FDA granted accelerated approval for Keytruda (pembrolizumab) for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
The indication was approved based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Keytruda received a Breakthrough Therapy designation for advanced melanoma, and is the first anti-programmed death receptor-1 therapy approved in the U.S.
The designation was granted based on the significance of early study findings and the unmet medical need. For the recommended 2 mg/kg dose based on data in 89 patients, the overall response rate was 24 percent (95% CI: 15, 34), with one complete response and 20 partial responses (21/89). At the time of analysis, 86 percent (18/21) of patients with objective responses had ongoing responses with durations ranging from 1.4+ to 8.5+ months, including eight patients with ongoing responses of 6 months or longer. Fourteen percent (3/21) had progression of disease 2.8, 2.9, and 8.2 months after initial response.
Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, and may affect both tumor cells and healthy cells. Immune-mediated adverse reactions occurred with Keytruda including pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism.
Merck, the drug’s sponsor, is conducting ongoing phase II and III clinical studies in advanced melanoma.
FDA approved a new indication for Xtandi (enzalutamide) capsules to treat patients with metastatic castration-resistant prostate cancer who have not received chemotherapy. This follows a priority review based on results of the phase III PREVAIL trial.
The agency initially approved Xtandi in August 2012 for use in patients with metastatic CRPC who previously received docetaxel.
In PREVAIL, men receiving Xtandi and GnRH therapy exhibited a statistically significant improvement in both overall survival and delayed time to radiographic progression or death as compared to those on placebo and GnRH therapy. Xtandi significantly reduced the risk of radiographic progression or death by 83 percent compared with placebo (HR=0.17; p < 0.0001).
Xtandi significantly reduced the risk of death by 29 percent compared with placebo (HR=0.71; p < 0.0001). When compared to placebo, treatment with Xtandi also delayed time to initiation of chemotherapy and time to a skeletal related event.
Xtandi is sponsored by Medivation Inc. and Astellas Pharma Inc.
FDA removed separate clinical holds on trials involving two agents: one on ipafricept, developed by OncoMed Pharmaceuticals Inc.; and another on PEGPH20, sponsored by Halozyme Therapeutics Inc.
Ipafricept is being studied in combination with standard-of-care in three phase Ib studies. Enrollment and dosing of new patients is expected to resume within the next few weeks as the study sites’ institutional review boards receive and approve the revised trial protocols.
“With important input from our clinical investigators and academic bone experts, the OncoMed team has developed modified study parameters intended to avoid potential risks while allowing us to evaluate the therapeutic impact of ipafricept for patients with pancreatic, hepatocellular and ovarian cancers in combination with standard therapy,” said Jakob Dupont, OncoMed’s chief medical officer. The amendments for the combination trials include modified dosing regimens, risk mitigation measures, such as increased monitoring and bone protection strategies, and modified enrollment criteria.
OncoMed voluntarily halted enrollment in its vantictumab and ipafricept Wnt pathway programs as a precautionary measure based on reported incidents of mild-to-moderate bone adverse events. The FDA concurred with the company’s decision and placed the studies on partial clinical hold, allowing for the continued dosing of patients who demonstrated benefit without significant drug-related adverse effects.
Ipafricept is a first-in-class fusion protein that inhibits the Wnt pathway. Ipafricept selectively binds Wnt ligands that are activators of Wnt signaling. Ipafricept has shown broad anti-CSC and anti-tumor activity in patient-derived xenograft tumor models.
The ongoing Ib/II clinical trial evaluating PEGPH20 in combination with modified FOLFIRINOX chemotherapy in patients with metastatic pancreatic adenocarcinoma will also resume under a revised protocol.
The trial, which will enroll approximately 170 patients, is being sponsored by SWOG.
The phase Ib portion of the study will be a limited dose de-escalation clinical trial examining the dose-limiting toxicities in 6 to 18 patients, to identify the optimal dose for PEGPH20 used in combination with mFOLFIRINOX in patients with newly diagnosed metastatic pancreatic adenocarcinoma in the phase II portion of the study. The mFOLFIRINOX treatment regimen consists of oxaliplatin, leucovorin, irinotecan and 5-fluorouracil.
The phase II portion will be a randomized, multicenter, parallel arm study enrolling approximately 152 patients to yield 138 evaluable patients.
The study will also explore the treatment impact on carbohydrate antigen 19-9, a biomarker often associated with tumor cell burden, as well as the correlation of plasma hyaluronan and tumor HA with OS, PFS and ORR.
Soligenix Inc. reached an agreement with FDA on the design of a phase III clinical trial evaluating SGX301 (synthetic hypericin) for the treatment of cutaneous T-cell lymphoma.
The trial is anticipated to begin in the first half of 2015 with primary data available in the second half of 2016. SGX301 is a novel, first-in-class, photodynamic therapy that is topically applied to skin lesions and activated by visible fluorescent light.
The upcoming protocol will be a double-blind, randomized, placebo-controlled, multicenter trial that seeks to enroll approximately 120 patients. Treatments will be administered twice weekly for the first 6 weeks and treatment response will be determined at the end of Week 8.
In the first treatment cycle, approximately 80 patients will receive SGX301 and 40 will receive placebo treatment of their index lesions. In the second cycle, all patients will receive SGX301 treatment of their index lesions and in the third (open-label) cycle all patients will receive SGX301 treatment of all their lesions. Subjects will be followed for an additional 6 months after the completion of treatment.
