Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors

Abstract

Background: Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies.

Methods: Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.0) and paclitaxel 200 mg/m2 (arm 1), docetaxel 75 mg/m2 (arm 2), or erlotinib 100 or 150 mg daily (arm 3); alternative schedules of MK-2206 135-200 mg QW or 90-250 mg Q3W were also tested.

Results: MTD of MK-2206 (N = 72) was 45 mg QOD or 200 mg Q3W (arm 1); MAD was 200 mg Q3W (arm 2) and 135 mg QW (arm 3). DLTs included skin rash (arms 1, 3), febrile neutropenia (QOD, arms 1, 2), tinnitus (Q3W, arm 2), and stomatitis (QOD, arm 3). Common drug-related toxicities included fatigue (68%), nausea (49%), and rash (47%). Two patients with squamous cell carcinoma of the head and neck (arm 1; Q3W) demonstrated a complete and partial response (PR); additional PRs were observed in patients (1 each) with melanoma, endometrial, neuroendocrine prostate, NSCLC, and cervical cancers. Six patients had stable disease ≥6 months.

Conclusion: MK-2206 plus carboplatin and paclitaxel, docetaxel, or erlotinib was well-tolerated, with early evidence of antitumor activity.

Trial registration: ClinicalTrials.gov NCT00848718.

Figure 1

Patterns of drug induced rash. The typical rash associated with MK-2206 was a widespread, reversible, generalized, erythematous, maculopapular, non-acneiform rash (A and B). In arm 3, some patients also demonstrated an acneiform rash affecting the head, face, neck, and trunk, in addition to the maculopapular MK-2206 related rash (C).

Figure 2

Best radiological response (RECIST) associated with MK-2206 combinations. CT scan slices demonstrating a CR in a male patient with SCC of the orbit (A). Waterfall plots of the best responses seen in all evaluable patients in arm 1, carboplatin and paclitaxel (B), arm 2, docetaxel (C), and arm 3, erlotinib (D). In arm 1, 6 patients treated in both schedules of MK-2206 with carboplatin and paclitaxel chemotherapy had PRs: with 4 of these being confirmed: melanoma (n = 1, 21-month duration—8 months while on study and 13 months after study discontinuation), neuroendocrine prostate (n = 1, 6-month duration), cervical (n = 1, 6-month duration), and endometrial (n = 1, 4-month duration); and 2 were unconfirmed: gastric (n = 1, 2-month duration) and SCC of the head and neck (n = 1, 2-month duration). In arm 2, a female patient with NSCLC who had progressed through pemetrexed-platinum and erlotinib achieved a PR with MK-2206 200 mg lasting 6 months. The patient withdrew from the study due to docetaxel-related toxicities, before documentation of progressive disease. No objective responses were observed in arm 3: the best response was SD lasting 7 and 6 months in a male patient with NSCLC and a patient with cervical cancer, respectively. Dashed lines indicate the threshold for PD (≥20% increase) and PR (≥30% decrease) based on the change in the sum of target lesions from baseline by Response Evaluation Criteria in Solid Tumors guidelines. CT = computed tomography; CR = complete response; SCC = squamous cell carcinoma; PR = particle response; NSCLC = non-small cell lung cancer; SD = stable disease; PD = progressive disease; QOD = alternate days; Q3W = every 3 weeks; QW = week.