Phase Ib study of safety and pharmacokinetics of the PI3K inhibitor SAR245408 with the HER3-neutralizing human antibody SAR256212 in patients with solid tumors

Vandana G. Abramson, Jeffrey G. Supko, Tarah Ballinger, James M. Cleary, John F. Hilton, Sara M. Tolaney, Nicole G. Chau, Daniel C. Cho, Joseph Pearlberg, Joanne Lager, Geoffrey I. Shapiro, Carlos L. Arteaga

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Purpose: This phase Ib study was designed to determine the MTD, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) mAb SAR256212 in combination with the oral PI3K inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors. Experimental Design: Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3 + 3 dose-escalation design until occurrence of disease progression or dose-limiting toxicity. Objective response rate, pharmacokinetics, pharmacodynamics, and PIK3CA mutational status were also evaluated. Results: Twenty-seven patients were enrolled. Thirteen of 20 patients tested (65%) had a hotspot-activating mutation in PIK3CA in their tumor. The MTD was determined to be SAR256212 at 40 mg/kg loading dose followed by 20 mg/kg weekly, plus SAR245408 200 mg daily. Dose-limiting toxicities included rash and hypotension; the most frequent treatment-related side effect was diarrhea (66.7%). Twenty-three patients were evaluable for efficacy, of which 12 patients (52.2%) had stable disease and 11 patients (47.8%) had progression of disease as best response. In this study with a limited sample size, there was no difference in best response between patients with PI3KCA-mutant versus PIK3CA wild-type tumors (P = 0.07). The concurrent administration of SAR245408 and SAR256212 did not appear to have an effect on the pharmacokinetics of either drug. Conclusions: The combination of SAR256212 and SAR245408 resulted in stable disease as the best response. Side effects seen in combination were similar to the profiles of each individual drug. Patient outcome was the same regardless of tumor PI3KCA mutation status.

Original languageEnglish (US)
Pages (from-to)3520-3528
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number14
DOIs
StatePublished - Jul 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Phase Ib study of safety and pharmacokinetics of the PI3K inhibitor SAR245408 with the HER3-neutralizing human antibody SAR256212 in patients with solid tumors'. Together they form a unique fingerprint.

  • Cite this

    Abramson, V. G., Supko, J. G., Ballinger, T., Cleary, J. M., Hilton, J. F., Tolaney, S. M., Chau, N. G., Cho, D. C., Pearlberg, J., Lager, J., Shapiro, G. I., & Arteaga, C. L. (2017). Phase Ib study of safety and pharmacokinetics of the PI3K inhibitor SAR245408 with the HER3-neutralizing human antibody SAR256212 in patients with solid tumors. Clinical Cancer Research, 23(14), 3520-3528. https://doi.org/10.1158/1078-0432.CCR-16-1764