Clinical trial NCT04514029: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Lymphoma
Keywords: Lymphoma
CAR-T
Neurotoxicity
CRS
Dexamethasone
Simvastatin
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2020-08-14
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Number of patients completing two-thirds of their assigned treatment
timeFrame: 30 days after initiation of CAR-T therapy
measure: Number of patients experiencing adverse events
timeFrame: From the day of 1st dose of simvastatin and until day +7 after the last dose of simvastatin.
Secondary outcomes:
measure: The change in IL-6 levels
timeFrame: One day prior to infusion and at days +1,+6, and +13 post infusion
measure: The change in IL-8 levels
timeFrame: One day prior to infusion and at days +1,+6, and +13 post infusion
measure: The change in IL-10 levels
timeFrame: One day prior to infusion and at days +1,+6, and +13 post infusion
measure: The change in MCP-1 levels
timeFrame: One day prior to infusion and at days +1,+6, and +13 post infusion
measure: The change in VEGF levels
timeFrame: One day prior to infusion and at days +1,+6, and +13 post infusion
measure: The change in PDGFR levels
timeFrame: One day prior to infusion and at days +1,+6, and +13 post infusion
measure: The change in cleaved-caspase 3 levels
timeFrame: One day prior to infusion and at days +1,+6, and +13 post infusion
measure: Number of participants experiencing severe NT
timeFrame: 30 days after initiation of CAR-T therapy
measure: Number of participants experiencing overall best response with CAR-T cell therapy
timeFrame: 30 days after initiation of CAR-T therapy
measure: The change in serum levels of ANG1 with statin therapy
timeFrame: 30 days after initiation of CAR-T therapy
measure: The change in serum levels of ANG2 with statin therapy
timeFrame: 30 days after initiation of CAR-T therapy
measure: The change in serum levels of IP10 with statin therapy
timeFrame: 30 days after initiation of CAR-T therapy
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Joseph Maakaron, MD
role: PRINCIPAL_INVESTIGATOR
References: