Neurotoxicity Prophylaxis With Intrathecal Dexamethasone and Simvastatin Post Axi-Cel

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Lymphoma
• Intervention / Treatment: Drug: Simvastatin; Drug: Dexamethasone

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 Type: Interventional
• Enrollment (Actual): 37
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Cancer Center Clinical Trials Office; Phone Number: 612 624 2620; Email: ccinfo@umn.edu

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center, University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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)

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

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Joseph Maakaron, MD, Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2020
• Primary Completion (Actual): November 3, 2023
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: August 12, 2020
• First Submitted That Met QC Criteria: August 12, 2020
• First Posted (Actual): August 14, 2020

Study Record Updates

• Last Update Posted (Actual): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 23, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: CAR-T; Lymphoma; Dexamethasone; Simvastatin; CRS; Neurotoxicity
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Nervous System Diseases; Poisoning; Neurotoxicity Syndromes; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antimetabolites; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Dexamethasone; Simvastatin
• Other Study ID Numbers: 2019LS161

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No