A Phase 1/2 Study of the Safety and Efficacy of the Arginase Inhibitor INCB001158 plus Chemotherapy in Patients with Advanced Biliary Tract Cancer

2021 Year in Review: Cholangiocarcinoma — December 17, 2021

Results of an open-label, phase 1/2 study indicate that addition of INCB001158 to the standard gemcitabine/cisplatin backbone was tolerable, did not result in significant additional toxicity, and showed modest clinical activity in the biliary tract cancers cohort.

This open-label, phase 1/2 study (ClinicalTrials.gov Identifier: NCT03314935) evaluated the safety, tolerability, and antitumor activity of the arginase inhibitor INCB001158 plus standard first-line chemotherapy in patients with advanced or metastatic solid tumors, including biliary tract cancers (BTCs). Preliminary efficacy and safety results from the BTC cohort were presented at the 2021 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

In this 2-part study, the phase 1 dose-escalation portion of the study evaluated the recommended phase 2 dose (RP2D) of INCB001158 (50 mg, 75 mg, and 100 mg twice daily) in combination with gemcitabine/cisplatin chemotherapy. In the phase 2 portion of the study, a Simon 2-stage design was used to evaluate the efficacy of INCB001158 RP2D plus gemcitabine (1000 mg/m2)/cisplatin (25 mg/m2 on days 1 and 8 of a 21-day cycle). Efficacy parameters included objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS). Data cutoff was July 1, 2020.

In the phase 1 dose-escalation part (n = 15), the RP2D of INCB001158 was established at 100 mg twice daily. In the phase 2 part of the study, 33 patients with BTC were treated with INCB001158 100 mg twice daily plus gemcitabine/cisplatin. Grade 3/4 treatment-emergent adverse events (TEAEs) associated with INCB001158 and/or chemotherapy were reported in 88% of patients, INCB001158-related adverse events occurred in 73% of patients, and gemcitabine/cisplatin-related adverse events were reported in 85% of patients. Common any-grade adverse events related to INCB001158 included fatigue, anemia, nausea, and neutrophil count decreased. Treatment interruption due to INCB001158-related TEAEs was reported in 30% of patients (n = 10); treatment discontinuation due to INCB001158 occurred in 3% of participants (n = 1).

Based on confirmed response per investigator’s assessment, an ORR of 24% was achieved, including 8 partial responses. Stable disease was attained by 42% of patients, for a DCR of 67%. Median DOR for INCB001158 plus gemcitabine/cisplatin was 5.8 months; median PFS was 8.5 months.

Based on these data, the researchers concluded that the addition of INCB001158 to the standard gemcitabine/cisplatin backbone was tolerable, did not result in significant additional toxicity, and demonstrated modest clinical activity in the BTC cohort. Additional studies are warranted, to define the role played by INCB001158 in patients with BTC and assess the impact of the agent on clinical practice.

Source: Javle M, Bridgewater JA, Gbolahan OB, et al. A phase I/II study of safety and efficacy of the arginase inhibitor INCB001158 plus chemotherapy in patients (Pts) with advanced biliary tract cancers. J Clin Oncol. 2021;39(suppl_3):311.

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