Irinotecan (Iri) and buparlisib (B) in previously treated patients (pts) with metastatic colorectal cancer (mCRC).
655 Background: The PIK3CA pathway has oncogenic role in mCRC. Buparlisib is an oral pan-class PIK3CA inhibitor. It is currently being studied in combination trials for various malignancies. The primary objective of this phase I trial was to identify the maximum tolerated dose (MTD) for Iri plus B in pts with previously treated mCRC, with or without previous Iri therapy. We also performed PK analysis of each drug alone and in combination, determined clinical response to the combination, and evaluated achieval FFPE samples for somatic mutations in a panel of cancer associated genes, including PIK3CA for clinical correlation. Methods: A 3+3 dose titration method was used. Iri was administered intravenously every 14 days (one cycle) and B orally daily. Pts received the first dose of Iri on Cycle1 Day1. B was started 24 hours after the first dose of Iri. Safety and toxicity assessments were performed every cycle. Results: Twenty patients were enrolled: 4 in cohort 0 (Iri 120 mg/m2 + B 50 mg/d), 11 in cohort 1 (Iri 150 mg/m2 + B 50 mg/d), 5 in cohort 2 (Iri 150 mg/m2 + B 80 mg/d). The most common Grades 3/4 adverse events were neutropenia and abdominal pain. The MTD was Iri 150 mg/m2 + B 50 mg/d. The DLTs include male genital mucositis, grade 3 diarrhea, and asymptomatic grade 3 hyponatremia. In cohort 1, one pt experienced grade 2 delirium and a pt in cohort 2 had grade 3 psychosis. Of the 4 pts who received 4 cycles of therapy 2 had stable and 2 had progressive disease. No objective responses were seen. There is no significant change in the PK of Iri between Cycles 1 and 2. B at 50 mg had no consistent effect on the disposition of Iri given at 120 mg/m2 and 150 mg/m2. The Cmax and AUC for B show clear dose proportionality. Using targeted re-sequencing, a 48-gene panel that included AKT1, BRAF, KRAS, and PTEN was performed. The complete analysis of the correlative study will be presented in the meeting. Conclusions: This first human trial established that Buparlisib (50 mg qd) and Iri (150 mg/m2 q14d) are tolerable in combination. However, it is too early to determine the activity of this combination in the treatment of mCRC. Clinical trial information: NCT01304602.