Ruxolitinib Phase III Trial Launching for COVID-19 Complications

The oncology drug ruxolitinib (Jakafi) is being explored in the planned phase III RUXCOVID trial as a treatment for cytokine storm in patients with COVID-19. Cytokine storm, which is a type of severe immune overreaction, can cause life-threatening respiratory complications.¹

The RUXCOVID trial will specifically evaluate the JAK1/2 inhibitor in combination with standard of care treatment versus standard of care alone in patients with severe COVID-19 pneumonia caused by SARS-CoV-2 infection. Novartis and Incyte, the covdevelopers of ruxolitinib, decided to launch the trial based on preclinical and preliminary clinical findings indicating ruxolitinib could lower the number of patients with these complications who need intensive care and mechanical ventilation.

In a press release, the companies reported that they plan to initiate a compassionate use program for patients with COVID-19 to have access to ruxolitinib.

“Novartis is taking a number of steps to address the urgent needs arising from the COVID-19 pandemic, including the evaluation of our existing therapies to assess if any can be utilized beyond their approved indications,” John Tsai, head of Global Drug Development and Chief Medical Officer, Novartis. “The potential that Jakavi could lead to faster recovery times for COVID-19 patients with fewer requiring intensive care and mechanical ventilation is encouraging and absolutely merits further investigation. We now are moving rapidly to finalize the study plan and then to enroll eligible patients, as well as put in place a process to provide access for patients unable to participate in the trial.”

The companies also noted in the press release that the decision to launch the trial is also supported by the substantial amount of efficacy and safety data for ruxolitinib for its approved indications in myeloproliferative neoplasms and acute graft-versus-host disease (aGVHD).

Most recently, the FDA approved ruxolitinib in May 2019 for the treatment of adult and pediatric patients ≥12 years of age with steroid-refractory aGVHD.

The approval was based on findings from the phase II REACH1 trial, which demonstrated that the combination of ruxolitinib with corticosteroids elicited a 57% overall response rate (ORR) at day 28 in patients with steroid-refractory aGVHD, with a complete response rate of 31%.²

The open-label, single-cohort, multicenter phase II REACH1 study accrued patients aged ≥12 years old who had received allogeneic hematopoietic stem cell transplantation and developed grade 2 to 4 steroid-refractory aGVHD. Patients had received up to 1 systemic treatment beyond corticosteroids for aGVHD. Of the 71 patients recruited on the trial, 49 patients were refractory to steroids alone, 12 patients had received ≥2 prior anti-GVHD therapies, and 10 patients did not otherwise meet the steroid-refractory definition by the FDA.

Ruxolitinib was administered at 5 mg twice daily, which could be increased to 10 mg twice daily if no cytopenias occurred. The primary endpoint was ORR at day 28; a key secondary endpoint was duration of response.

At the April 2, 2018, data cutoff for the primary analysis, 71 patients had received ≥1 dose of ruxolitinib. There was nearly an even number of male and female patients, and the mean age was 52.9 years (range, 18-73). At 28.2% each, acute myeloid leukemia and myelodysplastic syndrome were the most common primary malignancies.

The most commonly reported adverse events among all 71 patients were infections (55%) and edema (51%); the most common laboratory abnormalities were anemia (75%), thrombocytopenia (75%), and neutropenia (58%). Nine patients had cytomegalovirus infection, 4 had viremia, and 1 had chorioretinitis. Two patients died from sepsis and pulmonary hemorrhage) related to TEAEs.

In December 2014, the FDA has approved ruxolitinib as a treatment for patients with polycythemia vera who are resistant or intolerant to hydroxyurea, based on findings from the phase III RESPONSE trial.³ In the trial, hematocrit control without phlebotomy was achieved for 60% of patients treated with ruxolitinib compared with 20% receiving best available therapy. The primary endpoint of the trial looked specifically at the number of patients who achieved hematocrit control without phlebotomy from week 8 to 32 and experienced greater than a 35% reduction in spleen volume by week 32. Overall, 21% of patients in the ruxolitinib arm met this criteria compared with 1% for best available therapy, according to results presented at the 2014 ASCO Annual Meeting.

In the RESPONSE trial, 222 patients with polycythemia vera were randomized to ruxolitinib (n = 110) or best available therapy (n = 112), which included hydroxyurea, interferon, observation, and other treatments. By week 32, ruxolitinib was administered at 10 mg BID for 33.7% of patients and 32.7% received the drug at 15 mg. Doses ranged from <10 mg to 25 mg BID.

Approximately 95% of patients in both arms tested positive for a mutation in JAK2 V617F. Altogether, 96 patients in the best available therapy arm crossed over to receive ruxolitinib. Patient characteristics were balanced between the two arms.

Hematocrit control without phlebotomy was achieved for 60% of patients treated with ruxolitinib compared with 20% receiving best available therapy. Spleen volume was reduced by ≥35% in 38% of patients receiving ruxolitinib compared with 1% for best available therapy.

At week 32, 24% of patients treated with ruxolitinib achieved a complete hematologic remission (CHR) compared with 9% for best available therapy (P = .003). Additionally, 88.5% of patients maintained a CHR at week 48.

In total, 91% of patients maintained a response to ruxolitinib following 48 weeks of treatment. The probability of maintaining a primary response to ruxolitinib for 1 year was 94%. At a median follow-up of 81 weeks, 85% of patients randomized to ruxolitinib remained on therapy.

The rates of grade 3/4 anemia and thrombocytopenia were less in the ruxolitinib arm compared with best available therapy (1.8% vs 5.5% and 0% vs 3.6%, respectively). Symptom improvement by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) favored ruxolitinib, with 49% of patients experiencing a ≥50% improvement from baseline compared with 5% for best available therapy.

The FDA first approved ruxolitinib as a treatment for patients with intermediate and high-risk myelofibrosis in November 2011. This approval included the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. This approval was based on results from 2 studies that demonstrated a reduction in spleen size with the treatment.

Commenting on the launch of the RUXCOVID trial, Steven Stein, MD, chief medical officer, Incyte, said, "Our intent is to build on emerging evidence from independent studies to further establish the role ruxolitinib could play in balancing immune response to the infection and therefore potentially improving outcomes of patients with COVID-19 associated cytokine storm. We recognize the significant and urgent medical need of patients with severe COVID-19 infection, and we are working with the FDA in an effort to rapidly advance the RUXCOVID and EAP studies."⁴

References

1. Novartis announces plan to initiate clinical study of Jakavi® in severe COVID-19 patients and establish international compassionate use program. Published April 3, 2020. https://bit.ly/3aHA2dF. Accessed April 3, 2020.
2. FDA Approves Jakafi (ruxolitinib) for the Treatment of Patients with Acute Graft-Versus-Host Disease. Incyte. Published May 24, 2019. https://bit.ly/2WiRktX?rel=0. Accessed May 24, 2019.
3. FDA Approves Jakafi® (ruxolitinib) for the Treatment of Patients with Uncontrolled Polycythemia Vera. Posted December 4, 2014. https://bit.ly/2R8LWG1. Accessed April 3, 2020.
4. Incyte Announces Plans to Initiate a Phase 3 Clinical Trial of Ruxolitinib (Jakafi®) as a Treatment for Patients with COVID-19 Associated Cytokine Storm. Published April 3, 2020. https://yhoo.it/3bJIDg0. Accessed April 3, 2020.