This early phase I trial studies the side effects of dexamethasone and simvastatin to see how well they work in preventing neurotoxicity (damage to the nervous system) in patients receiving chimeric antigen receptor (CAR)-T treatment. CAR-T therapy uses a patient's own immune cells to attack cancer cells. This treatment carries a high risk of side effects, including severe neurotoxicity and cytokine release syndrome, or “CRS,” which can occur when the CAR-T cells grow rapidly and release a type of protein called a cytokine, which can contribute to inflammation. CRS can result in mild, moderate, or severe reactions. Symptoms and problems can include high fevers, chills and shaking, sweating, nausea, vomiting, diarrhea, swelling, or skin rashes. Oral and intravenous steroids are used to treat neurotoxicity, but these routes of administration do not directly target inflammation in the spinal cord and brain. Giving dexamethasone (an anti-inflammatory steroid) directly to the spinal cord may help reduce the inflammation in the spinal cord and treat neurotoxicity. Simvastatin may inhibit the release of inflammatory cytokines, and potentially prevent CRS. The purpose of this trial is to determine whether giving patients a combination of the drugs simvastatin and dexamethasone, is a reasonable, safe, and tolerable method to prevent neurotoxicity.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04514029.
PRIMARY OBJECTIVE:
I. To determine the feasibility and safety of simvastatin and intrathecal (IT) dexamethasone in patients receiving
CAR-T cells while providing initial estimates of efficacy.
SECONDARY OBJECTIVES:
I. Determine the serum and cerebrospinal fluid (CSF) levels of IL6, IL8, IL10, MCP-1, VEGF, PDGFR beta, cleaved-caspase 3 on days -1, +6, and 13 if it occurs; and serum levels at day +1.
II. To determine the incidence of severe neurotoxicity (NT) in patients participating in this clinical trial and receiving CAR-T cells within 30 days of the CAR-T infusion.
III. To determine the overall response rate of CAR-T cells according to Lugano for lymphoma and International Working Group for Leukemia and Myeloma for acute lymphoblastic leukemia (ALL) and multiple myeloma.
IV. To determine the incidence of severe cytokine release syndrome (CRS) at day +30.
V. To determine change in serum levels of ANG1, ANG2, and IP10 with statin therapy.
CORRELATIVE OBJECTIVES:
I. To determine pre- and post-infusion levels of a predefined cytokine profile as measured by a multiplex array in the serum and CSF of patients on above mentioned days at time of CRS and NT if samples available.
II. To determine whether serial procalcitonin follows the same kinetics as ferritin and CRP in the presence and absence of infections.
III. To determine whether the kinetics (rate of rise) of c-reactive protein (CRP), ferritin, procalcitonin and other inflammatory biomarkers can predict severity and/or response to treatment of CRS and NT.
IV. To determine changes in length of stay, acuity of patients and effect on total cost.
OUTLINE:
Patients receive simvastatin orally (PO) once daily (QD) starting at least 5 doses prior to apheresis until day +30 after CAR-T infusion in the absence of unacceptable toxicity. Patients also receive dexamethasone sodium phosphate IT over 90 minutes on days -1, +6, and with optional retreatment on day +13 per treating physician in the absence of unacceptable toxicity. Patients receive CAR-T via infusion on day 0 in the absence of disease progression or unacceptable toxicity. Active treatment continues until 30 days post CAR-T infusion. Patients also undergo lumbar punctures on study and collection of blood samples during screening and on study.
After completion of study treatment, patients are followed up at 6 months and 1 year.
Trial PhasePhase O
Trial Typesupportive care
Lead OrganizationUniversity of Minnesota/Masonic Cancer Center
Principal InvestigatorJoseph Maakaron
