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)

• Published in: Journal of neuro-oncology 2019-09, Vol.144 (2), p.303-311
• Main Authors: Hainsworth, John D., Becker, Kevin P., Mekhail, Tarek, Chowdhary, Sajeel A., Eakle, Janice Faulkner, Wright, David, Langdon, Robert M., Yost, Kathleen J., Padula, Gilbert Darin Anthony, West-Osterfield, Kimberly, Scarberry, Meredith, Shaifer, Candice A., Shastry, Mythili, Burris, Howard A., Shih, Kent
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adult; Aged; Aged, 80 and over; Aminopyridines - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Bevacizumab - administration & dosage; Brain cancer; Clinical Study; Drug Resistance, Neoplasm - drug effects; Female; Follow-Up Studies; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - pathology; Humans; Immunotherapy; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Middle Aged; Monoclonal antibodies; Mood; Morpholines - administration & dosage; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Neoplasms - drug therapy; Neoplasms - pathology; Neurology; Oncology; Phosphatidylinositol 3-Kinases - chemistry; Prognosis; Salvage Therapy; Solid tumors; Survival; Survival Rate; Targeted cancer therapy; Toxicity
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-019-03227-7

Background 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. Methods 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. Results 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. Conclusions 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.