The FDA placed a partial clinical hold on trials of CTI Biopharma Corp.'s lead candidate, pacritinib, citing fatal and life-threatening safety issues in patients treated with the drug vs. those provided best available therapy other than JAK inhibitors in the control arm of PERSIST-1, a phase III study of primary myelofibrosis (MF). The hold also impacts PERSIST-2, an ongoing study extending pacritinib treatment to patients with post-polycythemia vera MF and post-essential thrombocythemia MF.

In particular, the FDA said that it was concerned about heart failure, hemorrhage – including intracranial hemorrhage – and arrhythmias including sudden death. The agency also noted excess mortality in pacritinib-treated patients compared to the control arm in the PERSIST-1.

CTI shares (NASDAQ:CTIC) fell 60.7 percent on the news, closing at 44 cents per share on Monday. Shares have fallen 87.4 percent year to date. Baxalta Inc. (NYSE:BXLT), CTI's partner on the drug, also fell, shedding 4 percent to close at $36.46 amid a down day for major U.S. markets.

CTI has positioned the JAK2/FLT3 multikinase inhibitor as offering a potential advantage over Jakafi (ruxolitinib, Incyte Corp. and Novartis AG), offering an effective treatment option that leads to less treatment-emergent thrombocytopenia and anemia, the most common side effects associated with use of Jakafi in participants with polycythemia vera. Early results from PERSIST-1 seemed to show it delivering on the promise with a positive safety profile, lending credence to Baxter's decision to back the drug with up to $362 million, including a $60 million cash and equity up-front fee. (See BioWorld Today, March 10, 2015.)

On Monday, however, the Seattle-based company said that excess mortality seen in PERSIST-1 was evident during a period of the study in which patients randomized to the non-pacritinib arm were allowed to cross over to the pacritinib arm. Crossovers were allowed at 24 weeks if a patient's disease had progressed or they had met the study's 24-week measurement endpoint, a reduction in spleen volume from baseline of greater than or equal to 35 percent.

Spleen volume reduction is a surrogate endpoint on which CTI and Baxalta are seeking an accelerated approval of pacritinib for the treatment of patients with intermediate and high-risk myelofibrosis with low platelet counts of less than 50,000 per microliter.

Under the partial hold, investigators in PERSIST-1 and PERSIST-2, which recently achieved full enrollment, won't be allowed to enroll new patients or start pacritinib as initial or crossover treatment. Furthermore, patients not deriving benefit after 30 weeks of pacritinib treatment will be advised to stop using it.

In addition, the FDA has recommended that the CTI make certain modifications to its trial protocols, including modifying all protocols for randomized trials to disallow crossover to pacritinib, provide certain unspecified notifications, and revise relevant statements in the related investigator's brochure and informed consent documents, and take certain other actions.

As part of its most recent quarterly filing with the SEC, the company noted that "although crossover design of clinical trials may confound evaluation of survival, such designs are frequently used in cancer studies" and that the FDA has approved other cancer drugs allowing for crossovers during phase III studies.

The company also said that the independent data monitoring committee (IDMC) in place when it negotiated a special protocol assessment for PERSIST-2, had recommended that patients on the best available therapy arm "should not cross over to receive pacritinib due to non-statistically significant safety concerns in patients who crossover after 24 weeks, which crossover confounds evaluation of survival."

However, after receiving input from external independent experts and providing the FDA the PERSIST-1 data, the IDMC's recommendation and correspondence, CTI and Baxalta told the FDA that they would proceed with the SPA-agreed design.

CTI said that it intends to implement the FDA's recommendations and that all clinical investigators worldwide have been provided with notice of the hold. Citing its NDA under review, the company declined to provide an interview with CEO James Bianco.

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