The study was a randomized, double-blind, placebo controlled study conducted at 11 centers across the US. In the trial, heavily pre-treated patients with second or third-line metastatic colon cancer were randomized to receive capecitabine at 825mg/m2 BID (total daily dose of 1650mg/m2) on days 1 – 14 every 21 days, plus either perifosine or placebo at 50mg daily.
The study enrolled a total of 38 patients, 34 of which were third-line or greater. Of the 38 patients enrolled, 35 patients were evaluable for response (20 patients on the perifosine + capecitabine arm and 15 patients on the placebo + capecitabine arm). Three patients on the placebo + capecitabine arm were not evaluable for response (two patients were unevaluable due to toxicity (days 14, 46) and one was unevaluable due to a new malignancy on day six). All patients in the perifosine + capecitabine arm were evaluable for response.
The patients in the study were heavily pre-treated, with the arms well-balanced in terms of prior treatment regimens. Notably, all of the patients (with the exception of one CAP arm patient) had been treated with FOLFIRI and/or FOLFOX, almost 80% treated with Avastin, and half treated with an EGFR antibody.
The primary endpoint of this study was to measure Time to Progression (TTP). Overall Response Rate (ORR), defined as Complete Responses (CR) + Partial Responses (PR) by RECIST, and Overall Survival (OS) were measured as secondary endpoints.
The P-CAP arm demonstrated an advantage for TTP and OS, as well as for the percentage of patients achieving Stable Disease lasting 12 or more weeks (SD) or better, as compared to the CAP arm. The P-CAP arm demonstrated a greater than 60% improvement in OS, a more than doubling of median TTP, and almost a doubling of the percentage of patients achieving SD or better. In addition, the ORR was 20% (including one CR, and durable responses) in the P-CAP arm versus 7% in the CAP arm.
Of notable interest, and for the first time presented, were data showing benefits in median OS (more than a doubling) and TTP for the subset of patients who were refractory to a 5-FU (Fluorouracil) chemotherapy-based treatment regimen. 5-FU is a core component of the standard of care FOLFIRI and FOLFOX regimens, and capecitabine is a 5-FU pro-drug.
All 38 patients were evaluable for safety. The P-CAP combination was well-tolerated with Grade 3 and 4 adverse events of > 10% incidence for the P-CAP arm versus CAP arm as follows: anemia (15% vs 0%), fatigue (0% vs 11%), abdominal pain (5% vs 11%), and hand-foot syndrome (30% vs 0%).
Of note, incidence of Grade 1 and 2 hand-foot syndrome was similar in both the P-CAP and CAP arms (25% vs 22%, respectively). Hand-foot syndrome is a reported adverse event with capecitabine monotherapy. Patients who remained on treatment longer in the phase 2 study had a greater chance to develop hand-foot syndrome as illustrated by a median time to onset of Grade 3 and 4 hand-foot syndrome in the P-CAP arm of 19 weeks.