Cobimetinib in Pediatric and Young Adult Patients with Relapsed or Refractory Solid Tumors (iMATRIX-cobi): A Multicenter, Phase I/II Study
| Autor: | Tanya Trippett, Helen Toledano, Quentin Campbell Hewson, Arnauld Verschuur, Anne-Marie Langevin, Isabelle Aerts, Lisa Howell, Soledad Gallego, Claudia Rossig, Amy Smith, Darshak Patel, Leonardo R. Pereira, Sravanthi Cheeti, Luna Musib, Katherine E. Hutchinson, Clare Devlin, Ronald Bernardi, Birgit Geoerger |
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| Přispěvatelé: | Institut Català de la Salut, [Trippett T] Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, USA. [Toledano H] Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. [Campbell Hewson Q] Department of Paediatric and Adolescent Oncology, The Great North Children’s Hospital, Newcastle Upon Tyne, UK. [Verschuur A] Assistance Publique-Hopitaux de Marseille, Pediatric Oncology, Timone Children’s Hospital, Marseille, France. [Langevin AM] Department of Pediatrics, UT Health San Antonio, San Antonio, TX, USA. [Aerts I] Oncology Center SIREDO, Institut Curie, PSL Research University, Paris, France. [Gallego S] Servei d’Oncologia i Hematologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Adult
Cancer Research Adolescent Maximum Tolerated Dose Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] Other subheadings::Other subheadings::/drug therapy [Other subheadings] Pediatrics neoplasias [ENFERMEDADES] Young Adult Piperidines Neoplasms Humans fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::farmacocinética [FENÓMENOS Y PROCESOS] Pharmacology (medical) Enzyme Inhibitors Child Farmacocinètica Càncer - Tractament Glioma Investigative Techniques::Toxicity Tests::Maximum Tolerated Dose [ANALYTICAL DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT] Posologia Neoplasms [DISEASES] Oncology Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacokinetics [PHENOMENA AND PROCESSES] Child Preschool técnicas de investigación::pruebas de toxicidad::dosis máxima tolerada [TÉCNICAS Y EQUIPOS ANALÍTICOS DIAGNÓSTICOS Y TERAPÉUTICOS] Azetidines Neoplasm Recurrence Local Tablets |
| Zdroj: | Scientia |
| Popis: | Cobimetinib; Pediatrics; Refractory Solid Tumors Cobimetinib; Pediatria; Tumors sòlids refractaris Cobimetinib; Pediatría; Tumores sólidos refractarios Background: The MAPK pathway is an emerging target across a number of adult and pediatric tumors. Targeting the downstream effector of MAPK, MEK1, is a proposed strategy to control the growth of MAPK-dependent tumors. Objective: iMATRIX-cobi assessed the safety, pharmacokinetics, and anti-tumor activity of cobimetinib, a highly selective MEK inhibitor, in children and young adults with relapsed/refractory solid tumors. Patients and methods: This multicenter Phase I/II study enrolled patients aged 6 months to < 30 years with solid tumors with known/expected MAPK pathway involvement. Patients received cobimetinib tablet or suspension formulation on Days 1-21 of a 28-day cycle. Dose escalation followed a rolling 6 design. The primary endpoint was safety; secondary endpoints were pharmacokinetics and anti-tumor activity. Results: Of 56 enrolled patients (median age 9 years [range 3-29]), 18 received cobimetinib tablets and 38 cobimetinib suspension. Most common diagnoses were low-grade glioma (LGG; n = 32, including n = 12 in the expansion cohort) and plexiform neurofibroma within neurofibromatosis type 1 (n = 12). Six patients (11 %) experienced dose-limiting toxicities (including five ocular toxicity events), which established a pediatric recommended Phase II dose (RP2D) of 0.8 mg/kg tablet and 1.0 mg/kg suspension. Most frequently reported treatment-related adverse events were gastrointestinal and skin disorders. Steady state mean exposure (Cmax, AUC0-24) of cobimetinib at the RP2D (1.0 mg/kg suspension) was ~ 50 % lower than in adults receiving the approved 60 mg/day dose. Overall response rate was 5.4 % (3/56; all partial responses in patients with LGG). Conclusions: The safety profile of cobimetinib in pediatrics was similar to that reported in adults. Clinical activity was observed in LGG patients with known/suspected MAPK pathway activation. Cobimetinib combination regimens may be required to improve response rates in this pediatric population. |
| Databáze: | OpenAIRE |
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