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 þ 3 doseescalation stage (n ¼ 66) and a tumor-specific expansion stage (n ¼ 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 À1 to characterize pharmacokinetics. Atezolizumab was administered by intravenous infusion 1,200 mg every 3 weeks on day 1 of each cycle.Results: Patients (n ¼ 157) received navoximod at 6 dose levels (50-1,000 mg) in combination with atezolizu-mab. 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, nonsmall cell lung cancer, triple-negative breast cancer, renal cell carcinoma, urothelial bladder cancer): 6 (9%) doseescalation 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.

Phase I study of the indoleamine 2,3-dioxygenase 1 inhibitor navoximod (GDC-0919) as monotherapy and in combination with the PD-L1 inhibitor atezolizumab in Japanese patients with advanced solid tumours

“…The findings of this study are in line with those of the firstin-human study of navoximod monotherapy [13], and the combination study of navoximod and atezolizumab [12]. In the monotherapy study, 22 patients with advanced or recurrent solid tumours received monotherapy with navoximod 100 mg, 200 mg, 400 mg, 600 mg or 800 mg twice daily for 21 days, followed by 7 days without treatment, or 600 mg twice daily continuously.…”

“…As a result, the recommended dose of navoximod monotherapy was determined as 1000 mg twice daily. In combination with atezolizumab, the recommended dose of navoximod could not been determined because of early discontinuation of enrollment based on limited evidence of clinical activity in the clinical study conducted for the same time [12]. However, even though navoximod 1000 mg twice daily in combination with atezolizumab was administered in one patient, there was no safety concern, as such the navoximod 1000 mg twice daily in combination with atezolizumab 1200 mg every 21 days could be considered as recommended dose in our study.…”

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

“…In human patients, epacadostat monotherapy was not effective (163,164), while combined administration with PD-1 or cytotoxin T-lymphocyte-associated protein 4 (CTLA-4) inhibitors showed promising clinical activity in phase I/II studies (165)(166)(167)(168). Unfortunately, a recent trial with combined administration of epacadostat with pembrolizumab found no superiority over pembrolizumab alone (169).…”

Investigation of the absolute bioavailability and human mass balance of navoximod, a novel IDO1 inhibitor

“…Single and twice daily oral doses (up to the maximum assessed dose of 1000 mg) of navoximod monotherapy are well tolerated in clinical studies in cancer patients; therefore, a single 200 mg oral dose was considered suitable for this study. A 5 mg intravenous (IV) dose was selected based on pharmacokinetic simulations, with a predicted C max below the median C max of a 200 mg oral dose (assuming a conservative absolute bioavailability of 0.5).…”

“…Clinically, navoximod has favourable safety, tolerability and pharmacokinetic profiles when given as a monotherapy or in combination with atezolizumab, a PD‐L1 inhibitor . Navoximod is rapidly absorbed and demonstrates linear pharmacokinetics with dose‐proportional increases in exposure over the dose range of 50–1000 mg. Navoximod has a half‐life of approximately 12 hours, supporting a twice daily (BID) dosing regimen.…”