Pacritinib at Recommended Phase 3 Dose Showcases Clinical Activity in Myelofibrosis With Severe Thrombocytopenia

Pacritinib, when delivered at a twice-daily dose of 200 mg, was found to demonstrate clinical activity with an acceptable toxicity profile in patients with myelofibrosis and severe thrombocytopenia, according to data from the dose-finding PAC203 trial recently published in Blood Advances.

Results showed that the sustained virological response (SVR) rate was highest among patients who received the twice-daily, 200-mg dose of the agent vs those who received the agent at lower doses. The overall SVR rate was 9.3% in the 200-mg, twice-daily dose arm vs 0% in the 100-mg once-daily dose arm and 1.8% in the 100-mg twice-daily dose arm (P_trend = .012).

The median percent reduction in spleen volume was also greatest in the 200-mg, twice-daily arm versus the lower-dose arms, with a difference of 10.1% (interquartile range, -23.8% to 2.5%).

Moreover, the SVR rate was 16.7% in patients with severe thrombocytopenia (n = 4/24). In evaluable patients with spleen volume data available at week 24, the SVR rate at the 200-mg twice-daily dose was 18.5%; the SVR rate was 30.8% overall and in patient who had severe thrombocytopenia at baseline.

The total symptom score (TSS) response rate was comparable across the arms at week 24. In the evaluable population, the TSS response rate was 17.4% in the 100-mg once-daily arm, 14.8% in the 100-mg, twice-daily arm, and 16.7% in the 200-mg, twice-daily arm (P_trend >.05). Additionally, TSS reduction was observed in spleen- and cytokine-related symptoms, particularly in the 200-mg, twice-daily arm.

“Data from PAC203 and from dose- and exposure-response modeling demonstrate that pacritinib 200 mg twice per day provides greater efficacy compared with lower doses and has a manageable safety profile,” Aaron T. Gerds, MD, an assistant professor in medicine (Hematology and Oncology) at the Cleveland Clinic Taussig Cancer Institute, and colleagues, wrote in the article on the data.

Results from the phase 3 PERSIST-1 (NCT01773187) and PERSIST-2 (NCT02055781) trials have demonstrated that pacritinib has clinical benefit in patients with myelofibrosis vs best available therapy. Based on data from these trials, in October 2020, a rolling submission of a new drug application for pacritinib was initiated for patients with myelofibrosis and severe thrombocytopenia, defined as platelet counts of less than 50,000 μL.

In the open-label, randomized, dose-finding phase 2 trial, investigators set out to identify the recommended dose of pacritinib in patients with advanced myelofibrosis who were intolerant of, or who had developed resistant to, ruxolitinib (Jakafi). Key secondary objectives focused on examining the dose-response relationship with regard to safety and efficacy and to characterize the pharmacokinetics and pharmacodynamics of the agent.

To be eligible for enrollment, patients had to have primary or secondary myelofibrosis with intermediate-1, intermediate-2, or high-risk disease per the Dynamic International Prognostic Scoring System. They also needed to be intolerant of, or resistant to, ruxolitinib.

Moreover, patients had to have splenomegaly of 5 cm or more below the left costal margin, a TTS of 10 or greater, or a single symptom score of 5 or greater or 2 scores of 3 or greater. They needed to have an ECOG performance status of 0-2, a peripheral blast count of less than 10%, an absolute neutrophil count of greater than 0.5 × 10⁹/L, and acceptable liver, renal, and coagulation parameters, among other criteria.

In the trial, patients were randomized 1:1:1 to receive pacritinib at 1 of 3 doses: 100-mg once daily, 100-mg twice daily, or 200-mg twice daily. Patients were stratified by their platelet count at baseline and geographic region. All participants received treatment until week 24 or until disease progression, intolerable toxicity, or withdrawal from the trial. Those who achieved a clinical benefit with the agent at week 24 were given the opportunity to continue treatment until study completion. Upon completion, they had the option to transition to an expanded access program.

A total of 165 patients underwent randomization between July 2017 and January 2019; of these patients, 161 received treatment. When broken down by cohort, 52 received pacritinib at 100-mg once daily, 55 received it at 100-mg twice daily, and 54 received it at 200-mg twice daily.

Baseline characteristics were found to be well balanced across the cohorts analyzed. The median platelet count was 55 × 10³/μL and just under half of patients, or 44.1%, had a platelet count of less than 50 × 10³/μL. Approximately 70% of patients had hemoglobin that was less than 10 g/dL. Moreover, the median exposure to prior ruxolitinib was 1.7 years in these patients; 76% of patients had progressed on the agent, 73% had been intolerant, and 50% were both.

By the end of the study, 24.8% of patients were still receiving treatment with pacritinib; 34 of 40 patients opted to continue treatment off-study as part of the expanded access program.

With regard to safety, most of the frequently reported nonhematologic toxicities proved to be mild or moderate and rates were comparable across the arms analyzed; however, gastrointestinal effects were noted to be more frequently reported in those who received the 200-mg twice-daily dose vs the 100-mg once-daily and 100-mg twice-daily doses; these rates were 72.2%, 50.0%, and 54.5%, respectively. These toxicities were mostly grade 1 or 2 in severity and they typically presented within the first 8 weeks of treatment.

Moreover, although diarrhea was commonly experienced by patients who received pacritinib, it was found to be manageable through the use of antidiarrheal drugs. The median duration of pacritinib-associated diarrhea was 2 weeks in the cohort of patients who received the agent at 200-mg twice daily. About 3% of patients experienced neoplasms, all of which were skin cancers; however, no neoplasms were observed in the cohort of patients who received the 200-mg twice-daily dose of pacritinib.

“The results of this phase 2 study informed the dose selection for an ongoing phase 3 randomized study (PACIFICA; [NCT03165734]) comparing pacritinib 200 mg twice per day with physician’s choice therapy (including low-dose ruxolitinib) for patients with myelofibrosis and severe thrombocytopenia,” the authors concluded.

Reference

Gerds AT, Savona MR, Scott BL, et al. Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. Blood Adv. 2020;4(22):5825-5835. doi:10.1182/bloodadvances.2020003314