In the adjuvant setting for malignant melanoma, interferon α-2b and peg-interferon (PEG-IFN) α-2b are approved in the U.S. and several countries worldwide while no approvals have been obtained in Japan. To resolve the 'drug-lag' issue, development was requested by the Review Committee on Unapproved Drugs and Indications with High Medical Needs. Phase I study was hence designed to determine the safety and tolerability in Japanese patients treated with PEG-IFN α-2b, obtaining exploratorily the efficacy, pharmacokinetics (PK), and anti-drug antibody (ADA) data.
We conducted a multicenter, open-label, non-controlled phase I study in patients with AJCC 2009 stage II or III malignant melanoma who had undergone surgery. Same as EORTC18991 study, patients were to receive PEG-IFN α-2b 6 Âµg/kg subcutaneously (SC) weekly during an 8-week induction period, followed by a maintenance dosage of 3 Âµg/kg SC weekly for the remainder of a maximum of 5-year treatment period. Dose-limiting toxicity (DLT), PK, and ADA were assessed during the initial 8 weeks.
Nine patients were enrolled and the median treatment duration was 38.9 (range 2 to 72+) weeks. Two patients had DLT (2 cases of Grade 3 ALT increased, a Grade 3 AST increased and a Grade 1 retinopathy), and these toxicities were recovered after discontinuation of treatment. The most frequently reported adverse events (AEs) included pyrexia, neutrophil count decreased, white blood cell count decreased, and arthralgia. Treatment-related grade 3/4 AEs included neutrophil count decreased, hypertriglyceridaemia, ALT increased, AST increased, and white blood cell count decreased. No deaths and serious adverse events were reported. Distant metastasis occurred in one patient. No apparent differences in AUC and Cmax were observed between Japanese and historical non-Japanese PK data, suggesting no marked ethnic differences. No neutralizing antibody was detected in these patient samples.
PEG-IFN α-2b was tolerated in Japanese patients with malignant melanoma who had undergone surgery. Based on this and EORTC18991 study results, PEG-IFN α-2b was approved in Japan in May 2015 for adjuvant therapy in patients with Stage III malignant melanoma, as the first approval in Asia.
Clinical trial identification
MK-4031 P370 (SCH 54031 P08556)
Y. Kiyohara: research funding by Ono, Chugai, BMS, MSD, Merck Serono, and GSK; payment by Ono and Chugai for a role of safety review committee and a speaker. K. Matsuda, K. Yamamoto, T. Shimamoto: employee of MSD KK. All other authors have declared no conflicts of interest.