Study to Evaluate the Safety and Efficacy of Anti-CD38 CAR-T in Relapsed or Refractory Multiple Myeloma Patients

Study Overview
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Brief Summary
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The study is an open-label Phase 1 single dose-escalation safety study of CAR2 Anti-CD38 A2 CAR-T Cells in patients with Relapsed or Refractory Multiple Myeloma, who meet all other eligibility criteria.

Detailed Description
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All subjects who received investigational CAR-T therapy will be included in the analyses and summaries of safety, efficacy, pharmacokinetic, and pharmacodynamic assessments.

Official Title
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A Phase 1, Open-Label, Dose-Escalation, Pharmacokinetic, and Pharmacodynamic Study of the Safety and Efficacy of CAR2 Anti-CD38 A2 CAR-T Cells in Patients With Relapsed or Refractory Multiple Myeloma

Conditions
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Relapsed or Refractory Multiple Myeloma

Intervention / Treatment
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* Biological: CAR2 Anti-CD38 A2 CAR-T Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient must either have relapsed refractory multiple myeloma (RRMM) after receiving prior lines of anti-myeloma treatments that included at least lenalidomide (Revlimid®), pomalidomide (Pomalyst®), bortezomib (Velcade®), carfilzomib (Kyprolis®), and daratumumab (Darzalex®) (refractory MM is defined as the development of disease progression during therapy with an anti-myeloma regimen or within 60 days of the last dose of an anti-myeloma regimen or the achievement of less than a partial response (PR) after greater than or equal to 2 cycles; for relapsing patients the duration from the last dose of the last prior treatment regimen to relapse must be less than or equal to 12 months); OR have multiple myeloma that is refractory to or has relapsed within 1 year of receiving high-dose therapy [HDT]/autologous stem cell transplantation [ASCT] in first- or second-line (refractory is defined as the achievement of less than a PR at the Day 90 to 100 post-ASCT response assessment) Must have measurable disease as defined by the following: Serum M-protein greater than or equal to 1 g/dL; OR Urine M-protein greater than or equal to 200 mg/24 hours; OR Serum free light chain (FLC) assay; involved FLC level greater than or equal to 10 mg/dL provided the serum FLC ratio is abnormal; OR greater than or equal to 30% clonal plasma cells in the bone marrow aspirate or biopsy sample Must have a life expectancy of at least 12 weeks Subjects should be willing and able to comply with the study schedule and protocols Females of childbearing potential must have 2 negative pregnancy tests, agree to ongoing pregnancy testing during the study, and sexually active female and male subjects must be willing to use an effective method to avoid pregnancies. Exclusion Criteria: Subjects who received anticancer therapy or investigational drug within 28 days of first dose Subjects who received any approved anticancer chemotherapy within 21 days of first dose (exception cyclophosphamide as NMA conditioning) Subjects with unresolved toxicity greater than Grade 2 from previous therapies Have myeloma involvement of central nervous system (CNS) or a history of brain metastasis or spinal cord compression Subjects with an ECOG performance status greater than or equal to 3 Has received allogenic hematopoietic stem cell transplantation (HSCT) within 6 months, have active graft-versus-host disease (GVHD) following transplant, or receiving immunosuppressive therapy following a transplant Has received any CAR cell line therapies Has any clinically significant low baseline lab results for hemoglobin, platelet counts, and neutrophil counts, at screening unless resulting from underlying RRMM. Has any clinically significant elevated baseline lab results for serum creatinine, AST, and total bilirubin (except for patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome) at screening regardless of causality. Known HIV or acquired immunodeficiency syndrome-related illness, acute or history of chronic hepatitis B or C. Female subjects who are pregnant or breastfeeding Active bacterial, viral or fungal infections Has active plasma cell leukemia Has medical condition, abnormality, or psychiatric illness that would prevent study participation Left ventricular ejection fraction (LVEF) less than 40%

