Recently, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to a novel immunotherapy for the treatment of ovarian cancer as well as Breakthrough Therapy designation to treatments for HRAS-mutant head and neck squamous cell carcinoma and previously treated thyroid cancer. The FDA also cleared a Priority Review for ruxolitinib in steroid-refractory chronic graft-vs-host disease.
Fast Track Designation for GEN-1 in Advanced Ovarian Cancer
The FDA granted Fast Track designation to GEN-1, a DNA-mediated interleukin-12 (IL-12) immunotherapy currently in phase II development, for the treatment of advanced ovarian cancer. GEN-1 was designed using TheraPlas, a synthetic, nonviral nanoparticle delivery system platform.
GEN-1 is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system, which enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anticancer immunity acting through the induction of T-lymphocyte and natural killer cell proliferation.
The phase II OVATION 2 trial is studying the combination of GEN-1 with standard-of-care neoadjuvant chemotherapy in patients newly diagnosed with stage III/IV ovarian cancer. Neoadjuvant chemotherapy is designed to shrink the cancer as much as possible for optimal surgical removal after three cycles of chemotherapy. Following neoadjuvant chemotherapy, patients undergo interval debulking surgery, followed by three adjuvant cycles of chemotherapy and up to nine additional weekly GEN-1 treatments, the goal of which is to delay disease progression and improve overall survival. OVATION 2 is an open-label, 1:1 randomized trial, 80% powered to show the equivalent of a 33% improvement in progression-free survival, the primary endpoint, when comparing the treatment arm with the control arm.
Data from the phase I portion of the phase I/II OVATION 2 study showed successful tumor resections, with seven out of eight patients (88%) in the GEN-1 treatment arm having a complete tumor resection (R0), which indicates a microscopically margin-negative resection in which no gross or microscopic tumor remains in the tumor bed. The neoadjuvant chemotherapy–only treatment arm had an R0 resection rate of 50%.
Patients in the completed phase Ib dose-escalation OVATION I study showed good objective response rates, with 100% of patients in high-dose cohorts experiencing a complete or partial response and 67% of patients in lower-dose cohorts experiencing a complete or partial response. Further, R0 resections in the high-dose cohorts occurred in 88% of patients, compared with 33% in the low-dose cohorts.
In addition, the trial sponsor compared matched patient data in a synthetic control arm with results from the OVATION I study. Patients in the GEN-1 arm virtually demonstrated a doubling of control of their cancer compared with the synthetic control arm. Findings are not statistically significant due to the small number of patients.
Breakthrough Therapy Designation for Tipifarnib in Head and Neck Squamous Cell Carcinoma
Tipifarnib was granted Breakthrough Therapy designation by the FDA for the treatment of patients with recurrent or metastatic HRAS-mutant head and neck squamous cell carcinoma with variant allele frequency ≥ 20% after disease progression on platinum-based chemotherapy. Tipifarnib is currently being evaluated in an ongoing registration-directed clinical trial (AIM-HN) in this indication of high unmet need. Tipifarnib is a potent, selective and orally bioavailable inhibitor of farnesyl transferase.
The Breakthrough Therapy designation is based on data from RUN-HN, a phase II clinical trial evaluating tipifarnib in patients with recurrent or metastatic HRAS-mutant head and neck squamous cell carcinoma. Data from this trial showed an overall response rate of 50%, a median progression-free survival of 5.9 months, and a median overall survival of 15.4 months among 18 evaluable patients.
Breakthrough Therapy Designation for Cabozantinib for the Treatment of Patients with Previously Treated, Radioactive Iodine–Refractory Differentiated Thyroid Cancer
The FDA granted Breakthrough Therapy designation to cabozantinib as a potential treatment for patients with differentiated thyroid cancer that has progressed following prior therapy and who are radioactive iodine–refractory (if radioactive iodine is appropriate).
In December 2020, at a planned interim analysis, the phase III COSMIC-311 pivotal trial met its co-primary endpoint, demonstrating a significant reduction in the risk of disease progression or death of 78% with cabozantinib vs placebo (hazard ratio = 0.22, 96% confidence interval = 0.13 – 0.36, P < .0001) in patients with radioactive iodine–refractory differentiated thyroid cancer who had disease progression after up to two prior VEGFR-targeted therapies. The safety profile was consistent with that previously observed for cabozantinib.
Priority Review for Ruxolitinib in Chronic Graft-vs-Host Disease
The FDA accepted for Priority Review a supplemental new drug application for ruxolitinib for the treatment of steroid-refractory chronic graft-vs-host disease in adult and pediatric patients aged 12 years and older. The Prescription Drug User Fee Act target action date is June 22, 2021. Ruxolitinib is a first-in-class JAK1/JAK2 inhibitor.
The submission is based on results from the phase III, randomized REACH3 study comparing ruxolitinib with best available therapy in patients with steroid-refractory chronic graft-vs-host disease. In the REACH3 study, which was recently presented at the 62nd American Society of Hematology Annual Meeting & Exposition, patients treated with ruxolitinib experienced a significantly greater overall response rate compared to best available therapy at week 24, the primary endpoint (49.7% vs 25.6%, P < .0001).
For the key secondary endpoints, ruxolitinib was associated with a longer median failure-free survival than best available therapy at week 24 (not reached vs 5.7 months, hazard ratio = 0.370, P < .0001) and greater symptom improvement per the modified Lee Symptom Scale at week 24 (24.2% vs 11.0%, odds ratio = 2.62, P = .0011). The best overall response rate for patients receiving ruxolitinib was 76.4%. No new safety signals were observed, and adverse events were consistent with the known safety profile of ruxolitinib.
