Neurotoxicity Prophylaxis With Intrathecal Dexamethasone and Simvastatin Post Axi-Cel
- Conditions
- Lymphoma
- Interventions
- Registration Number
- NCT04514029
- Lead Sponsor
- Masonic Cancer Center, University of Minnesota
- Brief Summary
Open-label, single-arm, single center pilot study to assess safety and feasibility of administering dexamethasone intrathecally and simvastatin orally during axicabtagene ciloleucel (axi-cel) treatment. Feasibility will be measured by the proportion of patients completing two-thirds (2/3) of their assigned treatments. The study will be deemed feasible if 2/3 or more of the patients complete 2/3 or more of their allocated treatments.
- Detailed Description
This trial gathers preliminary information on the potential effect of the combination of dexamethasone and simvastatin on treating Neurotoxicity (NT) in the patient population. The rate of patients completing all required study treatments and the rate of NT will be determined.
Simvastatin 40 mg/day will be started at least 5 days prior to apheresis and will be continued until day +30 after infusion. Intrathecal dexamethasone 8 mg will be administered on days (related to CAR-T infusion) -1, +6, +13, (+/- 2 days). CSF samples (3 ml) will be collected at these time points. Peripheral blood samples of 4 ml will be collected on days -1, +1, +6, and +13. The care team will check weekly CK and LFTs to ensure safety of simvastatin. Patients who develop NT will be allowed to continue treatment if feasible along with standard of care management.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 37
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18- 80 years of age
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One of the following histologies:
- Diffuse large B-cell lymphoma (DLBCL) not otherwise specified, or
- Primary mediastinal B-cell lymphoma, or
- High grade B-cell lymphoma, or
- DLBCL arising from follicular lymphoma
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Disease status:
- Chemotherapy refractory disease after ≥2 lines of chemotherapy, or
- Relapsed with no remission after ≥1 lines of salvage chemotherapy, or
- Relapsed following autologous hematopoeitic stem cell transplantation (and failed at least 2 prior lines of therapy including high dose chemotherapy). If salvage therapy is given post auto HCT, the subject must have no complete response, or relapse after the last line of therapy
-
Performance Status
- ECOG performance status 0-2
-
Adequate organ function defined as:
-
Renal function defined as:
- eGFR ≥ 30 mL/min/1.73 m^2
-
Liver function defined as:
- ALT and AST ≤ 5 times the ULN for age (unless due to disease)
- Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert syndrome; may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN
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Hemodynamically stable and LVEF ≥ 40% confirmed by echocardiogram or MUGA
-
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Women of childbearing potential and men with partners of child-bearing potential must agree to use of contraception for the duration of treatment as outlined in axi-cel protocol.
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Able to provide written voluntary consent (or LAR consent for adults with diminished capacity) prior to the performance of any research related tests or procedures
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Availability of a certified practitioner to perform the lumbar punctures
- Allergies, or intolerance to simvastatin or dexamethasone
- Already receiving a statin drug for hypercholesterolemia and unwilling to change medication to 40 mg/day of simvastatin
- Active uncontrolled CNS lymphoma. Patients with history of CNS lymphoma who have been adequately treated are eligible
- Presence of Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD).
- Uncontrolled active hepatitis B or hepatitis C
- Active HIV infection
- Uncontrolled acute life threatening bacterial, viral or fungal infection
- Unstable angina and/or myocardial infarction
- Risk factors that preclude a safe lumbar puncture (high intracranial pressure, bleeding diathesis that cannot be reversed or corrected, need for uninterrupted anticoagulation, platelets < 50K that cannot be corrected with transfusional support
- Pregnant or breastfeeding as agents used in this study are Pregnancy Category C (dexamethasone) and X (simvastatin). Females of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days of study registration.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Simvastatin and Dexamethasone Simvastatin Simvastatin 40 mg/day will be started at least 5 days prior to apheresis and will be continued until day +30 after infusion. Intrathecal dexamethasone 8 mg will be administered on days (related to CAR-T infusion) -1, +6, +13, (+/- 2 days). Simvastatin and Dexamethasone Dexamethasone Simvastatin 40 mg/day will be started at least 5 days prior to apheresis and will be continued until day +30 after infusion. Intrathecal dexamethasone 8 mg will be administered on days (related to CAR-T infusion) -1, +6, +13, (+/- 2 days).
- Primary Outcome Measures
Name Time Method Number of patients completing two-thirds of their assigned treatment 30 days after initiation of CAR-T therapy The feasibility of administering Simvastatin and Dexamethasone will be measured by the proportion of the patients completing two-thirds (2/3) of their assigned treatments.
Number of patients experiencing adverse events From the day of 1st dose of simvastatin and until day +7 after the last dose of simvastatin. Safety of administering Simvastatin and Dexamethasone will be measured by the proportion of patients experiencing adverse events related to the study treatment.
- Secondary Outcome Measures
Name Time Method The change in PDGFR levels One day prior to infusion and at days +1,+6, and +13 post infusion Pre- and post-infusion levels of a cytokine profile will be measured by a Lumina multiplex array in the serum and CSF of patients at time of CRS and NT if samples available.
Number of participants experiencing severe NT 30 days after initiation of CAR-T therapy The incidence of severe NT in patients receiving CAR-T cell dexamethasone and simvastatin.
Number of participants experiencing overall best response with CAR-T cell therapy 30 days after initiation of CAR-T therapy The overall response rate of CAR-T cells as defined by Lugano criteria.
The change in serum levels of ANG1 with statin therapy 30 days after initiation of CAR-T therapy ANG1 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA)
The change in MCP-1 levels One day prior to infusion and at days +1,+6, and +13 post infusion Pre- and post-infusion levels of a cytokine profile will be measured by a Lumina multiplex array in the serum and CSF of patients at time of CRS and NT if samples available.
The change in cleaved-caspase 3 levels One day prior to infusion and at days +1,+6, and +13 post infusion Pre- and post-infusion levels of a cytokine profile will be measured by a Lumina multiplex array in the serum and CSF of patients at time of CRS and NT if samples available.
The change in IL-10 levels One day prior to infusion and at days +1,+6, and +13 post infusion Pre- and post-infusion levels of a cytokine profile will be measured by a Lumina multiplex array in the serum and CSF of patients at time of CRS and NT if samples available.
The change in serum levels of ANG2 with statin therapy 30 days after initiation of CAR-T therapy ANG2 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA)
The change in serum levels of IP10 with statin therapy 30 days after initiation of CAR-T therapy IP10 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA)
The change in IL-6 levels One day prior to infusion and at days +1,+6, and +13 post infusion Pre- and post-infusion levels of a cytokine profile will be measured by a Lumina multiplex array in the serum and CSF of patients at time of CRS and NT if samples available.
The change in IL-8 levels One day prior to infusion and at days +1,+6, and +13 post infusion Pre- and post-infusion levels of a cytokine profile will be measured by a Lumina multiplex array in the serum and CSF of patients at time of CRS and NT if samples available.
The change in VEGF levels One day prior to infusion and at days +1,+6, and +13 post infusion Pre- and post-infusion levels of a cytokine profile will be measured by a Lumina multiplex array in the serum and CSF of patients at time of CRS and NT if samples available.
Trial Locations
- Locations (1)
Masonic Cancer Center, University of Minnesota
🇺🇸Minneapolis, Minnesota, United States