Πέμπτη 19 Οκτωβρίου 2017

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

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: 24 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 6mg daily; vemurafenib 960mg twice daily) and cohort 3 (PX-866 8mg daily; vemurafenib 960mg twice daily), respectively. Of 23 response evaluable patients, 7 had confirmed partial responses (PRs), 10 had stable disease and 6 had disease progression. Decreases in intra-tumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by immunohistochemistry (80% vs 58%) and pathogenic PTEN mutations and/or deletions (57% vs 25%). Two patients with durable PRs had an increase in intra-tumoral CD8 T-cell infiltration following treatment with PX-866. Conclusions: PX-866 was well tolerated at its maximal tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increase CD8 T-cell infiltration in some patients.



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