Neurotoxicity Prophylaxis With Intrathecal Dexamethasone and Simvastatin Post Axi-Cel

Sponsor

Masonic Cancer Center, University of Minnesota (Other)

Overall Status

Recruiting

CT.gov ID

NCT04514029

Collaborator

(none)

Enrollment

Location

Arm

39.8

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Drug: Simvastatin Drug: Dexamethasone	Early Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Aug 6, 2020

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Simvastatin and Dexamethasone

Drug: Simvastatin

Simvastatin 40 mg started 2 weeks (+/-5 days) prior to apheresis through day +30

Drug: Dexamethasone

Intrathecal dexamethasone 8 mg on days -1, +6, +13 (+/-2 days)

Outcome Measures

Primary Outcome Measures

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

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 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 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 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.
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.
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.
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 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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.