Pacritinib is being explored in the phase 3 PRE-VENT trial as a treatment for cytokine storm in hospitalized patients with severe COVID-19.
The oncology drug pacritinib, an investigational JAK2, IRAK1, and CSF1R inhibitor, is being explored in the phase 3 PRE-VENT trial as a treatment for cytokine storm in hospitalized patients with severe COVID-19.1
Cytokine storm, a type of severe immune overreaction that has presented in severely ill patients with COVID-19, can cause life-threatening respiratory complications. Pacritinib has primarily been explored as a treatment for patients with myelofibrosis. PRE-VENT is comparing standard of care (SOC) plus either pacritinib or placebo in patients with COVID-19.
"Patients with severe COVID-19, particularly those with cancer, are at high risk for serious complications from the disease stemming from cytokine storm, an inflammatory response that causes white blood cells to not only fight the viral infection, but also damage tissue, primarily in the lungs," John Mascarenhas, MD, chief investigator of the PRE-VENT study and associate professor, Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, stated in a press release.
"Because pacritinib inhibits JAK2, IRAK-1, and CSF1R, there is real potential for pacritinib to prevent patients from developing an inflammatory response to the coronavirus infection and subsequent pulmonary failure, therefore reducing the need for a ventilator,” added Mascarenhas.
The target enrollment for the PRE-VENT trial is 358 patients with severe COVID-19, including patients with and without cancer. According to a press release from CTI BioPharma, the developer of pacritinib, the PRE-VENT trial is defining severe COVID-19 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.”
Enrollment is expected to begin in May at clinical locations in the United States and Europe. Patients will be randomized to SOC plus placebo or pacritinib (400 mg once daily on day 1 followed by 200 mg twice daily from days 2-14). Patients will receive treatment until day 14, or until unacceptable toxicity, withdrawal of consent, or commencement of a different investigational treatment. At the discretion of the investigator, a patient may receive his or her randomized treatment for another 7 days (maximum of 21 days overall). The assigned therapy will be completed as an outpatient if a study subject is discharged from the hospital.
Addressing the rational for studying pacritinib in this setting, CTI explained in the press release, “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 overactive 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.”
The drug has shown promise as an investigational treatment for patients with myelofibrosis, but has also had some safety concerns. In February 2016, the FDA placed a full clinical hold on pacritinib studies following reports of patient deaths related to intracranial hemorrhage, cardiac failure, and cardiac arrest in the PERSIST-2 myelofibrosis trial. To rectify the hold, CTI BioPharma provided the FDA with final clinical study reports from the PERSIST-1 and 2 myelofibrosis trials and initiated the PAC203 trial. In January 2017, the FDA lifted the clinical hold on trials exploring pacritinib.
In the open-label PERSIST-2 trial, patients with myelofibrosis and platelet counts ≤100,000/μL were randomized in a 2:1 ratio to pacritinib or best available therapy, which could include ruxolitinib.
In the PERSIST-1 trial, 327 patients were randomized 2:1 to receive 400 mg pacritinib daily versus physician’s choice of best available therapy, excluding ruxolitinib.2 The most frequently used treatments in the control arm were hydroxycarbamide (55.7%) and a watch-and-wait strategy (25.5%).
Patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythema-myelofibrosis were eligible for the trial. There was no required platelet level for enrollment, with 32% of patients having platelet levels <100,000/μL and 16% having platelet counts <50,000/μL. The primary endpoint of the study was spleen volume reduction ≥35%.
The median duration of treatment was 16.2 months with pacritinib compared with 5.9 months in the control arm. Overall, 79% of those in the control arm crossed over to receive pacritinib. After 24 weeks of follow-up, the spleen volume was reduced by ≥35% for 19.1% of patients treated with pacritinib versus 4.7% of those in the best available therapy arm (P = .0003).
In those with platelets <100,000/μL, spleen volume reduction was seen in 16.7% of patients treated with pacritinib versus 0% with best available therapy (P = .0086). In those with platelet counts <50,000/μL, 22.9% of patients treated with pacritinib experienced spleen volume reduction versus none in the control arm.
Additionally, more patients treated with pacritinib experienced a ≥50% reduction in total symptom score at 24 weeks using the Myeloproliferative Neoplasm Symptom Assessment. Overall, 24.5% of patients in the pacritinib arm experienced a symptom score reduction versus 9.9% in the control group (P <.0001).
Among patients who were dependent upon red blood cell transfusions, 25% in the pacritinib arm became independent during the trial compared with none of those on best available therapy (P <.05).
The most common adverse events (AEs) for pacritinib were diarrhea, nausea, and vomiting. There was a low incidence of grade 3 AEs. In the pacritinib arm, 3 patients discontinued therapy and 13 required dose interruptions for diarrhea. There were no grade 4 gastrointestinal events reported.
The most common all-grade AEs for pacritinib versus best available therapy, respectively, were diarrhea (53.2% vs 12.3%), nausea (26.8% vs 6.6%), anemia (22.3% vs 19.8%), thrombocytopenia (16.8% vs 13.2%), and vomiting (15.9% vs 5.7%).
Subsequent to the FDA lifting the clinical hold, the pivotal phase 3 PACIFICA trial was also launched. The study is comparing pacritinib to physician’s choice of therapy in adult patients with myelofibrosis with severe thrombocytopenia (platelet counts <50,000/μL).
"Given the unprecedented medical need to improve outcomes for patients with COVID-19, we have made a commitment to test pacritinib, a JAK2/IRAK-1/CSF-1R inhibitor, in hospitalized patients with severe COVID-19, with the goal of preventing progression to acute respiratory distress syndrome and mechanical ventilation," Adam R. Craig, MD, PhD, president and chief executive officer of CTI Biopharma, stated in the press release.
"Emerging evidence suggests that the attenuation of the cytokine storm associated with COVID-19 could be a potential treatment approach for this devastating disease, and it is hypothesized that pacritinib may have a role in treating these patients. We would like to thank the FDA for their expedited review of the PRE-VENT protocol. Enrollment is expected to commence in the coming weeks. With ample supply of pacritinib available, we continue to recruit patients on the pivotal phase 3 PACIFICA trial of pacritinib in myelofibrosis patients with severe thrombocytopenia," added Craig.
The primary end point of the trial is the percentage of patients who either die or require mechanical ventilation and/or extracorporeal membrane oxygenation by day 28. Following enrollment of the first 154 patients, there will be an interim analysis for futility. Data are anticipated by the end of the year.