A phase I clinical trial of radiation therapy, durvalumab and tremelimumab in recurrent gynecologic cancer

Abstract

Objective

Dual immune checkpoint blockade (ICB) may synergize with palliative radiotherapy (RT) to improve responses in patients with recurrent/metastatic gynecologic cancer. We conducted an open label prospective phase I trial to assess the safety and tolerability of ICB plus RT.

Methods

Patients with recurrent/metastatic endometrial, ovarian, cervical, vaginal or vulvar cancer were eligible. The safety lead-in cohort A was treated with programmed death ligand (PD-L1) inhibitor durvalumab 1500 mg IV q4 weeks and palliative RT of 25 Gy in 5 fractions to a single abdominopelvic lesion. Cohort B also received 4 cycles of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab 75 mg IV. The primary endpoint was the rate of dose-limiting toxicities (DLTs) in patients on protocol 8 weeks after RT. Secondary endpoints included the overall response rate (ORR) in non-irradiated lesions.

Results

16 patients were enrolled, with 12 able to be assessed for the primary endpoint. Zero DLTs occurred in cohort A and 1 in cohort B. One patient in cohort B with platinum resistant ovarian cancer with two metastatic sites (a pelvic mass irradiated prior to trial enrollment and a peritoneal nodule irradiated on protocol) had a dramatic reduction in disease burden and remains off all therapy >3 years. The ORR of non-irradiated lesions was 0 %.

Conclusions

Combining durvalumab, tremelimumab and RT to a single lesion had limited DLTs but no response in non-irradiated lesions in unselected patients with recurrent gynecologic malignancies. One patient with oligometastatic disease experienced prolonged durable benefit. Clinical trial information: NCT03277482