A Study of CC-97540, CD19-targeted NEX-T Chimeric Antigen Receptor (CAR) T Cells, in Subjects With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This is a Phase 1, first-in-human, open-label, multicenter study of CC-97540, CD19-targeted NEX-T chimeric antigen receptor (CAR) T cells, in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma. The study will consist of 2 parts: dose-escalation (Part A) and dose-expansion (Part B). The dose-escalation part (Part A) of the study is to evaluate the safety and tolerability of increasing dose levels of CC-97540 to establish a recommended Phase 2 dose (RP2D); and the dose-expansion part (Part B) of the study is to further evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of CC-97540 at the RP2D.

Official Title
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A Phase 1, Multicenter, Open-label Study of CC-97540, CD19-targeted NEX-T Chimeric Antigen Receptor (CAR) T Cells, in Subjects With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Conditions
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Lymphoma Non-Hodgkin, Agressive Lymphoma, Diffuse-large B-cell Lymphoma (DLBCL)

Intervention / Treatment
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* Biological: CC-97540


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must satisfy the following criteria to be enrolled in the study: Age ≥ 18 years at the time of informed consent. Signed written informed consent obtained prior to any study procedure. Willing and able to adhere to the study visit schedule and other protocol requirements. Relapsed and/or refractory aggressive B-cell NHL as defined: Histologically confirmed DLBCL not otherwise specified, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (HGBCL), transformed DLBCL from follicular (tFL) or marginal zone lymphoma (tMZL), primary mediastinal B-cell lymphoma (PMBCL), or FL grade 3b (FL3B) (Note: Subjects with Richter's transformation (transformed DLBCL from CLL) are ineligible) AND Have relapsed and/or refractory disease after at least 2 lines of systemic therapy which must include at least one anthracycline and rituximab (or other anti-CD20 monoclonal antibody). Note: Lines of therapy will exclude those given for prior indolent lymphoma. It is not required for subjects to have had anthracycline for their DLBCL if received for indolent disease AND/OR Have relapsed and/or refractory DLBCL failed to ASCT treatment. Note: ASCT failure is defined as either failure to achieve an objective response (PR or better), or disease progression after ASCT(Note: Subjects who were not candidates to receive ASCT treatment (due to age or other factors) are eligible; the reason for not receiving ASCT must be documented in the electronic case report form (eCRF). Positron emission tomography (PET)-positive disease as per the Lugano Classification (at screening or following bridging therapy, whichever is later). Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate organ function as detailed in the protocol. Adequate vascular access for leukapheresis. Willing and able to undergo tumor biopsies (in subjects with accessible disease). Agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals as detailed in the protocol. Female and male subjects agree to use effective contraception as detailed in the protocol. Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment: Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or unwillingness or inability to follow the procedures required in the protocol. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. Any condition that confounds the ability to interpret data from the study. Central nervous system (CNS)-only involvement by malignancy (note: subjects with pathologically-confirmed secondary CNS involvement are allowed).) Prior CAR T- cell or genetically-modified T- cell therapy, or prior CD19- targeted therapy (including, but not limited to, anti-CD19 mAbs or bispecific antibodies).) Treatment with the following therapies or procedure within the specified period: Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 14 days before leukapheresis administration. Physiologic replacement, topical, and inhaled steroids are permitted. Cytotoxic chemotherapeutic agents (eg, doxorubicin, vincristine, gemcitabine, oxaliplatin, carboplatin, etoposide) within 7 days of leukapheresis, with the exception of alkylating agents. Intrathecal therapy (eg, dexamethasone, methotrexate, cytosine arabinoside, cytarabine) within 7 days of leukapheresis. Oral chemotherapeutic agents, including lenalidomide and ibrutinib, are allowed if at least 5 half-lives have elapsed prior to leukapheresis. Alkylating agents (eg, cyclophosphamide, ifosfamide, bendamustine) within 4 weeks of leukapheresis. Any experimental therapy within 8 weeks (for biologics) or 5 half-lives (for small molecules) before leukapheresis Immunosuppressive therapies within 4 weeks of leukapheresis (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, immunosuppressive antibodies such as anti-TNF, anti-IL6, or anti-IL6R) Monoclonal antibodies (including rituximab, polatuzumab, etc.) within 7 days. Donor lymphocyte infusions within 6 weeks of leukapheresis Radiation within 6 weeks of leukapheresis. Subjects