In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. CT328-CT328
Abstract:
Introduction: Co-activation of Mek and Akt signaling pathways is common in solid tumors; in preclinical studies, combined Mek and Akt inhibition improves efficacy in models with dual activation. Cobimetinib is a potent, selective, allosteric Mek1/2 inhibitor (single-agent maximum tolerated dose [MTD] 60 mg once daily [QD] for 21-days-on/7-days-off [21/7]); ipatasertib is a potent, selective, ATP-competitive pan-Akt inhibitor (MTD 600 mg QD 21/7). Methods: This Phase Ib enrolled pts with advanced solid tumors in 3+3 dose-escalation to evaluate safety and pharmacokinetics (PK) of ipatasertib + cobimetinib on 2 dosing schedules: in Arm A, increasing doses of ipatasertib QD 21/7 + cobimetinib QD 21/7; in Arm B, increasing doses of ipatasertib QD 21/7 + cobimetinib QD on Days 1, 4, 8, 11, 15, 18 every 28 days (intermittent schedule). PK samples were collected on Cycle 1, Days 1 and 15, and archival tumors were collected for KRAS mutations (mut) by allele-specific PCR and PTEN status by immunohistochemistry. Results: 47 pts enrolled in dose-escalation (Arm A: 17, Arm B: 30). No dose-limiting toxicities (DLTs) occurred, but several pts had AEs that did not meet protocol-defined DLTs. Based on cumulative safety, combination MTD in Arm A was ipatasertib 200 mg QD 21/7 + cobimetinib 60 mg QD 21/7; in Arm B was ipatasertib 300 mg QD 21/7 + cobimetinib 150 mg intermittent. As of 29 July 2013, adverse events (AEs) of any grade (G) in ≥ 20% of pts, assessed by investigators as related to cobimetinib and/or ipatasertib (Table 1): Table 1.All Study Drug-Related AEs ≥ 20% of PtsAEArm AArm BAll GG ≥ 3All GG ≥ 3Diarrhea94%35%87%20%Nausea71%0%57%7%Vomiting65%0%67%7%Fatigue53%6%47%0%Blood CPK increased35%0%--Dehydration29%6%--Dermatitis acneiform29%0%63%3%Mucosal inflammation29%6%--Anemia24%0%--Decreased appetite24%0%23%0%Edema peripheral24%0%--Rash maculo-papular--30%7%Dysgeusia--27%0% There were 5 study drug-related serious AEs: Arm A (G3 diarrhea, G3 dehydration), Arm B (G3 nausea, G3 vomiting, G3 pneumonitis). Preliminary PK of cobimetinib + ipatasertib were not altered significantly. Partial responses by RECIST were seen in 3 pts with diagnostic-positive (Dx+) tumors: Arm A (KRAS-mut, PTEN-low ovarian), Arm B (KRAS-mut mesonephric cervical; KRAS-mut, PTEN-null endometrial cancer). Prolonged stable disease & gt; 6 months (mo) was seen in both arms in 4 pts, including PTEN-null endometrial cancer (16.6 mo+). Conclusions: Cobimetinib and ipatasertib can be tolerated at combination MTDs, and early signs of anti-tumor activity occurred in pts with Dx+ tumors. Enrollment is ongoing on Arm B schedule in two PTEN-low expansion cohorts: endometrial and triple-negative breast cancer. Citation Format: Johanna C. Bendell, Patricia LoRusso, Daniel C. Cho, Luna Musib, Yibing Yan, Ilsung Chang, Premal Patel, Iris T. Chang, Raymond D. Meng, Geoffrey I. Shapiro. Clinical results of a phase Ib dose-escalation study of the Mek inhibitor cobimetinib (GDC-0973) and the Akt inhibitor ipatasertib (GDC-0068) in patients (pts) with solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT328. doi:10.1158/1538-7445.AM2014-CT328
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-CT328
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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