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Blood Cancer Drug Pacritinib Meets Main Goal in Late-Stage Trial

Treatment reduces spleen volume compared with best available therapy

Positive results have been reported from a phase III registration trial evaluating pacritinib (CTI BioPharma Corp./Baxter International), a next-generation oral Janus kinase 2 (JAK2)/fms-like tyrosine kinase 3 (FLT3) multikinase inhibitor, for the treatment of patients with primary or secondary myelofibrosis.

The PERSIST-1 trial met its primary endpoint in the intent-to-treat population, with statistically significant activity observed in patients irrespective of their initial platelet count, including patients with severe or life-threatening thrombocytopenia at study entry. The primary endpoint was the proportion of patients achieving a 35% or greater reduction in spleen volume from baseline to week 24, as measured by magnetic resonance imaging or computerized tomography, when compared with physician-specified best available therapy (BAT), excluding treatment with JAK2 inhibitors.

PERSIST-1 was a randomized, open-label trial that compared the efficacy and safety of pacritinib with that of BAT (other than JAK2 inhibitors) in 327 patients with primary or secondary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis, without exclusion for low platelet counts. After the completion of 24 weeks of treatment or disease progression, crossover from the BAT arm to pacritinib was allowed.

Treatment with pacritinib provided a clinically and statistically significant response rate (P = 0.0003) in the reduction of spleen volume in patients with myelofibrosis compared with those receiving BAT. The trial results also demonstrated a significant difference among patients with platelet counts of less than 100,000 per microliter (mcL) and less than 50,000/mcL. The magnitude of the treatment effect was consistent with previously reported phase II results, with the greatest reduction observed among the sickest patients (platelet counts of less than 50,000/mcL).

Among 50 patients who were dependent on red blood cell (RBC) transfusions at study entry (six units or more of RBCs over 90 days pre-entry), treatment with pacritinib resulted in a clinically meaningful percentage of patients becoming transfusion-independent compared with those receiving BAT. Of the patients in the BAT arm, 79% crossed over to pacritinib.

The safety profile of pacritinib in the PERSIST-1 trial was consistent with data from prior phase II trials. While the most common treatment-emergent adverse events (AEs) were diarrhea, nausea, and vomiting, the incidence of grade 3 events was lower than that observed in phase II studies. No grade-4 gastrointestinal AEs were reported. Three patients discontinued therapy, and nine patients required dose reductions for diarrhea.

Pacritinib is an oral multikinase inhibitor with dual activity against JAK2 and FLT3. 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 are directly related to the development of several blood-related cancers, including myeloproliferative neoplasms (MPNs), leukemia, and lymphoma.

Although pacritinib suppresses the JAK2/STAT3 pathway, it does not cause myelosuppression and may offer an advantage over other JAK inhibitors in this regard. The kinase profile of pacritinib suggests that its potential therapeutic utility in patients with acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, or chronic lymphocytic leukemia is due to its potent inhibition of the proto-oncogene c-fms, of interleukin-1 receptor-associated kinase 1 (IRAK1), of JAK2, and of FLT3.

In August 2014, pacritinib was granted a “fast track” designation by the FDA for the treatment of patients with intermediate- or high-risk myelofibrosis, including patients with disease-related thrombocytopenia, patients experiencing treatment-emergent thrombocytopenia on other JAK2 therapy, or patients who are intolerant to or whose symptoms are sub-optimally managed on another JAK2 therapy.

Myelofibrosis is a serious and life-threatening chronic bone-marrow disorder caused by the accumulation of malignant bone-marrow cells, which triggers an inflammatory response and scars the bone marrow. The replacement of bone marrow with scar tissue limits the marrow’s ability to produce RBCs, prompting the spleen and liver to take over this function. Symptoms of the disease include splenonegaly, anemia, extreme fatigue, and pain.

Approximately 300,000 people in the U.S. have MPNs; of these individuals, approximately 18,000 have myelofibrosis. At the time of diagnosis, the median age of patients with myelofibrosis is 64 years. Approximately 20% of patients with the disease eventually develop myeloid leukemia. The median overall survival period for myelofibrosis patients is approximately 6 years.

Source: CTI BioPharma; March 6, 2015

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