A Phase 1B Study of Dulanermin in Combination With Modified FOLFOX6 Plus Bevacizumab in Patients With Metastatic Colorectal Cancer |
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| Authors: | Zev A Wainberg Wells A Messersmith Parvin F Peddi Amy V Kapp Avi Ashkenazi Stephanie Royer-Joo Chia C Portera Mark F Kozloff |
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| Institution: | 1. David Geffen School of Medicine, University of California, Los Angeles, CA;2. University of Colorado, Aurora, CO;3. Genentech, South San Francisco, CA;4. Ingalls Hospital and University of Chicago, Harvey, IL;1. Department of Microbiology and Immunology, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box: 35, Code: 123, Muscat, Oman;2. Department of Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box: 35, Code: 123, Muscat, Oman;3. Department of Hepatology, Armed Forces Hospital, Muscat, Oman;4. Department of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box: 35, Code: 123, Muscat, Oman;1. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan;2. Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh;3. Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka 1000, Bangladesh;1. Institute for Advanced Biosciences, Keio University, 14-1 Baba-cho, 997-0035, Tsuruoka, Japan;2. Systems Biology Program, Graduate School of Media and Governance, Keio University, 5322 Endo, 252-0882, Fujisawa, Japan;1. Pediatric Hematology/Oncology, Acute Lymphoblastic Leukemia—Berlin-Frankfurt-Münster Study Group, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Germany;2. Division of Stem Cell Transplantation and Immunotherapy, Department of Medicine II, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Germany;1. Mitochondrial Research Group and NIHR Biomedical Research Centre for Ageing and Age-Related Disease, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;2. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK;3. Institute of Cellular Medicine, Newcastle University, Newcastle NE1 7RU, UK;4. Institute of Health and Society, Newcastle Clinical Trials Unit, Newcastle University, Newcastle NE2 4HH, UK;5. Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa |
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| Abstract: | ObjectivesThe study objectives were to evaluate the safety, tolerability, and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced, recurrent, or metastatic colorectal cancer.Patients and MethodsA total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed.ResultsIn the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7).ConclusionsOverall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population. |
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| Keywords: | Apoptosis Apo2L/TRAIL Death receptor Dulanermin FOLFOX Metastatic colorectal cancer |
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