COVID-19 Ruxolitinib, Selinexor Trials Officially Begin Enrollment

COVID-19 trials exploring the oncology treatments ruxolitinib (Jakafi) and selinexor (Xpovio) have officially begun patient enrollment, according to the developers of the therapeutics.

Novartis and Incyte, the codevelopers of ruxolitinib, reported in a press release the official launch of the phase 3 RUXCOVID trial, exploring ruxolitinib in patients with COVID-19—associated cytokine storm.¹

In a separate press release, Karyopharm Therapeutics Inc., the manufacturer of selinexor, reported that the first patient has been dosed in the randomized phase 2 XPORT-CoV-1001 trial exploring low-dose oral selinexor in hospitalized patients with severe COVID-19.²

RUXCOVID Trial

The global, double-blind randomized phase 3 RUXCOVID trial (NCT04331665) is evaluating the JAK1/2 inhibitor ruxolitinib in combination with standard-of-care treatment versus standard of care alone in patients aged ≥12 years with COVID-19 associated cytokine storm. Cytokine storm, which is a type of severe immune overreaction, can cause life-threatening respiratory complications.

The primary outcome measure is a composite endpoint of the mortality rate, requirement of mechanical ventilation (respiratory failure), or requirement of placement in an intensive care unit by day 29.

According to the press release from Incyte and Novartis, "Secondary endpoints are comprised of various efficacy assessments including evaluation of clinical status using a 9-point ordinal scale; in-hospital outcomes (mortality rate; proportion of patients requiring mechanical ventilation; duration of hospitalization, ICU stay, supplemental oxygen, invasive mechanical ventilation); change in the National Early Warning Score (NEWS2); change in SpO2/FiO2 ratio; proportion of patients with no oxygen therapy (oxygen saturation of ≥94% on room air); and safety."

The target enrollment for RUXCOVID is 400 patients. There will also be an expanded access program in the United States during the trial period, which will allow eligible patients to receive ruxolitinib while it is under investigation in this setting.

"There is an unprecedented unmet medical need for treatments that prevent or reduce severe COVID-19 related complications to improve outcomes for patients and alleviate the overwhelming pressure on the global healthcare system," Steven Stein, MD, chief medical officer, Incyte, said in the press release. "We thank the FDA for the expedited review of the RUXCOVID study and hope to enroll this important clinical trial as quickly as possible to determine the potential utility of ruxolitinib for treatment of patients with severe COVID-19—associated cytokine storm."

Ruxolitinib has FDA-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%.³

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.

The most commonly reported adverse events (AEs) 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 treatment-emergent AEs.

In December 2014, the FDA approved ruxolitinib as a treatment for patients with polycythemia vera who are resistant or intolerant to hydroxyurea.⁴ The FDA first approved ruxolitinib in November 2011 as a treatment for patients with intermediate and high-risk myelofibrosis. 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.

XPORT-CoV-1001 Trial

The phase II XPORT-CoV-1001 trial (NCT04349098) is randomizing hospitalized patients with severe COVID-19 to low-dose selinexor or placebo. The accrual goal of the study is 230 patients at locations in the United States, Europe, and Israel.

"Selinexor is an oral selective inhibitor of nuclear export compound which blocks the cellular protein XPO1 which is involved in both the replication of SARS-CoV-2, the virus that causes COVID-19, and in the inflammatory response to the virus," Karyopharm explained in the press release.

The selinexor dosage in the XPORT-CoV-1001 trial is 20 mg orally 3 times a week for 2 weeks. At the discretion of the treating physician, patients responding to the treatment with acceptable toxicity are eligible to continue treatment for another 2 weeks. The primary end point is time to clinical improvement, with secondary outcomes measures including the mortality rate at day 28, and incidence of and time to mechanical ventilation.

"In my laboratory, we have now used two different approaches to investigate selinexor’s ability to inhibit the viral propagation of the SARS-CoV-2 virus in Vero cells, which are monkey cells commonly used in modeling human viral infections. In our first experiment, with the assistance of Jackelyn Murray in my lab, we demonstrated that selinexor inhibited the production of new virus by 90% at a low concentration (100 nM) from cells that were already infected with SARS-CoV2. This is very exciting as low oral doses of selinexor are expected to deliver levels over 300 nM," Ralph Tripp, PhD, a Georgia Research Alliance Eminent Scholar and Professor in the Department of Infectious Diseases in the College of Veterinary Medicine at the University of Georgia," said in the press release.

