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)

• Published in: Blood 2020-11, Vol.136 (Supplement 1), p.8-8
• Main Authors: Dilley, Kimberley, Harb, Jason, Jalaluddin, Muhammad, Hutti, Jessica E., Potluri, Jalaja
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2020-139247

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-XL, 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 1 prior JAK2i, and patients with platelets 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 opt