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A phase 1 study of buparlisib and bevacizumab in patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor-targeted therapies
- Source :
- Cancer. 122:2389-2398
- Publication Year :
- 2016
- Publisher :
- Wiley, 2016.
-
Abstract
- Background The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is dysregulated in patients with metastatic renal cell carcinoma (mRCC). Buparlisib is a pan-PI3K inhibitor with activity in advanced solid tumors. The primary objective of the current study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of buparlisib and bevacizumab in patients with mRCC. Secondary objectives included efficacy, biomarker discovery, and additional toxicity. Methods This was a standard 3 + 3 dose escalation study of buparlisib (at a dose of 60-100 mg/day) and bevacizumab (at a dose of 10 mg/kg every 2 weeks). After the MTD was defined, 15 patients were accrued to the expansion cohort. Results Thirty-two patients were accrued (3 were treated at 60 mg/day, 21 were treated at 80 mg/day, 6 were treated at 100 mg/day, and 2 patients never received therapy). The majority of patients had clear cell histology (87%) and 50% had received ≥2 prior lines of therapy. The MTD of buparlisib was 80 mg/day and that of bevacizumab was 10 mg/kg every 2 weeks. A total of 28 patients discontinued therapy: 17 because of disease progression, 7 because of toxicity, and 4 for other reasons. Dose-limiting toxicities included rash/pruritis, elevated lipase/amylase, anorexia, and psychiatric disorders (suicidal ideation, depression, and cognitive disturbances). Of the 30 patients who received at least 1 dose, 13% achieved a partial response (95% confidence interval, 4%-31%). Two patients harboring activating PI3KA mutations achieved 42% and 16% maximal tumor shrinkage, respectively. Conclusions Buparlisib at a dose of 80 mg/day with bevacizumab was found to be a tolerable regimen with preliminary activity in vascular endothelial growth factor-refractory mRCC. The benefit of this combination may be of interest for future mRCC trials, possibly in a selected patient population. Cancer 2016;122:2389-2398. © 2016 American Cancer Society.
- Subjects :
- 0301 basic medicine
Oncology
Cancer Research
medicine.medical_specialty
Bevacizumab
Buparlisib
Pharmacology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Renal cell carcinoma
Internal medicine
medicine
business.industry
Cancer
medicine.disease
Rash
Vascular endothelial growth factor
Regimen
030104 developmental biology
chemistry
030220 oncology & carcinogenesis
Toxicity
medicine.symptom
business
medicine.drug
Subjects
Details
- ISSN :
- 0008543X
- Volume :
- 122
- Database :
- OpenAIRE
- Journal :
- Cancer
- Accession number :
- edsair.doi...........54bf64eb84070d83093b67e2e3bd4e33