A phase 1 study of buparlisib and bevacizumab in patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor-targeted therapies.

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.

• Authors: Rana R McKay, Guillermo De Velasco, Lillian Werner, Joaquim Bellmunt, Lauren Harshman, Christopher Sweeney, Jonathan E Rosenberg, Michelle Hirsch, Sabina Signoretti, Eliezer M Van Allen, Meghara Walsh, Ulka Vaishampayan, David F McDermott, Toni K Choueiri
• Journal: Cancer (Cancer) Vol. 122 Issue 15 Pg. 2389-98 (Aug 01 2016) ISSN: 1097-0142 [Electronic] United States
• PMID: 27198170 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: © 2016 American Cancer Society.

Chemical References

• Aminopyridines
• Biomarkers
• Morpholines
• NVP-BKM120
• Vascular Endothelial Growth Factor A
• Bevacizumab

Topics

• Aminopyridines (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Bevacizumab (administration & dosage)
• Biomarkers
• Carcinoma, Renal Cell (drug therapy, pathology)
• Female
• Humans
• Kidney Neoplasms (drug therapy, pathology)
• Male
• Molecular Targeted Therapy
• Morpholines (administration & dosage)
• Neoplasm Metastasis
• Treatment Outcome
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)