/NCT02039674 ). The trial enrolled 123 patients with locally advanced or metastatic non-squamous nsclc and no prior systemic treatment for metastatic disease who were randomized either to pembrolizumab (200 mg) every 3 weeks, in combination with pemetrexed and carboplatin (PC) for 4 cycles followed by pembrolizumab for a maximum of 24 months (n=60) compared to PC alone (n=63). At the investigator’s discretion, patients in both arms may have been treated with pemetrexed as maintenance therapy. Randomization was stratified by PD-L1 tumor expression [tumor proportion score (TPS) <1% versus TPS >/=1%). An improvement in ORR and in PFS was noted in patients randomized to pembrolizumab plus PC. The ORR was 55% for the pembrolizumab plus PC arm and 29% for the PC alone arm (p=0.0032). Among responders, the proportion of patients with response durations of 6 months or longer was 93% in the pembrolizumab-containing arm and 81% in the PC alone arm. The PFS HR was 0.53 (p=0.0205) and median PFS was 13.0 months for the pembrolizumab plus PC arm and 8.9 months for the PC alone arm. Exploratory analyses of ORR were conducted in subgroups defined by PD-L1 tumor expression (TPS <1% and TPS =1%). In the TPS <1% subgroup, the ORR was 57% in the pembrolizumab plus PC and 13% in the PC alone arms, respectively. In the TPS >/=1% subgroup, the ORR was 54% and 38%, respectively. There is no survival advantage reported with pembrolizumab to date. AE and SAE were observed at a higher incidence with the addition of pembrolizumab to PC compared to PC alone. SAE were noted in 41% of the patients in the pembrolizumab plus PC arm compared with 28% in the PC alone arm. . The most common AE (all grades) in the pembrolizumab plus PC arm were fatigue (71%), nausea (68%), and constipation (51%). The most common Grade 3/4 AE were fatigue (3.4%), dyspnea (3.4%), nausea (1.7%), vomiting (1.7%), diarrhea (1.7%), and rash (1.7%). Pembrolizumab was discontinued for AE in 10% of patients. The most common AE resulting in discontinuation of pembrolizumab (>/= 2%) was acute kidney injury (3.4%). Immune-mediated AE that can occur with pembrolizumab include pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. The recommended pembrolizumab dose and schedule in nsclc is 200 mg as an IV infusion every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. This pembrolizumab plus chemotherapy regimen
In April 2017, the European Commission granted full approval to Darzalex (daratumumab) as combination therapy with lenalidomide and dexamethasone, or Velcade (bortezomib) and dexamethasone, for treating patients with relapsed or refractory multiple myeloma previously treated with a least one therapy. Approval is based on data from the POLLUX phase III clinical trial (protocol ID: CR103663; 54767414MMY3003; EudraCT 2013-005525-23; NCT02076009; https://clinicaltrials.gov/show/NCT02076009 ) and the CASTOR phase III clinical trial (protocol ID: CR103995; 2014-000255-85; 54767414MMY3004; MMY3004; NCT01620879; NCT02136134; https://clinicaltrials.gov/show/NCT02136134 ) that together enrolled more than 1000 patients. In these trials combination therapy including daratumumab reduced the risk of disease progression or death by 61% to 63% when compared with standard of care regimens. The EC’s clearance of Darzalex also converts to full approval a prior conditional approval granted in Europe last year for use of Darzalex as monotherapy for patients with multiple myeloma who had been previously treated with a proteasome inhibitor and immunomodulatory drug therapy and whose disease progressed on their last treatment. The conditional approval had been based on the SIRIUS phase II clinical trial (protocol ID: CR102651; 54767414; MMY2002; 2013-000752-18; NCT01985126; http://clinicaltrials.gov/show/NCT01985126 ) and the GEN501 phase I/II clinical trial (protocol ID: NCT00574288; http://clinicaltrials.gov/ct2/results?term=NCT00574288 ).and other supporting trials, but was dependent on Janssen providing subsequent data from the POLLUX.
In April 2017, Genmab became eligible for a $48 million milestone in its collaboration with Janssen Biotech to be triggered by the first commercial sales of daratumumab in Europe under the expanded label.
