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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04532372
Recruitment Status : Not yet recruiting
First Posted : August 31, 2020
Last Update Posted : August 31, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

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.

Condition or disease Intervention/treatment Phase
Hematopoietic and Lymphoid Cell Neoplasm Malignant Solid Neoplasm Symptomatic COVID-19 Infection Laboratory-Confirmed Other: Best Practice Drug: Leflunomide Drug: Placebo Administration Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Phase I single-arm dose-escalation design followed by a phase II randomized two-arm design
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Trial of Leflunomide for the Treatment of Severe COVID-19 in Patients With a Concurrent Malignancy
Estimated Study Start Date : September 18, 2020
Estimated Primary Completion Date : September 18, 2022
Estimated Study Completion Date : September 18, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Leflunomide

Arm Intervention/treatment
Experimental: Phase I (leflunomide, SOC)
Patients receive leflunomide PO QD on days 1-14. Patients may receive SOC drugs in addition to leflunomide.
Other: Best Practice
Receive standard of care drugs
Other Names:
  • standard of care
  • standard therapy

Drug: Leflunomide
Given PO
Other Names:
  • Arava
  • SU101

Experimental: Phase II 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.
Other: Best Practice
Receive standard of care drugs
Other Names:
  • standard of care
  • standard therapy

Drug: Leflunomide
Given PO
Other Names:
  • Arava
  • SU101

Drug: Placebo Administration
Given PO

Placebo Comparator: Phase II 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.
Other: Best Practice
Receive standard of care drugs
Other Names:
  • standard of care
  • standard therapy

Drug: Placebo Administration
Given PO




Primary Outcome Measures :
  1. Incidence of toxicity, graded according to the NCI CTCAE version 5 [ Time Frame: Up to 28 days after completion of study treatment ]
    Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study of treatment and reversibility or outcome.

  2. Maximum tolerated dose (MTD) (Phase 1) [ Time Frame: During the 28-day treatment period ]
    Will be based on the assessment of dose limiting toxicity (DLT).

  3. Clinical activity (Response)(Phase 2) [ Time Frame: At day 28 ]
    Defined as a >= 2-point change in clinical status from day 1 on a 7-point ordinal scale.


Secondary Outcome Measures :
  1. Time to Clinical activity (Response) [ Time Frame: Up to 28 days ]
    Defined as time from start of treatment to >= 2 point change in clinical status on a 7 point ordinal scale

  2. Overall Survival [ Time Frame: Up to 90 days ]
    Defined as time from start of treatment to death from any cause

  3. Oxygen Saturation improvement [ Time Frame: Up to 90 days ]
    Time from start of treatment to peripheral capillary oxygen saturation (SpO2) > 93% on room air

  4. SARS-CoV-2 resolution [ Time Frame: Up to 90 days ]
    Time from start of treatment to first negative severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) result assessed by polymerase chain reaction (PCR).

  5. Hospitalization [ Time Frame: Up to 90 days ]
    Hospitalized within first 90 days following start of treatment assessed as yes/no

  6. Mechanical Ventilation required [ Time Frame: Up to 90 days ]
    Indication as to whether or not the subject required mechanical ventilation at any time from start of treatment through 90 days post; assessed as yes/no

  7. Mechanical Ventilation duration [ Time Frame: Up to 90 days ]
    If the subject required mechanical ventilation, indicate number of days for first occurrence; measured in days.

  8. Vital status (alive/dead) [ Time Frame: Up to 90 days ]
    Vital status will be reported as yes/no

  9. Vital status (cause of death) [ Time Frame: Up to 90 days ]
    If vital status is dead, cause of death will be documented.


Other Outcome Measures:
  1. Viral load [ Time Frame: from start of treatment to 90 days ]
    Measured by PCR assay of viral ribonucleic acid (RNA) from nasopharyngeal swab.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04532372


Locations
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United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
Contact: Sanjeet S. Dadwal    626-218-8202    sdadwal@coh.org   
Principal Investigator: Sanjeet S. Dadwal         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Sanjeet S Dadwal City of Hope Medical Center
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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT04532372    
Other Study ID Numbers: 20291
NCI-2020-05746 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
20291 ( Other Identifier: City of Hope Comprehensive Cancer Center )
P30CA033572 ( U.S. NIH Grant/Contract )
First Posted: August 31, 2020    Key Record Dates
Last Update Posted: August 31, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Laboratory Infection
Neoplasms
Infection
Occupational Diseases
Leflunomide
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs