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

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.

Inclusion criteria

• Documented informed consent of the participant and/or legally authorized representative. Assent, when appropriate, will be obtained per institutional guidelines. Cognitively impaired subjects may enroll in the phase 2 portion if adequate psychosocial support is provided
• SARS-CoV-2 infection confirmed by a PCR-based test within 4 days prior to enrollment
• COVID-19 disease baseline severity of Severe according to FDA guidance, as defined by:

• Symptoms suggestive of severe systemic illness with COVID-19, which could include any symptom of fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, or shortness of breath at rest, or respiratory distress
• Clinical signs indicative of severe systemic illness with COVID-19, such as respiratory rate >= 30 per minute, heart rate >= 125 per minute, SpO2 =< 93% on room air at sea level or partial pressure of oxygen (PaO2)/the fraction of inspired oxygen (FiO2) < 300
• Active cancer requiring systemic treatment within the last 2 years. Subjects should not have received the following therapies for their malignancy within the indicated time frames:

• Local radiation therapy within 2 weeks prior to enrollment. If the involved field is small (single nodal area), 7 days prior to enrollment is allowed
• Chemotherapy within 2 weeks prior to enrollment
• Major surgery within 2 weeks prior to treatment
• Autologous hematopoietic stem cell infusion within 12 weeks prior to enrollment
• Antibody therapy, chimeric antigen receptor (CAR) T cells, or other biologic therapies within 12 weeks prior to enrollment
• Allogeneic hematopoietic stem cell infusion within 16 weeks prior to enrollment These time frames should be considered the minimum allowed interval and may be longer per the judgment of the investigator
• Adverse events related to prior cancer therapy must have recovered to =< grade 1 or to baseline
• Subjects must be able to forgo systemic cancer therapy for ~39 days (14 days treatment/placebo + 14 days monitoring + ~ 11 days cholestyramine)
• Absolute neutrophil cunt (ANC) >= 500/mm^3 (to be performed within 4 days prior to day 1 of protocol therapy unless otherwise stated)
• Platelets >= 25,000/mm^3 (to be performed within 4 days prior to day 1 of protocol therapy unless otherwise stated)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease) (to be performed within 4 days prior to day 1 of protocol therapy unless otherwise stated)
• Aspartate aminotransferase (AST) =< 2 x ULN (to be performed within 4 days prior to day 1 of protocol therapy unless otherwise stated)
• Alanine aminotransferase (ALT) =< 2 x ULN (to be performed within 4 days prior to day 1 of protocol therapy unless otherwise stated)
• Creatinine clearance of >= 60 mL/min per 24-hour urine test or the Cockcroft-Gault formula (to be performed within 4 days prior to day 1 of protocol therapy unless otherwise stated)
• Agreement by females and males of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity for the course of the study until teriflunomide levels are verified to be less than 0.02 mg/L (0.02 ug/mL) for patients given leflunomide, or until unblinding occurs for those given placebo. Contraception should also be used for the duration of administration of SOC drugs during this study for the duration recommended in the prescribing information.

• Childbearing potential is defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion criteria

• Evidence of acute respiratory distress syndrome (ARDS), defined by at least one of the following: endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates > 20 L/min with fraction of delivered oxygen >= 0.5), noninvasive positive pressure ventilation, extracorporeal membrane oxygenation (ECMO), or clinical diagnosis of respiratory failure (i.e., clinical need for one of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation)
• Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure < 60 mm Hg or requiring vasopressors)
• Evidence of multi-organ dysfunction/failure
• Pre-existing acute or chronic liver disease
• Patients with indolent local malignancies or pre-malignant conditions including but not limited to:

• Smoldering multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS)
• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix or breast
• Incidental histologic finding of prostate cancer (T1a or T1b using the tumor node metastasis [TNM] clinical staging system) or prostate cancer that is curative
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• Secondary bacterial, fungal, or viral infections that are not adequately controlled
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• If human immunodeficiency virus (HIV)-positive: CD4+ T cell count < 200
• Positive for tuberculosis antigen (e.g., T-spot test)
• Presence of liver metastasis
• Gastrointestinal (GI) malignancies associated with malabsorption and inability to take cholestyramine
• Steroids, except for low-dose replacement or high-dose for management of acute symptoms such as ARDS
• Any new immunosuppressive medication in the 4 weeks prior to enrollment, excepting agents used for treatment of COVID-19 that may also have immunosuppressive properties
• Medications that are CYP1A2 inducers, CYP2C8 inhibitors, and vitamin K antagonists, if these medications are not approved by the investigator. CYP1A2 inducers, CYP2C8 inhibitors, and vitamin K antagonists that are approved by the investigator are allowed
• Concurrent administration of live vaccines
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)