Results from a pooled analysis of data from completed Phase I and II studies of pacritinib, an oral JAK2/FLT3 inhibitor, demonstrated the safety and tolerability profile of pacritinib in patients with myelofibrosis. An integrated safety analysis of four completed Phase I and II studies totaled 191 patients who were treated with pacritinib for myeloid, primarily myelofibrosis, or lymphoid malignancies to quantify clinical toxicities, with a focus on hematologic effects.

Myelofibrosis is classified as a myeloproliferative neoplasm and is a chronic bone marrow disorder. Myelofibrosis is caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response, scarring the bone marrow and limiting 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. It is estimated that the prevalence of myelofibrosis is approximately 30,000 in the United States.[1]

Pacritinib is an oral, once-a-day, tyrosine kinase inhibitor (TKI) with dual activity against Janus kinase 2 (JAK2), the JAK2 mutant JAK2V617F and FLT3. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders. [2]

The JAK family of enzymes are 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.

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The use of JAK2 inhibitors to treat myelofibrosis has been a breakthrough for patients with myelofibrosis.

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Other JAK2 inhibitors have generally been associated with increases in treatment-emergent anemia and thrombocytopenia but this was not observed with pacritinib. This integrated safety data analysis showed that, regardless of initial platelet counts, pacritinib causes minimal further marrow suppression. Even patients with initial platelet counts <50,000/?L, a high-risk population, tolerated therapy, maintained stable blood and platelet counts and did not require dose reductions for thrombocytopenia. Grade 1 or 2 gastrointestinal events, particularly diarrhea, were the most common adverse events and may be controlled by early administration of standard anti-diarrheal agents.

The analysis was presented during a poster session at the 18th Annual Meeting of the European Hematology Association (EHA) held June 13-16, 2013 in Stockholm, Sweden.[3]

PERSIST-1
Pacritinib is currently being evaluated in a randomized Phase III clinical trial, known as PERSIST-1, in patients with myelofibrosis. Because of pacritinib’s relative lack of bone marrow suppression, there are no study entry restrictions due to thrombocytopenia or anemia and patients with platelet and red blood cell transfusion dependence are allowed to enroll in the ongoing PERSIST-1 trial.

Well-tolerated
“The use of JAK2 inhibitors to treat myelofibrosis has been a breakthrough for patients with myelofibrosis, however, there still exists a significant unmet need for less myelosuppressive agents given the nature of this disorder,” said Srdan Verstovsek, M.D., Ph.D., Professor, Leukemia Department, Division of Cancer Medicine, Chief, Section for Myeloproliferative Neoplasms, Leukemia Department, and Director, Clinical Research Center for MPNs at the University of Texas MD Anderson Cancer Center (photo). “This pooled safety analysis supports that pacritinib is well-tolerated with limited hematologic side effects that would allow it to be potentially used across all myelofibrosis patients, particularly in those with low blood cell count.”

Integrated Safety Analysis Results
A review of the safety database from four clinical studies included a Phase I/II study in advanced myeloid malignancies, a Phase I and Phase II study in advanced lymphoid malignancies, and a Phase I/II study in myelofibrosis. A total of 191 patients were treated with pacritinib: 129 with advanced myeloid malignancies, including 122 patients with myelofibrosis and 7 patients with acute myeloid leukemia; and 62 patients with advanced lymphoid malignancies, including 38 patients with non-Hodgkin lymphoma and 24 patients with Hodgkin lymphoma. Of the patients with myeloid disorders, 44% had baseline platelet counts <100,000/?l. Pacritinib was dosed from 100 to 600 mg daily during Phase I and 400 mg during Phase II. One hundred and forty-six patients were dosed at or greater than 400 mg daily. The median dose delivered was 98% of intended. The median treatment duration was 306 days (range 2-1210) for those with myeloid disorders and 90.5 days (range 1-631) for lymphoid disorders.

