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

NCT04532372 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 20291NCI-2020-05746P30CA033572
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I/II trial investigates the best dose and side effects of leflunomide and how well it works in treating patients with COVID-19 and a past or present cancer. Leflunomide has been used since the 1990s as a treatment for rheumatoid arthritis. Experiments done with human cells that were given severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19, showed that leflunomide was able to reduce the ability of the virus to make copies of itself. The coronavirus uses ribonucleic acid (RNA), a very long molecule that contains genetic information that is like a blueprint for making more copies of itself. Leflunomide inhibits the formation of RNA. The information gained from this study may help researchers to learn whether leflunomide is safe for use in treating patients with COVID-19, and whether it is potentially effective against the disease.

Conditions

Hematopoietic and Lymphoid Cell Neoplasm; Malignant Solid Neoplasm; Symptomatic COVID-19 Infection Laboratory-Confirmed

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) (Phase 1)

  MTD were based on the assessment of DLT (Dose Limiting Toxicity) during the 28-day treatment period.

  From the initial study treatment (Day 0) to Day 28.

• Clinical Activity (Response)(Phase 2)

  Defined as a \>= 2-point change in clinical status from day 1 on a 7-point ordinal scale. The ordinal scale is an assessment of the clinical status at a given study day. Each day, the worst (i.e., lowest ordinal) score from the previous day was recorded.

  At day 28

Secondary Outcomes (5)

• Time to Clinical Activity (Response)

  Up to 28 days

• Overall Survival (Phase 2)

  Up to 90 days

• Oxygen Saturation Improvement

  Up to 90 days

• Number of Participants Who Were Hospitalized

  Up to 90 days

• Number of Participants Who Were Mechanical Ventilation Required

  Up to 90 days

Study Arms (3)

Phase I (leflunomide, SOC)

EXPERIMENTAL

Patients receive leflunomide PO QD on days 1-14. Patients may receive SOC drugs in addition to leflunomide.

Other: Best Practice; Drug: Leflunomide

Phase II Arm I (leflunomide, SOC)

EXPERIMENTAL

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.

Other: Best Practice; Drug: Leflunomide; Drug: Placebo Administration

Phase II Arm II (placebo, SOC)

PLACEBO COMPARATOR

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.

Other: Best Practice; Drug: Placebo Administration

Interventions

Best Practice OTHER

Receive standard of care drugs

Also known as: standard of care, standard therapy

Phase I (leflunomide, SOC); Phase II Arm I (leflunomide, SOC); Phase II Arm II (placebo, SOC)

Leflunomide DRUG

Given PO

Also known as: Arava, SU101

Phase I (leflunomide, SOC); Phase II Arm I (leflunomide, SOC)

Placebo Administration DRUG

Given PO

Phase II Arm I (leflunomide, SOC); Phase II Arm II (placebo, SOC)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

MeSH Terms

Conditions

Hematologic Neoplasms

Interventions

Practice Guidelines as Topic; Standard of Care; Leflunomide

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Guidelines as Topic; Quality Assurance, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation; Quality Indicators, Health Care; Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Sanjeet Dadwal
• Organization: City of Hope Medical Center

sdadjeet@coh.org

626-359-8111

Study Officials

• Sanjeet S Dadwal

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase I single-arm dose-escalation design followed by a phase II randomized two-arm design

Study Record Dates

• First Submitted: August 25, 2020
• First Posted: August 31, 2020
• Study Start: January 7, 2021
• Primary Completion: August 26, 2021
• Study Completion: October 27, 2021
• Last Updated: July 3, 2024
• Results First Posted: July 3, 2024

Record last verified: 2024-07

Locations

US (1)