Study of Axicabtagene Ciloleucel Versus Standard of Care Therapy in Participants With Relapsed/Refractory Follicular Lymphoma

Study Overview
=================
Brief Summary
-----------------
The goal of this clinical study is test how well the study drug, axicabtagene ciloleucel, works in participants with relapsed/refractory follicular lymphoma

Detailed Description
-----------------
Five years after the last study participant is randomized, participants who have received axicabtagene ciloleucel will transition to a separate Long-term Follow-up study (study KT-US-982-5968) to complete the remainder of the 15-year follow-up assessments.

Official Title
-----------------
A Phase 3 Randomized, Open-Label, Multicenter Study Evaluating the Efficacy of Axicabtagene Ciloleucel Versus Standard of Care Therapy in Subjects With Relapsed/Refractory Follicular Lymphoma

Conditions
-----------------
Relapsed/Refractory Follicular Lymphoma

Intervention / Treatment
-----------------
* Biological: Axicabtagene Ciloleucel
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Lenalidomide
* Drug: Rituximab
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone
* Drug: Bendamustine


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Histologically-confirmed follicular lymphoma (FL) (Grade 1, 2, or 3a) Relapsed/refractory (R/r) disease after first-line chemoimmunotherapy and high-risk disease with relapse or progression within 24 months of the initial course of chemoimmunotherapy (ie, POD24), Or r/r disease after ≥ 2 prior systemic lines of therapy Clinical indication for treatment. At least 1 measurable lesion per the Lugano Classification {Cheson 2014} Adequate renal, hepatic, pulmonary, and cardiac function Key Exclusion Criteria: Presence of large B cell lymphoma or transformed FL Small lymphocytic lymphoma Lymphoplasmacytic lymphoma Full-thickness involvement of the gastric wall by lymphoma FL Grade 3b Prior CD19-targeted therapy Prior CAR therapy or other genetically modified T-cell therapy Uncontrolled fungal, bacterial, viral, or other infection Active Infection with human immunodeficiency virus, hepatitis B virus or hepatitis C virus History or presence of a clincially significant central nervous system (CNS) disorder. History of autoimmune disease Known history or CNS lymphoma involvement Cardiac lymphoma involvement History of clinically significant cardiac disease 6 months before randomization Neuropathy greater than grade 2 Females who are pregnant or breastfeeding Individuals of both genders who are not willing to practice birth control Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, G/J-tube, pleural/peritoneal/pericardial catheter, or Ommaya reservoirs). Dedicated central venous access catheters such as Port-a-Cath or Hickman catheter are permitted. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Axicabtagene Ciloleucel<br>Participants will receive cyclophosphamide 500 mg/m^2/day intravenously (IV) and fludarabine 30 mg/m^2/day IV lymphodepleting chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10^6 anti-cluster of differentiation (CD)19 chimeric antigen receptor (CAR) transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10^8 anti-CD19 CAR T cells will be administered. | Biological: Axicabtagene Ciloleucel<br>* A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells<br>* Other names: axi-cel;Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Fludarabine<br>* Administered intravenously<br>|
| Active Comparator: Standard of Care Therapy<br>Participants will receive the investigator's choice of one of the following therapies/dosing schedules: Rituximab plus lenalidomide (R^2) for 12 cycles (28-day cycle) Cycle 1: lenalidomide 20 mg/day on Day 1 through Day 21; rituximab 375 mg/m^2 on Day 1, Day 8, Day 15, and Day 22 Cycle 2 through Cycle 5: lenalidomide 20 mg/day on Day 1 through Day 21; Rituximab 375 mg/m2 on Day 1 Cycle 6 through Cycle 12: lenalidomide 20 mg/day on Day 1 through Day 21 Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for 6 cycles (21-day cycle) rituximab 375 mg/m^2 on Day 1 cyclophosphamide 750 mg/m^2 on Day 1 doxorubicin 50 mg/m^2 on Day 1 vincristine 1.4 mg/m^2 (maximum 2 mg) on Day 1 prednisone 40 mg/m^2 on Day 1 through Day 5 Rituximab plus bendamustine (BR) for 6 cycles (28-day cycle) rituximab 375 mg/m^2 on Day 1 bendamustine 90 mg/m^2 on Day 1 and Day 2 | Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Lenalidomide<br>* Administered orally<br>Drug: Rituximab<br>* Administered intravenously<br>Drug: Doxorubicin<br>* Administered intravenously<br>Drug: Vincristine<br>* Administered intravenously<br>Drug: Prednisone<br>* Administered orally<br>Drug: Bendamustine<br>* Administered intravenously<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) as Assessed by Blinded Central Assessment per Lugano Classification | PFS is defined as the time from randomization to disease progression or death due to any cause. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from randomization to death from any cause. | Up to 5 years | 
