Clinical Trials

Date: 2017-01-05

Type of information: update on patient enrollment

phase: 3

Announcement: update

Company: CTI BioPharma - previously known as Cell Therapeutics (USA - WA) - Baxalta (USA - IL)

Product: pacritinib

Action mechanism: kinase inhibitor/tyrosine kinase inhibitor. Pacritinib is an oral tyrosine kinase 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 have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia and lymphoma. 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, patients experiencing treatment emergent thrombocytopenia on other JAK2 therapy or patients who are intolerant to or whose symptoms are sub-optimally managed on other JAK2 therapy.

Disease: myelofibrosis

Therapeutic area: Cancer - Oncology

Country: Australia, Belgium, Czech Republic, France, Germany,Hungary, The Netherlands, New Zealand, Russian Federation,UK,USA

Trial details: The PERSIST-1 trial is the first of two Phase 3 trials in the pacritinib development program in myelofibrosis.  PERSIST-1 is a randomized (2:1), open-label, multinational Phase 3 clinical trial comparing the efficacy and safety of pacritinib with that of physician-specified best available therapy (BAT), other than JAK inhibitors, in 327 patients with primary and secondary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF), without exclusion for low platelet counts. The primary endpoint assessed the proportion of patients achieving a 35 percent or greater reduction in spleen volume from baseline to Week 24 as measured by MRI or CT, when compared with BAT, excluding treatment with JAK2 inhibitors. After the completion of 24 weeks of treatment or disease progression, crossover from the BAT arm to pacritinib was allowed. PERSIST-2 is a randomized (2:1), open-label multinational Phase 3 clinical trial evaluating pacritinib compared to BAT, including the approved JAK1/JAK2 inhibitor dosed according to product label for patients with myelofibrosis whose platelet counts are less than or equal to 100,000 per microliter. Patients will be randomized to receive 200 mg pacritinib twice daily (BID), 400 mg pacritinib once daily (QD) or BAT. The trial is designed to enroll up to 300 patients in North America, Europe, Australia, New Zealand and Russia . In October 2013, CTI BioPharma reached agreement with the FDA on a Special Protocol Assessment (SPA) for the PERSIST-2 trial, which is a written agreement between CTI BioPharma and the FDA regarding the planned design, endpoints and statistical analysis approach of the trial to be used in support of a potential NDA submission. Under the SPA, the agreed upon co-primary endpoints are the proportion of patients achieving a 35 percent or greater reduction in spleen volume from baseline to Week 24 of treatment and the proportion of patients achieving a Total Symptom Score (TSS) reduction of 50 percent or greater using MPN-SAF TSS 2.0 diary from baseline to Week 24. (NCT01773187)

Latest news:

