The investigational agent pacritinib (CTI BioPharma) holds promise as a treatment option for patients with myelofibrosis and baseline thrombocytopenia, and previous concerns that led to a hold on clinical trials have now been dispelled.
In a pivotal trial, PERSIST-2, pacritinib was significantly more effective than the best available therapy, including ruxolitinib (Jakafi, Incyte), in reducing splenomegaly and trended toward a reduction in total symptom score in patients with myelofibrosis and thrombocytopenia.
The study was published online March 8 in JAMA Oncology.
Ruxolitinib, which was approved in 2011 and the first drug ever approved for myelofibrosis, is not safe for patients with low platelet counts.
"The label on ruxolitinib states it is for patients with platelet counts above 50,000, so it isn't a viable option for those with thrombocytopenia," said lead author, John Mascarenhas, MD, associate professor of medicine, hematology and medical oncology, at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York.
"Thrombocytopenia is a well-known negative prognostic factor, and what this new drug has shown is that it can treat myelofibrosis and low platelets, and not induce the same anemia and thrombocytopenia as one would see with other agents, including ruxolitinib," Mascarenhas explained in an interview. "It would fill an urgent unmet need for this population."
Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CSF1R, with negligible activity against JAK1 that also suppresses the interleukin-1–directed inflammatory pathway via inhibition of interleukin-1 receptor–associated kinase.
"The profile of pacritinib, and the kinases it inhibits is quite different from that of ruxolitinib," he said. "Ruxolitinib acts as an inhibitor of JAK1 and JAK2, and there are also a variety of differences in the effect they have on cytokines and on the spleen. It's probably because of this profile that we see less myelosuppression and that's an important point."
Mascarenhas noted that moving forward, he can see this drug used in two populations: in patients with myelofibrosis and low platelet counts, who are not eligible for ruxolitinib, and in patients receiving second-line treatment after ruxolitinib failure.
Clinical Hold Lifted
An earlier trial, the phase 3 PERSIST-1 trial (Lancet Haematol. 2017;4:e225-e236), compared daily pacritinib with the best available therapy (excluding ruxolitinib) and found that pacritinib demonstrated "significant and durable" spleen volume reduction and symptom control irrespective of baseline platelet count.
The current study (PERSIST-2) is a follow-up that assessed the use of pacritinib in patients with myelofibrosis and thrombocytopenia.
However, the US Food and Drug Administration (FDA) placed a full clinical hold on pacritinib on February 8, 2016, because of concerns over bleeding and cardiovascular events and deaths observed in PERSIST-1. All clinical trial patients currently receiving pacritinib had to discontinue the agent immediately, and no further patients could be enrolled or start pacritinib for initial or crossover treatment.
The clinical hold subsequently led to early termination of PERSIST-2, which resulted in incomplete data. The FDA was provided with the final clinical study reports from PERSIST-1 and PERSIST-2 and ultimately requested an additional study to determine whether a lower dose of pacritinib would be safer while maintaining efficacy.
This led to the phase 2 PAC203 trial, explained Mascarenhas, which is enrolling patients and will assess the safety and efficacy of lower doses of pacritinib (100 mg once daily, 100 mg twice daily, and 200 mg twice daily). After the FDA reviewed the mature data from PERSIST-1 and the complete PERSIST-2 data, along with the PAC203 study protocol, the clinical hold was removed a year later on January 5, 2017.
In the PERSIST-2 study, Mascarenhas and colleagues randomly assigned (1:1:1) 311 patients with myelofibrosis whose platelet counts were 100,000 100,000/μL or less to receive 200 mg pacritinib twice daily, 400 mg pacritinib once daily, or best available therapy (including ruxolitinib). Crossover to pacritinib was permitted for progression of splenomegaly or after 24 weeks of treatment, with or without progression. The results of this trial were initially presented at the American Society of Hematology annual meeting in December 2016.
The co-primary endpoints were the percentage of patients who attained both a spleen volume reduction of at least 35% as assessed by imaging and a 50% reduction in symptom burden after 24 weeks of therapy.
The agents used in the control group were ruxolitinib (n = 44 [45%]), hydroxyurea (n = 19 [19%]), and prednisone and/or prednisolone (n = 13 [13%]). In addition, 19 patients (19%) were followed with watchful waiting only.
Overall, pacritinib given twice daily led to significant improvements in both endpoints compared with the control group.
At week 24 (database lock on August 19, 2016), 27 patients (18%) receiving pacritinib (n = 11 [15%] once daily and n = 16 [22%] twice daily) achieved spleen volume reduction of 35% or more vs 2 patients (3%) receiving best available therapy (P = .001, P = .02, P = .001, respectively).
For the second endpoint, 37 patients (25%) receiving pacritinib (n = 13 [17%] once daily and n = 24 [32%] twice daily) achieved a reduction in symptom burden of 50% or greater compared with 10 controls (14%) receiving best available therapy (P = .08, P = .65, and P = .01, respectively).
In addition, 6 patients (19%) who received ruxolitinib reduced their symptom burden by 50% or more. Among those receiving pacritinib, 3 patients (10%) reduced their symptom by at least 50%, as did 10 patients (32%) who had previously been treated with ruxolitinib. The median percentage changes in total symptom score were −27%, −41%, and −15% in patients receiving pacritinib once daily, pacritinib twice daily, and controls, respectively.
When researchers looked at overall survival, the differences among the three study groups did not reach significance (hazard ratios vs controls for pacritinib once daily and twice daily: 1.18 [95% confidence interval (CI), 0.57 - 2.44] and 0.68 [95% CI, 0.30 - 1.53]). The overall death rate was lower for patients who crossed over to pacritinib (4 patients [8%]) than for those who did not (10 patients [20%]).
The most common (>10%) grade 3/4 adverse events observed in the three groups were thrombocytopenia (31%, 32%, 18%) and anemia (27%, 22%, 14%) for patients receiving pacritinib once daily, pacritinib twice daily, and controls, respectively. Discontinuation due to adverse events was higher in the pacritinib groups, and occurred in 14%, 9%, and 4% of patients (pacritinib once daily, pacritinib twice daily, and controls).
The abrupt cessation of the trial due the FDA clinical hold limited complete enrollment and sufficient time for the entire cohort to reach 24 weeks of therapy, for a full analysis, Mascarenhas noted. However, despite this limitation, the study did meet its endpoint of statistical significance for spleen volume reduction, although not symptom response.
Importantly, the initial concerns regarding excessive deaths due to pacritinib treatment were not observed in the full analysis of mature data, and the survival curves in the three cohorts were not statistically different. The new phase 2 PAC203 trial, which will explore lower doses of pacritinib, will provide further pharmacokinetic data that will help determine the optimal dose and schedule for this agent.
"Road of Broken Dreams"
In an invited commentary, Maximilian Stahl, MD, and Amer M. Zeidan, MBBS, MHS, both from Yale University, New Haven, Connecticut, point out the need for new therapies and the difficulties in getting new treatments to market.
Ruxolitinib, the only approved drug for myelofibrosis, is "not without significant limitations," is not curative, and has a limited disease-modifying effect at best. "The development of newer JAK inhibitors to overcome some of these limitations has been a difficult road full of failures," they write.
One failure is momelotinib, another JAK inhibitor, which "made a stop in the road of broken dreams." It failed to show superiority in patients after ruxolitinib failure compared to best alternative therapies. Another drug, fedratinib, was also far along in trials when the manufacturer discontinued all studies after the FDA imposed a clinical hold because several patients developed Wernicke encephalopathy in 2013.
"In the spirit of the German poet Goethe, there is still a long road ahead and significant effort will be required to get both more effective and safer JAK inhibitors approved," say the editorialists. "It remains to be seen whether other novel non–JAK2-mediated therapies will be the future of progress in [myelofibrosis] therapy."
The study was supported by CTI BioPharma Corp. Mascarenhas has received research funding from CTI BioPharma Corp, Incyte, and Promedior; several coauthors also report relationships with industry, including CTI BioPharma Corp. Zeidan served as a consultant for and received honoraria from Ariad, Gilead, Pfizer, Incyte, and Celgene.
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Cite this: Pacritinib Can Fill Unmet Need in Myelofibrosis - Medscape - Mar 13, 2018.