Neurotoxicity Prophylaxis With Intrathecal Dexamethasone and Simvastatin Post Axi-Cel

Study Overview
=================
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.

Official Title
-----------------
Neurotoxicity Prophylaxis With Intrathecal Dexamethasone and Simvastatin in Adults Receiving Axicabtagene Ciloleucel (Axi-Cel) Treatment

Conditions
-----------------
Lymphoma

Intervention / Treatment
-----------------
* Drug: Simvastatin
* Drug: Dexamethasone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18- 80 years of age 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 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 Hemodynamically stable and LVEF ≥ 40% confirmed by echocardiogram or MUGA 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. 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 Availability of a certified practitioner to perform the lumbar punctures Exclusion Criteria: 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simvastatin and Dexamethasone<br>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). | Drug: Simvastatin<br>* Simvastatin 40 mg started 2 weeks (+/-5 days) prior to apheresis through day +30<br>Drug: Dexamethasone<br>* Intrathecal dexamethasone 8 mg on days -1, +6, +13 (+/-2 days)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients completing two-thirds of their assigned treatment | 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. | 30 days after initiation of CAR-T therapy | 
| Number of patients experiencing adverse events | Safety of administering Simvastatin and Dexamethasone will be measured by the proportion of patients experiencing adverse events related to the study treatment. | From the day of 1st dose of simvastatin and until day +7 after the last dose of simvastatin. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in IL-6 levels | 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. | One day prior to infusion and at days +1,+6, and +13 post infusion | 
| The change in IL-8 levels | 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. | One day prior to infusion and at days +1,+6, and +13 post infusion | 
| The change in IL-10 levels | 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. | One day prior to infusion and at days +1,+6, and +13 post infusion | 
| The change in MCP-1 levels | 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. | One day prior to infusion and at days +1,+6, and +13 post infusion | 
| The change in VEGF levels | 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. | One day prior to infusion and at days +1,+6, and +13 post infusion | 
| The change in PDGFR levels | 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. | One day prior to infusion and at days +1,+6, and +13 post infusion | 
| The change in cleaved-caspase 3 levels | 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. | One day prior to infusion and at days +1,+6, and +13 post infusion | 
| Number of participants experiencing severe NT | The incidence of severe NT in patients receiving CAR-T cell dexamethasone and simvastatin. | 30 days after initiation of CAR-T therapy | 
| Number of participants experiencing overall best response with CAR-T cell therapy | The overall response rate of CAR-T cells as defined by Lugano criteria. | 30 days after initiation of CAR-T therapy | 
| The change in serum levels of ANG1 with statin therapy | ANG1 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA) | 30 days after initiation of CAR-T therapy | 
| The change in serum levels of ANG2 with statin therapy | ANG2 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA) | 30 days after initiation of CAR-T therapy | 
| The change in serum levels of IP10 with statin therapy | IP10 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA) | 30 days after initiation of CAR-T therapy | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Lymphoma, CAR-T, Neurotoxicity, CRS, Dexamethasone, Simvastatin