1. Phase I/II study of bevacizumab with BKM120, an oral PI3K inhibitor, in patients with refractory solid tumors (phase I) and relapsed/refractory glioblastoma (phase II)
- Author
-
Kevin P. Becker, John D. Hainsworth, Tarek Mekhail, David Wright, Howard A. Burris, Sajeel A. Chowdhary, Janice Faulkner Eakle, Kimberly West-Osterfield, Gilbert Darin Anthony Padula, Mythili Shastry, Meredith Scarberry, Kent C. Shih, Robert M. Langdon, Candice A. Shaifer, and Kathleen Yost
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Maximum Tolerated Dose ,Bevacizumab ,Morpholines ,Aminopyridines ,Gastroenterology ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Neoplasms ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,In patient ,PI3K/AKT/mTOR pathway ,Aged ,Aged, 80 and over ,Salvage Therapy ,business.industry ,Middle Aged ,Prognosis ,medicine.disease ,Survival Rate ,Regimen ,Phase i ii ,Neurology ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Relapsed refractory ,Female ,Neurology (clinical) ,Neoplasm Recurrence, Local ,Glioblastoma ,business ,030217 neurology & neurosurgery ,Follow-Up Studies ,medicine.drug - Abstract
Current bevacizumab-based regimens have failed to improve survival in patients with recurrent glioblastoma. To improve treatment efficacy, we evaluated bevacizumab + BKM120, an oral pan-class I PI3K inhibitor, in this patient population. A brief phase I study established the optimal BKM120 dose to administer with standard-dose bevacizumab. BKM120 60 mg PO daily + bevacizumab 10 mg/kg IV every 2 weeks in 28-day cycles was then administered to patients with relapsed/refractory glioblastoma in the phase II portion. Eighty-eight patients enrolled (phase I, 12; phase II, 76). In phase I, BKM120 80 mg PO daily produced dose limiting toxicity in 3 of 6 patients; a BKM120 dose of 60 mg PO daily was established as the maximum tolerated dose. In phase II, the median progression-free survival (PFS) was 4.0 months (95% CI 3.4, 5.4), PFS at 6 months was 36.5%, and the overall response rate was 26%. Forty-two patients (57%) experienced one or more serious treatment related toxicities. The most common CNS toxicities included mood alteration (17%) and confusion (12%); however, these were often difficult to classify as treatment- versus tumor-related. The efficacy seen in this study is similar to the efficacy previously reported with single-agent bevacizumab. This regimen was poorly tolerated, despite the low daily dose of BKM120. Further development of this combination for the treatment of glioblastoma is not recommended.
- Published
- 2019