A Phase 2 Multicenter Study of Axicabtagene Ciloleucel in Subjects With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This study will enroll approximately 160 adult participants who have relapsed or refractory (r/r) iNHL to be infused with the study treatment, axicabtagene ciloleucel, to see if their disease responds to this experimental product and if this product is safe. Axicabtagene ciloleucel is made from the participants own white blood cells which are genetically modified and grown to fight cancer. An objective response rate of 70% is targeted.

Detailed Description
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All enrolled participants will be screened for eligibility then will undergo leukapheresis to collect white blood cells for manufacturing. In preparation for the infusion with axicabtagene ciloleucel, participants will undergo conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days to help the study treatment be effective. After the product is manufactured and conditioning chemotherapy period is complete, participants will be infused with axicabtagene ciloleucel and then monitored in a hospital for a minimum of 7 days. After completing at least 60 months (FL participants) or at least 24 months (MZL participants) of assessments in this study since the initial axicabtagene ciloleucel infusion and after agreement by the Sponsor, participants will transition to a long-term follow-up (LTFU) study, KT-US-982-5968 where they will complete the remainder of the 15 year follow-up assessments.

Official Title
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A Phase 2 Multicenter Study of Axicabtagene Ciloleucel in Subjects With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma (iNHL)

Conditions
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Follicular Lymphoma, Marginal Zone Lymphoma, Indolent Non-Hodgkin Lymphoma

Intervention / Treatment
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* Biological: axicabtagene ciloleucel
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Individual has [follicular lymphoma or marginal zone lymphoma that has progressed after at least 2 lines of treatment with combination chemoimmunotherapy] (e.g. R-bendamustine, R-CHOP). Individual has [measurable disease]. Individual has no known presence or history of central nervous system (CNS) involvement by lymphoma. If individual is on conventional systemic therapy or systemic inhibitory/stimulatory immune checkpoint therapy, individual is able to stop conventional therapy 2 weeks or 5 half-lives, whichever is shorter, or immune checkpoint therapy 3 half-lives prior to planned leukapheresis. Individual has Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and adequate renal, hepatic, pulmonary, and cardiac function Individual is not pregnant or breastfeeding (female individuals only) and is willing to use birth control from the time of consent through 12 months following chimeric antigen receptor (CAR) T cell infusion (both male and female individuals). Key Exclusion Criteria: Transformed follicular lymphoma (FL) or marginal zone lymphoma (MZL) Small lymphocytic lymphoma Histological Grade 3b FL Individual will have undergone autologous transplant within 6 weeks of planned leukapheresis or has undergone allogeneic transplant. Individual has evidence of involvement of the heart by lymphoma or requirement for urgent therapy due to ongoing or impending oncologic emergency (e.g. mass effect, tumor lysis syndrome, etc.) Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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: axicabtagene ciloleucel<br>Participants will receive a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, followed by a single infusion of CAR transduced autologous T cells. | Biological: axicabtagene ciloleucel<br>* A single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered intravenously.<br>* Other names: Yescarta®;Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Fludarabine<br>* Administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate per central read | Complete response (CR) + partial response (PR) per the Lugano Classiciation (Cheson et al, 2014). | Up to 15 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR Rate per central read | CRR is defined as the incidence of CR as best response to treatment by the Lugano Classification (Cheson et al, 2014) | Up to 15 years | 
| DOR | DOR is defined only for subjects who experience an objective response and is the time from the first objective response to disease progression per (Cheson et al, 2014) or disease-related death, whichever comes first. | Up to 15 years | 
| PFS | PFS is defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per (Cheson et al, 2014) or death from any cause. | Up to 15 years | 
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events |  | Up to 15 years | 
| Overall Survival (OS) | OS is defined as the time from KTE-C19 infusion to the date of death. | Up to 15 years | 
| Levels of anti-CD19 CAR T cells in blood |  | At enrollment, Day 7, Week 2, Week 4, Month 3, Month 6, Month 12, Month 18, Month 24, annually up to year 5. | 
| Levels of cytokines in serum |  | At enrollment, prior to axicabtagene ciloleucel infusion on Day 0, Day 3, Day 7, Week 2, Week 4 | 
| Percentage of Participants experiencing anti-axicabtagene ciloleucel antibodies |  | At enrollment, Week 4, Month 3, every 3 months up to Month 12 | 
| Percentage of Participants Experiencing clinically significant changes in lab values |  | Up to 5 years | 
| Time to next Therapy | Time from axi-cel infusion date to the start of the subsequent new lymphoma therapy or death from any cause. | Up to 15 years | 
| Objective response rate among participants with 3 or more lines of prior therapy | Complete response (CR) + partial response (PR) per the Lugano Classiciation (Cheson et al, 2014) for participants with 3 or more lines of prior therapy. | Up to 15 years | 
| Complete response rate among those participants with 3 or more lines of prior therapy | Complete response rate is defined as the incidence of CR as best response to treatment by the Lugano Classification (Cheson et al, 2014) for participants with 3 or more lines of prior therapy. | Up to 15 years | 
| Objective Response Rate as Determined by the Investigator Read | ORR per investigator read is defined as the incidence of a CR or a PR by the Lugano Classification. | Up to 15 years | 
| Best Objective Response per Central Read or Investigator Read | Best objective response is defined as the incidence of CR, PR, stable disease (SD), PD, or non-evaluable (NE) as best response to treatment by the Lugano Classification | Up to 15 years |