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CTI BioPharma Provides Update On Clinical Hold Of Investigational Agent Pacritinib And New Drug Application In U.S.
SEATTLE, Feb. 9, 2016 /PRNewswire/ -- CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) today provided an update regarding the clinical studies being conducted under the Company's Investigational New Drug ("IND") application for pacritinib. Following the issuance of the Company's February 8, 2016, press release describing the partial clinical hold issued by the U.S. Food and Drug Administration (FDA) regarding those clinical studies, the Company received an oral communication from the FDA followed by a letter notifying the Company that the Company's IND for pacritinib has been placed on full clinical hold. The Company has withdrawn its New Drug Application (NDA) until the Company has had a chance to review the safety and efficacy data from the PERSIST-2 Phase 3 clinical trial and decide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.

All clinical investigators worldwide have been delivered a notice of the full clinical hold.
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Source: press release, 2/09/16. http://investors.ctibiopharma.com/phoenix.zhtml?c=92775&p=irol-newsArtic...

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CTI BioPharma Provides Update On Investigational Agent Pacritinib
FDA Places Partial Clinical Hold on Pacritinib IND; Currently Enrolled Patients Benefiting from Pacritinib Can Continue Receiving Pacritinib
Phase 3 Clinical Trial (PERSIST-2) Evaluating Pacritinib for Patients with Myelofibrosis and Platelet Counts of ≤100,000/μL has Completed Enrollment
SEATTLE, Feb. 8, 2016 /PRNewswire/ -- CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA:CTIC) today announced that the Company received written communication from the U.S. Food and Drug Administration (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 ("IND") 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.

The Company intends to work together with the FDA and expects to submit modifications and revisions that address the recommendations noted above. 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.

After submission of the required information, the FDA has indicated that it would notify the Company whether it can continue the clinical studies under the IND.
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Source: press release, 2/08/16. http://investors.ctibiopharma.com/phoenix.zhtml?c=92775&p=irol-newsArtic...

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CTI Opens Enrollment for PERSIST-2 Phase 3 Trial of Pacritinib for Patients with Myelofibrosis Who Have Low Platelet Counts

- This Trial, Together with PERSIST-1, to Support Registration in the U.S. and Europe -

SEATTLE, March 3, 2014 /PRNewswire/ -- Cell Therapeutics, Inc. (CTI) (NASDAQ and MTA: CTIC) today announced the initiation of a Phase 3 clinical trial, known as PERSIST-2, which will evaluate pacritinib, a novel, investigational JAK2/FLT3 inhibitor, in patients with myelofibrosis whose platelet counts are less than or equal to 100,000 per microliter (uL). The trial is expected to enroll up to 300 patients in North America, Europe, Australia and New Zealand within 12 to 14 months. In October 2013, CTI reached agreement with the U.S. Food and Drug Administration (FDA) on a Special Protocol Assessment (SPA) 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 New Drug Application, or NDA, submission. PERSIST-2 is the second of two planned Phase 3 trials in the pacritinib development program for myelofibrosis.

"JAK2 inhibitors have revolutionized the treatment of myelofibrosis by providing patients with an effective way to manage their disease," said Srdan Verstovsek, MD, PhD, principal investigator of PERSIST-2 and 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. "However, I believe there remains a significant unmet medical need for new therapies, particularly for patients who present with or develop thrombocytopenia while on treatment. We are pleased to have the PERSIST-2 trial underway to evaluate the ability of pacritinib to address this issue."

PERSIST-2 is a randomized, open-label, multi-center clinical trial evaluating pacritinib in patients with myelofibrosis (a myeloproliferative neoplasm and chronic bone marrow disorder) whose platelet counts are less than or equal to 100,000/uL. The trial will evaluate pacritinib as compared to best available therapy, including approved JAK2 inhibitors that are dosed according to the product label for myelofibrosis patients with thrombocytopenia. Patients will be randomized (1:1:1) to receive 200 mg pacritinib twice daily (BID), 400 mg pacritinib once daily (QD) or best available therapy. Under the SPA, the agreed upon co-primary endpoints are the percentage of patients achieving a 35 percent or greater reduction in spleen volume measured by MRI or CT scan from baseline to 24 weeks of treatment and the percentage of patients achieving a Total Symptom Score (TSS) reduction of 50 percent or greater using six key symptoms as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks. Additional trial details are available at www.clinicaltrials.gov.

"With the initiation of the PERSIST-2 trial, we believe that the registration program for pacritinib is on track for a potential NDA submission in the latter part of 2015," said James A. Bianco, MD, President and CEO of CTI. "We have seen meaningful clinical benefits and good tolerability with pacritinib in myelofibrosis patients in Phase 2 trials without apparent drug-related thrombocytopenia or anemia. As such, we have had strong interest in site participation for this trial and will work diligently to activate these sites over the next several months."

Pacritinib Development Program in Myelofibrosis

Based on pacritinib's efficacy and tolerability profile demonstrated to date, CTI is pursuing a broad approach to advancing this therapy for myelofibrosis patients by conducting two Phase 3 clinical trials: one in a broad set of patients without limitations on blood platelet counts, the ongoing PERSIST-1 trial, and the other in patients with low platelet counts, the PERSIST-2 trial, as described above.