• • On January 5, 2017, CTI BioPharma announced that the full clinical hold (February 2016) implemented by the FDA on all clinical trials conducted under the Investigational New Drug (IND) application for pacritinib has now been removed. The Company's complete response submission included, among other items, final Clinical Study Reports for both PERSIST-1 and 2 trials and a dose-exploration clinical trial protocol that the FDA requested. The new trial, PAC203 plans to enroll up to approximately 105 patients with primary myelofibrosis who have failed prior ruxolitinib therapy to evaluate the safety and the dose response relationship for efficacy (spleen volume reduction at 24 weeks) of three dose regimens: 100 mg once-daily, 100 mg twice-daily (BID) and 200 mg BID. The 200 mg BID dose regimen was used in PERSIST-2. The Company expects to start the trial in the second quarter of 2017.
• • On December 6, 2016, CTI BioPharma announced 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) Annual Meeting. Data presented at ASH (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. 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 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/?L), 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.
• • On August 29, 2016, CTI BioPharma announced results from PERSIST-2, a randomized, controlled Phase 3 clinical trial comparing pacritinib with physician-specified best available therapy, including ruxolitinib, for the treatment of patients with myelofibrosis whose platelet counts are less than 100,000 per microliter. Three hundred eleven (311) patients were enrolled in the study, which formed the basis for the safety analysis. Two hundred twenty-one (221) patients who had a chance to reach Week 24 (the primary analysis time point) at the time the clinical hold was imposed and constituted the intent-to-treat (ITT) analysis population utilized for the evaluation of efficacy. Preliminary results demonstrated that the PERSIST-2 trial met one of the co-primary endpoints showing a statistically significant response rate in spleen volume reduction (SVR) in patients with myelofibrosis treated with pacritinib compared to BAT, including the approved JAK2 inhibitor ruxolitinib (p<0.01). Although the PERSIST-2 trial did not meet the other co-primary endpoint of greater than 50 percent reduction in Total Symptom Score (TSS), the preliminary analysis approached marginal significance compared to BAT (p=0.0791).
• The most common treatment emergent adverse events for pacritinib were generally manageable diarrhea, nausea and vomiting. The incidence of cardiac and bleeding adverse events (all grades and grade 3-4 including deaths) were similar across the arms. Overall mortality rates were comparable between arms. Additional data from ongoing analyses along with top-line results from PERSIST-2 will be submitted for presentation at an upcoming scientific meeting. • On June 7, 2016, CTI BioPharma announced long-term safety and efficacy results from the pivotal Phase 3 PERSIST-1 trial evaluating pacritinib versus best available therapy, excluding treatment with JAK2 inhibitors (BAT), in patients with myelofibrosis. As previously reported, the PERSIST-1 trial met its primary endpoint in the intent-to-treat population with statistically significant reduction in spleen volume when compared to patients receiving BAT. The results represent an update on the efficacy and safety for all patients regardless of their initial platelet count, including patients with very low platelet counts at study entry, a condition known as severe or life-threatening thrombocytopenia. The most frequently occurring adverse events with pacritinib were gastrointestinal events and incidence decreased over time. For patients crossing over to receive pacritinib treatment (84 percent of BAT patients), less than 5 percent of patients had diarrhea with only one patient experiencing grade 3. Patients in the BAT arm that crossed over to receive pacritinib treatment had a similar rate of events as patients initially randomized to BAT or pacritinib. A planned analysis of the study up to 72 weeks demonstrated treatment with pacritinib led to durable reductions in spleen volume and symptom burden, two key measures of disease control, in patients with myelofibrosis, including patients with low platelets at baseline (less than 50,000 per microliter and less than 100,000 per microliter). Patients who crossed over to pacritinib from BAT