Leflunomide for the Treatment of Severe COVID-19 in Patients With a Concurrent Malignancy

Summary

Participation Requirements

Description

PRIMARY OBJECTIVES: I. Assess the safety and tolerability of leflunomide when combined with coronavirus disease 2019 (COVID-19) standard of care (SOC) by evaluation of toxicities including: type, frequency, severity, attribution and duration. (Phase 1) II. Determine the maximum tolerated dose (MTD) ...

PRIMARY OBJECTIVES: I. Assess the safety and tolerability of leflunomide when combined with coronavirus disease 2019 (COVID-19) standard of care (SOC) by evaluation of toxicities including: type, frequency, severity, attribution and duration. (Phase 1) II. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of leflunomide when given in combination with SOC. (Phase 1) III. Evaluate the clinical activity of leflunomide plus SOC (Arm 1) and placebo plus SOC (Arm 2) on the basis of clinical improvement (response) rate in each treatment arm, as assessed by a 7-point ordinal scale. (Phase 2/Pilot) IV. Evaluate the safety and tolerability of leflunomide plus SOC (Arm 1) and placebo plus SOC (Arm2). (Phase 2/Pilot) SECONDARY OBJECTIVES I. Evaluate the clinical activity of leflunomide when combined with SOC on the basis of clinical improvement (response) rate. (Phase 1) II. Estimate the following (Phase 1 and Phase 2): IIa.Time to clinical improvement (days). IIb. Time to peripheral capillary oxygen saturation (SpO2) > 93% on room air (days). IIc. Time to first negative SARS-CoV-2 polymerase chain reaction (PCR) (days). IId. Duration of oxygen therapy (days). IIe. Duration of hospitalization (days). IIf. Duration of mechanical ventilation. IIg. All cause mortality at day 28. III. Measure trough plasma concentrations of the active metabolite teriflunomide on days 1 through 14, day 21, and day 28, and evaluate relationships between teriflunomide levels and pharmacodynamic biomarkers (e.g., viral load, cytokines), response, safety, and concomitant medications. (Phase 1 and Phase 2) EXPLORATORY OBJECTIVES I. Investigate inflammatory response by measuring changes before and after leflunomide treatment in: Ia. Circulating cytokines (e.g., IL-6, IL-8, TNF-alpha, IL-12, interferons [IFNs] and granulocyte-macrophage colony-stimulating factor ([GM-CSF]). Ib. Immune effector cell phenotype associated with monocyte, T cell, and natural killer (NK) cell activation. II. Assess the kinetics of viral replication through serial measurements of viral load by nasopharyngeal swab and tracheal aspirates (if on ventilator and can be safely obtained). OUTLINE: This is a phase I dose-escalation study, followed by a phase II study. PHASE I: Patients receive leflunomide orally (PO) once daily (QD) on days 1-14. Patients may receive SOC drugs in addition to leflunomide. PHASE II: Patients are randomized to 1 of 2 arms. ARM I (LEFLUNOMIDE + SOC): Patients receive leflunomide PO QD on days 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive SOC. ARM II (PLACEBO + SOC): Patients receive placebo PO QD on days 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive SOC. After completion of study treatment, patients are followed up for 90 days.

Tracking Information