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Evofosfamide (TH-302) in combination with gemcitabine in previously untreated patients with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma: Primary analysis of the randomized, double-blind phase III MAESTRO study.
Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract
Background: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced stage and has poor clinical outcome. Hypoxia is a significant negative prognostic factor in PDAC. Evofosfamide (Evo, previously known as TH-302) is a hypoxia-activated prodrug of bromo-isophosphoramide mustard that is preferentially activated under hypoxic conditions. Combining Evo with gemcitabine (Gem) significantly improved progression-free survival (PFS) in a randomized phase II trial in advanced PDAC (NCT01144455).
Methods: MAESTRO is an international, randomized, double-blind, placebo-controlled phase III trial of Evo/Gem vs Placebo/Gem in patients (pts) with measurable, locally advanced unresectable or metastatic PDAC (NCT01746979). Evo and Gem were administered intravenously at a dose of 340 mg/m2 and 1,000 mg/m2, respectively, on days 1, 8, and 15 of a 28-day cycle. Treatment continued until disease progression. Key eligibility criteria included ECOG PS 0/1 and no neoadjuvant or adjuvant chemotherapy <6 months prior to entry. Key eligibility criteria included ECOG PS 0/1 and no neoadjuvant or adjuvant chemotherapy <6 months prior to entry. The primary endpoint was overall survival (OS) with the study designed to detect a HR of 0.75 with 90% power. Secondary endpoints included PFS and objective response rate (ORR), using a hierarchical testing procedure with a 2-sided α=0.05 at each level to adjust for multiplicity.
Results: 346 pts were randomized to Evo/Gem and 347 to Pla/Gem. Baseline pt characteristics were generally similar between arms.
|Median OS, months (95% CI)||7.6 (6.7, 8.3)||8.7 (7.6, 9.9)|
|HR: 0.84 (95% CI 0.71, 1.01)|
|Median PFS, months (95% CI)||3.7 (3.6, 3.8)||5.5 (4.8, 5.6)|
|HR: 0.77 (95% CI 0.65, 0.92)|
|ORR, % (95% CI)||15 (12, 19)||19 (15, 24)|
|OR: 1.31 (95% CI 0.88, 1.95)|
Grade ≥3 hematologic events were reported more frequently in pts treated with Evo/Gem than Pla/Gem: neutropenia (32.5% vs 20.8%); thrombocytopenia (31.7% vs 5.6%); anemia (22.2% vs 12.0%).
Conclusions: Although the primary endpoint was not met, Evo/Gem showed signs of antitumor activity. No new clinically significant safety findings were observed. Clinical trial information: NCT01746979
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