Abstract 1151
Background
Navoximod is a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1) which catalyzes the oxidation of L-tryptophan (Trp) into kynurenine (Kyn). This study aimed to investigate maximum tolerated dose (MTD), safety, pharmacokinetics (PK) and pharmacodynamics of navoximod as monotherapy and in combination with atezolizumab, an anti-PD-L1 antibody, in Japanese patients (pts) with advanced solid tumors.
Methods
Phase 1, open-label, 3 + 3 dose-escalation study. Primary endpoints were safety, tolerability, and PK. Pts received navoximod (400, 600 or 1000 mg orally twice daily [BID], for 21 days/cycle) monotherapy (Stage 1) or navoximod (200, 400, 600 or 1000 mg orally BID, for 21 days/cycle) in combination with atezolizumab (1200 mg IV, every 21 days) (Stage 2).
Results
Twenty pts were enrolled in the 400 mg (n = 3), 600 mg (n = 4) and 1000 mg (n = 3) cohorts of Stage 1, and in the 200 mg (n = 3), 400 mg (n = 3), 600 mg (n = 3) and 1000 mg (n = 1) cohorts of Stage 2. Across all cohorts, no DLT was observed and MTD was not reached in either stages. In Stage 1, treatment related adverse events (TRAEs) of any grade occurring in ≥ 20% of pts were chromaturia (50%) and maculopapular rash (20%). Grade ≥ 3 TRAEs were reported in 2 pts (20%), including maculopapular rash and lipase increased. In Stage 2, TRAEs ≥ 20% were fatigue (20%), chromaturia (60%), decreased appetite (40%), hyponatremia (20%), AST increased (20%), ALT increased (20%) and lymphopenia (20%). Grade ≥ 3 TRAEs were reported in 3 pts (30%), including hyponatremia, AST increased, ALT increased, lymphopenia and neutropenia. Cmax and AUC of navoximod as monotherapy were dose-proportional from 400 to 1000 mg and PK profile was similar in combination with atezolizumab. Reduction of Kyn in plasma was observed in accordance with concentration of navoximod. Stable disease (SD) was observed in 5 pts including 2 pts with SD > 4months in Stage 1, and in 8 pts including 4 pts with SD > 4months in Stage 2, respectively.
Conclusions
Navoximod as monotherapy and in combination with atezolizumab was generally well-tolerated in Japanese pts with linear PK and evidence of systemic inhibition of IDO1.
Clinical trial identification
JapicCTI-163330.
Legal entity responsible for the study
Chugai Pharmaceutical Co., Ltd.
Funding
Chugai Pharmaceutical Co., Ltd.
Editorial Acknowledgement
Disclosure
N. Yamamoto: Advisory board: Eisai, Takeda, OncoTherapy Science, Otsuka, Boehringer Ingelheim; Corporate sponsored research: Quintiles, Astellas, Chugai, Esai, Taiho, BMS, Pfizer, Novartis, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Takeda, ONO. Y. Fujiwara: Advisory board: Bristol-Myers Squibb; Corporate-sponsored Research: Chugai, Incyte Corporation, MSD, Bristol-Myers Squibb. S. Iwasa: Corporate sponsored research: Bristol-Myers Squibb, Chugai. S. Kitano: Advisory board: Bristol-Myers Squibb, MSD. T. Shimizu: Corporate sponsored research: Bristol-Myers Squibb. N. Sato, K. Nakai, M. Inatani: Employment: Chugai. K. Tamura: Advisory Board: MSD; Corporate sponsored research: Chugai, Bristol-Myers Squibb, MSD. All other authors have declared no conflicts of interest.
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