In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 105-105
Kurzfassung:
105 Background: GDC-0919, a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1), reduces tryptophan catabolism and kynurenine production within the tumor microenvironment that may promote normal effector T cell activity and an immunogenic state. IDO1 inhibition may complement targeting of PD-L1 with atezolizumab. Methods: A Phase Ib, open-label, study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity (RECIST v1.1) of GDC-0919 and atezolizumab in pts with locally advanced or metastatic solid tumors. Pts were given escalating doses of GDC-0919 (50-1000 mg orally twice daily, for 21 days) and atezolizumab (1200 mg IV, every 3 weeks) using a standard 3+3 design. Results: As of 14Dec2016, 52 pts were treated in 6 cohorts of GDC-0919 plus atezolizumab. The median number of prior systemic therapies was 3 (range 1-9); 2 pts received prior immunotherapy. Pts received a median of 4 cycles of GDC-0919 and atezolizumab (range 1-17). No MTD was identified. Across all dose levels, 1 DLT was observed (Grade [G] 3 sepsis syndrome at GDC-0919 200 mg); no G4/5 AEs were attributed to study treatment. G3+ AEs, regardless of causality were reported in 34 (65%) pts. Related G3 AEs were reported in 7 (13%) pts, included nausea, rash, sepsis syndrome, fatigue, and pneumonitis. Two pts (4%) had AEs leading to treatment discontinuation, related in 1/2 (G3 pneumonitis). Combination PK was consistent with single agent observations and supports BID dosing of GDC-0919. Peripheral PD showed dose-dependent decreases in plasma kynurenine, consistent with systemic modulation of IDO1. Preliminary efficacy data from 45 pts with ≥ 1 on-treatment tumor assessments included 4 patients (9%) with partial response and 11 (24%) pts with stable disease. Conclusions: The combination of GDC-0919 and atezolizumab was generally well-tolerated and demonstrated peripheral IDO1 modulation and preliminary efficacy in a heterogeneous patient population during dose escalation. The study is currently enrolling pts with select tumor types in expansion cohorts to assess tumor PD and combination efficacy. Clinical trial information: NCT02471846.
Materialart:
Online-Ressource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2017.35.15_suppl.105
Sprache:
Englisch
Verlag:
American Society of Clinical Oncology (ASCO)
Publikationsdatum:
2017
ZDB Id:
2005181-5
