A Phase 3, Open-Label, Randomized Study Evaluating the Efficacy and Safety of Navitoclax Plus Ruxolitinib Versus Best Available Therapy in Patients with Relapsed/Refractory Myelofibrosis (TRANSFORM-2)

Background: Myelofibrosis (MF) is a rare myeloproliferative neoplasm with limited treatment options and a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potential cure, most patients remain ineligible; other therapies, including approved JAK inhibitors (JAKi), do not control the broad array of manifestations associated with MF.

Navitoclax is a potent, small molecule inhibitor of the antiapoptotic B-cell lymphoma 2 (BCL-2) family members BCL-X_L, BCL-2, and BCL-w and has been shown to potently enhance cytotoxicity of chemotherapy and radiation in cells derived from multiple tumor types. Preclinical data indicate that navitoclax may overcome JAK2 inhibitor resistance. Preliminary data from a Phase 2 study (NCT03222609) of navitoclax with ruxolitinib, a JAK1/2i, for patients with primary or secondary MF who have previously received ruxolitinib suggest favorable spleen response rates and an acceptable safety profile (Harrison et al. EHA 2020. EP1081). TRANSFORM-2 aims to evaluate the combination of navitoclax and ruxolitinib vs best available therapy (BAT) in adults with relapsed or refractory MF that is resistant to JAK2 inhibition.

Study Design and Methods: This Phase 3, open-label study (NCT04468984) is designed to recruit patients aged ≥18 years with intermediate-2 or high-risk MF, measurable splenomegaly, and who are experiencing MF-related symptoms. Patients must have received a single prior JAK2i for ≥24 weeks that was stopped due to lack of efficacy or for <24 weeks with disease progression while on therapy. Candidates for allo-HSCT, patients who have received prior treatment with a BH3-mimetic compound or >1 prior JAK2i, and patients with platelets <100 × 10⁹/L will be excluded. The study will be conducted at approximately 173 sites in 23 countries. The planned sample size is 330 patients.

Patients will be randomized 1:1 to receive either navitoclax plus ruxolitinib, or BAT. Navitoclax will be administered orally at a starting dose of 200 mg (platelet count >150 × 10⁹/L) or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days (platelet count ≤150 × 10⁹/L); navitoclax may be increased to 300 mg once daily after Week 25 Day 1 at the investigator's discretion, based on platelet count for patients with suboptimal spleen response; ruxolitinib will be administered orally at the prior stable dose if on ruxolitinib at study entry or at a dose of 10 mg twice daily if no longer on ruxolitinib. BAT options include hydroxyurea, interferon, ruxolitinib, fedratinib, or danazol, which will be administered at standard doses. Randomization stratification will be by region (US vs Japan vs EU vs rest of world), by Dynamic International Prognostic Scoring System Plus score at randomization (intermediate-2 vs high risk), and by stable ruxolitinib dosing at randomization vs not on ruxolitinib/JAK2i. Treatment can continue until the end of clinical benefit, unacceptable toxicity, or discontinuation criteria have been met; disease assessments will be performed after 12 and 24 weeks even if discontinuing therapy, after which patients will enter posttreatment follow-up (discontinuation without progression) or survival follow-up (after progression).

The primary endpoint is ≥35% reduction in spleen volume from baseline (SVR₃₅) at Week 24, measured by magnetic resonance imaging, per International Working Group criteria. Secondary endpoints include ≥50% reduction in total symptom score from baseline at Week 24, SVR₃₅, duration of SVR₃₅, change in fatigue from baseline, time to deterioration of physical functioning, anemia response, overall survival, leukemia-free survival, overall response, composite response, and reduction in grade of bone marrow fibrosis from baseline. Safety will be assessed via adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram variables, and clinical laboratory testing. AEs will be graded per National Cancer Institute Common Terminology Criteria for AEs v5.0.

Statistical analysis of the primary endpoint and binary secondary endpoints will be conducted using a stratified Cochran-Mantel-Haenszel test. Time-to-event secondary endpoints will be analyzed using a stratified log-rank test and Kaplan-Meier methodology. Hazard ratios will be estimated using stratified Cox proportional hazards model.