O-0022 X-Pect Study Results: A Phase III Randomized Study of Perifosine Plus Capecitabine vs. Placebo Plus Capecitabine in Refractory mCRC Patients

Abstract

ABSTRACT Introduction Perifosine (P) is an oral, synthetic alkylphospholipid that inhibits or modifies signal transduction pathways including AKT, NFkB and JNK. A randomized phase II study examined perifosine plus capecitabine (P-CAP) vs. placebo plus capecitabine (CAP) in patients (pts) with 2nd or 3rd line metastatic colorectal cancer (mCRC). This study showed improvement in mTTP (HR 0.254 [0.117, 0.555]) and mOS (HR 0.370 [0.180,0.763]). Based on these results, a randomized, double-blind, placebo controlled phase III study of P-CAP vs. CAP with a primary endpoint of overall survival (OS) in pts with refractory mCRC was initiated. Methods Eligible pts had mCRC refractory to all standard therapies [progressive disease (PD) on or within 6 months of 5-FU, oxaliplatin, irinotecan, bevacizumab, and EGFR antibody (if Kras WT)]. Pts who discontinued oxaliplatin due to toxicity (tox) were eligible. Pts may not have had prior capecitabine in the metastatic setting outside of radiosensitizing doses. Baseline tumor block collection and a biomarker cohort of pts with pre- and on-treatment tumor and blood samples were performed. This phase III study was a prospective, randomized, double-blind, placebo-controlled randomized trial. Pts were randomized 1:1 to P-CAP (P 50 mg PO QD + CAP 1000 mg/m2 PO BID d1-14) or CAP (placebo + CAP 1000 mg/m2 PO BID d 1-14). One cycle was 21 days. Stratification: prior oxaliplatin (tox vs. PD) and Kras status. Statistical analysis includes a log-rank test with two-sided Type 1 error rate of 0.05 which will be used to compare OS between the two treatment arms. Approximately 360 death events were required to achieve 90% power to detect a treatment difference at the two-sided 0.05 significance level. It was planned that approximately 430 pts would be enrolled over 16 months and followed for an estimated 12 months. In the sample size calculation, it is assumed the mOS for the P-CAP group is 7.75 months and 5.5 months for the CAP group. Results Between 3/31/10 and 8/12/11, 468 pts were randomized: Kras MT/WT (52%/48%) and oxaliplatin discontinuation tox/PD (34%/66%). The median duration of follow up is 6.6 months. Planned analysis for OS, PFS, ORR and safety will occur by 6/1/2012 and will be presented.