A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma

• DOI: 10.1007/s11060-019-03337-2
• Publication Date: 2019-11-27T07:02:40Z
• Authors: Martin van den Bent; Analia Azaro; Filip De Vos; Juan Sepulveda; W. K. Alfred Yung; Patrick Y. Wen; Andrew B. Lassman; Markus Joerger; Ghazaleh Tabatabai; Jordi Rodon; Ralph Tiedt; Sylvia Zhao; Tiina Kirsilae; Yi Cheng; Sergio Vicente; O. Alejandro Balbin; Hefei Zhang; Wolfgang Wick
• Keywords: Adult; Male; 0301 basic medicine; Cancer Research; PTEN; Maximum Tolerated Dose; Morpholines; Clinical Neurology; Cervell - Càncer - Quimioteràpia; Aminopyridines; Glioblastoma multiforme; :Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Glioma::Astrocytoma::Glioblastoma [DISEASES]; 03 medical and health sciences; SDG 3 - Good Health and Well-being; :Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT]; Antineoplastic Combined Chemotherapy Protocols; :Neoplasms::Neoplastic Processes::Neoplasm Recurrence, Local [DISEASES]; Humans; Tissue Distribution; c-Met; Aged; :neoplasias::procesos neoplásicos::recurrencia neoplásica local [ENFERMEDADES]; Triazines; Brain Neoplasms; INC280; :terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS]; Imidazoles; PTEN Phosphohydrolase; Middle Aged; Proto-Oncogene Proteins c-met; Prognosis; :neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::glioma::astrocitoma::glioblastoma [ENFERMEDADES]; 3. Good health; Capmatinib; Oncology; Neurology; Benzamides; Buparlisib; Clinical Study; Female; Neoplasm Recurrence, Local; Glioblastoma; Follow-Up Studies

Abstract Purpose To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D) for combined INC280 and buparlisib in patients with recurrent glioblastoma with homozygous phosphatase and tensin homolog (PTEN) deletion, mutation or protein loss.

Methods This multicenter, open-label, Phase Ib/II study included adult patients with glioblastoma with mesenchymal-epithelial transcription factor (c-Met) amplification. In Phase Ib, patients received INC280 as capsules or tablets in combination with buparlisib. In Phase II, patients received INC280 only. Response was assessed centrally using Response Assessment in Neuro-Oncology response criteria for high-grade gliomas. All adverse events (AEs) were recorded and graded.

Results 33 patients entered Phase Ib, 32 with altered PTEN. RP2D was not declared due to potential drug–drug interactions, which may have resulted in lack of efficacy; thus, Phase II, including 10 patients, was continued with INC280 monotherapy only. Best response was stable disease in 30% of patients. In the selected patient population, enrollment was halted due to limited activity with INC280 monotherapy. In Phase Ib, the most common treatment-related AEs were fatigue (36.4%), nausea (30.3%) and increased alanine aminotransferase (30.3%). MTD was identified at INC280 Tab 300 mg twice daily + buparlisib 80 mg once daily. In Phase II, the most common AEs were headache (40.0%), constipation (30.0%), fatigue (30.0%) and increased lipase (30.0%).

Conclusion The combination of INC280/buparlisib resulted in no clear activity in patients with recurrent PTEN-deficient glioblastoma. More stringent molecular selection strategies might produce better outcomes. Trial registration: NCT01870726.