664TiP - A phase I trial of irinotecan (IRI) and BKM120 in previously treated patients (pts) with metastic colorectal cancer (mCRC)

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Colon Cancer
Rectal Cancer
Presenter Joaquina Baranda
Authors J.C. Baranda1, G. Reed2, S. Williamson1, E. Dickman1, M. Stoltz1, R. Madan3, L. Wright1, K. Bhalla1, A. Godwin3
  • 1Hematology And Medical Oncology, University of Kansas Cancer Center, 66205 - Westwood/US
  • 2Pharmacology. Toxicology And Therapeutics, University of Kansas Medical Center, 66160 - Kansas City/US
  • 3Pathology And Laboratory Medicine, University of Kansas Medical Center, 66160 - Kansas City/US

Abstract

Background

Reversal of Iri resistance may result with use of Iri plus anti-EGFR antibody in pts with kras wild-type mCRC. BKM120 is an oral pan-class PI3K inhibitor. The published results of a phase I trial of single agent BKM120 showed that BKM120 was well-tolerated and safe with favorable PK profile and promising anti-tumor effect.

Methods

The primary objective of this phase I trial is to identify the maximum tolerated dose (MTD) for Iri and BKM120 combination in previously treated mCRC. The secondary objectives are to characterize the PK of Iri with or without BKM120 as well as PK of BKM120 when administered with Iri, to determine clinical response to the combination, and to correlate the expression of biomarkers associated with PI3K signaling pathway with clinical response to the combination of Iri plus BKM120. A traditional 3 + 3 dosing scheme is used for dose escalation. Iri is given intravenously every 14 days and BKM daily. Iri starts on cycle 1 day 1 while BKM120 starts after 24 hours after the first dose of Iri to allow us to monitor the PK of Iri both in the absence and presence of BKM120. The patients are assessed for safety and toxicities every cycle (q14 days).

Results

Eleven pts have been enrolled: six were evaluable for toxicity: 3 in cohort 0 (Iri 120 mg/m2 + BKM120 50 mg/d) and 3 in cohort 1 (Iri 150 mg/m2 + BKM 120 50 mg/d). The most common drug related adverse events were nausea and vomiting, diarrhea, fatigue, hyperglycemia, and elevation of transaminases. One dose limiting toxicity (DLT), genital mucositis, was observed in a male pt in Cohort 1. This resolved in less than 7 days but pt missed more than 7 days of BKM120. The MTD has not been reached. Of the 4 pts who have completed 4 cycles of therapy 3 had stable disease and one had progressive disease. The cycle 1 vs cycle 2 PK for cohort 0 showed SN-38 mean Cmax2/Cmax1 was 0.89 + 0.16 and mean AUC2/AUC1 1.07 + 0.16. The Iri PKs for subsequent cohorts and BKM120 PKs as well as the molecular correlates will be presented.

Conclusion

This is the first human trial of the combination of Iri and BKM120. No significant toxicities have been observed and the PK of Iri does not seem to be affected by BKM120. These preliminary data support continuing the effort to find the MTD for the combination of Iri and BKM120 for use in phase II trials and to identify potential biomarkers of response and toxicities.

Disclosure

J.C. Baranda: Research Funds: Novartis, Roche.

K. Bhalla: Novartis, Research Funding Novartis, honorarium, advisor.

All other authors have declared no conflicts of interest.