On December 6, 2016 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) reported data from PERSIST-2, a randomized Phase 3 clinical trial comparing pacritinib with physician-specified best available therapy (BAT), for the treatment of high risk, thrombocytopenic myelofibrosis patients (platelet counts less than 100,000 per microliter) in a late-breaking oral session at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, December 3-6 in San Diego, CA (Press release, CTI BioPharma, DEC 6, 2016, View Source [SID1234516956]). Pacritinib is an investigational oral multikinase inhibitor. Data presented at ASH (Free ASH Whitepaper) (Abstract #LBA-5) show that in myelofibrosis patients a statistically significant response rate in spleen volume reduction (SVR) with pacritinib therapy was observed compared to BAT that included use of the approved JAK1/JAK2 inhibitor ruxolitinib (p=0.001). The co-primary endpoint of reduction of Total Symptom Score (TSS) was not achieved (p=0.079) but trended toward improvement in TSS. Irrespective of prior ruxolitinib treatment, pacritinib therapy resulted in a statistically significant higher proportion of patients with SVR than patients on BAT.

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"Patients with myelofibrosis who have low platelet counts are often intolerant of ruxolitinib therapy and have no effective treatment options," said John Mascarenhas, M.D., Associate Professor, The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai and the presenter of the results in an oral presentation at ASH (Free ASH Whitepaper). "Data from PERSIST-2 suggest that pacritinib dosed on a twice-daily schedule may prove to be effective therapy for thrombocytopenic myelofibrosis patients with an adequate safety profile to fill an important unmet clinical need."

PERSIST-2 Results Presented at ASH (Free ASH Whitepaper)

PERSIST-2 was a randomized (1:1:1), controlled, open-label, multinational Phase 3 clinical trial evaluating pacritinib compared to best available therapy (BAT), including the approved JAK1/JAK2 inhibitor ruxolitinib, for patients with myelofibrosis whose platelet counts were less than or equal to 100,000 per microliter (≤100,000/μL). Three hundred eleven (311) patients were randomized to receive 200 mg pacritinib twice daily (BID), 400 mg pacritinib once daily (QD) or BAT. Clinical studies for pacritinib are currently subject to a full clinical hold issued by the U.S. Food and Drug Administration (FDA) in February 2016. At the time, the FDA noted interim overall survival results from the PERSIST-2 showing a detrimental effect on survival were consistent with the results from PERSIST-1. Two hundred twenty-one (221) patients (74 pacritinib BID; 75 pacritinib QD; 72 BAT) were enrolled at least 24 weeks prior to the full clinical hold and were potentially evaluable for the Week 24 efficacy endpoint (ITT efficacy population). In the ITT efficacy population at study entry, 46 percent (101/221) of patients had platelet counts less than 50,000 per microliter (<50,000/μL), and 59 percent (130/221) were anemic (hemoglobin <10 g/dL). Normal platelet counts range from 150,000 to 450,000 per microliter. The percentage of patients in the ITT efficacy population who received prior ruxolitinib was as follows: 41 percent (31/75) pacritinib QD; 42 percent (31/74) pacritinib BID; and 46 percent (33/72) BAT.

Safety analyses were based on all patients exposed to study treatment of any duration.

The co-primary endpoints of the trial were the proportion of patients achieving a 35 percent or greater reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computerized tomography (CT) and the proportion of patients achieving a Total Symptom Score (TSS) reduction of 50 percent or greater using the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to Week 24. The primary objective of the study was to compare pooled pacritinib arms versus BAT and the secondary objectives were to compare pacritinib BID and QD arms individually to BAT. Study was designed to evaluate the study objectives with sample size of 300. At the time of clinical hold, study enrollment was completed with 311 patients randomized, but only 221 patients had the potential to be evaluated for efficacy endpoints at Week 24.

As previously reported, the PERSIST-2 trial met one of the co-primary endpoints showing a statistically significant response rate in SVR in patients with myelofibrosis treated with pacritinib combining the once- and twice-daily arms compared to BAT. Although the PERSIST-2 trial did not meet the other co-primary endpoint of greater than 50 percent reduction in TSS, the results approached marginal significance compared to BAT. Although secondary objectives could not be evaluated formally due to the study not achieving one of the primary objectives, when the two pacritinib dosing arms were evaluated separately versus BAT, pacritinib given twice daily showed a higher percent of SVR and TSS responses compared to BAT; whereas, pacritinib given once daily showed only a higher percent SVR responses compared to BAT.

Spleen Volume Reduction of ≥35%; Total Symptom Score Reduction of ≥50% at Week 24


Pacritinib
BAT
p-value*
Pooled BID and QD – Primary objectives
SVR
18%
3%
0.001
TSS
25%
14%
0.079

BID – 200 mg twice daily – Secondary objectives
SVR
22%
3%
0.001
TSS
32%
14%
0.011

QD – 400 mg once daily – Secondary objectives
SVR
15%
3%
0.017
TSS
17%
14%
0.652

* p-value for the secondary objectives were nominal p-values and used for reference.


A total of 45 percent of the BAT patients randomized received ruxolitinib at some point on the study.

