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.

Elimination half-lives of interleukin-6 and cytokine-induced neutrophil chemoattractant-1 synthesized in response to inflammatory stimulation in rats

“…IFN conjugated with polyethylene glycol slows down the decomposition of IFN [ 17 18 19 ]. Moreover, these IFNs were subcutaneously administered in humans and slowly absorbed [ 20 ], suggesting that IFN slowly is absorbed and decomposes. Based on these results, the half-lives of IL-6 and CINC-1 estimated in this study were considered to be appropriate.…”

Targeted Therapy and Immunotherapy for Melanoma in Japan

“…High-dose or pegylated IFN-alfa has been shown to improve the RFS; however, its efficacy in terms of the OS is marginal, and the incidence of severe AEs is relatively high [ 59 , 60 , 80 – 82 ]. In Japan, pegylated-IFN-alfa was approved in May 2015 after the completion of a phase I trial [ 61 ]. Another type I IFN, IFN-β, has also been used for melanoma in Japan.…”

A Novel Signature of 23 Immunity-Related Gene Pairs Is Prognostic of Cutaneous Melanoma

“…CM is associated with strong immunogenicity; thus, immunotherapy is a promising treatment alternative (5). Initial clinical trials using interferon-a (6) and high-dose interleukin-2 for advanced cases of CM (7) reported successful results. In addition, immune checkpoint inhibitors (ICIs), such monoclonal antibodies against cytotoxic T-lymphocyteassociated protein (CTLA-4) (8) and programmed cell death protein 1 (PD-1) (9), have provided meaningful results in the clinical outcomes against advanced melanoma, as demonstrated by improved survival and a greater curative effect for an increasing proportion of patients with CM.…”