A dose escalation phase 1 study of radiotherapy (RT) in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab (Ipi) in patients (pts) with metastatic melanoma

Background

A synergy between RT and anti-CTLA-4 monoclonal antibody has been demonstrated preclinically and preliminary clinical data suggest that it could be due to an abscopal effect of RT. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of RT combined with Ipi in pts with metastatic melanoma.

Methods

A 3 + 3 dose escalation design was used with 9, 15, 18 and 24 Gy of RT (in 3 fractions) at week 4 combined with 10 mg/kg Ipi (every 3 weeks for 4 doses). Pts with evidence of clinical benefit at week 12 were eligible for maintenance Ipi at 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression based on immune-related response criteria (irRC). The adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for AEs, version 4.0. Tumors and blood were collected before and during treatment for translational research analyses.

Results

19 pts received Ipi between August 2011 and July 2015. 9 pts received the 4 doses of Ipi and 2 pts received maintenance Ipi (1 and 2 cycles respectively). All pts received the combined RT at week 4 in 3 fractions. All pts presented at least one AE of any grade. The most common AEs were asthenia, diarrhea, fever, nausea and vomiting. Grade 3 AEs occurred in 8 pts. They included colitis (n = 3), hepatitis (n = 2), anemia (n = 2), asthenia (n = 1), thyroid disorders (n = 1) and nausea/vomiting (n = 1). 9 pts discontinued the study owing to treatment-related adverse events including colitis (n = 6), hepatitis (n = 2) and DRESS syndrome (Drug Rash with Eosinophilia and systemic syndrome) (n = 1). DLT occurred in 2/6 pts in the cohort receiving 15 Gy. No drug-related death occurred. According to irRC, 4 partial responses (ORR: 21%) and 4 stable diseases were observed at week 24. The MTD was 9 Gy. One pt out of 12 treated in the 9 Gy cohort presented a DLT (grade 3 colitis).

Conclusions

When combined with Ipi at 10 mg/kg, in the present design, the MTD of RT was 9 Gy. This combination appears to be associated with antitumor activity. Translational research results will be available and presented.

Clinical trial identification

EUDRACT 2010-020317-93 (release date not applicable)

Legal entity responsible for the study

N/A

Funding

Gustave Roussy, Villejuif, France

Disclosure

C. Mateus: Consultant of BMS and Merck. E. Routier: Consultant of and BMS and Roche. J-C. Soria: Consultant of Astra-Zeneca, Merus, MSD, Pfizer, Roche, Servier and Symphogen. A. Eggermont: Member of the Scientific Advisory Board of BMS, Incyte, Medimmune and Merck. C. Robert: Consultant of Amgen, BMS, GSK, Merck, Novartis and Roche. All other authors have declared no conflicts of interest.