Hematopoietic and Lymphatic System Neoplasm
Conditions
Brief summary
This phase II trial tests how well cytarabine (Ara-C), methotrexate, and hydrocortisone given between the spinal cord and the membranes that protect it (intrathecal \[IT\]) works in preventing high-grade immune effector-associated neurotoxicity syndrome (ICANS) in patients receiving chimeric antigen receptor (CAR) T-cell therapy. ICANS is a challenging complication of CAR T-cell therapy that causes neurological effects varying from mild headaches or temporary confusion to hallucinations, swelling in the brain, and seizures. Between 20%-70% of patients receiving CAR T-cell therapy show symptoms of neurotoxicity.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate the efficacy of IT chemotherapy in the prevention of high grade ICANS. SECONDARY OBJECTIVES: I. To evaluate the efficacy of IT chemotherapy in the prevention of any grade ICANS. II. To evaluate safety of IT chemotherapy. III. To evaluate the effect of IT chemotherapy on corticosteroid use. IV. To evaluate the effect of IT chemotherapy on anakinra use. EXPLORATORY OBJECTIVES: I. To evaluate the effect of IT chemotherapy on time to ICANS onset. II. To evaluate the effect of IT chemotherapy on duration of ICANS. III. To evaluate the burden of treatment mediated serious adverse events (SAEs). OUTLINE: Patients receive cytarabine IT, methotrexate IT, and hydrocortisone IT over 3-5 minutes via lumbar puncture (LP) on day 4 post-standard of care (SOC) Axi-cel (Yescarta) or Brexu-cel (Tecartus) in the absence of unacceptable toxicity or development of ICANS. Patients who do not develop ICANS of any grade, also receive hydrocortisone IT on day 7 post SOC CAR T-cell therapy. Additionally, patients undergo cerebrospinal fluid (CSF) sample collection throughout the study. After completion of study treatment, patients are followed for up to 30 days.
Interventions
PROCEDUREBiospecimen Collection
Undergo CSF sample collection
DRUGCytarabine
Given IT
PROCEDURELumbar Puncture
Undergo lumbar puncture
DRUGMethotrexate
Given IT
DRUGTherapeutic Hydrocortisone
Given IT
Sponsors
OHSU Knight Cancer Institute
Oregon Health and Science University
American Society of Clinical Oncology
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
* Written informed consent. Participant or legally authorized representative (LAR) must provide written informed consent prior to any study-specific procedures or interventions * Age ≥ 18 years. All genders, races, and ethnic groups will be included * Must be receiving SOC Yescarta® or Tecartus® in the inpatient setting * Agree to adhere to institutional guidelines for contraception during the first 30 days post CAR-T * Rationale for eligibility criteria based on contraception and pregnancy (both participants and partners of a sperm-producing participant): It shall be known to all participants that the effects of CAR-T or IT chemotherapy on the developing human fetus are unknown. For this reason, persons of reproductive potential must agree to use adequate contraception. Should a participant or participant's sexual partner become pregnant or suspect a pregnancy while participating in this study, the individual should inform their treating physician immediately * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 * Platelet count \> 50,000/mm\^3 (μL) * Adequate coagulation tests including international normalized ratio (INR) \< 1.6 and fibrinogen \> 100
Exclusion criteria
* Active/concurrent diagnosis of any central nervous system (CNS) hematologic malignancy * History or presence of CNS disorder such as poorly controlled seizure disorder (seizure within the 12 months), transverse myelitis, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement * Known history of hypersensitivity to IT chemotherapy * Subject has a contraindication to LP including: * Presence of a posterior fossa mass * Skin infection near puncture site * Uncorrected bleeding diathesis * Suspicion of increased intracranial pressure * Acute spinal cord trauma * Subject is receiving an antiplatelet and/or anticoagulant that cannot be held prior to LP according to best available evidence * Known bleeding disorders * Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgement, make the participant inappropriate for study participation or would put the participant at risk
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of American Society for Transplantation and Cellular Therapy (ASTCT) ≥ grade 3 immune-effector cell associated neurotoxicity syndrome (ICANS) | From first dose of intrathecal (IT) chemotherapy (chimeric antigen receptor [CAR]-T day 4) to CAR-T day 30 | Will be reported using the efficacy set. Point estimate, along with exact two-sided 95% confidence interval will be reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of ASTCT any grade ICANS | From first dose of IT chemotherapy (CAR-T day 4) to CAR-T day 30 | Will be reported using the efficacy set. Point estimate, along with exact two-sided 95% confidence interval will be reported. |
| Incidence of lumbar puncture/IT treatment related adverse events (AEs) and serious adverse events (SAEs) | From first dose of IT chemotherapy (CAR-T day 4) to CAR-T day 30 | Will be reported using the safety set. AEs will be tabulated by the Medical Dictionary for Regulatory Activities version (v) 21.1. preferred term and system organ class and a preferred term. The severity of the AE will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version (CTCAE) v 5.0. Descriptive statistics using the safety evaluable population, will be used to report on all on-study AEs, grade 3-4 AEs, treatment-related AEs, grade 3-4 treatment-related AEs, SAEs, treatment-related SAEs, and AEs leading to discontinuation per CTCAE v 5.0. Grade 3-4 laboratory abnormalities will be summarized using worst grade NCI CTCAE v 5.0 criteria. |
| Mean (range) cumulative dose of corticosteroid use | From first dose of IT chemotherapy (CAR-T day 4) to CAR-T day 30 | Will be reported using the efficacy set. The cumulative dose will be calculated as the sum of all corticosteroid administered over the study period, expressed in milligrams (mg) of prednisone-equivalent. |
| Incidence of anakinra use | From first dose of IT chemotherapy (CAR-T day 4) to CAR-T day 30 | Will be reported using the efficacy set. Point estimate, along with exact two-sided 95% confidence interval will be reported. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORStephen E Spurgeon
OHSU Knight Cancer Institute
Outcome results
None listed