Phase I study of pegylated interferon-alpha-2b as an adjuvant therapy in Japanese patients with malignant melanoma

Abstract

In the adjuvant setting for malignant melanoma, interferon (IFN)-α-2b and pegylated (PEG) IFN-α-2b were approved in several countries including the USA before these were approved in Japan. To resolve the "drug-lag" issue, this phase I study was designed to evaluate the safety and tolerability in Japanese patients with stage II or III malignant melanoma who had undergone surgery, by treating with PEG IFN-α-2b. As with a previously reported phase III study, patients were to receive PEG IFN-α-2b 6 μg/kg per week s.c. during an 8-week induction phase, followed by a maintenance phase at a dose of 3 μg/kg per week up to 5 years. Dose-limiting toxicity and pharmacokinetics were assessed during the initial 8 weeks. Of the nine patients enrolled, two patients had dose-limiting toxicities that resolved after discontinuation of treatment. The most frequently reported drug-related adverse events (DRAE) included pyrexia, decreased neutrophil and white blood cell counts, and arthralgia. Grade 3 DRAE included decreased neutrophil count. No deaths, serious adverse events and grade 4 adverse events were reported. Distant metastasis occurred in one patient. No apparent differences in area under the concentration-time curve and maximum observed serum concentration were observed between Japanese and historical non-Japanese pharmacokinetic data, suggesting no marked racial differences. No neutralizing antibody was detected in these patient samples. PEG IFN-α-2b was tolerated in Japanese patients, and eventually approved in Japan in May 2015 for adjuvant therapy in patients with stage III malignant melanoma. Because the number of patients was limited, further investigation would be crucial.

Keywords: Japanese; adjuvant therapy; melanoma; peg-interferon α-2b; phase I.

© 2016 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.

Figures

Figure 1

Dose‐limiting toxicity (DLT) was evaluated stepwise: step 1 in three patients, and step 2 in nine patients, adding 6. If four or less of the nine patients exhibited DLT, the dose was considered tolerable.

Figure 2

Overall study flow. Two patients discontinued in the induction phase because of dose‐limiting toxicity (DLT). Four patients discontinued in the maintenance phase by adverse events or distant metastasis. Treatment was ongoing at approval in three patients. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Figure 3

(a) Serum concentration–time profile by 6 μg/kg per week dosing of pegylated interferon‐α‐2b (MK‐4031) (arithmetical mean ± standard deviation [SD]). One patient data who was not administrated treatment at week 7 was excluded from calculation at week 8. (b) Trough level profile of serum concentration by 6 μg/kg per week dosing of pegylated interferon‐α‐2b (MK‐4031) (arithmetical mean). Data for five patients who completed administration from weeks 1 to 8 are shown.