A Study of a Fully Human BCMA-targeting CAR (CT103A) Combined With Selinexor in Patients With Relapsed/Refractory Extramedullary Multiple Myeloma

Study Overview
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Brief Summary
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This study is a single-center, open Phase I study, to observe the effectiveness and safety of CT103A combined with different doses of Selinexor in patients with relapsed/refractory extramedullary multiple myeloma, and the pharmacokinetics of Selinexor and CT103A Kinetic and pharmacodynamic characteristics.

Detailed Description
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In this study, two dose groups of 20 mg/week and 40 mg/week will be set for Selinexor, and the dose of CT103A is 1.0×106 cells/Kg. Subjects in all dose groups will firstly receive a single dose infusion of CT103A, at least 1 month post infusion and platelet recovery to ≥50×109/L. Then subjects began to take Selinexor once a week for one year. Each dose group level will include 8-10 subjects, and a total of 16-20 subjects are expected to be enrolled.

Official Title
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Phase I Clinical Study of a Fully Human BCMA-targeting CAR (CT103A) Combined With Selinexor in the Treatment of Patients With Relapsed/Refractory Extramedullary Multiple Myeloma

Conditions
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Extramedullary Multiple Myeloma

Intervention / Treatment
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* Drug: Selinexor
* Drug: CT103A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must satisfy all the following criteria to be enrolled in the study: age ≥18 years old, male or female. Subjects with diagnosed relapsed or refractory extramedullary multiple myeloma according to IMWG criteria and have had at least 3 prior lines of therapy Evidence of cell membrane BCMA expression, as determined by a validated immunohistochemistry (IHC) or flow cytometry of tumor tissue(e.g., bone marrow biopsies, or plasmacytoma). Subjects with extramedullary myeloma require extramedullary lesions with a maximum diameter of ≥2cm ECOG score is ≤ 2 Estimated life expectancy ≥ 12 weeks. Subjects should have adequate organ function: Absolute neutrophil count (ANC) ≥1×10^9 /L; absolute lymphocyte count (ALC) ≥0.3×10^9 /L; platelets ≥50×10^9 /L; hemoglobin ≥60 g/L. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×upper limit of normal (ULN); total serum bilirubin ≤ 1.5×ULN. Creatinine clearance rate (CrCl) calculated according to Cockcroft-Gault formula ≥ 40 ml/min. Fibrinogen ≥ 1.0 g/L; activated partial thromboplastin time (APTT) ≤ 1.5×ULN, prothrombin time (PT) ≤1.5×ULN. SpO2 > 91%. Left ventricular ejection fraction (LVEF) ≥ 50%. 8. The subject and his/her spouse agree to use an effective contraceptive tool or medication (excluding safety period contraception) from the date of the subject's informed consent to one year post CAR T cell infusion. 9. Subject must sign the informed consent form approved by the ethics board in person before starting any screening procedure. Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment: Subjects who are known to be resistant to Selinexor; Subjects who need to use immunosuppressive agents for a long time due to graft-versus-host disease (GVHD) or autoimmune diseases. Subjects have received any anti-cancer treatment as follows: monoclonal antibody for treating multiple myeloma within 21 days before leukapheresis, or cytotoxic therapy or proteasome inhibitors within 14 days before leukapheresis, or immunomodulatory agents within 7 days before leukapheresis, or anti-tumor treatments other than those listed above within 30 days before leukapheresis. Subjects who were receiving a used therapeutic dose of corticosteroid treatment (defined as prednisone or equivalent > 20mg) within 7 days prior to screening, except for physiological alternatives, inhalation, or topical use. Subjects with hypertension that cannot be controlled by medication Subjects with serious heart disease: including but not limited to unstable angina, myocardial infarction (within 6 months prior to screening), congestive heart failure (NYHA classification ≥III), and severe arrhythmias. Subjects with systemic diseases that the investigator determined to be unstable include, but are not limited to, severe liver and kidney or metabolic diseases requiring medical treatment. Subjects with second malignancies in addition to MM within the past 5 years before the screening, exceptions to this criterion: successfully treated cervical carcinoma in situ and non-metastatic basal or squamous cell skin carcinoma, local prostate cancer after radical surgery, and ductal carcinoma in situ of the breast after radical surgery. Subjects with a history of organ transplantation. Subjects have received major surgery within 2 weeks prior to leukapheresis or plan to receive surgery during the study or within 2 weeks after the study treatment (excluding local anesthesia) Subjects participated in another interventional clinical study within 1 month before signing the informed consent (ICF). Subjects with any uncontrolled active infection needed to receive systemic therapy within 7 days before leukapheresis. Positive for any of the following tests: Hepatitis B virus (HBV) surface antigen (HBsAg) or hepatitis B core antibody-positive and detectable HBV DNA in peripheral blood Hepatitis C virus (HCV) antibody and hepatitis C virus RNA in peripheral blood Human immunodeficiency virus (HIV) antibody Cytomegalovirus (CMV) DNA Treponema Pallidum antibody Pregnant or lactating women. Subjects with mental illness or consciousness disorder or disease of the central nervous system Other conditions that researchers consider inappropriate for enrollment.

