Disulfiram for Preventing Treatment Complications in Patients Undergoing CAR T-cell Therapy for Relapsed or Refractory Diffuse Large B-cell Lymphoma
A Single Center, Phase I/II Study of Disulfiram for the Prevention of Immunotoxicity in Patients Undergoing CAR T-Cell Therapy
This phase I/II trial tests the safety, best dose, and effectiveness of disulfiram for preventing treatment complications in patients with large B-cell lymphoma that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory) and who are undergoing chimeric antigen receptor (CAR) T-cell therapy. Two major complications of CAR T-cell therapy include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS results from inflammation in the body when the immune system responds too aggressively to the modified T cells working to attack cancer cells. ICANS is inflammation of the brain or nerves. CRS is most often a prelude to ICANS, and both of these toxicities currently require immunosuppression for treatment, which can inhibit CAR T-cell response. Disulfiram has been found to impact several biologic pathways that cause CRS. Disulfiram may be safe and effective for reducing the incidence and severity of reactions to CAR T-cell therapy without inhibiting CAR T-cell response.
Study Overview
Status
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: Tracey Churay
- Phone Number: 1-800-865-1125
- Email: tchuray@umich.edu
Study Locations
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-
Michigan
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Ann Arbor, Michigan, United States, 48109
- University of Michigan Rogel Cancer Center
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Contact:
- Tracey Churay
- Phone Number: 800-865-1125
- Email: tchuray@umich.edu
-
Principal Investigator:
- Marcus Geer
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Histologic diagnosis of relapsed/refractory large B-cell lymphoma
- >= 18 years of age at the time of signing informed consent (ICF)
- Understands and voluntarily signs the ICF prior to conduct of any study-related assessments or procedures
- Willing to adhere to the study visit schedule and other protocol requirements
- Willing/able to abstain from any drug/substance at risk for reaction with disulfiram for the duration of treatment
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Eligible for therapy with axicabtagene ciloleucel per institutional criteria
- Confirmation of a manufactured CAR T-cell product within clinical specifications for axicabtagene ciloleucel
- Females and males of childbearing potential must be willing to use effective methods of contraception from the time of informed consent until 12 months (female) or 4 months (males with female partners of reproductive potential) after the cyclophosphamide infusion
- Willingness to consent / co-enroll on the University of Michigan cellular therapy long-term follow-up study - HUM00043287 (UMCC2001-0234)
Exclusion Criteria:
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Serious or uncontrolled infection defined as not having cleared infection despite being on appropriate antimicrobial therapy for 5 days would be excluded. Also any infection which, in the opinion of the investigator, places the patient at an unacceptable risk for treatment-related complications, could impede the ability to safely administer therapy, or could interfere with evaluation of study intervention
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Active hepatitis B or C (latent hepatitis B will not be excluded), or HIV. Entecavir prophylaxis can be used for latent hepatitis B. A patient's viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing at screening
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Total bilirubin of >= 1.5 x upper limit of normal (ULN) unless attributed to Gilbert's syndrome or underlying primary malignancy. Patients with Gilbert syndrome or underlying primary malignancy involving the liver with total bilirubin >= 2.5 x ULN (or absolute total bilirubin >= 3 mg/dL) should be excluded. Aspartate aminotransferase (AST): >= 2.5 x ULN, alanine aminotransferase (ALT): >= 2.5 x ULN
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Active concurrent autoimmune disease requiring systemic immunosuppression
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Active primary or secondary central nervous system (CNS) lymphoma
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Active clinically relevant central nervous system disease including but not limited to:
- Seizures/Epilepsy
- Stroke or unstable neurologic deficits within the past 12 months prior to enrollment
- Cerebral edema
- Aphasia
- Severe brain injury
- Cerebellar disease
- Documented history of dementia as confirmed by neuropsychiatric testing
- Parkinson's disease
- Psychosis
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Any other significant medical condition (including neurological or psychiatric) which, in the opinion of the investigator, places the participant at an unacceptable risk for treatment-related complications, could interfere with the successful or safe delivery of therapy, or could interfere with evaluation of study intervention or interpretation of participant safety or study results. Including but not limited to:
- Diabetes with associated autonomic dysfunction
- Uncontrolled Hypothyroidism
- Chronic or acute nephritis
- Hepatic cirrhosis/insufficiency
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Pregnant or nursing females
