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Clinical Trial
. 2019 Mar 20;7(1):80.
doi: 10.1186/s40425-019-0562-8.

Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma

Geoffrey T Gibney  1   2 , Omid Hamid  3 , Jose Lutzky  4 , Anthony J Olszanski  5 , Tara C Mitchell  6 , Thomas F Gajewski  7 , Bartosz Chmielowski  8 , Brent A Hanks  9 , Yufan Zhao  10 , Robert C Newton  10 , Janet Maleski  10 , Lance Leopold  10 , Jeffrey S Weber  11   12
Affiliations
Clinical Trial

Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma

Geoffrey T Gibney et al. J Immunother Cancer. .

Abstract

Background: Epacadostat is a potent inhibitor of the immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. We present phase 1 results from a phase 1/2 clinical study of epacadostat in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, in advanced melanoma (NCT01604889).

Methods: Only the phase 1, open-label portion of the study was conducted, per the sponsor's decision to terminate the study early based on the changing melanoma treatment landscape favoring exploration of programmed cell death protein 1 (PD-1)/PD-ligand 1 inhibitor-based combination strategies. Such decision was not related to the safety of epacadostat plus ipilimumab. Patients received oral epacadostat (25, 50, 100, or 300 mg twice daily [BID]; 75 mg daily [50 mg AM, 25 mg PM]; or 50 mg BID intermittent [2 weeks on/1 week off]) plus intravenous ipilimumab 3 mg/kg every 3 weeks.

Results: Fifty patients received ≥1 dose of epacadostat. As of January 20, 2017, 2 patients completed treatment and 48 discontinued, primarily because of adverse events (AEs) and disease progression (n = 20 each). Dose-limiting toxicities occurred in 11 patients (n = 1 each with epacadostat 25 mg BID, 50 mg BID intermittent, 75 mg daily; n = 4 each with epacadostat 50 mg BID, 300 mg BID). The most common immune-related treatment-emergent AEs included rash (50%), alanine aminotransferase elevation (28%), pruritus (28%), aspartate aminotransferase elevation (24%), and hypothyroidism (10%). Among immunotherapy-naive patients (n = 39), the objective response rate was 26% by immune-related response criteria and 23% by Response Evaluation Criteria in Solid Tumors version 1.1. No objective response was seen in the 11 patients who received prior immunotherapy. Epacadostat exposure was dose proportional, with clinically significant IDO1 inhibition at doses ≥25 mg BID.

Conclusions: When combined with ipilimumab, epacadostat ≤50 mg BID demonstrated clinical and pharmacologic activity and was generally well tolerated in patients with advanced melanoma.

Trial registration: ClinicalTrials.gov identifier, NCT01604889 . Registration date, May 9, 2012, retrospectively registered.

Keywords: Epacadostat; IDO1; Immune checkpoint inhibition; Ipilimumab; Melanoma.

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Conflict of interest statement

Ethics approval and consent to participate

This report was conducted in accordance with the provisions of the Declaration of Helsinki, as described in the International Council for Harmonisation Guidelines for Good Clinical Practice, and was approved by the institutional review board at each participating institution. All patients provided informed consent before initiation of treatment.

Consent for publication

Not applicable.

Competing interests

GTG served as a consultant for Array BioPharma, Genentech, Novartis, Incyte Corporation, Newlink Genetics, Jounce, and Bristol-Myers Squibb; and served on a speakers bureau for Genentech. OH served consulting or advisory roles with Amgen, Novartis, Roche, Bristol-Myers Squibb, and Merck; served on speakers bureaus for Bristol-Myers Squibb, Genentech, Novartis, and Amgen; and received research funding from AstraZeneca, Bristol-Myers Squibb, Celldex, Genentech, Immunocore, Incyte, Merck, Merck Serono, MedImmune, Novartis, Pfizer, Rinat, and Roche. JL served as an advisory board consultant for Bristol-Myers Squibb. AJO served consulting or advisory roles with Merck, Takeda, Bristol-Myers Squibb, and G1 Therapeutics; received research funding from Takeda, Immunocore, EMD Serono, Amgen, Incyte, Kyowa Hakko Kirin, Lilly, Advaxis, Mirati Therapeutics, Ignyta, Novartis, Pfizer, Bristol-Myers Squibb, and Kura; and received travel/accommodation expenses from Takeda. TCM served consulting or advisory roles with Novartis, Bristol-Myers Squibb, Merck, and Incyte; and received research funding from Merck, Incyte, Bristol-Myers Squibb, and Roche. TFG has received consultancy fees from Merck, Roche-Genentech, AbbVie, Bayer, Jounce, Aduro, Fog Pharma, Adaptimmune, FivePrime, and Sanofi; has received research support from Roche-Genentech, Bristol-Myers Squibb, Merck, Incyte, Seattle Genetics, Celldex, Ono, Evelo, Bayer, and Aduro; has intellectual property/licensing agreements with Aduro, Evelo, and Bristol-Myers Squibb; and is a cofounder/shareholder with Jounce. BC has nothing to disclose. BAH received research funding from Merck, OncoMed Pharmaceuticals, MedPacto Inc., GlaxoSmithKline, AstraZeneca, D3 A*STAR, and Tempest; served consulting or advisory roles for G1 Therapeutics and FujiFilm Pharmaceuticals; and served on speakers bureaus for CE Concepts and Merck. YZ was an employee and stockholder of Incyte Corporation at the time of data analysis. RCN, JM, and LL are employees and stockholders of Incyte Corporation. JSW owns equity in Biond, Altor, and CytomX; is named on patents for Biodesix (PD-1 biomarker) and Moffitt (CTLA-4 biomarker; neither of which were used in the current work); and has received consulting fees for advisory boards for Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Incyte Corporation, Genentech, AstraZeneca, Celldex, Sellas, CytomX, EMD Serono, and Pfizer.

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Figures

Fig. 1
Fig. 1
Change From Baseline in Target Lesions in Immunotherapy-Naive Patients by irRC. a Best percentage change from baseline in target lesions and (b) percentage change in target lesions over time. BID, twice daily; irRC, immune-related response criteria. * 50 mg BID intermittent; best change from baseline was 0.98%. Of 39 efficacy-evaluable immunotherapy-naive patients, data are shown for the 31 patients with postbaseline scans that included assessment of target lesions. Y axis values were shown as a maximum of 100% for readability; actual values for the first 4 bars from the left in (a) were 687, 259, 181, and 117%
Fig. 2
Fig. 2
Survival Estimates by Prior Immunotherapy Status. a Kaplan-Meier–estimated PFS by irRC, (b) Kaplan-Meier–estimated PFS by RECIST, and (c) Kaplan-Meier–estimated OS. irRC, immune-related response criteria; NE, not evaluable; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors
See this image and copyright information in PMC

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