Sophie Postel-Vinay1, Laurence Collette2, Xavier Paoletti3, Elisa Rizzo2, Christophe Massard4, David Olmos5, Camilla Fowst6, Bernard Levy7, Pierre Mancini8, Denis Lacombe2, Percy Ivy9, Lesley Seymour10, Christophe Le Tourneau11, Lillian L Siu12, Stan B Kaye13, Jaap Verweij14, Jean-Charles Soria15. 1. Gustave Roussy Cancer Campus, DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), 114 rue Edouard Vaillant, 94800 Villejuif, France; Université Paris-Sud XI, 63, rue Gabriel Péri, 94276 Le Kremlin-Bicêtre, France. Electronic address: Sophie.postel-vinay@gustaveroussy.fr. 2. EORTC Headquarters, Avenue Emmanuel Mounier 83/11, B-1200 Brussels, Belgium. 3. Statistics Department and INSERM U900, Institut Curie, 126 rue d'Ulm, 75006 Paris, France. 4. Gustave Roussy Cancer Campus, DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), 114 rue Edouard Vaillant, 94800 Villejuif, France; Université Paris-Sud XI, 63, rue Gabriel Péri, 94276 Le Kremlin-Bicêtre, France. 5. Department of Medical Oncology and INSERM U900, Institut Curie, 126 rue d'Ulm, 75006 Paris and St Cloud, France; Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fernandez Almagro, 3, 28029 Madrid, Spain. 6. Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Norte-Sanchinarro, Calle Oña 10, 28050 Madrid, Spain. 7. Pfizer Oncology, Clinical Development, Pfizer Italia S.p.A., Via A.M. Mozzoni 12, Milan 20152, Italy. 8. Roche TCRC Inc., 430 East 29th StreetNew York, NY 10016, USA. 9. Sanofi R&D, 13, quai Jules Guesde - BP 14, 94403 Vitry-sur-Seine Cedex, France. 10. National Cancer Institute and Cancer Therapy Evaluation Program, 9609 Medical Center Drive, Bethesda, MD 20892, USA. 11. NCIC Clinical Trials Group, Queen's University Kingston, Ontario K7L 3N6, Canada. 12. Princess Margaret Cancer Centre, 610 University Ave, Toronto, ON 5MG 2M9, Canada. 13. Drug Development Unit, Royal Marsden Hospital/The Institute of Cancer Research, Downs Rd, Sutton, Surrey SM2 5P, United Kingdom. 14. Department of Medical Oncology, Erasmus MC Cancer Institute, Doctor Molewaterplein 50-60, Rotterdam, Netherlands. 15. Gustave Roussy Cancer Campus, DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), 114 rue Edouard Vaillant, 94800 Villejuif, France; Université Paris-Sud XI, 63, rue Gabriel Péri, 94276 Le Kremlin-Bicêtre, France. Electronic address: Jean-charles.soria@gustaveroussy.fr.
Abstract
INTRODUCTION: Traditional dose-limiting toxicity (DLT) definition, which uses grade (G) 3-4 toxicity data from cycle 1 (C1) only, may not be appropriate for molecularly targeted agents (MTAs) of prolonged administration, for which late or lower grade toxicities also deserve attention. PATIENTS AND METHODS: In collaboration with pharmaceutical companies and academia, an European Organisation for Research and Treatment of Cancer (EORTC)-led initiative, Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies (DLT-TARGETT), collected data from completed phase 1 trials evaluating MTAs as monotherapy. All toxicities at least possibly related to the study drugs that occurred during C1-6, their type, grade (CTCAEv3.0), and duration as well as patients' relative dose-intensity (RDI), were recorded. RESULTS: The 54 eligible trials enrolled 2084 evaluable adult patients with solid tumours between 1999 and 2013, and evaluated small molecules (40), antibodies (seven), recombinant peptides (five) and antisense oligodeoxynucleotides (two). A maximum tolerated dose was set in 43 trials. Fifteen percent of the patients received <75% of the intended RDI in C1, but only 9.1% of them presented protocol-defined DLTs. After C1, 16-19% of patients received <75% of the intended RDI. A similar proportion of G ⩾ 3 toxicities was recorded in C1 and after C1 (936 and 1087 toxicities, respectively), with the first G⩾3 toxicity occurring after C1 in 18.6% of patients. CONCLUSION: Although protocol-defined DLT period is traditionally limited to C1, almost 20% of patients present significant reductions in RDI at any time in phase 1 trials of MTAs. Recommended phase 2 dose assessment should incorporate all available information from any cycle (notably lower grade toxicities leading to such RDI decrease), and be based on achieving >75% RDI.
