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Neurotoxicity Prophylaxis With Intrathecal Dexamethasone and Simvastatin Post Axi-Cel

Primary Purpose

Lymphoma

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Simvastatin
Dexamethasone
Sponsored by
Masonic Cancer Center, University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Lymphoma focused on measuring Lymphoma, CAR-T, Neurotoxicity, CRS, Dexamethasone, Simvastatin

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • Masonic Cancer Center, University of MinnesotaRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Simvastatin and Dexamethasone

Arm Description

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).

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
Number of participants experiencing severe NT
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
The overall response rate of CAR-T cells as defined by Lugano criteria.
The change in serum levels of ANG1 with statin 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
ANG2 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA)
The change in serum levels of IP10 with statin therapy
IP10 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA)

Full Information

First Posted
August 12, 2020
Last Updated
November 2, 2022
Sponsor
Masonic Cancer Center, University of Minnesota
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1. Study Identification

Unique Protocol Identification Number
NCT04514029
Brief Title
Neurotoxicity Prophylaxis With Intrathecal Dexamethasone and Simvastatin Post Axi-Cel
Official Title
Neurotoxicity Prophylaxis With Intrathecal Dexamethasone and Simvastatin in Adults Receiving Axicabtagene Ciloleucel (Axi-Cel) Treatment
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 6, 2020 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Masonic Cancer Center, University of Minnesota

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoma
Keywords
Lymphoma, CAR-T, Neurotoxicity, CRS, Dexamethasone, Simvastatin

7. Study Design

Primary Purpose
Prevention
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Simvastatin and Dexamethasone
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Simvastatin
Intervention Description
Simvastatin 40 mg started 2 weeks (+/-5 days) prior to apheresis through day +30
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Intervention Description
Intrathecal dexamethasone 8 mg on days -1, +6, +13 (+/-2 days)
Primary Outcome Measure Information:
Title
Number of patients completing two-thirds of their assigned treatment
Description
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.
Time Frame
30 days after initiation of CAR-T therapy
Title
Number of patients experiencing adverse events
Description
Safety of administering Simvastatin and Dexamethasone will be measured by the proportion of patients experiencing adverse events related to the study treatment.
Time Frame
From the day of 1st dose of simvastatin and until day +7 after the last dose of simvastatin.
Secondary Outcome Measure Information:
Title
The change in IL-6 levels
Description
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.
Time Frame
One day prior to infusion and at days +1,+6, and +13 post infusion
Title
The change in IL-8 levels
Description
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.
Time Frame
One day prior to infusion and at days +1,+6, and +13 post infusion
Title
The change in IL-10 levels
Description
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.
Time Frame
One day prior to infusion and at days +1,+6, and +13 post infusion
Title
The change in MCP-1 levels
Description
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.
Time Frame
One day prior to infusion and at days +1,+6, and +13 post infusion
Title
The change in VEGF levels
Description
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.
Time Frame
One day prior to infusion and at days +1,+6, and +13 post infusion
Title
The change in PDGFR levels
Description
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.
Time Frame
One day prior to infusion and at days +1,+6, and +13 post infusion
Title
The change in cleaved-caspase 3 levels
Description
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.
Time Frame
One day prior to infusion and at days +1,+6, and +13 post infusion
Title
Number of participants experiencing severe NT
Description
The incidence of severe NT in patients receiving CAR-T cell dexamethasone and simvastatin.
Time Frame
30 days after initiation of CAR-T therapy
Title
Number of participants experiencing overall best response with CAR-T cell therapy
Description
The overall response rate of CAR-T cells as defined by Lugano criteria.
Time Frame
30 days after initiation of CAR-T therapy
Title
The change in serum levels of ANG1 with statin therapy
Description
ANG1 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA)
Time Frame
30 days after initiation of CAR-T therapy
Title
The change in serum levels of ANG2 with statin therapy
Description
ANG2 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA)
Time Frame
30 days after initiation of CAR-T therapy
Title
The change in serum levels of IP10 with statin therapy
Description
IP10 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA)
Time Frame
30 days after initiation of CAR-T therapy

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Cancer Center Clinical Trials Office
Phone
612 624 2620
Email
ccinfo@umn.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joseph Maakaron, MD
Organizational Affiliation
Masonic Cancer Center, University of Minnesota
Official's Role
Principal Investigator
Facility Information:
Facility Name
Masonic Cancer Center, University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joseph Maakaron, MD
Email
maaka001@umn.edu

12. IPD Sharing Statement

Learn more about this trial

Neurotoxicity Prophylaxis With Intrathecal Dexamethasone and Simvastatin Post Axi-Cel

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