In January 2013, CTI initiated PERSIST-1, which is a 270 patient randomized, open-label, multicenter Phase 3 trial comparing the efficacy and safety of pacritinib with that of best available therapy in patients with myelofibrosis. Best available therapy includes any physician-selected treatment other than JAK inhibitors and there is no exclusion by patient platelet count. The trial is currently enrolling patients at clinical sites in Europe, Australia, Russia and the United States. More details on the PERSIST-1 study can be found at www.clinicaltrials.gov.
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Source: press release, 3/03/14. http://investors.celltherapeutics.com/phoenix.zhtml?c=92775&p=irol-newsA...

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A Randomized Controlled Phase 3 Study of Oral Pacritinib Versus Best Available Therapy in Patients With Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis
Enrollment: 327
Study Start Date: December 2012
Estimated Study Completion Date: January 2018
Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
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Source: clinical trials.gov. http://clinicaltrials.gov/ct2/show/NCT01773187?term=pacritinib&rank=2

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
PacritinibOncology HematologicMyelofibrosisJanus-associated Kinase InhibitorsJanus-associated Kinase 2 (JAK2)

Mechanism of action: Pacritinib is an orally bioavailable inhibitor of Janus kinase 2 (JAK2) and the JAK2 mutant JAK2V617F with potential antineoplastic activity. Pacritinib competes with JAK2 for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and so caspase-dependent apoptosis. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders; the JAK2V617F gain-of-function mutation involves a valine-to-phenylalanine modification at position 617. The JAK-STAT signaling pathway is a major mediator of cytokine activity.

Phase of Development: III

Event Type: Data: Phase III trial results

Dates: 2015-04-01 - 2015-09-30

Results:

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PERSIST-2 Phase 3 Study Of Pacritinib Versus Best Available Therapy Shows Encouraging Clinical Activity In High-Risk Patients With Advanced Myelofibrosis In Late-Breaking Session At ASH Annual Meeting
Trial demonstrates statistically significant improvement in spleen volume reduction with pacritinib compared to best available therapy including ruxolitinib, irrespective of prior anti-JAK treatment
SEATTLE, Dec. 6, 2016 /PRNewswire/ -- CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) today 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, December 3-6 in San Diego, CA. Pacritinib is an investigational oral multikinase inhibitor. 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.

"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. "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

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 press program. The presentation will be available at www.ctibiopharma.com following the conclusion of the meeting.
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Source: press release, 12/06/16. http://investors.ctibiopharma.com/phoenix.zhtml?c=92775&p=irol-newsArtic...

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CTI BioPharma Announces Top-Line Results From PERSIST-2 Phase 3 Trial Of Pacritinib For High-Risk Patients With Advanced Myelofibrosis
Trial demonstrates statistically significant improvement in spleen volume reduction (SVR) with pacritinib compared to best available therapy (BAT), including ruxolitinib
Oral pacritinib is the only JAK2 inhibitor evaluated in a randomized clinical trial in patients with thrombocytopenia (<100,000 platelets) to demonstrate a significant improvement in SVR, including in patients who had inadequate responses on marketed anti-JAK2 or failed prior anti-JAK2
SEATTLE, Aug. 29, 2016 /PRNewswire/ -- CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) today announced top-line results from PERSIST-2, a randomized, controlled Phase 3 clinical trial comparing pacritinib, an investigational oral multikinase inhibitor, with physician-specified best available therapy (BAT), including ruxolitinib, for the treatment of patients with myelofibrosis whose platelet counts are less than 100,000 per microliter -- a patient population with high-risk advanced disease. 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).

"Unlike patients with myelofibrosis who have normal baseline platelet counts where median survival is reported at 88 months, we recently reported from our institution's experience that patients with severe thrombocytopenia (low platelets) had a median survival of about 14 months," 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. "These patients represent up to 30 percent of all myelofibrosis patients and an unmet medical need. Data from the PERSIST-2 prospective randomized, controlled trial is encouraging because we need an effective therapy to treat the most challenging patients with low platelet counts we see in our practice."

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 MPN-SAF TSS 2.0 diary from baseline to Week 24.

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.

Myelofibrosis is associated with significantly reduced quality of life and shortened survival. Spleen enlargement (splenomegaly) is a common and debilitating symptom of myelofibrosis. As the disease progresses, the body slows production of important blood cells and within one year of diagnosis the incidence of disease-related thrombocytopenia (very low blood platelet counts), severe anemia and red blood cell transfusion requirements increase significantly.

"Having analyzed data from two Phase 3 trials with the only JAK inhibitor to be studied in severely thrombocytopenic patients, including patients on JAK2 therapy or those who failed prior JAK2, we are encouraged by pacritinib's clinical profile in this difficult-to-treat group of patients with myelofibrosis," said James A. Bianco, M.D., President and Chief Executive Officer, CTI BioPharma. "We are grateful for the support and commitment of the investigators, our steering committee and, most importantly, all the patients who participated in PERSIST-2."
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Source: press release, 8/29/16. http://investors.ctibiopharma.com/phoenix.zhtml?c=92775&p=irol-newsArtic...

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