FDA Grants Peptide Vaccine Orphan Status for Ovarian Cancer

Marc Mansour, PhD

The FDA has granted an orphan drug designation to the immunotherapy DPX-Survivac as a treatment for women with ovarian cancer, based on early-phase research showing a robust immune response with the therapy in combination with low-dose cyclophosphamide.

"Receiving orphan drug designation for ovarian cancer underlines the fact that DPX-Survivac may address a significant unmet medical need for this important disease," Marc Mansour, PhD, chief executive officer of Immunovaccine, the company developing the vaccine, said in a statement. "Immunotherapy could change the way we treat all cancers in the future and we plan to continue to study of DPX-Survivac for the treatment of ovarian cancer as well as other solid tumor types and blood cancers."

DPX-Survivac is a lipid depot-based vaccine that contains survivin HLA class I peptides. The therapy is designed to elicit immunopotentiating and antineoplastic activity through a cytotoxic T cell response against survivin, which is commonly expressed on ovarian cancer cells and is thought to play a role in apoptosis, proliferation, and angiogenesis.

In a phase I/Ib study, which was presented at the 2015 ASCO Annual Meeting,¹ 40 patients with stage III/IV ovarian cancer were enrolled, with 39 receiving treatment with the DPX-Survivac immunotherapy with or without low dose cyclophosphamide. Prior to entering the study, all patients had responded favorably to platinum-based chemotherapy.

The median age of patients was 60 years (range, 35-77). The majority had stage III disease (79.5%) and 59% were treated in the study directly following first-line therapy. Patients were randomized to 6 cohorts, 1 (n = 7) that received the vaccine alone and 5 that received the immunotherapy at various doses with low-dose cyclophosphamide. DPX-Survivac was administered as a subcutaneous injection to the thigh every 3 weeks.

The primary endpoint of the study was safety in the combination cohorts. Secondary objectives assessed cell-mediated immunity and clinical regression by radiologic assessment and CA-125.

The majority of DPX-Survivac-related adverse events (AEs) were grade 1/2 injection site reactions, including induaration, erythema, pain, dryness, pruritus, and warmth. These adverse events occurred in almost all patients treated with the vaccine, and consisted primarily of all-grade erythema. Grade 3 infusion site ulcerations were noted across cyclophosphamide containing cohorts and were most commonly seen at the highest DPX-Survivac dose (0.5 mL; 33% of patients).

High levels of sustained CD4- T cell and CD8 T lymphocyte responses were induced by DPX-Survivac, with the best responses seen in patients who received the highest dose of the vaccine (0.5 mL) with cyclophosphamide. Additionally, in the combination arm, immune responses were more robust with the 0.5 mL dose of the vaccine compared with 0.1 mL (P = .013).

Findings from the phase I portion of the study that were published in the journal OncoImmunology indicated that a majority of patients treated in the study did not have measurable disease or evaluable CA-125 levels.² Of those who did (n = 5), a classical objective response was not demonstrated with the vaccine therapy. However, after 6 months of follow-up, 67% of patients had stable disease and continued to be monitored. When including those in the phase Ib portion of the study, the stable disease rate was 43%.

“The future of cancer treatment lies in rationally developing combination immunotherapy that can both generate cancer specific T cells and reduce the cancer-mediated immune inhibitory mechanism,” lead author of the OncoImmunology paper Neil Berinstein, MD, Department of Medicine at the University of Toronto, said when the results were published in early July. “Combining complementary immunotherapies is going to become increasingly important in the management of many malignancies.”

Based on an earlier assessment of the study, the FDA granted DPX-Survivac a fast track designation for patients with ovarian cancer in December 2014. Under this program, Immunovaccine is able to interact with the FDA more frequently. Additionally, the company can complete a rolling submission of data for a biologics license application.

“This fast track designation highlights the urgent need for new, innovative ovarian cancer treatments that can maintain patients in remission longer and ultimately increase survival,” said Mansour.

References

1. Villella JA, Wilson MK, Berinstein NL, et al. Safety, immunogenicity, and clinical activity of the immunotherapeutic vaccine, DPX-Survivac, in a Phase 1/1b trial of women with ovarian, fallopian tube, or peritoneal cancer. J Clin Oncol. 2015;33 (suppl; abstr 3072).
2. Berinstein NL, Karkada M, Oza AM, et al. Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients. OncoImmunology. 2015; 4(8):e1026529.