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

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 ph...

Celý popis

Uloženo v:
Podrobná bibliografie
Vydáno v:Clinical cancer research Ročník 25; číslo 11; s. 3220
Hlavní autoři: Jung, Kyung Hae, LoRusso, Patricia, Burris, Howard, Gordon, Michael, Bang, Yung-Jue, Hellmann, Matthew D, Cervantes, Andrés, Ochoa de Olza, Maria, Marabelle, Aurelien, Hodi, F Stephen, Ahn, Myung-Ju, Emens, Leisha A, Barlesi, Fabrice, Hamid, Omid, Calvo, Emiliano, McDermott, David, Soliman, Hatem, Rhee, Ina, Lin, Ray, Pourmohamad, Tony, Suchomel, Julia, Tsuhako, Amy, Morrissey, Kari, Mahrus, Sami, Morley, Roland, Pirzkall, Andrea, Davis, S Lindsey
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.06.2019
Témata:
Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized - administration & dosage
Antibodies, Monoclonal, Humanized - pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
B7-H1 Antigen - antagonists & inhibitors
Biomarkers, Tumor
Humans
Imidazoles - administration & dosage
Imidazoles - pharmacokinetics
Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors
Indoles - administration & dosage
Indoles - pharmacokinetics
Magnetic Resonance Imaging
Middle Aged
Neoplasm Metastasis
Neoplasm Staging
Neoplasms - diagnosis
Neoplasms - drug therapy
Neoplasms - etiology
Neoplasms - metabolism
Tomography, X-Ray Computed
Treatment Outcome
ISSN:1557-3265, 1557-3265
On-line přístup:Zjistit podrobnosti o přístupu
Tagy: Přidat tag
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
Popis
Shrnutí: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. The study consisted of a 3+3 dose-escalation stage ( = 66) and a tumor-specific expansion stage ( = 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. Patients ( = 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. 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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1557-3265
1557-3265
DOI:10.1158/1078-0432.CCR-18-2740