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

Journal of Hematology & Oncology

Susan Minton²  Anthony W Tolcher³  Johann S de Bono⁷  Kyriakos P Papadopoulos³  Amita Patnaik³  Lillian L Siu⁴  Ernestina Tetteh¹  Andrea Biondo⁵  Eric Chen⁴  Philippe A Cassier⁶  Daniel M Sullivan²  Adriane M Zernhelt¹  Joanna Vitfell-Rasmussen⁵  Li Yan¹  L Rhoda Molife⁵ 

[1] Merck & Co., Inc., One Merck Drive, Whitehouse Station, NJ 08889, USA;H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA;South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX 78229, USA;Drug Development Programme, Princess Margaret Hospital, 610 University Avenue, 5-700, Toronto, ON M5G 2 M9, Canada;Drug Development Unit, The Institute of Cancer Research/The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK;Department of Medicine, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France;Division of Clinical Sciences, The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK

关键词: Solid tumors;    Combination therapy;    Chemotherapy;    Phase 1;    Protein serine-threonine kinase;    AKT inhibitor;    MK-2206;   

Others  :  802254
DOI  :  10.1186/1756-8722-7-1

 received in 2013-09-26, accepted in 2013-12-24,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Molife et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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