Clinical Study of XPO-1 Inhibitors Plus CAR-T Cells in Relapsed Refractory B-cell Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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Aim of this study will evaluate the Efficacy and Safety of XPO-1 inhibitors in combination with CAR-T cells in relapsed refractory B-cell non-Hodgkin's lymphoma

Detailed Description
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B-cell non-Hodgkin's lymphoma (B-NHL) is the most common hematological malignancy originating from lymphohematopoietic tissue. Lymphoma is now one of the most rapidly growing malignancies worldwide, with approximately 350,000 new cases and over 200,000 deaths worldwide each year.With the use of rituximab in combination with standard chemotherapy regimens, progression-free survival (PFS) and overall survival (OS) in B-NHL have improved significantly, yet primary resistance or relapse progression still occurs in 40%-50% of B-NHL patients.The most widely used CAR-T therapy for R/R B-NHL in clinical practice is CAR-T therapy targeting CD19, which has a complete remission rate (CR) of 40%-53% and an overall remission rate (ORR) of 52%-82%.XPO1 inhibitors are potential drugs to enhance the anti-lymphoma effect of CD19 CAR-T cells, this study will evaluate the efficacy and safety of XPO-1 inhibitors in combination with CAR-T cells in relapsed refractory B-cell non-Hodgkin's lymphoma.

Official Title
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Clinical Study of the Efficacy and Safety of XPO-1 Inhibitors in Combination With CAR-T Cells in Relapsed Refractory B-cell Non-Hodgkin's Lymphoma

Conditions
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Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Selinexor
* Drug: Flu
* Drug: CTX
* Drug: CAR-T


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Pathological immunohistochemistry or flow cytometry confirmed that R/ R B-cell Non-Hodgkin's Lymphoma with measurable (diameter greater than 1.5cm) lesions meets any of the following conditions: 1> After 4 courses of standard first-line therapy or 2 courses of more than two-line therapy, the lesions were reduced by <50%; 2> R/ R B-cell Non-Hodgkin's Lymphoma with disease progression after first-line or induction therapy; 3> After hematopoietic stem cell transplantation, new lesions appear or the size of previously affected lesions increased by more than 50%. Previously treated with 2 or more lines of therapy. ECOG≤2#. The main organ functions need to meet the following conditions:LVEF≥50%;CR≤132 umol/l or CCr≥60 ml/min; ALT and AST≤2.5 times normal range#TB≤2 times ULN#Lung function≤Level 1; dyspnea(CTCAE v5.0),and blood oxygen saturation without oxygen absorption> 90%. Pass the T-cell amplification test. Voluntary tissue puncture/biopsy for tumor tissue retrieval before and after treatment. Subjects of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study until the follow-up one year period of the study. Estimated survival time ≥3 months. Voluntary signing of informed consent and good compliance. Exclusion Criteria: Have used immunosuppressants or hormones within 2 weeks prior to signing informed consent, or plan to have to use immunosuppressants or high-dose hormones (e.g. prednisone >15mg) after signing informed consent, specifically systemic treatment, excluding treatment with topical or inhaled corticosteroids. The presence of bacterial, fungal, viral, mycoplasma or other types of infection that, in the judgment of the investigator, are difficult to control. Active hepatitis B or active hepatitis C. HIV infection. Active acute or chronic graft-versus-host disease (GVHD) at the time of signing the informed consent form. Participated in an investigational clinical trial of any other drug within 30 days prior to signing the informed consent form. Received CAR-T cell therapy within 3 months prior to signing the informed consent form. Received an allogeneic hematopoietic stem cell transplant within 6 months prior to signing the informed consent form. Presence of contraindications to XPO-1 inhibitor. Prior malignancy (other than Relapsed Refractory B-cell Non-Hodgkin's Lymphoma), except for cured malignant tumors with no active lesions for 3 years;Adequate treatment of inactive lesions in non-melanoma skin cancer,malignant tonsilloma or carcinoma in situ. Pregnant or breasting-feeding women. Conditions deemed by the researcher to be inappropriate for participation in this clinical trial.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XPO-1 Inhibitor+CAR-T Cells<br>XPO-1 Inhibitor plus CAR-T Cells | Drug: Selinexor<br>* 40-60mg QW,w-3～d-3,PO<br>* Other names: XPO-1 Inhibitor;Drug: Flu<br>* 25-30 mg/m2，d-5 ～d-3，qd，ivgtt<br>* Other names: Fludarabine;Drug: CTX<br>* 250-500 mg/m2，d-5 ～d-3，qd，ivgtt<br>* Other names: Cyclophosphamide;Drug: CAR-T<br>* 2-5×10^6 CAR-T/kg，ivgtt。<br>* Other names: Chimeric antigen receptor-modified T (CAR-T) cell therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | To measure the duration of response to XPO-1 Inhibitor Plus CAR-T Cells over a follow-up period of 12 months | up to 12 months | 
| Duration of Response(DOR) Duration of Response(DOR) | Duration of overall response will be assessed from the first XPO-1 Inhibitor Plus CAR-T cells given to progression,death or last follow-up. | up to 12 months | 
| Adverse events profile | Number of participants with adverse events. Frequencies of toxicities based on the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 will be tabulated. | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate | Number of patients who achieved complete response after treatment by XPO-1 Inhibitor plus CAR-T cells. | up to 12 months | 
| Progression-free Survival | To measure the duration of response to XPO-1 Inhibitor plus CAR-T cells over a follow-up period of 12 months. | up to 12 months | 
| Overall Survival | OS will be assessed from the first XPO-1 Inhibitor plus CAR-T cells given to death or last follow-up. | up to 12 months | 
| Peak Plasma Concentration | the peak amplification of CART in peripheral blood. | Measured from start of treatment until 28 days after last dose | 
| Time to Peak Amplification | The time to peak amplification of CART in peripheral blood. | Measured from start of treatment until 28 days after last dose | 
| AUC0-28 | The area under the curve (AUC0-28) obtained by plotting the number of CAR-T cells in serum against the visit time from 0 to 28 days after reinfusion. | Measured from start of treatment until 28 days after last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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XPO-1 Inhibitor, CAR-T Cells, Relapsed Refractory B-cell Non-Hodgkin's Lymphoma