CTI BioPharma has enrolled the first patient in the Phase 3 PRE-VENT trial (NCT04404361) of pacritinib in hospitalized patients with severe COVID-19. PRE-VENT, a randomized, double-blind, placebo-controlled multicenter study, will compare pacritinib plus standard of care versus placebo and standard of care in 358 hospitalized patients with severe COVID-19, including patients with and without cancer. The primary endpoint of the trial will assess the proportion of patients who progress to invasive mechanical ventilation and/or extracorporeal membrane oxygenation or die by Day 28.
"Initiation of patient enrollment in the PRE-VENT Phase 3 trial is an important step for CTI as we work towards providing a new therapeutic option for patients with severe COVID-19," said Adam R. Craig, M.D., Ph.D., President and Chief Executive Officer of CTI BioPharma. "As a multi-kinase inhibitor, pactrinib has the potential to reduce the effects of the cytokine storm that occurs with the novel coronavirus infection, an inflammatory response that frequently leads to respiratory failure and need for mechanical ventilation."
"Preventing COVID-19 patients from developing the severe inflammatory response that leads to respiratory failure is critical as the medical community works to ameliorate the effects of the ongoing pandemic," said John Mascarenhas, M.D., Associate Professor, Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York and Chief Investigator of the PRE-VENT Study. "Because the cytokine storm occurs when multiple inflammatory cytokines are activated, including IL-1 and IL-6, a multi-kinase inhibitor such as pacritinib has the potential to inhibit the inflammatory response and improve patient outcomes."
Cytokine storm is a pathological immune reaction that can be triggered by viral infection and can lead to serious complications, including acute respiratory distress syndrome (ARDS). Multiple inflammatory cytokines are upregulated in patients with severe COVID-19, including IL-1 and IL-6, and some patients have evidence of over-active macrophage activation. As a JAK2/IRAK-1 inhibitor, pacritinib may ameliorate the effects of cytokine storm via inhibition of IL-6 and IL-1 signaling. Furthermore, as a CSF-1R inhibitor, pacritinib may mitigate effects of macrophage activation syndrome. Of particular importance in this indication, pacritinib has not been associated with increased risk in infections in prior randomized studies, likely because it does not have inhibitory effects on JAK1.
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PRE-VENT is expected to enroll 358 patients randomized 1:1 to receive pacritinib (400 mg once daily on Day 1, then 200 mg twice daily from Day 2 to Day 14) + SOC or placebo + SOC. Assigned treatment will continue for up to Day 14 or until the patient experiences intolerable adverse events, withdraws consent, initiates another investigational therapy, or until the study is terminated. Assigned therapy may be given for an additional 7 days (for a total of 21 days) at the discretion of the investigator. In the event of hospital discharge, patients will complete treatment with the assigned therapy on an outpatient basis. Severe COVID-19 will be defined as an oxygen saturation (SO2) ≤93% on room air at sea level, respiratory frequency >30 breaths per minute, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300, or lung infiltrates >50% on radiographic imaging.
The primary endpoint is the effect of treatment on the proportion of patients who require invasive mechanical ventilation and/or extracorporeal membrane oxygenation, or die by Day 28. An interim analysis will be conducted for futility after 154 patients have been enrolled. Safety will be assessed through 30 days of follow-up after the last dose of study treatment and assessed by the cumulative incidence, severity and seriousness of treatment-emergent AEs, drug discontinuations, laboratory values, and clinical assessments.