Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors

Purpose: IDO1 induces immune suppression in T cells through L-tryptophan (Trp) depletion and kyneurinine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T-cells and hyperactivating Tregs. Navoximod is an investigational small molecule inhibitor of IDO1. This Phase I study evaluated safety, tolerability, PK and PD of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer. Experimental Design: The study consisted of a 3+3 dose-escalation stage (n=66) and a tumor-specific expansion stage (n=92). Navoximod was given orally every 12 hours (q12h) continuously for 21 consecutive days of each cycle with the exception of Cycle 1, where navoximod administration started on Day -1 to characterize PK. Atezolizumab was administered by IV infusion 1200 mg q3w on Day 1 of each cycle. Results: Patients (n=157) received navoximod at 6 dose levels (50-1000 mg) in combination with atezolizumab. MAD was 1000 mg BID; the MTD was not reached. Navoximod demonstrated a linear PK profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, HNSCC, cervical, neural sheath, NSCLC, TNBC, RCC, UBC): 6 (9%) dose escalation patients achieved PR, 10 (11%) expansion patients achieved PR or CR. Conclusions: The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and PK for patients with advanced cancer. Although activity was observed, there was no clear evidence for benefit of adding navoximod to atezolizumab.

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