Randomized phase III study of canfosfamide (C, TLK286) plus pegylated liposomal doxorubicin (PLD) versus PLD as second-line therapy in platinum (P) refractory or resistant ovarian cancer (OC)

Abstract

5552 Background: Canfosfamide (C) is a glutathione analog prodrug activated by glutathione S-transferase P1–1. C is synergistic with PLD and PLD increases the expression of GST P1–1 and sensitivity to C in OC cells. Methods: 244 pts were planned with P refractory or resistant (progression within 6 mos. after P) OC following ≤ 2 P regimens, and measurable disease (RECIST). Pts received C at 1,000 mg/m2 and PLD at 50 mg/m2 IV or PLD at 50mg/m2 q4wks until tumor progression. Randomization was stratified by ECOG PS, best prior P response and bulky disease (≥ 5cm). Results: This multinational study randomized 125 pts until June 4, 2007 when the study was temporarily placed on clinical hold to review another C trial. The 65/60 pts were well-balanced for disease characteristics and received a median 3/3.5 cycles per patient (range 1–11/0–17) of C + PLD/PLD, 35 pts (21/14) discontinued study treatment(s) due to the hold, respectively. Most common adverse events (AEs) for C + PLD were hematologic at 66% vs. 44% for PLD and were manageable with dose reductions. Non-hematologic AEs were similar for both arms, except the incidence of Grade 2–3 Palmar-Plantar Erythrodysesthesia (PPE) (9% vs. 21%) and stomatitis (17% vs. 23%) was lower and less severe with C+PLD vs. PLD. Grade 4 PPE (2%) was only observed on the PLD arm. Overall median PFS, the primary endpoint, was 5.6 mos. for C + PLD and 3.7 mos. for PLD (p = 0.7243, HR = 0.92). Objective response rate (ORR) by RECIST was 12.3% for C + PLD vs. 8.3% for PLD. In a planned analysis, 75 pts (40 /35) who were P refractory or primary P resistant observed a median PFS of 5.6 mos. for C + PLD vs. 2.9 mos. for PLD (p = 0.0425, HR = 0.55). ORR for C + PLD was 15.0% (with 1 CR) vs. 5.7% for PLD. Stable disease was observed 42.5% on C + PLD and 37.1% on PLD; median duration of SD was 7.4 mos. and 4.1 mos., respectively (p = 0.0439, HR = 0.49). The median time to response was 2.8 mos. on C + PLD vs. 4.8 mos. on PLD. Conclusions: The overall PFS showed a positive but not statistically significant trend for C +PLD vs. PLD. In the P refractory or primary P resistant population, the median PFS was significantly longer for C+PLD than PLD alone. C may ameliorate the AEs of stomatitis and PPE known to be associated with PLD. [Table: see text]