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Clin Cancer Res. 2019 Jun 1;25(11):3220-3228. doi: 10.1158/1078-0432.CCR-18-2740. Epub 2019 Feb 15.

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.

Author information

1
Asan Medical Center, University of Ulsan College of Medicine, Seoul, (South) Korea. khjung@amc.seoul.kr.
2
Yale Cancer Center, New Haven, Connecticut.
3
Sarah Cannon Research Institute, Nashville, Tennessee.
4
HonorHealth Research Institute, Scottsdale, Arizona.
5
Seoul National University College of Medicine, Seoul, Korea.
6
Memorial Sloan Kettering Cancer Center, New York, New York.
7
CIBERONC, Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
8
Hospital Universitario Vall d'Hebron, Barcelona, Spain.
9
Gustave Roussy, Université Paris-Saclay, Département d'Innovation Thérapeutique et d'Essais Précoces, INSERM U1015, Villejuif, France.
10
Dana-Farber Cancer Center, Boston, Massachusetts.
11
Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea.
12
Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
13
Aix Marseille University; CNRS, INSERM, CRCM, Assistance Publique Hôpitaux de Marseille, Centre d'Essais Précoces en Cancérologie de Marseille CLIP2, Marseille, France.
14
The Angeles Clinic and Research Institute, Los Angeles, California.
15
START Madrid - CIOCC, Centro Integral Oncológico Clara Campal, Hospital HM Sanchinarro, Madrid, Spain.
16
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
17
Moffit Cancer Center and Research Institute, Tampa, Florida.
18
Genentech, Inc., South San Francisco, California.
19
University of Colorado Cancer Center, Aurora, Colorado.

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.

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