Feasibility and Safety of Collecting and Combining Autologous Hematopoietic Stem Cells With Chimeric Antigen Receptor (CAR) T-Cell Therapy in Subjects With Relapsed/Refractory Hematological Malignancies

Study Overview
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Brief Summary
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The study is designed to examine the feasibility and safety of collecting autologous hematopoietic stem cells (HSCs) to be combined with CAR T-cell therapy for patients with relapsed/refractory (r/r) hematological disease. The study will evaluate feasibility of collecting the target dose of HSCs from at least 50% of enrolled patients. The study will assess safety based on incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in the first 60 days post CAR T dosing, and also through the collection of adverse events (AEs) and serious adverse events (SAEs) as well as the durability of response after treatment with HSCs with CAR T. The study follows an open-label, single-center and single non-randomized cohort design. 20 subjects with r/r hematological malignancies will be enrolled and treated to evaluate the feasibility and preliminary safety of collecting autologous HSCs and combining them with CAR T-cell therapy.

Official Title
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IIT2022-04-Sasine-CAR-T: A Phase 1 Single-arm, Open-label Study to Evaluate the Feasibility and Safety of Collecting and Combining Autologous Hematopoietic Stem Cells With Chimeric Antigen Receptor (CAR) T-Cell Therapy in Subjects With Relapsed/Refractory Hematological Malignancies

Conditions
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Hematologic Malignancy, Large B-cell Lymphoma, Acute Lymphoblastic Leukemia, Mantle Cell Lymphoma, Multiple Myeloma, Diffuse Large B Cell Lymphoma

Intervention / Treatment
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* Biological: autologous hematopoietic stem cells added to planned CAR T


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 85 years. Histologically proven hematological malignancy according to the World Health Organization 2016 classification criteria for which a commercially available, FDA-approved CAR T product exists. Relapsed or refractory disease, defined by the following: Disease progression after last regimen, or Refractory disease: failure to achieve a partial response (PR) or complete remission (CR) to the last regimen At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy for the malignancy at the time the subject is planned for leukapheresis. Toxicities due to prior therapy must be stable or recovered to ≤ Grade 1 with the exception of alopecia. Subjects with an active uncontrolled infection should not start CAR T treatment until the infection has resolved. Eastern cooperative oncology group (ECOG) performance status 0 - 2. Adequate hematologic, hepatic, and cardiac function Serum pregnancy test for women of childbearing potential (WOCBP) at Screening. Willing to comply to research specimen collection as specified in the protocol. Written informed consent obtained from subject and ability for subject to comply with the requirements of the study. Exclusion Criteria: Autologous hematopoietic cell transplant intent or execution within 8 weeks of planned CAR T infusion. History of allogeneic cell transplantation within 8 weeks of planned CAR T infusion. Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management at time of screening. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment. History of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, or any autoimmune disease with CNS involvement. Doses of corticosteroids of greater than or equal to 5 mg/day of prednisone or equivalent doses of other corticosteroids and other immunosuppressive drugs are not allowed prior to enrollment. A washout period of 10 days prior to leukapheresis and 10 days prior to anti-CD19 CAR T cell administration is required. Any medical condition likely to interfere with assessment of feasibility or safety of study treatment. Live vaccine ≤ 6 weeks prior to planned start of conditioning regimen. History of severe immediate hypersensitivity reaction to any of the agents used in this study. Current pregnancy or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Subjects of both sexes who are not willing to practice birth control from the time of consent through 6 months after the completion of conditioning chemotherapy. Females who have undergone surgical sterilization or who have been postmenopausal for at least 1 year are not considered to be of childbearing potential. In the investigator's judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation. Patients with obvious myeloid clonal hematopoiesis on the screening bone marrow biopsy will be excluded based on the risk of developing myeloid neoplasms with aHSC infusion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: CAR T Therapy with Autologous Hematopoietic Stem Cells (aHSCs)<br> | Biological: autologous hematopoietic stem cells added to planned CAR T<br>* Autologous hematopoietic stem cells (aHSCs) infused on Day 10 after CAR T (any FDA-approved CAR T product) infusion on Day 0.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess feasibility of collecting the target HSC cell dose for at least 50% of enrolled patients. | Target dose collection of autologous HSCs (2 to 5 x 106 CD34+ cells/kg) defined as collection from at least 50% of patients enrolled in this study by Day 10. | From Day 0 (CAR T infusion) to Day 10 (aHSC infusion). | 
| To assess safety of aHSC to planned CAR T therapy in the first 60 days through the incidence, severity, and duration of CRS based on the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system. | Safety will be assessed by incidence, severity, and duration of CRS per ASTCT consensus grading system. ASTCT CRS Consensus grading (Grade scale is 1-4) is based on 3 CRS parameters: fever, hypotension, and hypoxia. Higher grade indicates worse outcome. | From Day 0 to Day 60. | 
| To assess safety of aHSC to planned CAR T therapy in the first 60 days through the incidence, severity, and duration of ICANS based on the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system. | Safety will be assessed by incidence, severity, and duration ICANS per ASTCT consensus grading system. ASTCT ICANS Consensus grading (Grade scale is 1-4) is based on 5 neurotoxicity domains: Immune Effector Cell-Associated Encephalopathy (ICE) score, level of consciousness, seizure, motor findings, raised intracranial pressure (ICP)/cerebral edema. Higher grade indicates worse outcome. | From Day 0 to Day 60. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate of CAR T at 6 weeks. | Response rate of CAR T will be defined as the proportion of subjects who experience partial response (PR) or complete response (CR) assessed at 6 weeks or day 60. Response criteria used will be according to type of disease: Response by International Myeloma Working Group (IMWG) Criteria (for multiple myeloma); Response by Center for International Blood and Marrow Transplant Research (CIMBTR) Criteria (for acute lymphoblastic leukemia); Response by Lugano Criterial (for lymphoma). | From Day 0 to Day 60. | 
| Assess rate of recovery of absolute neutrophil count (ANC) by Day 28. | Recovery assessed by the proportion of patients with ANC recover to ≥ 500/µL. | From Day 0 to Day 28. | 
| Assess red blood cell (RBC) count and transfusion independence by Day 28. | The proportion of patients with RBC transfusion independence by Day 28. | From Day 0 to Day 28. | 
| Assess platelet count and transfusion independence rate by Day 28. | The proportion of patients with platelet transfusion independence by Day 28. | From Day 0 to Day 28. | 
| Assess safety and tolerability of combining aHSCs with an FDA-approved CAR T regimen within first 52 weeks of aHSC infusion. | Safety and tolerability will be assessed by the number of adverse events (AEs) and serious adverse events (SAEs) related to study treatment according to CTCAE v.5, up to Week 52. | From Day 0 to Week 52. | 
| Median progression-free survival (PFS) for the duration of the study | PFS will be assessed from time of CAR T infusion until confirmation of disease progression or withdrawal of consent, whichever comes first. | From Day 0 until disease progression or withdrawal. Assessed up to 3 years. | 
| Median overall survival (OS) for the duration of the study | OS will be assessed from date of CAR T infusion until date of death due to any cause or withdrawal of consent, whichever comes first. | From Day 0 until death due to any cause or withdrawal of consent. Assessed up to 3 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR T-cell therapy, autologous hematopoietic stem cells, CAR T, CAR T therapy