INTRODUCTION: Traditional dose-limiting toxicity (DLT) definition, which uses grade (G) 3-4 toxicity data from cycle 1 (C1) only, may not be appropriate for molecularly targeted agents (MTAs) of prolonged administration, for which late or lower grade toxicities also deserve attention. PATIENTS AND METHODS: In collaboration with pharmaceutical companies and academia, an European Organisation for Research and Treatment of Cancer (EORTC)-led initiative, Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies (DLT-TARGETT), collected data from completed phase 1 trials evaluating MTAs as monotherapy. All toxicities at least possibly related to the study drugs that occurred during C1-6, their type, grade (CTCAEv3.0), and duration as well as patients' relative dose-intensity (RDI), were recorded. RESULTS: The 54 eligible trials enrolled 2084 evaluable adult patients with solid tumours between 1999 and 2013, and evaluated small molecules (40), antibodies (seven), recombinant peptides (five) and antisense oligodeoxynucleotides (two). A maximum tolerated dose was set in 43 trials. Fifteen percent of the patients received <75% of the intended RDI in C1, but only 9.1% of them presented protocol-defined DLTs. After C1, 16-19% of patients received <75% of the intended RDI. A similar proportion of G ⩾ 3 toxicities was recorded in C1 and after C1 (936 and 1087 toxicities, respectively), with the first G⩾3 toxicity occurring after C1 in 18.6% of patients. CONCLUSION: Although protocol-defined DLT period is traditionally limited to C1, almost 20% of patients present significant reductions in RDI at any time in phase 1 trials of MTAs. Recommended phase 2 dose assessment should incorporate all available information from any cycle (notably lower grade toxicities leading to such RDI decrease), and be based on achieving >75% RDI.
Authors: Alexander Drilon; Anne A Eaton; Katja Schindler; Mrinal M Gounder; David R Spriggs; Pamela Harris; S Percy Ivy; Alexia Iasonos; Mario E Lacouture; David M Hyman Journal: Cancer Date: 2016-02-24 Impact factor: 6.860
Authors: Shing M Lee; Daniel Backenroth; Ying Kuen Ken Cheung; Dawn L Hershman; Diana Vulih; Barry Anderson; Percy Ivy; Lori Minasian Journal: J Clin Oncol Date: 2016-02-29 Impact factor: 44.544
Authors: Gita Thanarajasingam; Lori M Minasian; Frederic Baron; Franco Cavalli; R Angelo De Claro; Amylou C Dueck; Tarec C El-Galaly; Neil Everest; Jan Geissler; Christian Gisselbrecht; John Gribben; Mary Horowitz; S Percy Ivy; Caron A Jacobson; Armand Keating; Paul G Kluetz; Aviva Krauss; Yok Lam Kwong; Richard F Little; Francois-Xavier Mahon; Matthew J Matasar; María-Victoria Mateos; Kristen McCullough; Robert S Miller; Mohamad Mohty; Philippe Moreau; Lindsay M Morton; Sumimasa Nagai; Simon Rule; Jeff Sloan; Pieter Sonneveld; Carrie A Thompson; Kyriaki Tzogani; Flora E van Leeuwen; Galina Velikova; Diego Villa; John R Wingard; Sophie Wintrich; John F Seymour; Thomas M Habermann Journal: Lancet Haematol Date: 2018-06-18 Impact factor: 18.959