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Current or previous treatment with any other agents explicitly for prophylaxis of CRS or ICANS, including corticosteroids and investigational agents during the study enrollment period. Corticosteroids given for disease treatment should have a washout of at least 5 half-lives prior to cell infusion. Use of prophylactic antiseizure medications is not contraindicated
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History of, or a concurrent, clinically significant illness, medical condition or laboratory abnormality that, in the investigator's opinion, could affect the conduct of the study
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Concurrent use of prohibited medications or substances at risk of precipitating a disulfiram reaction
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Hypersensitivity to disulfiram or to other thiuram derivatives used in pesticides and rubber vulcanization
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Supportive Care
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Supportive care (disulfiram)
Patients receive disulfiram PO QD on days -5 to +21. Patients receive cyclophosphamide IV and fludarabine IV on days -5 to -3 and then receive axi-cel IV on day 0. Patients also undergo CT or PET/CT at screening and follow-up and undergo collection of blood samples throughout the trial. |
Given IV
Other Names:
Undergo collection of blood samples
Other Names:
Undergo CT or PET/CT
Other Names:
Undergo PET/CT
Other Names:
Given IV
Other Names:
Given IV
Other Names:
Given PO
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Incidence of dose-limiting toxicities
Time Frame: Within day +35 post-chimeric antigen receptor (CAR) T-cell therapy
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At the end of the trial, will report number of patients assigned to each dose, as well as the number of patients experiencing toxicity at each dose. |
Within day +35 post-chimeric antigen receptor (CAR) T-cell therapy
|
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Proportion of patients that are alive and free from grade 2-4 cytokine release syndrome (CRS) with no intervening treatment of CRS
Time Frame: Through day +28 post-CAR T-cell therapy
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At the end of the trial, will report number of patients assigned to each dose, as well as the number of patients experiencing efficacy outcomes at each dose. |
Through day +28 post-CAR T-cell therapy
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Incidence of grade 2-4 CRS
Time Frame: By day +28 post-CAR T-cell therapy
|
The occurrence of severe CRS will be considered binary, and the rate will be defined as number of patients with severe CRS divided by the number of evaluable patients. The rate will be reported along with the 95% exact binomial confidence interval. |
By day +28 post-CAR T-cell therapy
|
|
Incidence of all-grade CRS
Time Frame: By day +28 post-CAR T-cell therapy
|
The occurrence of CRS will be considered binary, and the rate will be defined as number of patients with CRS divided by the number of evaluable patients. The rate will be reported along with the 95% exact binomial confidence interval. |
By day +28 post-CAR T-cell therapy
|
|
Incidence of all-grade immune effector cell associated neurotoxicity syndrome (ICANS)
Time Frame: By day +28 post-CAR T-cell therapy
|
The occurrence of severe ICANS will be considered binary and the rate will be defined as number of patients with severe ICANS divided by the number of evaluable patients. The rate will be reported along with the 95% exact binomial confidence interval. |
By day +28 post-CAR T-cell therapy
|
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Incidence of disulfiram-related grade 2 to 5 non-hematologic toxicity
Time Frame: By day +28 post-CAR T-cell therapy
|
Will be assessed by Common Terminology Criteria for Adverse Events, version 5.0. The occurrence of drug related grade 2-5 non-hematologic toxicity with at least a 'possible' attribution to disulfiram will be considered binary, and the rate will be defined as number of patients experiencing toxicity divided by the number of evaluable patients. The rate will be reported along with the 95% exact binomial confidence interval. |
By day +28 post-CAR T-cell therapy
|
Collaborators and Investigators
Investigators
- Principal Investigator: Marcus Geer, University of Michigan Rogel Cancer Center
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms
- Immune System Diseases
- Neoplasms by Histologic Type
- Lymphatic Diseases
- Lymphoproliferative Disorders
- Immunoproliferative Disorders
- Lymphoma, Non-Hodgkin
- Lymphoma, B-Cell
- Lymphoma
- Hemic and Lymphatic Diseases
- Lymphoma, Large B-Cell, Diffuse
- Sulfur Compounds
- Organic Chemicals
- Investigative Techniques
- Clinical Laboratory Techniques
- Diagnostic Techniques and Procedures
- Diagnosis
- Hydrocarbons
- Acids, Acyclic
- Carboxylic Acids
- Chemistry Techniques, Analytical
- Spectrum Analysis
- Phosphoramide Mustards
- Nitrogen Mustard Compounds
- Mustard Compounds
- Hydrocarbons, Halogenated
- Phosphoramides
- Organophosphorus Compounds
- Sulfides
- Carbamates
- Ditiocarb
- Thiocarbamates
- Disulfides
- Cyclophosphamide
- Disulfiram
- Specimen Handling
- Magnetic Resonance Spectroscopy
- fludarabine
- axicabtagene ciloleucel
Other Study ID Numbers
- UMCC 2025.132
- NCI-2026-05448 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- HUM00287270 (Other Identifier: University of Michigan Rogel Cancer Center)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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