Transform-1: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, International Phase 3 Study of Navitoclax in Combination with Ruxolitinib Versus Ruxolitinib Plus Placebo in Patients with Untreated Myelofibrosis

Background: Janus kinase inhibitors (JAKis) provide symptom improvement and spleen volume reduction in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis (MF). There remains a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival. The COMFORT-1 and -2 studies established JAKi monotherapy as standard-of-care with spleen volume reduction of ≥35% at Week 24 (SVR 35W24) of 42% and SVR 35W48 of 29%, respectively. In combination with the JAKi ruxolitinib, navitoclax, an orally available inhibitor of antiapoptotic B-cell lymphoma 2 proteins (BCL-X L, BCL-2, BCL-W), was shown to have pronounced antitumor activity in patients with MF in the phase 2 REFINE trial (NCT03222609). TRANSFORM-1 is an ongoing, phase 3, double-blind, placebo-controlled, multicenter, international study evaluating the safety and efficacy of navitoclax plus ruxolitinib (NAV + RUX) compared with placebo plus ruxolitinib (PBO + RUX) in JAK2i-naïve adults with MF. Methods: TRANSFORM-1 (NCT04472598) enrolled adult patients with intermediate-2 or high-risk MF with measurable splenomegaly, evidence of MF-related symptoms, no prior JAK2i treatment, and ECOG Performance Score ≤2. Patients were randomized 1:1 to receive NAV (starting dose of 200 mg [platelet {PLT} >150 × 10 9/L] or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days [PLT ≤150 × 10 9/L]) or PBO, plus RUX at label dose, based on stratification factors of intermediate-2 vs high-risk MF and PLT ≤200 × 10 9/L vs >200 × 10 9/L. The primary endpoint was SVR 35W24. Secondary endpoints included change in total symptom score at Week 24 (TSS W24) assessed using 7-item MFSAF v4.0 (scale 0-70), SVR 35 at any time, duration of SVR 35, anemia response (per International Working Group criteria), reduction in marrow fibrosis, overall survival, leukemia-free survival, reduction in PROMIS Fatigue scale, and improvement in EORTC QLQ-C30 physical functioning scale. Exploratory endpoints include progression-free survival. Results: At data cutoff, April 13, 2023, 252 patients were enrolled with a median (range) follow-up of 14.9 (0.0-29.5) months; 125 patients were randomized to receive NAV + RUX and 127 to receive PBO + RUX. Most patients were male (57%), median (range) age was 69 (37-87) years, and patient demographics were similar between treatment arms ( Table 1). TRANSFORM-1 met its primary endpoint, with 79 patients (63.2%) in the NAV + RUX a