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: To determine DLT and MTD, the design uses a 3+3 rule-based design. Dose escalation is permitted between successive cohorts based upon a specified algorithm, using discrete dosage steps.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAR2 Anti-CD38 A2 CAR-T Cells<br>Relapsed or Refractory Multiple Myeloma | Biological: CAR2 Anti-CD38 A2 CAR-T Cells<br>* Autologous IV infusion; dose-escalation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the MTD | The MTD is assessed according to a 3+3 dose-escalation design by the occurrence of treatment-emergent dose-limiting toxicities during the 28-day Treatment Period in the dose-escalation phase of the study | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the CAR2 Anti-CD38 A2 CAR-T cell blood concentrations (Pharmacokinetic [PK] Profile) to evaluate the Cmax | CAR2 Anti-CD38 A2 CAR-T cell blood concentrations will be measured at different time points during the 28-day treatment period to evaluate the maximum concentration (Cmax). | 28 days | 
| Determine the CAR2 Anti-CD38 A2 CAR-T cell blood concentrations (Pharmacokinetic [PK] Profile) to evaluate the AUC | CAR2 Anti-CD38 A2 CAR-T cell blood concentrations will be measured at different time points during the 28-day treatment period to evaluate the area under the curve (AUC). | 28 days | 
| Evaluate the safety of Anti-CD38 A2 CAR-T cells in Patients with RRMM by incidence of treatment-emergent adverse events | The evaluation of safety will be measured by an assessment of the incidence of treatment-emergent adverse events for each patient in the dose-escalation and expansion phases of the study. | 6 months | 
| Assess preliminary efficacy by response rate in accordance with the modified International Myeloma Working Group (IMWG) criteria | As a measure of activity, overall response rate will be assessed according to the modified International Myeloma Working Group (IMWG) criteria. Response will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol. | 6 months | 
| Assess preliminary efficacy by depth of response in accordance with the modified International Myeloma Working Group (IMWG) criteria. | As a measure of activity, depth of response (ie, category of response) will be assessed according to the modified International Myeloma Working Group (IMWG) criteria. This will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol. | 6 months | 
| Assess preliminary efficacy by duration of response in accordance with the modified International Myeloma Working Group (IMWG) criteria. | As a measure of activity, duration of response will be assessed according to the modified International Myeloma Working Group (IMWG) criteria. This will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol. | 6 months | 
| Assess preliminary efficacy by progression-free survival. | As a measure of activity, Progression-free survival (PFS) will be assessed. The events for the assessment of PFS are disease progression and death events. This time to event endpoint will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate. | 6 months | 
| Assess preliminary efficacy by overall survival. | As a measure of activity, Overall Survival (OS) will be assessed. The events for the assessment of OS are death events. Time to event endpoints will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate. | 6 months | 
| The determination of the recommended phase 2 dose (RP2D) will be based on an evaluation of treatment-emergent events. | The RP2D will be assessed by the incidence of treatment-emergent adverse events during the Treatment and Observation Periods. | 6 months | 
| The determination of the recommended phase 2 dose will be based on an evaluation of overall response rate. | The rate of response as a determination factor for the RP2D will be assessed by the incidence of responses of at least partial response according to the IMWG criteria during the Treatment and Observation Periods. | 6 months | 
| The determination of the recommended phase 2 dose (RP2D) will be based on an evaluation of depth of response. | The depth of response as a determination factor for the RP2D will be assessed by the IMWG categories for response according to changes from baseline in M-protein levels in serum and urine, per cent plasma cells in the bone marrow, and size (area) of soft tissue extramedullary plasmacytomas (if applicable). This will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol. | 6 months | 
| The determination of the recommended phase 2 dose (RP2D) will be based on an evaluation of duration of response. | The duration of response as a determination factor for the RP2D will be assessed by the IMWG criteria for disease progression following the achievement of a response of at least a partial response according to changes in M-protein levels in serum and urine, per cent plasma cells in the bone marrow, the appearance of new lytic bone lesions, and/or the development of new soft tissue extramedullary plasmacytomas during the Treatment and Observation periods. | 6 months | 
| The determination of the recommended phase 2 dose (RP2D) will be based on an evaluation of progression-free survival. | Progression-free survival as a determination factor for the RP2D will be assessed by the IMWG criteria for disease progression events and death events. This time to event endpoint will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate. Progression-free survival will be evaluated during the Treatment and Observation Periods of the study. | 6 months | 
| The determination of the recommended phase 2 dose (RP2D) will be based on an evaluation of overall survival. | Overall survival as a determination factor for the RP2D will be assessed by death events that occur during the Treatment and Observation Periods. Time- to-event endpoints will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR2 Anti-CD38 A2 CAR-T Cells