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: Single Group Assignment
Interventional Model Description: The efficacy and safety, as well as the pharmacokinetic and pharmacodynamic characteristics of CT103A combined with different doses of Selinexor will be assessed in patients with relapsed/refractory extramedullary multiple myeloma. In this study, CT103A will be infused at the dose of 1.0×10^6 cells/Kg, while Selinexor was set as two dosage groups of 20 mg/week and 40 mg/week. Subjects in all dose groups received a single infusion of CT103A, and at least 1 month after the infusion of CT103A, Selinexor was administered orally once a week for one year when platelet count recovered to ≥50×10^9 /L. 8 to 10 subjects were enrolled at each dose group level, with a total of 16 to 20 subjects expected to be enrolled.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CT103A combined with Selinexor<br>All subjects will be assigned to two Selinexor dose groups of 20 mg/week and 40 mg/week after receiving a single dose infusion of CT103A. | Drug: Selinexor<br>* Selinexor, 20 mg/tablet, is a first-in-class, oral Selective-Inhibitor-of-Nuclear-Export (SINE) compound that impedes XPO-1which is a major nuclear export protein of macromolecular cargo frequently overexpressed in MM.<br>Drug: CT103A<br>* CT103A consists of autologous T lymphocytes transduced with anti-BCMA CAR lentiviral vector that containing a unique CAR structure with a fully human single-chain variable fragment (scFv).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | The time from the start of CT103A treatment for the subjects to the first disease progression or death for any reason. | 1 year post CT103A infusion | 
| Objective response rate (ORR) | The percentage of subjects who achieved sCR、CR、VGPR、PR. | 1 year post CT103A infusion | 
| Duration of response (DOR) after administration | DOR will be calculated among responders (with a PR or better response) from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, as defined in the IMWG criteria | 1 year post CT103A infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS is measured from the date of the initial infusion of CT103A to the date of the participant's death. | 1 year post CT103A infusion | 
| Minimal Residual Disease (MRD) efficacy evaluation | MRD evaluation according to IMWG, including the proportion of subjects who achieved MRD negative and the duration of MRD negative. | 1 year post CT103A infusion | 
| Type and incidence of adverse events (AEs) and serious adverse events (SAEs) by dose group | Calculate type and incidence of adverse events (AE), serious adverse event (SAE), including those happened after lymphodepletion and after infusion, those related to study drug and lymphodepletion, or those that led to withdrawal from the study. They will also be aggregated by systematic organ classification (SOC), preferred term (PT), and severity | 1 year post CT103A infusion | 
| Pharmacokinetics - Cmax of CT103A | The maximum transgene level at Cmax fo CT103A | 1 year post CT103A infusion | 
| Pharmacokinetics - Tmax of CT103A | The maximum transgene level at Tmax fo CT103A | 1 year post CT103A infusion | 
| Pharmacokinetics - AUC0-28days of CT103A | Area under the curve of CT103A cells from time zero to Day 28 of CT103A | 1 year post CT103A infusion | 
| Pharmacokinetics - AUC0-90days of CT103A | Area under the curve of CT103A cells from time zero to Day 90 of CT103A | 1 year post CT103A infusion | 
| Pharmacokinetics of Selinexor | The changes of concentration of Selinexor in peripheral blood will be assessed. | 1 year post CT103A infusion | 
| PD endpoints | The concentration levels of CAR-T-related serum cytokines such as Ferritin and IL-6 | 1 year post CT103A infusion | 
| Health-related quality of life assessment | HRQoL will be assessed by the European Organization for Cancer Research and Treatment Quality of Life Questionnaire (EORTC-QLQ-C30) | 1 year post CT103A infusion | 
| Appraisal of life quality | Appraisal of life quality of the subjects will be assessed by the Quality of Life Multiple Myeloma Module Questionnaire (QLQ-MY20) | 1 year post CAR-T cell infusion | 
| Evaluation of lymphocyte subsets | Lymphocyte subsets will be assessed by FACS | 1 year post CAR-T cell infusion | 
| Concentration of immunoglobulins | The levels of Immunoglobulins in peripheral blood will be assessed to monitor changes at each time point | 1 year post CAR-T cell infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CT103A, Selinexor