Most patients had no decline in hemoglobin or platelet count during the studies. Of the 30 patients with myeloid disorder with baseline platelet counts <50,000/?L from Phase I and II studies, the median decline in platelet count observed at the end of study was 3,000/?L. In the 11 patients with myelofibrosis with baseline platelet counts <50,000/?L enrolled in Phase II studies, no dose reduction were required for worsening thrombocytopenia.

The most common adverse events were gastrointestinal, particularly diarrhea, most of which were grade 1 or 2. Per the protocols, anti-diarrheal prophylaxis was not used routinely in these early studies; however, anecdotal data from treating physicians where used suggests toxicity is readily controlled with early administration of standard anti-diarrheal agents. Time to onset of diarrhea was ?30 days in 89% of those affected but rarely caused drug discontinuation (1%). The most common serious adverse events reported (?2%) included pneumonia (4.7%) and anemia (3.1%).

“Myelofibrosis is a chronic disease which will require prolonged dosing potentially for years if we are to attempt modifying the disease and its natural history,” said Steven Benner, M.D., M.H.S., Chief Medical Officer at CTI. “We believe this analysis shows that pacritinib is well-tolerated and could potentially serve to treat these patients over an extended period of time.”

PK/PD data
In addition to detailed safety results, pharmacokinetic (PK)/pharmacodynamic (PD) data were also presented at the conference (Abstract #P983)[4]

The PK/PD data was based on two single-dose PK studies conducted in healthy volunteers to assess the effect of food and the inter- and intra-individual variability of pacritinib. Pooled efficacy data from completed Phase I/II studies with patients treated up to 600 mg daily were utilized to construct the exposure-response relationship for the clinical response of pacritinib in myelofibrosis. With pacritinib at a100 mg daily dose, mean steady-state plasma levels exceed the in vitro IC50 values for inhibition of the targeted kinases (JAK2/FLT3). A total of 26 out of 65 (40%) myelofibrosis patients that received the 400 mg daily dose regimen of pacritinib achieved ? 50% reduction in spleen size by physical exam assessed through 24 weeks. PK assessments showed slow absorption and dose-related increases in systemic exposure demonstrating a long elimination half-life supporting a daily regimen of pacritinib.

Comparison of drug concentrations on days 1 and 15 showed a 1.5-to 2-fold increase in exposure at steady-state. There was only minimal incr
ease in systemic exposure at doses beyond 400 mg daily suggesting involvement of a saturable process in oral absorption of pacritinib. There is no significant effect of food on pacritinib PK allowing pacritinib to be orally administered without regard to timing of meals. In summary, pacritinib’s exposure-response relationship supports selection of the 400 mg daily regimen of pacritinib in the ongoing Phase III pivotal trials.

References:
[1] MPN Research Foundation. What is Primary Myelofibrosis. Last accessed on June 14, 2013 .[Read Article]
[2]NCI Drug Dictionary – pacritinib
[3] Abstract #P278 (Poster session). Safety Overview of Phase 1-2 Studies of Pacritinib, a Non-Myelosuppressive JAK2/FLT3 Inhibitor, in Patients with Hematological Malignancies. Date: Friday, June 14, 5:45 to 7:00 p.m. CEST.
[4] Abstract #P983 (Poster session). Characterization of the Pharmacokinetic and Pharmacodynamic Properties of Pacritinib, a Novel Oral JAK2/FLT3 Inhibitor, in Patients with Myelofibrosis, AML and Lymphoma. Date: Saturday, June 15, 5:45 to 7:00 p.m. CEST.

Photo: Srdan Verstovsek, M.D., Ph.D., Professor, Leukemia Department, Division of Cancer Medicine, Chief, Section for Myeloproliferative Neoplasms, Leukemia Department, and Director, Clinical Research Center for MPNs at the University of Texas MD Anderson Cancer Center. Photo Courtesy: University of Texas MD Anderson Cancer Center.

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