A Phase I Trial of IGF-1R Inhibitor Cixutumumab and mTOR Inhibitor Temsirolimus in Metastatic Castration-resistant Prostate Cancer |
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| Institution: | 1. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;2. Department of Medicine, Weill Cornell Medical College, New York, NY;1. Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy;2. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy;3. Department of Radiology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy;1. Department of Radiology and Nuclear Medicine, University Medical Center, Huispost E01.132, Postbus 85500, Utrecht 3508 GA, Netherlands;2. The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 601 N. Caroline St., Baltimore, MD 21287, USA;1. University of Texas M. D. Anderson Cancer Center, Houston, TX, United States;2. Orlando Health, University of Florida Health Cancer Center, Orlando, FL, United States;3. Johns Hopkins University, Baltimore, MD, United States;4. Emory University School of Medicine, Atlanta, GA, United States;5. Vanderbilt University Medical Center, Nashville, TN, United States;6. The University of Chicago, Chicago, IL, United States;7. Wake Forest Baptist Medical Center, Winston-Salem, NC, United States;8. ImClone Systems LLC, a wholly-owned subsidiary of Eli Lilly and Company, Bridgewater, NJ, United States;9. Dana Farber Cancer Institute, Boston, MA, United States;1. Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy;2. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy;3. Department of Statistical Sciences “Paolo Fortunati”, University of Bologna, Bologna, Italy;4. Centre of Molecular Genetics, “CARISBO Foundation”, University of Bologna, Bologna, Italy;5. “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna, Italy;1. University Hospitals Leuven, KU Leuven, Leuven, Belgium;2. Washington University School of Medicine, St. Louis, MO, USA;3. University Claude Bernard Lyon, Centre Léon Bérard, Lyon, France;4. Institute Jules Bordet, Université Libre de Bruxelles, Belgium;5. Department of Medicine, University of Colorado, Aurora, CO, USA;6. Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie, Warszawa, Poland;7. MD Anderson Cancer Center, Orlando, FL, USA;8. Ziopharm Oncology, Inc., Boston, MA, USA;9. Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands;10. ImClone Systems LLC, a wholly-owned subsidiary of Eli Lilly and Company, Bridgewater, NJ, USA;1. Department of General Surgery, Wenzhou People’s Hospital, Wenzhou No. 3 Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325000, China;2. Department of Oncology, Lishui Central Hospital, Lishui, Zhejiang Province, 323000, China;3. The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China |
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| Abstract: | BackgroundDespite frequent PTEN (phosphatase and tensin homologue) loss and Akt/mammalian target of rapamycin (mTOR) signaling in prostate cancer, the disease is insensitive to single-agent mTOR inhibition. Insulin-like growth factor-1 receptor inhibition might mitigate the feedback inhibition by Torc1 inhibitors, suppressing downstream Akt activation and, thus, potentiating the antitumor activity of mTOR inhibition.Patients and MethodsIn the present phase I study, patients with metastatic castration-resistant prostate cancer received 6 mg/kg cixutumumab and 25 mg temsirolimus intravenously each week. The primary objective was safety and tolerability. Temsirolimus was decreased if ≥ 2 dose-limiting toxicities (DLTs) were observed in 6 patients. The correlative analyses included measurement of circulating tumor cells, 18F]-fluoro-2-deoxyglucose positron emission tomography, 16β-18F]-fluoro-α-dihydrotestosterone positron emission tomography, and tumor biopsy.ResultsA total of 16 patients were enrolled across 3 cohorts (1, −1, −2). Two DLTs (grade 3 oral mucositis) were observed in cohort 1 (temsirolimus, 25 mg), and 1 DLT (grade 3 lipase) in cohort −1 (temsirolimus, 20 mg). The most common adverse events included hyperglycemia (100%; 31% grade 3), oral mucositis (63%; 19% grade 3), and diarrhea (44%; 0 grade 3). Low-grade pneumonitis occurred in 7 of 11 patients (44%; 0 grade 3), prompting the opening of a 3-weekly cohort (temsirolimus, 20 mg/kg), without pneumonitis events. No patient had a >50% decline in prostate-specific antigen from baseline. The best radiographic response was stable disease, with median study duration of 22 weeks (range, 7-63 weeks).ConclusionsDespite a strong scientific rationale for the combination, temsirolimus plus cixutumumab demonstrated limited antitumor activity and a greater than expected incidence of toxicity, including low-grade pneumonitis and hyperglycemia. Hence, the trial was stopped in favor of alternative androgen receptor/phosphatidylinositol 3-kinase–directed combinatorial therapies. |
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| Keywords: | Akt AR FDHT PTEN Reciprocal feedback |
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