There was no significant difference in overall survival (OS) across treatment arms, censored at the time of clinical hold. Hazard ratios (95% confidence intervals (CI)) were 0.68 (0.30-1.53) for pacritinib BID versus BAT and 1.18 (0.57-2.44) for pacritinib QD versus BAT. Overall mortality rates at that time were comparable between arms: 9 percent BID versus 14 percent QD and 14 percent BAT.

The most common treatment-emergent adverse events (AEs), occurring in 20 percent or more of patients treated with pacritinib within 24 weeks, of any grade, were gastrointestinal (generally manageable diarrhea, nausea and vomiting) and hematologic (anemia and thrombocytopenia) and were generally less frequent for BID versus QD administration. The most common serious treatment-emergent AEs (incidence of ≥5 percent reported in any treatment arm irrespective of grade) were anemia, thrombocytopenia, pneumonia and acute renal failure none of which exceeded 8 percent individually in any arm.

"In this randomized Phase 3 clinical trial in thrombocytopenic patients with advanced myelofibrosis that allowed for prior therapy with a JAK inhibitor and allowed use of ruxolitinib in the best available therapy arm," said Srdan (Serge) Verstovsek, M.D., Ph.D., Director, Clinical Research Center for MPNs at the University of Texas MD Anderson Cancer Center and principal investigator for the PERSIST-2 Phase 3 clinical trial of pacritinib, "the data demonstrates pacritinib’s activity in this challenging patient population and shows the potential for pacritinib to effectively retreat patients following failure of anti-JAK2 treatment."

"CTI BioPharma would like to thank all the patients and physicians that participated in the PERSIST-2 trial," said Richard Love, Interim President and CEO of CTI BioPharma. "We are committed to bringing pacritinib to the many myelofibrosis patients in need of new therapies and will continue to work with the regulatory agencies to move the process forward."

Data will be presented today by John Mascarenhas, M.D., in a late-breaking oral session at 8:30 a.m. PT and was selected as part of the official ASH (Free ASH Whitepaper) press program. The presentation will be available at www.ctibiopharma.com following the conclusion of the meeting.

About the Phase 3 Development Program of Pacritinib

Pacritinib was evaluated in two Phase 3 clinical trials, known as the PERSIST program, for patients with myelofibrosis, with one trial in a broad set of patients without limitations on platelet counts, the PERSIST-1 trial; and the other in patients with low platelet counts, the PERSIST-2 trial. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis including, but not limited to, patients with disease-related thrombocytopenia (low platelet counts); patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy; or patients who are intolerant of, or whose symptoms are not well controlled (sub-optimally managed) on other JAK2 therapy.

Clinical studies under the CTI BioPharma investigational new drug (IND) for pacritinib are currently subject to a full clinical hold issued by the U.S. Food and Drug Administration in February 2016. At the time, the FDA noted interim overall survival results from the PERSIST-2 showing a detrimental effect on survival were consistent with the results from PERSIST-1 and that deaths in PERSIST-2 in pacritinib-treated patients include intracranial hemorrhage, cardiac failure and cardiac arrest.

PERSIST-1 was a randomized (2:1), controlled, open-label, multinational Phase 3 trial evaluating the efficacy and safety of pacritinib compared to BAT, excluding JAK2 inhibitors, which included a broad range of currently utilized treatments – in 327 patients with myelofibrosis (primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis), regardless of the patients’ platelet counts. The study included patients with severe or life-threatening thrombocytopenia. Patients were randomized to receive 400 mg pacritinib once daily or BAT, excluding JAK2 inhibitors. As previously reported, the trial met its primary endpoint of spleen volume reduction (35 percent or greater from baseline to Week 24 by MRI/CT scan) in the intent-to-treat population (ITT).

About Pacritinib

Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia and lymphoma. In addition to myelofibrosis, the kinase profile of pacritinib suggests its potential therapeutic utility in conditions such as acute myeloid leukemia, or AML, myelodysplastic syndrome, or MDS, chronic myelomonocytic leukemia, or CMML, and chronic lymphocytic leukemia, or CLL, due to its inhibition of c-fms, IRAK1, JAK2 and FLT3.

About Myelofibrosis and Myeloproliferative Neoplasms

Myelofibrosis is one of three main types of myeloproliferative neoplasms (MPN), which are a closely related group of progressive blood cancers. The three main types of MPNs are primary myelofibrosis (PMF), polycethemia vera (PV) and essential thrombocythemia (ET).1

Myelofibrosis is a serious and life-threatening bone marrow disorder caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response and scars the bone marrow. The replacement of bone marrow with scar tissue limits its ability to produce red blood cells, prompting the spleen and liver to take over this function. Symptoms that arise from this disease include enlargement of the spleen, anemia, extreme fatigue and pain.

The estimated prevalence of MPNs suggest there are approximately 300,000 people living with the disease in the U.S., of which myelofibrosis accounts for approximately 18,000 patients.2 In Europe, there is a wide variation of prevalence observed across data sources. Myelofibrosis has a median age of 64 at the time of diagnosis3 and is a progressive disease with approximately 20 percent of patients eventually developing acute myeloid leukemia (AML).4 The median survival for high-risk myelofibrosis patients is less than 1.5 years, while the median survival for patients with myelofibrosis overall is approximately 6 years.4