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
| العنوان: | 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 |
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| المؤلفون: | Jung, Kyung Hae, LoRusso, Patricia, Burris, Howard, Gordon, Michael, Bang, Yung-Jue, Hellmann, Matthew, Cervantes, Andres, de Olza, Maria Ochoa, Marabelle, Aurélien, Hodi, F Stephen, Ahn, Myung-Ju, Emens, Leisha, 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, Hodi, F. Stephen, Davis, S. Lindsey |
| المساهمون: | Karmanos Cancer Institute (Detroit), Universitat de València (UV), Equipe 11, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Tumor Immunology and Breast Cancer Research Programs, Johns Hopkins University School of Medicine, Assistance Publique - Hôpitaux de Marseille (APHM), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Cedars-Sinai Medical Center, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA instname Clinical Cancer Research Clinical Cancer Research, American Association for Cancer Research, 2019, 25 (11), pp.3220-3228. ⟨10.1158/1078-0432.CCR-18-2740⟩ Clinical Cancer Research, 2019, 25 (11), pp.3220-3228. ⟨10.1158/1078-0432.CCR-18-2740⟩ Clin Cancer Res |
| بيانات النشر: | AMER ASSOC CANCER RESEARCH, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Adult, Cancer Research, Indoles, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Pharmacology, Antibodies, Monoclonal, Humanized, Article, B7-H1 Antigen, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Atezolizumab, Renal cell carcinoma, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, medicine, Biomarkers, Tumor, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Neoplasm Metastasis, Aged, Neoplasm Staging, Aged, 80 and over, Bladder cancer, business.industry, Melanoma, Imidazoles, Middle Aged, medicine.disease, Magnetic Resonance Imaging, 3. Good health, 030104 developmental biology, Treatment Outcome, Oncology, Tolerability, 030220 oncology & carcinogenesis, Pharmacodynamics, PD-L1 inhibitor, business, Tomography, X-Ray Computed |
| الوصف: | 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. |
| تدمد: | 1557-3265 1078-0432 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::97784b8a4ed5b767c2db064581ed9c52Test https://www.fundanet.incliva.es/publicaciones/ProdCientif/PublicacionFrw.aspx?id=2838Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....97784b8a4ed5b767c2db064581ed9c52 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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