experienced similar reductions in spleen volume and symptom burden as patients initially randomized to pacritinib, including patients with low platelets. •  On February 9, 2016, CTI BioPharma provided an update regarding the clinical studies being conducted under the Company's Investigational New Drug application for pacritinib. Following the oral communication from the FDA followed by a letter notifying the Company that its IND for pacritinib has been placed on full clinical hold, CTI BioPharma has withdrawn its New Drug Application (NDA) until the company has had a chance to review the safety and efficacy data from the PERSIST-2 Phase 3 clinical trial and decide next steps.The FDA's February 8, 2016, letter notes the interim overall survival results from PERSIST-2 show a detrimental effect on survival consistent with the results from PERSIST-1. The deaths in PERSIST-2 in pacritinib-treated patients include intracranial hemorrhage, cardiac failure and cardiac arrest. The FDA made recommendations that supersede the recommendations made by the FDA in connection with the partial clinical hold imposed by the FDA on February 4, 2016. The current recommendations include conducting dose exploration studies for pacritinib in patients with myelofibrosis, submitting final study reports and datasets for PERSIST-1 and PERSIST-2, providing certain notifications, revising relevant statements in the related Investigator's Brochure and informed consent documents and making certain modifications to protocols. In addition, the FDA recommended that the Company request a meeting prior to submitting a response to full clinical hold. Under the full clinical hold, all patients currently on pacritinib must discontinue pacritinib immediately and no patients can be enrolled or start pacritinib as initial or crossover treatment.
• •  On February 8, 2016, CTI BioPharma announced that the company received written communication from the FDA on February 4, 2016, that the FDA has placed a partial clinical hold on the clinical studies being conducted under the Company's Investigational New Drug  application for pacritinib. This clinical hold impacts part of the clinical work currently being conducted under the IND and will also affect planned clinical trials. Under the partial clinical hold, clinical investigators may not enroll new patients or start pacritinib as initial or crossover treatment, and patients not deriving benefit after 30 weeks of pacritinib treatment should stop using pacritinib.
• In addition, the FDA has recommended that the company make certain modifications of protocols, including modifying all protocols for randomized trials to disallow crossover to pacritinib, provide certain notifications, revise relevant statements in the related investigator's brochure and informed consent documents, and take certain other actions. The company intends to implement the FDA's recommendations. All clinical investigators worldwide have been delivered a notice of the partial clinical hold.
• In its written notification, the FDA cited the reasons for the partial clinical hold were that there was excess mortality and other adverse events in pacritinib-treated patients compared to the control arm in the PERSIST-1 trial. The excess mortality was most evident during the non-randomized crossover period following the initial 24 weeks of randomized treatment, during which patients in the control arm could switch to pacritinib treatment. In prior correspondence, the FDA acknowledged the difficulty addressing non-significant results, and that crossover designs can confound the interpretation of safety as well as the evaluation of survival.
• Additionally, CTI BioPharma announced that as of February 3, 2016, it has completed patient enrollment in the PERSIST-2 Phase 3 clinical trial of pacritinib for the treatment of patients with myelofibrosis. PERSIST-2 is evaluating pacritinib for patients with myelofibrosis whose platelet counts are less than or equal to 100,000 per microliter (?100,000/?L). Under the FDA partial clinical hold referenced above, patients currently receiving pacritinib may continue to do so unless they are not deriving benefit after 30 weeks of pacritinib treatment, and crossover of patients from the control arm to the pacritinib arm will not be allowed.
