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Invest New Drugs. 2019 Apr 24. doi: 10.1007/s10637-019-00776-6. [Epub ahead of print]

Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors.

Author information

1
Dana-Farber Cancer Institute, Mayer 446, 450 Brookline Avenue, Boston, MA, 02215, USA. geoffrey_shapiro@dfci.harvard.edu.
2
Yale Cancer Center, New Haven, CT, USA.
3
Massachusetts General Hospital Cancer Center, Boston, MA, USA.
4
Beth Israel Deaconess Medical Center, Boston, MA, USA.
5
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Stephenson Cancer Center University of Oklahoma, Oklahoma City, OK, USA.
7
Dana-Farber Cancer Institute, Mayer 446, 450 Brookline Avenue, Boston, MA, 02215, USA.
8
Wayne State University, Detroit, MI, USA.
9
Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
10
Genentech, Inc., South San Francisco, CA, USA.

Abstract

Purpose We investigated the combination of the MEK inhibitor, cobimetinib, and the pan-PI3K inhibitor, pictilisib, in an open-label, phase Ib study. Experimental Design Patients with advanced solid tumors were enrolled in 3 dose escalation schedules: (1) both agents once-daily for 21-days-on 7-days-off ("21/7"); (2) intermittent cobimetinib and 21/7 pictilisib ("intermittent"); or (3) both agents once-daily for 7-days-on 7-days-off ("7/7"). Starting doses for the 21/7, intermittent, and 7/7 schedules were 20/80, 100/130, and 40/130 mg of cobimetinib/pictilisib, respectively. Nine indication-specific expansion cohorts interrogated the recommended phase II dose and schedule. Results Of 178 enrollees (dose escalation: n = 98), 177 patients were dosed. The maximum tolerated doses for cobimetinib/pictilisib (mg) were 40/100, 125/180, and not reached, for the 21/7, intermittent, and 7/7 schedules, respectively. Six dose-limiting toxicities included grade 3 (G3) elevated lipase, G4 elevated creatine phosphokinase, and G3 events including fatigue concurrent with a serious adverse event (SAE) of diarrhea, decreased appetite, and SAEs of hypersensitivity and dehydration. Common drug-related adverse events included nausea, fatigue, vomiting, decreased appetite, dysgeusia, rash, and stomatitis. Pharmacokinetic parameters of the drugs used in combination were unaltered compared to monotherapy exposures. Confirmed partial responses were observed in patients with BRAF-mutant melanoma (n = 1) and KRAS-mutant endometrioid adenocarcinoma (n = 1). Eighteen patients remained on study ≥6 months. Biomarker data established successful blockade of MAP kinase (MAPK) and PI3K pathways. The metabolic response rate documented by FDG-PET was similar to that observed with cobimetinib monotherapy. Conclusions Cobimetinib and pictilisib combination therapy in patients with solid tumors had limited tolerability and efficacy.

KEYWORDS:

Clinical trial; Drug combination; KRAS mutation; MAPK pathway; PI3K pathway

PMID:
31020608
DOI:
10.1007/s10637-019-00776-6

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