must have progressive disease in irradiated lesions or have additional non-irradiated, PET-positive lesions to be eligible. Radiation to a single lesion, if additional non-irradiated PET-positive lesions are present, is allowed up to 14 days prior to leukapheresis. Autologous stem-cell transplant (SCT) (ie, Day 0 receipt of hematopoietic stem cells) within 3 months of leukapheresis Washout of prior therapy (eg, bridging therapy for disease control) Active autoimmune disease requiring immunosuppressive therapy. Allogenic SCT (ie, Day 0 receipt of hematopoietic stem cells) within 6 months of leukapheresis or presence of ongoing symptoms or treatment for chronic graft-versus host disease (GVHD).) Hypersensitivity to fludarabine and/or cyclophosphamide. Prior history of malignancies, other than studied NHL, unless the subject has been free of the disease for ≥ 2 years except for the following non-invasive malignancies: Basal or squamous cell carcinoma of the skin Carcinoma in situ of the cervix or the breast Incidental histologic finding of prostate cancer (T1a or T1b using the TNM (tumor, nodes, metastasis) clinical staging system) or prostate cancer that is curative Other completely resected stage 1 solid tumor with low risk for recurrence Active hepatitis B, hepatitis C, or any human immunodeficiency virus (HIV) infection at the time of screening. Uncontrolled or active systemic fungal, bacterial, viral or other infection despite appropriate anti-infection treatment at the time of leukapheresis or pre-treatment evaluation. History of any one of the following cardiovascular conditions within the 6 months prior to screening: Class III or IV heart failure as defined by the New York Heart Association, myocardial infarction, unstable angina, angioplasty or stenting, or other clinically significant cardiac disease. History or presence of clinically significant CNS pathology such as seizure disorder, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, or cerebellar disease. Presence of clinically active psychosis. History of ≥ Grade 2 hemorrhage within 30 days of screening. Pregnant or nursing (lactating) women. Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to leukapheresis or initiation of LD chemotherapy. -Acute symptoms must have resolved and based on investigator assessment in consultation with the Sponsor Medical Monitor, there are no sequelae that would place the subject at a higher risk of receiving study treatment. Previous SARS-CoV-2 vaccine within 14 days prior to leukapheresis or initiation of LD 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-97540 monotherapy<br>Subjects will be assigned to receive CC-97540 followed by 3 consecutive doses of lymphodepleting chemotherapy (fludarabine IV (30 mg/m2/day) and cyclophosphamide IV (300 mg/m2/day). | Biological: CC-97540<br>* Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) to produce CC 97540. During CC 97540 production, subjects may receive bridging chemotherapy for disease control. Upon successful generation of CC 97540 product, subjects will receive treatment with CC 97540 therapy. Each cycle will include lymphodepleting chemotherapy followed by one dose of CC 97540 administered by intravenous (IV) injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) | An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE.ject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the sub | From the time of informed consent and follow up to 2 years after infusion of CC-97540 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate (CRR) | The proportion of subjects with a best overall response of complete response (CR). | Up to 2 years after CC-97540 infusion | 
| Overall response Rate (ORR) | The proportion of subjects achieving CR or partial response (PR). | Up to 2 years after CC-97540 infusion | 
| Duration of response (DOR) | The time from first response to progressive disease (PD) or death. | Up to 2 years after CC-97540 infusion | 
| Time to response (TTR) | Time from CC-97540 infusion to the first documentation of response (CR or PR). | Up to 2 years after CC-97540 infusion | 
| Time to complete response (TTCR) | Time from CC-97540 infusion to the first documentation of CR | Up to 2 years after CC-97540 infusion | 
| Progression free survival (PFS) | Time from CC-97540 infusion to the first documentation of PD, or death from any cause, whichever occurs first | Up to 2 years after CC-97540 infusion | 
| Overall survival (OS) | Time from CC-97540 infusion to death | Up to 2 years after CC-97540 infusion | 
| Pharmacokinetics - peak expansion (Cmax) | Maximum blood concentration | Up to 2 years after CC-97540 infusion | 
| Pharmacokinetics -time to peak expansion (tmax) | Time to peak (maximum) blood concentration | Up to 2 years after CC-97540 infusion | 
| Pharmacokinetics - elimination half-life (t1/2) | Elimination half-life | Up to 2 years after CC-97540 infusion | 
| Pharmacokinetics - Area under curve (AUC) | Area under the curve | Up to 2 years after CC-97540 infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, B-cell non-Hodgkin lymphoma, Agressive Lymphoma, Diffuse-large B-cell Lymphoma, DLBCL, NHL, CC-97540, CD19, NEX-T chimeric antigen receptor (CAR) T cells, CAR-T, CART