• • On December 5, 2015, CTI BioPharma and Baxalta announced results from a new analysis of the pivotal Phase 3 trial, PERSIST-1, evaluating pacritinib versus best available therapy, excluding treatment with JAK2 inhibitors (BAT), in patients with myelofibrosis. Data examining patient outcomes across baseline demographic factors that are associated with prognosis – including age, baseline hemoglobin, baseline platelet count, ECOG status, JAK2 mutation status and red blood cell transfusion dependency – showed that treatment with pacritinib resulted in consistent rates of spleen volume reduction and control of disease-related symptoms across all intermediate or high-risk myelofibrosis subgroups. These findings were presented by Alessandro M. Vannucchi, M.D., associate professor of Hematology, University of Florence, Italy, during an oral presentation at the 57th American Society of Hematology (ASH 2015) Annual Meeting & Exposition in Orlando. Findings presented at ASH 2015 were based on the analysis of baseline patients' characteristics from PERSIST-1, a randomized Phase 3 registration-directed trial comparing the efficacy and safety of pacritinib to BAT that included a broad range of currently utilized treatments. 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. The subgroup analysis discussed above assessed results observed in patients achieving 35 percent or greater spleen volume reduction from baseline or a decrease of 50 percent or more in Total Symptom Score (TSS) by baseline characteristics or risk factors, including initial platelet count, JAK2V617F mutation status, red blood cell transfusions and bone pain. Findings showed that results (from the primary analysis) were consistent across all subgroups evaluated. Achievement of 35 percent or greater spleen volume reduction was independent of most risk factors assessed and a 50 percent or more decrease in TSS was independent of characteristics evaluated, except bone pain score greater than three at baseline. The most common adverse events in the pacritinib arm vs. BAT that showed more than 5 percent difference were diarrhea (57 percent vs. 12 percent), nausea (29 percent vs. 6 percent) and vomiting (19 percent vs. 5 percent). No Grade 4 gastrointestinal events were reported.
• Also presented were patient-reported outcome data that examined the relationship between myelofibrosis-associated symptoms (based on the TSS) and changes in splenomegaly and health-related quality of life (HRQoL) outcomes in the PERSIST-1 overall patient population and in patients with baseline thrombocytopenia. The analysis showed TSS response was associated with improvements in spleen volume response and perceived Overall Health State; this trend was also observed in patients with low baseline platelet counts (<50,000/µL and <100,000/ µL). In all patient populations analyzed, TSS response was significantly associated with improvements in fatigue, a major contributor to poor HRQoL in patients with myelofibrosis. Significant improvements in social functioning, appetite loss and insomnia were also observed in patients with baseline thrombocytopenia. These data were presented in a poster presentation by Ruben Mesa, M.D., Chair, Hematology and Medical Oncology Division, Mayo Clinic, Scottsdale.
• * On June 12, 2015, CTI BioPharma and Baxter International's BioScience business announced new patient-reported outcome (PRO) data for pacritinib from the Phase 3 PERSIST-1 study. As recently reported at the American Society of Clinical Oncology (ASCO) annual meeting, results show a significant reduction in the Total Symptom Score (TSS) (the proportion of patients with a 50 percent or greater reduction in TSS from baseline to Week 24), and in each individual common disease-related symptom, from baseline to Week 24, in patients treated with pacritinib compared to best available therapy (exclusive of a JAK inhibitor) (BAT). As previously reported, the PERSIST-1 trial met its primary endpoint of spleen volume reduction of 35 percent or greater from baseline to Week 24 as measured by MRI/CT scan. (Patient-Reported Outcomes (PROS) in PERSIST-1: A Randomized, Multi-Country Phase III Trial of the JAK2 Inhibitor Pacritinib (PAC) VS. Best Available Therapy (BAT) in Myelofibrosis (MF) - Abstract #: LB2072 - First Author: Ruben Mesa, M.D., Deputy Director, Mayo Clinic Cancer Center, Chair of the Division of Hematology & Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ and one of the principal investigators for PERSIST-1)
• New data presented at EHA, which included results from multiple PROs measurement tools, showed:
• Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS and MPN-SAF TSS 2.0): When using the MPN-SAF TSS and MPN-SAF TSS 2.0, each of the six common disease-related symptoms from the TSS results showed improvements in abdominal discomfort (46 percent improvement with pacritinib vs no improvement with BAT); bone pain (32 percent improvement with pacritinib vs 8 percent improvement with BAT); feeling of early fullness (45 percent improvement with pacritinib vs 1 percent worsening with BAT); itching (48.5 percent improvement with pacritinib vs 10 percent improvement with BAT); night sweats (69.5 percent improvement with pacritinib vs no improvement with BAT); and fatigue (27.5 percent improvement with pacritinib vs 4 percent worsening with BAT). MPN-SAF TSS and MPN-SAF TSS 2.0 are specific sets of questions patients answer daily (via electronic diary) and which are based on a questionnaire originally developed by Ruben A. Mesa, M.D., Deputy Director of the Mayo Clinic Cancer Center in Scottsdale, Arizona, USA.
• Patient Global Impression of Change (PGIC): Based on the PGIC assessment – which measures a patient's assessment of overall health on a 7-point scale ranging from "very much worse" to "very much improved" – approximately 80 percent of evaluable patients treated with pacritinib rated their condition as improved compared to approximately 20 percent with BAT.
• European Organization for Research and Treatment of Cancer Quality-of-Life 30 Questionnaire (EORTC QLQ-C30) A greater improvement was also reported by evaluable patients treated with pacritinib vs BAT across all components of the EORTC QLQ-C30 questionnaire, a well-validated measure of quality of life in cancer patients.
• The most common adverse events occurring with pacritinib within 24 weeks, of any grade, were mild to moderate diarrhea (53.2 percent vs 12.3 percent with BAT), nausea (26.8 percent vs 6.6 percent with BAT), anemia (22.3 percent vs 19.8 percent with BAT), thrombocytopenia (16.8 percent vs 13.2 percent with BAT), and vomiting (15.9 percent vs 5.7 percent with BAT). Of the patients treated with pacritinib, 3 discontinued therapy and 13 patients required dose interruption (average one week) for diarrhea. Patients received a daily full dose of pacritinib over the duration of treatment. Gastrointestinal symptoms typically lasted for approximately one week and few patients discontinued treatment due to side effects. There were no Grade 4 gastrointestinal events reported.
• • On May 30, 2015, CTI BioPharma and Baxter International's Bioscience business  announced data from PERSIST-1 – a randomized Phase 3 registration-directed trial examining pacritinib for the treatment of myelofibrosis – in a late-breaking oral session at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO), May 29-June 2, 2015 in Chicago, Ill. Data presented at ASCO (Abstract #LBA7006) show that compared to best available therapy (exclusive of a JAK inhibitor), pacritinib therapy resulted in a significantly higher proportion of patients with spleen volume reduction and control of disease-related symptoms.
• PERSIST-1 Findings Presented at ASCO PERSIST-1 is a randomized (2:1), controlled Phase 3 registration-directed trial comparing the efficacy and safety of pacritinib to best available therapy (BAT) – which included a range of currently utilized off-label treatments – in 327 patients with myelofibrosis (primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis), regardless of the patients' platelet counts. At study entry, 46 percent of patients were thrombocytopenic; 32 percent of patients had platelet counts less than 100,000 per microliter (<100,000/uL); and 16 percent of patients had platelet counts less than 50,000 per microliter (<50,000/uL); normal platelet counts range from 150,000 to 450,000 per microliter. The median duration of treatment was 16.2 months in patients treated with pacritinib, compared to 5.9 months in patients treated with BAT. The majority (79 percent) of patients on the BAT arm eventually crossed over to receive pacritinib therapy.
• 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). These results included patients with severe or life-threatening thrombocytopenia. Data presented at ASCO show that when measuring the volume of spleen reduction, the greatest difference in treatment arms was observed in evaluable patients with the lowest platelet counts (<50,000/uL platelets) (33.3 percent with pacritinib vs 0 percent with BAT) (p=0.037).
• Spleen Volume Reduction of ?35% at Week 24 by Platelet Levels

