A Randomized, Placebo-Controlled, Phase 2 Study of Efatutazone Maintenance Therapy in Patients with Advanced Colorectal Cancer Who Have Achieved Disease Control Following First-Line Chemotherapy

Abstract

Introduction: Approximately 50% of patients with metastatic colorectal cancer (CRC) achieve complete or partial response (CR/PR) and a further 20% have stable disease (SD) within 6 months of beginning standard first-line therapy. The benefit of continued treatment until progression remains uncertain, though studies suggest that maintenance therapy may increase progression-free survival (PFS). Efatutazone, a novel thiazolidinedione (TZD), is a highly selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist that has demonstrated anti-cancer activity with an acceptable tolerability profile in early clinical trials. This study compared efatutazone versus placebo in CRC patients who have achieved disease control (CR, PR or SD) following standard first-line therapy. Methods: A double-blind, placebo-controlled, phase 2 study randomized 84 adults with metastatic or locally-advanced CRC. Inclusion criteria included Eastern Cooperative Oncology Group performance status ≤2, treatment with standard first-line fluoropyrimidine-based combination chemotherapy, and no progressive disease. Those concomitantly using other TZDs were excluded. Patients entered the trial within 8 weeks of completing first-line therapy, and were randomized to oral efatutazone 0.5 mg twice daily or oral placebo twice daily, in 3-week treatment cycles. Disease assessments were performed at baseline and every 2 cycles thereafter. Treatment was continued until disease progression (PD), unacceptable toxicity or withdrawal of consent. The primary end point was PFS rate at 18 weeks. Secondary end points included PFS, overall survival (OS) and overall response rate (ORR). Treatment response was assessed in accordance with RECIST criteria, Version 1.0. Results: Of 84 randomized patients, 41 received efatutazone and 43 received placebo. Demographic characteristics were similar between treatment arms. Mean age was 62.4 years; 54.8% of patients were male. Best response to first-line therapy was SD in 60.7% of patients and PR/CR in 39.3%. PFS rate at 18 weeks was 39.9% (95% confidence interval [CI]: 23.5-55.7) with efatutazone vs 25.0% (13.0-39.0) with placebo (hazard ratio 0.66; P < 0.0001). Efficacy results are summarized in the Table. The predominant adverse event (AE) related to efatutazone was fluid retention (12.2%) and associated secondary effects (eg, weight gain [51.2%], anaemia [36.6%]). No grade 4 or 5 AEs related to efatutazone occurred. Although no drug-related deaths were reported for either treatment arm, 8 (19.5%) patients in the efatutazone arm discontinued due to a drug-related treatment-emergent AE, vs none in the placebo arm. The study was terminated early due to changes to the CRC standard of care; i.e. the study was designed when patient monitoring/no treatment was viable for this CRC patient population, but this is no longer true in many countries. A confirmatory phase 3 study of similar design was thus not possible. Conclusion: In patients with CRC who achieved disease control following standard first-line chemotherapy, there was a significant improvement in PFS with efatutazone maintenance treatment vs placebo. OS showed a positive trend in favour of efatutazone, but the trial was not powered to detect a statistical difference. Consistent with phase 1 studies, the predominant AE of efatutazone was fluid retention and its associated secondary effects. (Table Presented).