"In the second experiment, we showed that even lower levels of selinexor, only 10nM, could reduce the ability of the virus to infect new cells by about 99%. I am highly encouraged by these results and thrilled to see how quickly Karyopharm is able to test these scientific findings in patients so dramatically impacted by the current COVID-19 pandemic," added Tripp.

In July 2019, the FDA granted an accelerated approval to selinexor for use in combination with dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory drugs, and a CD38-targeted monoclonal antibody.⁵

The approval was based on data from a prespecified subgroup analysis of 83 patients of Part 2 of the multicenter, single-arm, open-label, phase II STORM trial. In this subpopulation, patients’ disease was refractory to bortezomib, carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), and daratumumab (Darzalex), and the benefit-risk ratio appeared to be greater in this more heavily pretreated subgroup than in the overall population with an ORR of 25.3%. Thirty-seven percent (n = 31) of patients had a minimal response or better to selinexor.

Safety findings of the 202 total patients enrolled in Parts 1 and 2 of the STORM trial who received the combination of selinexor/dexamethasone showed that the most common (≥20%) AEs were thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infections.

Twenty-seven percent of patients discontinued due to AEs, and 53% of patients experienced dose reductions; 65.3% had selinexor dose interruptions. The most frequent AEs requiring permanent discontinuation in ≥4% of patients who received selinexor included fatigue, nausea, and thrombocytopenia. Fatal AEs occurred in 8.9% of patients.

Also in myeloma, selinexor in combination with bortezomib (Velcade) and low-dose dexamethasone led to a statistically significant increase in progression-free survival (PFS) compared with bortezomib/dexamethasone alone in patients with multiple myeloma who have received 1 to 3 prior lines of therapy, according to topline findings from the phase III BOSTON trial.⁶

Results showed that the median PFS in the selinexor arm was 13.93 months compared with 9.46 months with bortezomib/dexamethasone alone, leading to a 30% reduction in the risk of disease progression or death (HR, 0.70; P = .0066). Karyopharm plans to submit a supplemental new drug application to the FDA based on these data.

Beyond myeloma, the FDA granted a priority review designation to a supplemental new drug application for selinexor as a treatment for adult patients with relapsed/refractory diffuse large B-cell lymphoma, not otherwise specified, who have received ≥2 prior therapies.⁷

The application includes updated results from the phase IIb SADAL trial, in which the agent demonstrated a 28.3% ORR in patients with relapsed/refractory DLBCL, including an 11.8% complete response rate and a median duration of response of over 9 months.

References

1. Incyte Announces Initiation of Phase 3 RUXCOVID Study Evaluating Ruxolitinib (Jakafi^®) as a Treatment for Patients with COVID-19 Associated Cytokine Storm. Published April 20, 2020. https://bit.ly/34VfWKX. Accessed April 20, 2020.
2. Karyopharm Announces Dosing of First Patient in Randomized Study Evaluating Low Dose Selinexor in Patients with Severe COVID-19. Published April 20, 2020. https://bit.ly/3bpPfjZ. Accessed April 20, 2020.
3. 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.
4. 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.
5. Karyopharm Announces FDA Approval of XPOVIO™ (selinexor) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma. Karyopharm. Published July 3, 2019. https://bit.ly/2XMo1k0. Accessed July 3, 2019.
6. Karyopharm announces phase 3 BOSTON study meets primary endpoint with significant increase in progression-free survival in patients with multiple myeloma following one to three prior lines of therapy [news release]: Newton, MA. Karyopharm Therapeutics. Published March 2, 2020. https://bit.ly/3csGuXA. Accessed March 2, 2020.
7. Karyopharm reports updated data from the phase 2b SADAL study at the 2019 International Conference on Malignant Lymphoma [news release]: Newton, MA. Karyopharm Therapeutics, Inc. Published June 19, 2019. https://bit.ly/2PO7qrc. Accessed December 23, 2019.

Patients will be randomized 2:1 to ruxolitinib (5 mg orally twice daily ) or placebo for 14 days. Patients on both arms will also receive investigator’s choice of standard-of-care therapy. If after 14 days a patient’s symptoms are the same or worse, but the potential benefit still outweighs the potential risks, that patient is eligible to receive an additional 14 days of study treatment. Overall, patients are being followed for 29 days from when they are randomized.