In April 2017, NICE published its Final Appraisal Determination (FAD) recommending Blincyto (blinatumomab) as an option for treating adults with Philadelphia-chromosome-negative (Ph-) relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL), on the basis of the discount agreed in the patient access scheme (https://www.nice.org.uk/guidance/gid-ta10093/documents/final-appraisal-determination-document ). This move is consistent with a previous decision from the Scottish Medicines Consortium, ending the variations in access between England and Scotland. The clinical evidence behind the recommendation by NICE is based on TOWER, a phase III clinica trial (protocol ID: 00103311; NCT02013167; http://clinicaltrials.gov/ct2/show/NCT02013167 ) and a phase II clinical trial (protocol ID: MT103-211; 2011-002257-61; NCT01466179; http://clinicaltrials.gov/ct2/show/NCT01466179 ). According to results from the TOWER trial, median OS was 7.7 months for blinatumomab versus 4.0 months for standard of care chemotherapy (HR=0.71; p=0.01).
In April 2017, the FDA expanded the approved use of Stivarga (regorafinib) to include treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This is the first FDA-approved treatment for liver cancer in almost a decade. This is the first time patients with HCC have had an FDA-approved treatment that can be used if their cancer has stopped responding to initial treatment with sorafenib. The safety and efficacy of Stivarga for treatment of HCC were studied in RESORCE (REgorafenib after SORafenib in patients with hepatoCEllular carcinoma), a multicenter (n=152), international (n=21), placebo-controlled phase III clinical trial (protocol ID: 15982; 2012-003649-14; NCT01774344; https://clinicaltrials.gov/show/NCT01774344 ) that investigated Stivarga in patients with HCC that progressed during treatment with Nexavar (sorafenib). The trial’s outcome measures were OS, PFS, and ORR. Median OS for patients on Stivarga was 10.6 months compared to 7.8 months for those on placebo, median PFS was 3.1 months versus 1.5 months and the ORR was 11% compared to 4%, respectively.
In April 2017, the European Union (EU) granted osimertinib (Tagrisso) full approval for the treatment of patients with locally advanced or metastatic EGFr T790M mutation-positive non–small cell lung cancer (nsclc), irrespective of previous treatment with an EGFr tyrosine kinase inhibitor (TKI). Conditional marketing authorization for Tagrisso (80 mg) once daily tablets for this indication had been granted by the European Commission (EC) in February 2016. Approval is based on AURA3, a multicenter (n=131), randomized, open label, active-controlled phase III clinical trial (protocol ID: D5160C00003; NCT02151981; https://clinicaltrials.gov/show/NCT02151981 ), conducted in patients with metastatic EGFr T790M mutation-positive nsclc that had progressed following first line EGFr TKI therapy. All patients were required to have EGFR T790M mutation-positive nsclc identified by the cobas EGFR mutation test performed in a central laboratory. AURA3 randomized 419 patients (2:1), 279 patients to osimertinib (80 mg) orally once daily or 140 patients to platinum-based doublet chemotherapy, either pemetrexed (500 mg/m²) with carboplatin (AUC5), or pemetrexed (500mg/m²) with cisplatin (75 mg/m²), on day 1 of every 21-day cycle for up to 6 cycles followed by pemetrexed maintenance therapy. Patients on the chemotherapy arm with radiological progression according to both investigator and blinded independent central review were offered osimertinib at progression. An improvement in investigator-assessed PFS was noted with osimertinib (HR=0.30; p<0.001). The estimated median PFS was 10.1 months in the osimertinib arm and 4.4 months in the chemotherapy arm. Confirmed ORR, according to investigator assessment, was 65% and 29% in the osimertinib and chemotherapy arms, respectively (p<0.0001). Estimated median response durations were 11 months and 4.2 months in the osimertinib and chemotherapy arms, respectively. In patients with measurable central nervous system (CNS) lesions on baseline brain scans, the confirmed CNS ORR, assessed by independent central review, was 57% and 25% in the osimertinib and chemotherapy arms, respectively. The median CNS response duration was not reached in the osimertinib arm (range=1.4 to 12.5 months) and was 5.7 months (range=1.4, 5.7 months) in the chemotherapy arm. Overall survival data are immature. Serious AE were evaluated in 833 patients treated with osimertinib. The most serious AE were interstitial lung disease/pneumonitis (3.5%), QTc interval prolongation (0.7%), cardiomyopathy (1.9%), and keratitis (0.7%). The most common AE (occurring in at least 20% of patients) were diarrhea, rash, dry skin, nail toxicity, and fatigue (Mok TS, etal, NEJM, 16 Feb 2017;376(7):629-640; https://www.ncbi.nlm.nih.gov/pubmed/27959700 ).
(Additional Marketed Drugs Updates available in the Archives)