A multicenter phase I study evaluating dual PI3K and BRAF inhibition with PX-866 and vemurafenib in patients with advanced BRAF V600-mutant solid tumors

Clinton Yam, Xiaowei Xu, Michael A. Davies, Phyllis A. Gimotty, Jennifer J.D. Morrissette, Michael T. Tetzlaff, Khalida M. Wani, Shujing Liu, Wanleng Deng, Meghan Buckley, Jianhua Zhao, Ravi K. Amaravadi, Naomi B. Haas, Ragini R. Kudchadkar, Anna C. Pavlick, Jeffrey A. Sosman, Hussein Tawbi, Luke Walker, Lynn M. Schuchter, Giorgos C. KarakousisTara C. Gangadhar

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7 Scopus citations

Abstract

Purpose: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination. Experimental Design: We conducted a phase I, open-label, dose-escalation study in patients with advanced BRAF V600-mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment. Results: Twenty-four patients were enrolled. The most common treatment-related adverse events were gastrointestinal side effects. One dose-limiting toxicity (DLT) of grade 3 rash and one DLT of grade 3 pancreatitis were observed in cohort 2 (PX-866 6 mg daily; vemurafenib 960 mg twice daily) and cohort 3 (PX-866 8 mg daily; vemurafenib 960 mg twice daily), respectively. Of 23 response-evaluable patients, seven had confirmed partial responses (PR), 10 had stable disease, and six had disease progression. Decreases in intratumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by IHC (80% vs. 58%) and pathogenic PTEN mutations and/or deletions (57% vs. 25%). Two patients with durable PRs had an increase in intratumoral CD8 + T-cell infiltration following treatment with PX-866. Conclusions: PX-866 was well tolerated at its maximum tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720 mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increaseCD8 + T-cell infiltration in some patients.

Original languageEnglish (US)
Pages (from-to)22-32
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number1
DOIs
StatePublished - Jan 1 2018

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yam, C., Xu, X., Davies, M. A., Gimotty, P. A., Morrissette, J. J. D., Tetzlaff, M. T., Wani, K. M., Liu, S., Deng, W., Buckley, M., Zhao, J., Amaravadi, R. K., Haas, N. B., Kudchadkar, R. R., Pavlick, A. C., Sosman, J. A., Tawbi, H., Walker, L., Schuchter, L. M., ... Gangadhar, T. C. (2018). A multicenter phase I study evaluating dual PI3K and BRAF inhibition with PX-866 and vemurafenib in patients with advanced BRAF V600-mutant solid tumors. Clinical Cancer Research, 24(1), 22-32. https://doi.org/10.1158/1078-0432.CCR-17-1807