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Neurotoxicity Prophylaxis With Intrathecal Dexamethasone and Simvastatin Post Axi-Cel

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04514029
Recruitment Status : Recruiting
First Posted : August 14, 2020
Last Update Posted : August 25, 2021
Sponsor:
Information provided by (Responsible Party):
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.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : August 6, 2020
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023


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)




Primary Outcome Measures :
  1. Number of patients completing two-thirds of their assigned treatment [ Time Frame: 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.

  2. Number of patients experiencing adverse events [ Time Frame: 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 :
  1. The change in IL-6 levels [ Time Frame: 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.

  2. The change in IL-8 levels [ Time Frame: 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.

  3. The change in IL-10 levels [ Time Frame: 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.

  4. The change in MCP-1 levels [ Time Frame: 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.

  5. The change in VEGF levels [ Time Frame: 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.

  6. The change in PDGFR levels [ Time Frame: 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.

  7. The change in cleaved-caspase 3 levels [ Time Frame: 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.

  8. Number of participants experiencing severe NT [ Time Frame: 30 days after initiation of CAR-T therapy ]
    The incidence of severe NT in patients receiving CAR-T cell dexamethasone and simvastatin.

  9. Number of participants experiencing overall best response with CAR-T cell therapy [ Time Frame: 30 days after initiation of CAR-T therapy ]
    The overall response rate of CAR-T cells as defined by Lugano criteria.

  10. The change in serum levels of ANG1 with statin therapy [ Time Frame: 30 days after initiation of CAR-T therapy ]
    ANG1 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA)

  11. The change in serum levels of ANG2 with statin therapy [ Time Frame: 30 days after initiation of CAR-T therapy ]
    ANG2 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA)

  12. The change in serum levels of IP10 with statin therapy [ Time Frame: 30 days after initiation of CAR-T therapy ]
    IP10 levels in serum will be measured using an enzyme-linked immunosorbent assay (ELISA)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04514029


Contacts
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Contact: Cancer Center Clinical Trials Office 612 624 2620 ccinfo@umn.edu

Locations
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United States, Minnesota
Masonic Cancer Center, University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Joseph Maakaron, MD         
Contact       maaka001@umn.edu   
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
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Principal Investigator: Joseph Maakaron, MD Masonic Cancer Center, University of Minnesota
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Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT04514029    
Other Study ID Numbers: 2019LS161
First Posted: August 14, 2020    Key Record Dates
Last Update Posted: August 25, 2021
Last Verified: August 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Masonic Cancer Center, University of Minnesota:
Lymphoma
CAR-T
Neurotoxicity
CRS
Dexamethasone
Simvastatin
Additional relevant MeSH terms:
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Neurotoxicity Syndromes
Nervous System Diseases
Poisoning
Chemically-Induced Disorders
Dexamethasone
Simvastatin
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors