Trial of an Investigational Drug After Rejecting the Relapse of an Allogeneic Transplant

Study Overview
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Brief Summary
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Most patients with multiple myeloma (MM) die due to relapse resistant to current treatment, including treatment with anti-B cell maturation antigen (BCMA) CAR-T cells. To overcome some of the potential limitations of this therapy, a new and optimized Anti-BCMA CAR-T has been developed, with the aim of using it in patients with MM who relapse after Allogeneic Haematopoietic Haematopoietic Progenitor. This trial is a prospective phase I/II trial with a 3+3 design. Once Dose Limiting Toxicity is identified, Phase II will begin to assess the efficacy of the procedure.

Detailed Description
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This trial is a prospective phase I/II trial with a 3+3 design. Once Dose Limiting Toxicity is identified (up to a maximum dose of 6x106 CAR-T/kg divided over 2 days), phase II of the trial will begin to assess the efficacy of the procedure. A number of 25 patients will be included to evaluate.

Official Title
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Anti-BCMA Chimeric Antigen Receptor (CARTemis-1) T-lymphocyte Therapy in the Treatment of Patients With Multiple Myeloma in Relapse After Allogeneic Transplant: EGFR Expression as a Control Mechanism of Treatment-derived Complications

Conditions
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Multiple Myeloma, Allogeneic Stem Cell Transplantation

Intervention / Treatment
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* Genetic: CARTemis-1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients > 18 years old with a diagnosis of post-allogeneic transplant relapse multiple myeloma. Measurable disease at the time of screening Previous treatment with ≥2 lines before and/or after allogeneic transplant. Patients who are not receiving immunosuppressants at least 1 month before inclusion and who do not have active graft-versus-host disease. Eastern Cooperative Oncology Group functional status from 0 to 1. Life expectancy greater than 3 months (at the time of screening) Patients who give their consent by signing the Informed Consent document. Exclusion Criteria: Active systemic immunosuppressive treatment Patients who have previously received treatment with CAR-T Anti-BCMA. Absolute lymphocyte count <0.2x109/L Previous neoplasm, except if it has been in complete remission >3 years, with the exception of skin carcinoma (non-melanoma) Active infection requiring treatment. Active HIV, hepatitis B virus or hepatitis C virus infection. Uncontrolled medical illness. Severe organic disease that meets any of the following criteria: left ventricular ejection fraction <40%, carbon monoxide diffusion test <40%, glomerular filtration rate <50 ml/min, bilirubin >3 normal value (except Gilbert syndrome). Previous diagnosis of symptomatic amyloid light chain or primary amyloidosis or POEMS Syndrome. Pregnant or lactating women. Women of childbearing age, unable or unwilling to use highly effective contraceptive methods. Men who cannot or do not wish to use highly effective contraceptive methods. Contraindication to receive lymphodepleting chemotherapy.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CARTemis-1<br>Dose escalation sequential cohorts CARTemis-1 will be self-administered intravenously one or two days, depending on the dose administered. | Genetic: CARTemis-1<br>* A dose escalation design will be applied in successive patient cohorts until identification of Dose Limiting Toxicity (maximum dose: 6x10^6 CAR-T/kg divided over 2 days).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Purity of CARTemis-1 | Number of cases in which, after performing apheresis, the manufacturing process is completed and CARTemis-1 cells are infused | Immediately after infusion | 
| Maximum tolerated dose | To determine the maximum tolerated dose of CarTemis-1 | Up to 30 days | 
| Infusion reactions | To appearance of any of the following symptoms after intravenous administration of CARTemis-1: cardiac events, chills, dyspnea, fatigue, sudden hypertension, hypotension, nausea, pain, fever, skin rash, and urticaria. | Immediately after intravenous administration of CARTemis-1 | 
| Tumor lysis syndrome | To increase nucleic acids, potassium, and phosphate in the blood | Up to 30 days after treatment administration | 
| Serious Adverse Event | Type, incidence, severity (graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0), timing, intensity, and relatedness of adverse events). | Up to 36 months after treatment administration | 
| Suspected Unexpected Serious Adverse Reaction | Describe the adverse event that occurs in a clinical trial subject, which is assessed by the sponsor and or study investigator as being unexpected, serious and as having a reasonable possibility of a causal relationship with the study drug. | Up to 36 months after treatment administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with cytopenias | Neutropenias or thrombopenias | During the first 90 days after administration of CARTemis-1 | 
| Number of Participants with prolonged cytopenias | Neutropenias or thrombopenias (grade ≥3) for more than 6 weeks | Up to 12 months after treatment administration | 
| Duration of clinical response | Duration of clinical response as assessed by Urinalysis (immunofixation, proteinuria and 24-h urine proteinogram), Blood tests (total immunoglobulin A, G and M, immunofixation and proteinogram (M component) in serum; serum free light chains), Bone Marrow Aspirate and Positron Emission Tomography. | Screening, day -5, -4, -3, +28, +56, +100 and months +4, +5, 6, +7, +8, +9, +10, +11, +12, +15 , +18, +21, +27, +30, +33, +36 or progression | 
| Overall response rate | Overall response rate as assessed by criteria of the International Myeloma Working Group | 3, 6 and 12 months after CARTemis-1 infusion | 
| Time to complete remission | Duration of clinical response as assessed by Urinalysis (immunofixation, proteinuria and 24-h urine proteinogram), Blood tests (total immunoglobulin A, G and M, immunofixation and proteinogram (M component) in serum; serum free light chains), Bone Marrow Aspirate and Positron Emission Tomography | Up to 36 months after treatment administration | 
| Time to best response | Duration of clinical response as assessed by Urinalysis (immunofixation, proteinuria and 24-h urine proteinogram), Blood tests (total immunoglobulin A, G and M, immunofixation and proteinogram (M component) in serum; serum free light chains), Bone Marrow Aspirate and Positron Emission Tomography | Up to 36 months after treatment administration | 
| Negative Minimum Residual Disease Rate | Residual amount of malignant cells in the bone marrow | 3, 6 and 12 months after CARTemis-1 infusion | 
| Response rate of extramedullary disease | To measure of the metabolic activity of the human body by Positron Emission Tomography | 3 months after CARTemis-1 infusion | 
| Progression-free survival. | Quantification of time between administration of CARTemis-1 and disease progression or death | Up to 36 months after treatment administration | 
| Overall survival | the time elapsed between the infusion of CARTemis-1 and the patient's death from any cause. | Up to 36 months after treatment administration | 
| Persistence of CARTemis-1 | Presence of CARTemis-1 in peripheral blood and bone marrow | Peripheral blood:days 3,7,10,14,17 (only in cohort 3 and 4),21,30,56,90,128 and 156, and months 6,9,12,15,18,24 and relapse or month 36 post-infusion; Marrow: 1,3,6,12,18 and 24 months post-infusion and in the progression or month | 
| CART cell quality | Evaluation of the biological characteristics of CARTemis-1 performed by flow cytometry to identify the optimal time of expansion as well as to study the dynamics of CAR T cells during the manufacturing process and how the manufacturing impacts on CAR T cell features and, therefore, CAR T cell quality. | During the manufacturing process, at the time of infusion and at Month+1, Month+3, Month+6, Month+12, Month+18 and Month+24 post-infusion | 
| Expression of B cell maturation antigen (BCMA) | Genetic expression of BCMA at selection and at relapse in patients | Screening and at the time of follow up when a relapse occurs, an average after 1 year | 
| B cell maturation antigen (BCMA) levels | Serum soluble BCMA levels pre-treatment and during treatment | Screening, Day -5, Day 0, +1, +3, +7 y +28 and months +3, +6, +12, +18 and +24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chimeric antigen receptor-T cell therapy, B-Cell Maturation Antigen