Randomized, multicenter phase III study of ranpirnase plus doxorubicin (DOX) versus DOX in patients with unresectable malignant mesothelioma (MM)

Abstract

7507 Background: Ranpirnase (Onconase), a novel ribonuclease with preclinical activity against various tumors, has led to a median survival of 8.3 ms (one year survival: 42%) in a multicentre phase II trial in chemonaive and pretreated pts whom met the Cancer and Leukemia Group B (CALGB) prognostic criteria for group 1–4 (Mikulski, J Clin Oncol 20, 2001). Methods: This multicenter controlled phase III trial compared efficacy and safety of Dox (one of the most active single agents when the study was planned) with or without ranpirnase. Primary endpoint was overall survival (OS), secondary endpoints included progression-free survival, response rate, safety and disease related symptoms. Eligibility criteria: histologically proven unresectable MM; CALGB group 1–4, ECOG PS 0–1, adequate organ function. Stratification was performed according to CALGB group and histology (epitheloid vs. non-epitheloid). One line of prior therapy was permitted. Between 08/01 and 09/07 413 eligible pts were randomized to DOX 60 mg/m 2 every 3 wks with or without ranpirnase 240 μg/m 2 weekly (cycle 1) and 480 μg/m 2 in subsequent cycles (maximum 6) if no severe toxicity had occurred. The study was designed to detect an increase of 4 ms (9 vs. 13) in median OS (MST) using a two-sided logrank test (α = 5%) with 90% power. Results: Both arms were well balanced (DOX + ranpirnase / DOX: 203/210 pts): Mean age 62.2/61.8 yrs; males 157/156; PS 0 52/60; PS 1 151/150; prior chemo 65/65 pts (pemetrexed 35/35; other chemo 30/30). CALGB groups 14/14 (1), 45/51 (2), 117/115 (3), 27/30 (4). In the intent to treat population (ITT) there was no significant difference in OS (MST: 11.1 vs 10.7 ms; HR 1.02, 95% CI 0.82–1.26) whilst in a preplanned analysis including 130 pretreated patients a significant advantage in survival in favor of DOX + ranpirnase was found (MST: 10.5 vs 9 ms; HR 1.49, 95% CI 1.02–2.17). The safety profile for both treatment arms was similar. Most frequent side effects reported for both treatment groups included nausea, fatigue and alopecia. Conclusions: Combination of ranpirnase and DOX is a safe and feasible treatment in unresectable MM and showed a significant impact on survival of pretreated patients compared to DOX alone. [Table: see text]