A Phase 3, Double-Blind, Placebo-Controlled, Randomized Study Evaluating Navitoclax in Combination with Ruxolitinib in Patients with Myelofibrosis (TRANSFORM-1)

Background: Myelofibrosis (MF) is a rare myeloproliferative neoplasm with poor clinical outcomes. It is characterized by bone marrow fibrosis and an array of constitutional symptoms that impair quality of life. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potential curative therapy for MF, but HSCT is only accessible to a minority of patients and is associated with high morbidity and high rates of transplant-related mortality. JAK inhibitors (JAKi), including the JAK1/2i ruxolitinib and JAK2i fedratinib, are approved for the treatment of primary and secondary MF based on reduction in splenomegaly and disease-related symptoms; however, they have little impact on bone marrow fibrosis and are not effective at managing all clinical manifestations of MF. Therefore, a substantial clinical need for novel therapies to improve the disease course of MF exists.

Navitoclax is an oral, potent, small-molecule inhibitor of the antiapoptotic B-cell lymphoma 2 (BCL-2) family proteins BCL-X_L, BCL-2, and BCL-w and has demonstrated cell-killing activity in myeloproliferative neoplasm-derived cell lines and primary specimens ex vivo. Preliminary data from a Phase 2 study (NCT03222609) of ruxolitinib-experienced patients with primary or secondary MF have shown favorable spleen responses and tolerability with navitoclax plus ruxolitinib (Harrison et al. EHA 2020. EP1081). TRANSFORM-1 aims to evaluate the combination of navitoclax and ruxolitinib vs placebo and ruxolitinib in adults with primary or secondary MF who have not previously received a JAK2i.

Study Design and Methods: In this Phase 3, double-blind, placebo-controlled study (NCT04472598), patients aged ≥18 years with intermediate-2 or high-risk MF with measurable splenomegaly, evidence of MF-related symptoms, no prior treatment with JAK2i, and Eastern Cooperative Oncology Group Performance Score ≤2 will be eligible for enrollment. Candidates for allo-HSCT and those who have received prior treatment with a BH3-mimetic compound or BET inhibitor will be excluded. Patients will be enrolled across 130 sites in approximately 17 countries. Planned target enrollment is 230 patients.

Patients will be randomized 1:1 to receive navitoclax or placebo, plus ruxolitinib. Randomization stratification factors include intermediate-2 vs high-risk MF and platelet count ≤200 × 10⁹/L vs >200 × 10⁹/L. 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). Ruxolitinib will be administered orally at a starting dose of 20 mg (platelet count >200 × 10⁹/L) or 15 mg (platelet count 100-200 × 10⁹/L) twice daily. Treatment may continue until the end of clinical benefit, unacceptable toxicity, or discontinuation criteria have been met. Patients who discontinue without progression will enter post-treatment follow-up; after disease progression or initiation of post-treatment cancer therapy, patients will enter survival follow-up.

The primary endpoint of the study is ≥35% reduction in spleen volume from baseline (SVR₃₅) at Week 24, as measured by magnetic resonance imaging or computed tomography, per International Working Group (IWG) criteria. Secondary endpoints include ≥50% reduction in total symptom score from baseline at Week 24 (measured by Myelofibrosis Symptom Assessment Form v4.0), duration of SVR₃₅, change in fatigue from baseline, time to deterioration of physical functioning, anemia response per IWG criteria, SVR₃₅ per IWG, reduction in grade of bone marrow fibrosis from baseline, overall survival, leukemia-free survival, and overall response and composite response per IWG criteria. Exploratory endpoints include progression-free survival. Safety will be assessed throughout the study 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.

The primary statistical analysis will be conducted using a stratified Cochran-Mantel-Haenszel test, and 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.