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

Abstract

Purpose: IDO1 induces immune suppression in T cells through l-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer.

Patients and methods: 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 continuously for 21 consecutive days of each cycle with the exception of cycle 1, where navoximod administration started on day -1 to characterize pharmacokinetics. Atezolizumab was administered by intravenous infusion 1,200 mg every 3 weeks on day 1 of each cycle.

Results: Patients (n = 157) received navoximod at 6 dose levels (50-1,000 mg) in combination with atezolizumab. The maximum administered dose was 1,000 mg twice daily; the MTD was not reached. Navoximod demonstrated a linear pharmacokinetic 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, head and neck squamous cell carcinoma, cervical, neural sheath, non-small cell lung cancer, triple-negative breast cancer, renal cell carcinoma, urothelial bladder cancer): 6 (9%) dose-escalation patients achieved partial response, and 10 (11%) expansion patients achieved partial response or complete response.

Conclusions: The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Although activity was observed, there was no clear evidence of benefit from adding navoximod to atezolizumab.

Trial registration: ClinicalTrials.gov NCT02471846.

©2019 American Association for Cancer Research.

Figures

Figure 1.

Study design. a Backfill patients were enrolled after each preceding dose level cleared the DLT window. Optional biopsies were collected at baseline and 2–3 weeks after Cycle 1, Day 1. bSingle agent run-in navoximod (Biopsy A) or atezolizumab (Biopsy B) in patients with either melanoma, HNSCC, gastric, ovarian, cervical, Merkel cell, or endometrial cancer. NSCLC: non-small cell lung carcinoma; UBC: urothelial bladder cancer; RCC: renal cell carcinoma; TNBC: triple negative breast cancer; CIT: immunotherapy.

Figure 2.

Navoximod plasma concentrations following multiple BID doses. Single dose (SD) and multiple dose (MD) pharmacokinetic parameters for navoximod. Cmax = maximum observed concentration; tmax = time of maximum observed concentration; AUC0–8 = area under the curve, measured from 0 to 8 hours post-navoximod dose; t1/2 = half-life; Geometric mean (geometric CV%) results are presented unless otherwise indicated aMedian (minimum, maximum) results are presented for tmax

Figure 3.

Time on study treatment for dose escalation patients.a PDL1, programmed cell death ligand-1; IC, tumor-infiltrating immune cell; TC, tumor cell; BOR, best overall response. a BOR for PD-L1 positive patients (n=30): PR 4 pts (13%), SD 6 pts (20%), PD 19 pts (63%); BOR for PD-L1 negative patients (n=29): PR 2 pts (7%), SD 4 pts (14%), PD 23 pts (79%); BOR for all patients (n=66) regardless of PD-L1 status: PR 6 pts (9%), SD 11 pts (17%), PD 47 pts (71%).

Figure 4.

(A) Mean change in plasma Kyn at Cycle 1 Day 1 following a single oral dose of navoximod relative to start of treatment levels. Ribbons represent 95% confidence intervals and dashed horizontal lines represent no change from baseline. (B) Mean change in plasma Kyn at Cycle 1 Day 8 following a single oral dose of navoximod relative to start of treatment levels. Ribbons represent 95% confidence intervals and dashed horizontal lines represent no change from baseline. (C) Serial tumor biopsy evaluation of IDO1, PD-L1, TIL, and CD8. Mean changes in percent positivity and 95% confidence intervals are indicated in each case.