CTI Announces New Data Presented at EHA 2013 Congress Demonstrating the Safety and Tolerability Profile of Pacritinib in Patients with Myelofibrosis
- Pooled Analysis from Four Phase 1 and Phase 2 Clinical Studies Demonstrates Persistence of Treatment -
SEATTLE, June 17, 2013 /PRNewswire/ — Cell Therapeutics, Inc. (CTI) (NASDAQ and MTA: CTIC) today announced results from a pooled analysis of data from completed Phase 1 and 2 studies of pacritinib, an oral JAK2/FLT3 inhibitor, demonstrating the safety and tolerability profile of pacritinib in patients with myelofibrosis. An integrated safety analysis of four completed Phase 1 and 2 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. Other JAK2 inhibitors have generally been associated with increases in 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/µL, 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 18(th) Congress of the European Hematology Association (EHA) held June 13-16, 2013 in Stockholm, Sweden.
Pacritinib is currently being evaluated in a randomized Phase 3 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. More details on this study can be found at www.clinicaltrials.gov. Pacritinib has orphan drug designation in the United States and Europe.
Abstract #P278: Safety Overview of Phase 1-2 Studies of Pacritinib, a Non-Myelosuppressive JAK2/FLT3 Inhibitor, in Patients with Hematological Malignancies. Poster session, Friday, June 14, 5:45 to 7:00 p.m. CEST.
“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. “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 1/2 study in advanced myeloid malignancies, a Phase 1 and Phase 2 study in advanced lymphoid malignancies, and a Phase 1/2 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 percent had baseline platelet counts <100,000/µl. Pacritinib was dosed from 100 to 600 mg daily during Phase 1 and 400 mg during Phase 2. One hundred and forty-six patients were dosed at or greater than 400 mg daily. The median dose delivered was 98 percent 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.
Hematologic Safety is summarized in the table below.
Safety population (n=189) Hb shift from Platelet shift from baseline to last baseline to last value value (>1 post-baseline value) ----------------------- --- No shift 101(53.4%) 108 (57.1%) -------- -------- ---------- Cytopenia Improvement --------------------- 1 grade improvement 28 (14.8%) 17 (9%) ------------------- --------- ------ 2-4 grade improvement 6 (3.2%) 2 (1.1%) --------------------- ------- ------- Cytopenia Decline ----------------- 1-2 grade decline 51 (27%) 52 (27.5%) ----------------- ------- --------- 3-4 grade decline 1 (0.5%) 8 (4.2%) ----------------- ------- ------- Note: 2 patients did not have Common Terminology Criteria (CTC grades) at baseline or post-baseline due to missing laboratory normal ranges.
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/µL from Phase 1 and 2 studies, the median decline in platelet count observed at the end of study was 3,000/µL. In the 11 patients with myelofibrosis with baseline platelet counts <50,000/µL enrolled in Phase 2 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 percent of those affected but rarely caused drug discontinuation (1%). The most common serious adverse events reported (>=2 percent) included pneumonia (4.7 percent) and anemia (3.1 percent).
“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.”
In addition to detailed safety results, pharmacokinetic (PK)/pharmacodynamic (PD) data were presented at the conference.
Abstract #P983: Characterization of the Pharmacokinetic and Pharmacodynamic Properties of Pacritinib, a Novel Oral JAK2/FLT3 Inhibitor, in Patients with Myelofibrosis, AML and Lymphoma. Poster session, Saturday, June 15, 5:45 to 7:00 p.m. CEST.
Two single-dose PK studies were 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 1/2 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 IC(50) values for inhibition of the targeted kinases (JAK2/FLT3). A total of 26 out of 65 (40 percent) myelofibrosis patients that received the 400 mg daily dose regimen of pacritinib achieved >= 50 percent 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 increase 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 3 pivotal trials.
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 JAK2 and FLT3. 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. Pacritinib may offer an advantage over other JAK inhibitors through effective treatment of symptoms while having less treatment-emergent thrombocytopenia and anemia than has been seen in currently approved and in-development JAK inhibitors.
About Cell Therapeutics, Inc.
Cell Therapeutics (NASDAQ and MTA: CTIC) is a biopharmaceutical company committed to the development and commercialization of an integrated portfolio of oncology products aimed at making cancer more treatable. CTI is headquartered in Seattle, WA. For additional information and to sign up for email alerts and get RSS feeds, please visit www.CellTherapeutics.com.
Safe Harbor Statement
This press release includes forward-looking statements that involve a number of risks and uncertainties the outcome of which could materially and/or adversely affect actual future results and the market price of CTI’s securities. Specifically, the risks and uncertainties that could affect the development of pacritinib include risks associated with preclinical and clinical developments in the biopharmaceutical industry in general, and with pacritinib in particular, including, without limitation, the potential failure of pacritinib to prove safe and effective for the treatment of patients with myelofibrosis, either alone or in combination regimens, as determined by the U.S. Food and Drug Administration and/or the European Medicines Agency; that pacritinib may not satisfy a medical need not currently addressed with existing non-selective JAK1/JAK2 inhibitors; that adverse events from treatment with pacritinib may not be controllable; that the PERSIST-1 clinical trial of pacritinib may not occur as planned; that 270 patients may not enroll in the PERSIST-1 clinical trial; that the second Phase 3 clinical trial of pacritinib may not occur as planned; that CTI may not be able to successfully implement its plans, strategies and objectives related to the development of pacritinib; that CTI may not be able to continue to raise capital as needed to fund its operations and other risks, including, without limitation, competitive factors, technological developments, costs of developing, producing and selling PIXUVRI, pacritinib and CTI’s other product candidates; and the risk factors listed or described from time to time in CTI’s filings with the Securities and Exchange Commission including, without limitation, CTI’s most recent filings on Forms 10-K, 10-Q and 8-K. Except as may be required by law, CTI does not intend to update or alter its forward-looking statements whether as a result of new information, future events, or otherwise.
- MPN Research Foundation. Available at http://www.mpnresearchfoundation.org/Primary-Myelofibrosis. Accessed May 2013.
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