Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours |
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| Affiliation: | 1. The University of Texas MD Anderson Cancer Center, Houston, TX, USA;2. UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA;3. DITEP, Gustave Roussy, Cancer Campus, Grand Paris, Villejuif, France;4. Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology VHIO, Barcelona, Spain;5. Oslo University Hospital, Oslo, Norway;6. Merck & Co., Inc., Kenilworth, NJ and North Wales, PA, USA;7. H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA;1. Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham, Nottingham NG7 2RD, UK;2. The Nottingham Health Science Biobank (NHSB), Nottingham University Hospitals NHS Trust, Nottingham NG7 2RD, UK;3. Program in Solid Tumor and Biomarkers, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain;4. Centre Hospitalier Universitaire de Nice, Louis Pasteur Hospital, Laboratory of Clinical and Experimental Pathology, Hospital-Integrated Biobank, University of Nice Sophia Antipolis, Nice 06003, France;5. Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain;6. Myriad Genetics, Inc., Salt Lake City, UT 84108, USA;7. Department of Pathology, Nottingham University Hospitals, Nottingham NG7 2RD, UK;8. Department of Respiratory Medicine, Nottingham University Hospitals, Nottingham NG5 1PB, UK;1. Medical Imaging Group, Laboratory of Electronics, Computer Science and Imaging, (Le2I), CNRS 6306, University of Burgundy, France;2. Department of Radiation Oncology, University Hospital of Besançon, France;3. Department of Radiation Oncology, Georges François Leclerc Cancer Center, Dijon, France;4. Department of Statistics, Georges François Leclerc Cancer Center, Dijon, France;5. Department of Medical Physics, University Hospital of Besançon, France;6. Department of Medical Physics, Georges François Leclerc Cancer Center, Dijon, France;1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany;2. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;3. Charité Comprehensive Cancer Center, University of Berlin, Berlin, Germany;4. University Hospital Essen, Essen, Germany;1. L.V. Kirensky Institute of Physics SB RAS, 660036 Krasnoyarsk, Russia;2. Siberian State Aerospace University, 660014 Krasnoyarsk, Russia;3. Institute for High Pressure Physics, 142098 Troitsk, Moscow Region, Russia |
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| Abstract: | BackgroundThe phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K-AKT-mTOR) signalling pathway is aberrantly activated in several cancers. Notch signalling maintains cell proliferation, growth and metabolism in part by driving the PI3K pathway. Combining the mTOR inhibitor ridaforolimus with the Notch inhibitor MK-0752 may increase blockade of the PI3K pathway.MethodsThis phase I dose-escalation study (NCT01295632) aimed to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of combination oral ridaforolimus (rising doses starting at 20 mg, 5 days/week) and oral MK-0752 (1800 mg once weekly) in patients with solid tumours. No intrapatient dose escalation was permitted.ResultsTwenty eight patients were treated on study. Ridaforolimus doses were escalated from 20 to 30 mg/day. Among 14 evaluable patients receiving ridaforolimus 20 mg, one DLT (grade 2 stomatitis, second episode) was reported. Among eight evaluable patients receiving ridaforolimus 30 mg, three DLTs were reported (one each grade 3 stomatitis, grade 3 diarrhoea, and grade 3 asthenia). The MTD was 20 mg daily ridaforolimus 5 days/week + 1800 mg weekly MK-0752. The most common drug-related adverse events included stomatitis, diarrhoea, decreased appetite, hyperglycaemia, thrombocytopenia, asthenia and rash. Two of 15 (13%) patients with head and neck squamous cell carcinoma (HNSCC) had responses: one with complete response and one with partial response. In addition, one patient experienced stable disease ?6 months.ConclusionsCombined ridaforolimus and MK-0752 showed activity in HNSCC. However, a high number of adverse events were reported at the MTD, which would require careful management during future clinical development. |
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| Keywords: | Ridaforolimus mTOR inhibitor MK-0752 Notch inhibitor Head and neck cancer Phase I |
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