Pacritinib Outperforms Best Available Therapy for Myelofibrosis

Investigators working with FDA on safety signal

Results from a recent study show better efficacy with pacritinib therapy for myelofibrosis than best available treatment in use. However, the FDA has placed a full clinical hold on pacritinib, so more surveillance and review are needed before investigators can move forward.

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Findings from the PERSIST-2 phase 3 trial showed that two dosing regimens of pacritinib (PAC) both led to greater spleen volume reduction (SVR) than the best available treatment (BAT), which included ruxolitinib, for myelofibrosis patients with platelet counts of less than 100,000/μL. The BID dosing appeared slightly more effective than QD dosing, and researchers hope this data will help to lift the FDA hold placed on PAC — an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R — last February and advance it further in the clinical process.

“The fact that we were able to see these types of spleen responses is a big deal. I believe these are pretty striking results,” says hematologist Aaron T. Gerds, MD, MS, staff in the Cleveland Clinic Hematology and Oncology Department. “About one in five patients experienced a large reduction in their spleen volume despite having low platelets, which is indeed very meaningful.” Dr. Gerds is an investigator in the study and one of its abstract authors.

The abstract was offered as an oral presentation at the 2016 American Society of Hematology Annual Meeting  in San Diego. [Update: Data was published in full in 2018 in JAMA Oncology.]

The PERSIST-1 phase 3 study demonstrated that PAC was well tolerated by patients with myelofibrosis and more effective for reducing spleen volume and controlling symptoms than BAT. PERSIST-2 was conducted to further explore the efficacy of pacritinib and hone in on patients with low platelet counts.

Dr. Gerds explains the reasoning behind this: “PERSIST-1 looked at all patients with myelofibrosis, irrespective of platelets, and we saw that patients with very low platelet counts still responded to pacritinib. About 26 percent of myelofibrosis patients have platelet counts below 100,000/μL, and ruxolitinib either requires a reduced dose (if <100,000/μL) or is not recommended (if <50,000/μL) for them per the package insert. So that led us to think about whether ruxolitinib is adequate for treating these patients, and if pacritinib could be better.”

The PERSIST-2 phase 3 study

Researchers evenly randomized 311 patients with myelofibrosis and platelet counts of <100,000/μL to pacritinib BID (107), pacritinib QD (104) or BAT (100) for 24 weeks. The co-primary efficacy endpoints were the percentage of patients achieving ≥35 percent SVR and ≥50 percent reduction in total symptom score (TSS), and the primary objective was to compare the efficacy of pooled PAC to BAT.

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A total of 221 participants were included in the intention-to-treat (ITT) efficacy population, and 32 (44 percent) of those in the BAT arm received ruxolitinib at some point in the study. Results indicated that a significantly higher percentage of patients in the pooled PAC arm achieved a SVR ≥35 percent [18 percent (27/149)] than the BAT arm [3 percent (2/72)], while 25 percent of the PAC arm displayed a ≥50 percent TSS reduction compared to 14 percent of BAT patients.

Secondary analyses revealed that pacritinib BID and pacritinib QD each demonstrated significant improvements in both endpoints when compared independently to BAT. There were no significant differences in overall survival across all treatment arms, and the most common treatment-emergent adverse events associated with PAC were gastrointestinal and hematologic, which were generally less frequent with BID than QD dosing.

“The side effects that occurred were common but controllable, and I would say that the profiles between pacritinib and ruxolitinib are comparable but different,” Dr. Gerds says. “But given its efficacy and side-effect profile, I think that BID will likely be the preferred dosing moving forward.”

Safety signal from PERSIST-1

The FDA placed a full clinical hold on pacritinib in February 2016 due to concerns over excess deaths and cardiac and hemorrhagic complications in PERSIST-1. Fortunately, a mechanism for an access protocol opened by the FDA shortly thereafter did allow patients benefitting from PAC to get back on it, but no new patients have begun treatment with the drug since the hold, Dr. Gerds says.

Despite this setback, Dr. Gerds is hopeful that the new data will influence the FDA’s position: “The investigators have been working very hard over the last several months to finalize the data collection for PERSIST-2, which is now being shared with the FDA,” he says. “Once they see the aggregate safety data, we are hopeful they will amend the hold. My impression is that the FDA just wanted all the available information before moving forward with a positive or negative decision.”

The path forward

In the event the hold is lifted, Dr. Gerds is not certain as to what the process will look like to get PAC approved. He suspects that terms will include additional clinical studies — which may be a single-arm phase 4 marketing study or another randomized-controlled trial with BID dosing — but he sees a path to regulatory approval.

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“If pacritinib passes the safety tests and moves forward, it will have a huge impact on myelofibrosis treatment,” he says. “In addition to being potentially practice-changing for the many myelofibrosis patients with low platelet counts, it may also spill over into other hematologic malignancies since pacritinib has off-target effects on other tyrosine kinases as well.”

Dr. Gerds also notes the value of seeing things through with PAC, both in terms of potential improvements in efficacy and as it relates to this specific population, in which patients often have very low platelet counts.

“If we look at all patients with myelofibrosis, 16 percent will have platelet counts of less than 50,000. Roughly 10 percent will have platelet counts of 50 to 100,000. Add that up and it’s a huge number. So many patients will need a dose reduction or it may be potentially unsafe to treat them with ruxolitinib,” he says.

“Many people have written pacritinib off, but it can still be an important advancement for treating myelofibrosis,” Dr. Gerds concludes. “Those of us in the community are excited about this compound, moreover, the prospect of having a new trement for patients with low platelet counts. Hopefully we will get a favorable safety signal and it can move forward.”