A Phase 2 Open-Label Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Subjects With Myelofibrosis (REFINE)

Participants must have received ruxolitinib for at least 12 weeks and on stable dose of ≥10 mg tablets orally twice daily (BID) for ≥8 weeks prior to the 1st dose of navitoclax. Navitoclax tablets are administered once daily (QD) at a starting dose of 50 mg. This was increased after approximately ≥7 days to next dose level if platelet count is ≥75 × 10^9/L up to a maximum dose of navitoclax 300 mg QD. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).

Participants must have received ruxolitinib for at least 12 weeks and on stable dose of ≥10 mg tablets orally twice daily (BID) for ≥8 weeks prior to the 1st dose of navitoclax. Navitoclax tablets are administered once daily (QD) at a starting dose of 50 mg. This was increased after approximately ≥7 days to next dose level if platelet count is ≥75 × 10^9/L up to a maximum dose of navitoclax 300 mg QD. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).

Those receiving ruxolitinib at Screening must be on a stable dose ≥10 mg tablets orally twice daily (BID) for ≥ 4 weeks prior to 1st dose of navitoclax. Those not receiving ruxolitinib at Screening received 10 mg ruxolitinib BID starting on Day 1. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (>150 × 10^9/L starting dose of 200 mg; ≤150 × 10^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose was increased to 300 mg QD at discretion of the Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).

Those receiving ruxolitinib at Screening must be on a stable dose ≥10 mg tablets orally twice daily (BID) for ≥ 4 weeks prior to 1st dose of navitoclax. Those not receiving ruxolitinib at Screening received 10 mg ruxolitinib BID starting on Day 1. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (>150 × 10^9/L starting dose of 200 mg; ≤150 × 10^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose was increased to 300 mg QD at discretion of the Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).

Participants must have received prior treatment with a Janus Kinase 2 (JAK-2) inhibitor. Those with Baseline platelet count >150 × 10^9/L initiated navitoclax film-coated tablets orally once daily (QD) at the starting dose of 200 mg. Those with a Baseline platelet count ≤150 × 10^9/L initiated navitoclax film-coated tablets orally once daily (QD) at the starting dose of 100 mg, which could be increased to 200 mg once daily after 7 days provided the platelet count is ≥75 × 10^9/L. Navitoclax didn't exceed 200 mg QD for the first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose may be increased to 300 mg QD at discretion of the Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).

Prior treatment with a Janus Kinase 2 (JAK-2) or Bromodomain and Extra-Terminal motif (BET) proteins inhibitor was prohibited. Ruxolitinib tablets administered orally twice daily (BID) based on Baseline platelet count as per the local approved label. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (>150 × 10^9/L starting dose of 200 mg; ≤150 × 10^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose may be increased to 300 mg QD at discretion of Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).

Prior treatment with a Janus Kinase 2 (JAK-2) or Bromodomain and Extra-Terminal motif (BET) proteins inhibitor was prohibited. Ruxolitinib tablets administered orally twice daily (BID) based on Baseline platelet count as per the local approved label. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (>150 × 10^9/L starting dose of 200 mg; ≤150 × 10^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose may be increased to 300 mg QD at discretion of Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).