Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Mantle Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory Mantle Cell Lymphoma
Conditions
Brief summary
This phase II studies how well natalizumab works in preventing immune effector cell associated neurologic syndrome (ICANS) in patients with diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL) that has come back after a period of improvement (recurrent) or that does not respond to treatment (refractory) receiving chimeric antigen receptor (CAR) T-cell therapy. A major complication of CAR T-cell therapy is ICANS. ICANS is inflammation of the brain or nerves. ICANS currently requires high-dose corticosteroid treatment which can inhibit CAR T-cell response. Natalizumab prevents immune cells from traveling from the blood to the fluid around the brain, which is a process thought to play a major role in CAR T-cell related brain injury. Natalizumab may be safe and effective in decreasing the frequency of severe ICANS in patients with DLBCL or MCL receiving CAR T-cell therapy.
Interventions
BIOLOGICALAxicabtagene Ciloleucel
Given axicabtagene ciloleucel
PROCEDUREBiospecimen Collection
Undergo collection of blood
BIOLOGICALBrexucabtagene Autoleucel
Given brexucabtagene autoleucel
PROCEDUREComputed Tomography
Undergo PET/CT
DRUGCyclophosphamide
Given IV
DRUGFludarabine
Given IV
BIOLOGICALNatalizumab
Given IV
PROCEDUREPositron Emission Tomography
Undergo PET/CT
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient must be ≥ 18 years of age at the time of signing informed consent (ICF) * Patient must understand and voluntarily sign the ICF prior to conduct of any study-related assessments or procedures * Patient must be willing to adhere to the study visit schedule and other protocol requirements * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 * Patient must be eligible per institutional criteria for therapy with commercial axicabtagene ciloleucel or brexucabtagene autoleucel for treatment of relapsed or refractory diffuse large B-cell lymphoma or mantle cell lymphoma * Per institutional protocol: Females and males of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of 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. The two contraception methods can consist of two barrier methods or a barrier method plus a hormonal method. Female participants must agree to inform their male partners that they must use the methods of birth control required by the protocol. The use of intrauterine devices is excluded due to the risk of infection or bleeding
Exclusion criteria
* Uncontrolled systemic fungal, bacterial, viral, or other infection despite appropriate antibiotics or treatment * Patients with infections controlled on antibiotics are not excluded * Prior history or current infection with John Cunningham (JC) virus * Active hepatitis B or C (latent hepatitis B will not be excluded), or HIV. Entecavir prophylaxis can be used for latent hepatitis B. Patients' viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing at screening * Bilirubin: ≥ 2.0 x upper limit of normal (ULN), unless attributed to Gilbert's Syndrome or to the patient's primary malignancy * Aspartate aminotransferase (AST): ≥ 5 x ULN, alanine aminotransferase (ALT): ≥ 5 x ULN * Active concurrent autoimmune disease requiring immunosuppressive therapy * Active central nervous system (CNS) lymphoma * Active clinically relevant central nervous system disease including but not limited to: * Seizures/epilepsy * Stroke within the past 12 months, or unstable neurologic deficits within the past 12 months * Cerebral edema * Aphasia * Severe brain injury * Cerebellar disease * Documented history of dementia by clinical diagnosis * Parkinson's disease * Psychosis * Pregnant or nursing females * History of or active progressive multifocal leukoencephalopathy (PML) * Prior history or active herpes encephalitis or meningitis infection * Current treatment with any other agents for prophylaxis of CRS or ICANS, including investigational agents. Use of antiseizure medications does not exclude patients * History of prior exposure to natalizumab due to risk of neutralizing antibody formation * History of hypersensitivity reaction to natalizumab or the formulation excipients * Consider adding: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of chimeric antigen receptor therapy (CAR-T)-associated neurotoxicity (immune effector cell associated neurotoxicity syndrome [ICANS]) | Up to CAR-T day +28 | Any grade per American Society for Transplantation and Cellular Therapy Cytokine Release Syndrome (ASTCT) criteria. Will be considered binary and the rate will be defined as number of patients without ICANS of any grade divided by the number of evaluable patients. These rates will be reported along with the 95% exact binomial confidence interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of severe CAR-T-associated neurotoxicity (ICANS of grade 3 or greater) | Up to CAR-T day +28 | Defined by ASTCT consensus criteria. Will be considered binary and the rate will be defined as number of patients with severe ICANS divided by the number of evaluable patients. These rates will be reported along with the 95% exact binomial confidence interval. |
| Occurrence of severe cytokine release syndrome (cytokine release syndrome [CRS] of grade 3 or greater) | Up to CAR-T day +28 | Defined by ASTCT consensus criteria. Will be considered binary, and the rate will be defined as number of patients with severe CRS divided by the number of evaluable patients. These rates will be reported along with the 95% exact binomial confidence interval. |
| Occurrence of adverse events related to natalizumab | Up to CAR-T day +28 | Treatment emergent adverse events will be tabulated, and the rate will be defined as number of patients with treatment emergent adverse events divided by the number of evaluable patients. These rates will be reported along with the 95% exact binomial confidence interval. |
| Occurrence of complete response or partial response | At CAR-T day +60 | Assessed per Lugano classification on day +60 positron emission tomography/computed tomography. Will be defined as number of patients with treatment emergent adverse events divided by the number of evaluable patients. These rates will be reported along with the 95% exact binomial confidence interval. |
| Occurrence of serious adverse events related to natalizumab | Up to CAR-T day +28 | Treatment emergent serious adverse events will be tabulated, and the rate will be defined as number of patients with treatment emergent adverse events divided by the number of evaluable patients. These rates will be reported along with the 95% exact binomial confidence interval. |
Countries
United States
Contacts
CONTACTTracey Churay
PRINCIPAL_INVESTIGATORMonalisa Ghosh
University of Michigan Rogel Cancer Center
Outcome results
None listed