Pacritinib	BAT	p-value
All Platelet Levels
ITT*	19.1% (n=220)	4.7% (n=107)	0.0003
Evaluable**	25.0% (n=168)	5.9% (n=85)	<0.0001
<100,000/uL platelets
ITT	16.7% (n=72)	0% (n=34)	0.0086
Evaluable	23.5% (n=51)	0% (n=24)	0.0072
<50,000/uL platelets
ITT	22.9% (n=35)	0% (n=16)	0.0451
Evaluable	33.3% (n=24)	0% (n=11)	0.0370

• * ITT - primary analysis included all patients randomized. Patients who missed MRI or CT scans at baseline or at Week 24 were counted as non-responders. ** Evaluable - analysis included patients who had assessment at both baseline and at Week 24.
• Beyond the statistically significant reductions in spleen volume, patients treated with pacritinib also experienced a sustained improvement in myelofibrosis-associated symptoms or Total Symptom Score (TSS) as measured by the Myeloproliferative Neoplasm Symptom Assessment Form electronic diary (MPN-SAF TSS and MPN-SAF TSS 2.0). The patient-reported outcomes instrument captures in an electronic diary how a patient feels or functions in relation to their health condition or treatment, including: fatigue, concentration, early satiety/fullness, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. When measuring the secondary endpoint (the proportion of patients with a 50 percent or greater reduction in TSS from baseline to Week 24), patients treated with pacritinib experienced greater improvement in their symptoms when compared to BAT, regardless of their baseline platelet counts (ITT patient population: 24.5 percent of pacritinib-treated patients vs 6.5 percent of BAT-treated patients) (p<0.0001); Evaluable patient population: 40.9 percent of pacritinib-treated patients vs 9.9 percent of BAT-treated patients) (p<0.0001).
• Twenty-five percent (25%) of patients treated with pacritinib who were severely anemic and transfusion dependent – requiring at least six units of blood in the 90 days prior to study entry – became transfusion independent, compared to zero patients treated with BAT (p<0.05). Among patients with the lowest baseline platelets (<50,000/uL) who received treatment with pacritinib, a significant increase in platelet counts was observed over time compared to BAT (p=0.003) – with a 35 percent increase in platelet counts from baseline to Week 24.
• The most common adverse events, occurring in 10 percent or more of patients treated with pacritinib within 24 weeks, of any grade, were: mild to moderate diarrhea (53.2 percent vs 12.3 percent with BAT), nausea (26.8 percent vs 6.6 percent with BAT), anemia (22.3 percent vs 19.8 percent with BAT), thrombocytopenia (16.8 percent vs 13.2 percent with BAT), and vomiting (15.9 percent vs 5.7 percent with BAT). Of the patients treated with pacritinib, 3 discontinued therapy and 13 patients required dose interruption (average one week) for diarrhea. Patients received a daily full dose of pacritinib over the duration of treatment. Gastrointestinal symptoms typically lasted for approximately one week and few patients discontinued treatment due to side effects. There were no Grade 4 gastrointestinal events reported. Data have been presented by Ruben Mesa, M.D., Deputy Director, Mayo Clinic Cancer Center, Chair of the Division of Hematology & Medical Oncology, Mayo Clinic Cancer Center.
• • On March 16, 2015, CTI BioPharma Corp announced that results of a Phase 2 study of pacritinib, in patients with myelofibrosis were published in the journal Blood. Results of the Phase 2 study demonstrated that pacritinib is active in patients with myelofibrosis, resulting in spleen volume reduction, while producing substantial and prolonged improvement in disease-related symptoms without causing clinically significant myelosuppression.
• Phase 2 Study Design and Results: The multicenter, single-arm, open-label Phase 2 study evaluated the safety and efficacy of pacritinib in the treatment of patients with myelofibrosis who had clinical splenomegaly poorly controlled with standard therapies or were newly diagnosed with intermediate- or high-risk disease and not considered candidates for standard therapy. Patients were allowed to enroll irrespective of their degree of thrombocytopenia, anemia or neutropenia. A total of 35 patients were enrolled and treated with pacritinib 400 mg administered once daily in 28-day cycles. The median age of the patients was 69 years. The endpoint of the study was assessment of the spleen response rate, defined as the proportion of subjects achieving 35 percent or greater reduction in spleen volume from baseline up to Week 24 as measured by magnetic resonance imaging (MRI). Other endpoints included the proportion of patients with 50 percent or greater reduction in spleen size as determined by physical exam and the proportion of patients with 50 percent or greater reduction in total symptom score (TSS), including symptoms of abdominal pain, bone pain, early satiety, fatigue, inactivity, night sweats and pruritus, from baseline up to Week 24.
• Results showed that up to Week 24: 30.8 percent of evaluable patients (8/26) had 35 percent or greater reduction in spleen volume by computerized tomography (CT) or MRI scan with 42 percent of patients reaching 35 percent or greater reduction by end of treatment
• 42.4 percent of evaluable patients (14/33) achieved 50 percent or greater reduction in spleen size by physical exam
• 48.4 percent of evaluable patients (15/31) achieved 50 percent or greater reduction in TSS
• The most common treatment-emergent adverse events were Grade 1-2 diarrhea (69%) and nausea (49%), which caused one patient to discontinue treatment. The study drug was discontinued in nine patients (26%) due to adverse events, of which three were deemed unrelated to study drug. There were five deaths, three of which were due to serious adverse events. Of those, one (subdural hematoma) was considered possibly related to study drug. Anemia and thrombocytopenia adverse events were reported in 12 (34.3%) and eight (22.9%) patients, respectively.
• The publication, is titled "Results of a Phase 2 Study of Pacritinib (SB1518), a JAK2/JAK2(V617F) Inhibitor, in Patients with Myelofibrosis,. Preliminary data from the study were presented at the 15th Congress of the European Hematology Association in 2010 and at the American Society of Hematology 2011 Annual Meeting.
• * On March 9, 2015, CTI BioPharma and Baxter  announced positive top-line results for the primary endpoint from PERSIST-1, the randomized, controlled Phase 3 registration clinical trial examining pacritinib, a next generation oral JAK2/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 very low platelet counts at study entry, a condition known as severe or life-threatening thrombocytopenia. The primary endpoint of the trial was 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) when compared with physician-specified best available therapy (BAT), excluding treatment with JAK2 inhibitors. The PERSIST-1 trial demonstrated that pacritinib treatment provided a clinically and statistically significant response rate (p = 0.0003) in spleen volume reduction in patients with myelofibrosis when compared to BAT. Importantly, the trial results also demonstrated a significant difference among patients with platelet counts of less than 100,000 per microliter and less than 50,000 per microliter, both subgroups that were stratified at randomization. The magnitude of treatment effect was consistent with previously reported Phase 2 results, with the greatest reduction observed among the sickest patients (platelet counts <50,000 per microliter). Among 50 patients who were red blood cell ( RBC ) transfusion dependent at study entry (= 6 units of RBC over 90 days pre entry), pacritinib therapy resulted in a clinically meaningful percentage of patients becoming transfusion independent compared to BAT. Seventy-nine percent (79%) of patients in the BAT arm of the study crossed over to pacritinib therapy. The safety profile in the PERSIST-1 trial was consistent with prior Phase 2 trials. While the most common treatment emergent adverse events were diarrhea, nausea and vomiting, the incidence of grade 3 events was lower than observed in Phase 2 trials. No grade 4 gastrointestinal adverse events were reported. Three patients discontinued therapy and nine patients required dose reduction for diarrhea. Preliminary analysis suggests that very few patients discontinued treatment while on pacritinib or required a dose reduction due to treatment-related anemia or thrombocytopenia. Additional data from ongoing analyses along with top-line results from PERSIST-1 will be submitted for presentation at an upcoming scientific meeting.
• Pacritinib is currently being evaluated in two Phase 3 clinical trials, known as the PERSIST program, for patients with myelofibrosis. The PERSIST clinical trials are intended to support a New Drug Application (NDA) to the FDA.
• • On July 1, 2014, CTI BioPharma announced that it has completed recruitment in the PERSIST-1 pivotal Phase 3 clinical trial of pacritinib, a novel oral JAK2/FLT3 inhibitor that is being evaluated for the treatment of myelofibrosis. Under the development and commercialization agreement for pacritinib with Baxter, CTI expects to receive a $20 million development milestone payment in connection with the first treatment dosing of the last patient enrolled in PERSIST-1. CTI expects to achieve this milestone and receive payment by mid-third quarter 2014. The PERSIST-1 trial is the first of two Phase 3 trials in the pacritinib development program in myelofibrosis. The second Phase 3 trial, PERSIST-2 is currently evaluating pacritinib for the treatment of patients with low platelet counts compared to best available therapy, including approved JAK2 inhibitors at their recommended dose and schedule for myelofibrosis patients with thrombocytopenia. The two clinical trials are intended to support an anticipated New Drug Application (NDA) regulatory submission in the U.S. in late 2015, followed by an anticipated Marketing Authorization Application (MAA) in Europe in 2016.
• In March 2014, CTI announced the initiation of the PERSIST-2 trial, which will evaluate pacritinib in patients with myelofibrosis whose platelet counts are less than or equal to 100,000/uL. The trial is designed to enroll up to 300 patients in North America, Europe, Australia, New Zealand and Russia. In October 2013, CTI reached agreement with the FDA on a Special Protocol Assessment for the PERSIST-2 trial, which is a written agreement between CTI and the FDA regarding the planned design, endpoints and statistical analysis approach of the trial to be used in support of a potential NDA submission.

Is general: Yes