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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.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Jun 01; Vol. 25 (11), pp. 3220-3228. Date of Electronic Publication: 2019 Feb 15. - Publication Year :
- 2019
-
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.<br />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.<br />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.<br />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.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized administration & dosage
Antibodies, Monoclonal, Humanized pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols adverse effects
Biomarkers, Tumor
Humans
Imidazoles administration & dosage
Imidazoles pharmacokinetics
Indoles administration & dosage
Indoles pharmacokinetics
Magnetic Resonance Imaging
Middle Aged
Neoplasm Metastasis
Neoplasm Staging
Neoplasms diagnosis
Neoplasms etiology
Neoplasms metabolism
Tomography, X-Ray Computed
Treatment Outcome
Antineoplastic Combined Chemotherapy Protocols therapeutic use
B7-H1 Antigen antagonists & inhibitors
Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors
Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 25
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 30770348
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-18-2740