| Complete Response (CR) Rate as Assessed by Blinded Central Assessment per Lugano Classification | CR rate is defined as the proportion of participants with best overall response of CR during the study prior to any subsequent off-protocol anti-follicular lymphoma (FL) therapy. | Up to 5 years | 
| Objective Response Rate (ORR) as Assessed by Blinded Central Assessment per Lugano Classification | Objective response rate is defined as the proportion of participants with best overall response of either a complete response or a partial response during the study prior to any subsequent off-protocol anti-FL therapy. | Up to 5 years | 
| Duration of Response (DOR) as Assessed by Blinded Central Assessment per Lugano Classification | DOR is defined as the time from first objective response to disease progression or death from any cause. | Up to 5 years | 
| Duration of CR as Assessed by Blinded Central Assessment per Lugano Classification | Duration of CR is defined as the time from first CR to disease progression or death from any cause. | Up to 5 years | 
| Event Free Survival (EFS) as Assessed by Blinded Central Assessment per Lugano Classification | EFS is defined as the time from randomization to the earliest date of disease progression, the initiation of subsequent off-protocol anti-FL therapy, or death from any cause. | Up to 5 years | 
| Time to Next Treatment (TTNT) | TTNT is defined as the time from randomization to the start of subsequent off-protocol anti-lymphoma therapy or death from any cause. | Up to 5 years | 
| Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) |  | Randomization up to 5 years plus 30 days | 
| Percentage of Participants Experiencing Clinically Significant Changes in Safety Laboratory Values |  | Randomization up to 5 years plus 30 days | 
| Percentage of Participants with Replication-competent Retrovirus in Blood Over time |  | Up to 5 years | 
| Change From Baseline in the Global Health Status Quality of Life Scale of the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire-30 (EORTC QLQ-C30) | The EORTC-QLQ-C30 is a multi-item questionnaire measuring the following content five (5) multi-item functional scales, three (3) multi-item symptom scales, one (1) global health status scale, and one (1) global health-related quality of life (HRQoL) each scale is measured from 0 to 100 after a linear transformation. Higher scores for functioning scales and for the Global Health Status or Global HRQoL scales indicate a higher level of functioning and a better HRQoL respectively, whereas higher scores in symptom scales represent a higher level of symptoms. | Baseline, up to 5 years | 
| Change From Baseline in the Physical Functioning Domain of the EORTC QLQ-C30 | The EORTC-QLQ-C30) is a multi-item questionnaire measuring the following content five (5) multi-item functional scales, three (3) multi-item symptom scales, one (1) global health status scale, and one (1) global health-related quality of life (HRQoL) each scale is measured from 0 to 100 after a linear transformation. Higher scores for functioning scales and for the Global Health Status or Global HRQoL scales indicate a higher level of functioning and a better HRQoL respectively, whereas higher scores in symptom scales represent a higher level of symptoms. | Baseline, up to 5 years | 
| Change From Baseline in the Global Health Status Quality of Life Scale of the Low Grade Non-Hodgkin Lymphoma-20 (NHL-LG20) | The NHL-LG20 is is a 20-item supplement questionnaire that was specifically developed to assess HRQoL in participants with low-grade non-Hodgkin lymphomas (such as follicular lymphoma). The NHL-LG20 includes multi-item scales of symptom burden, physical condition/fatigue, worries/fears on health and functioning, and emotional impact; and is administered in conjunction with the EORTC QLQ-C30. Each scale is measured from 0 to 100 after a linear transformation. Higher scores for functional scales and for the global health status or global HRQoL scales indicate a higher level of functioning and a better HRQoL, whereas higher scores in symptom scales represent a higher level of symptoms. | Baseline, up to 5 years | 
| Change From Baseline in the Physical Functioning Domain of the NHL-LG20 | The NHL-LG20 is is a 20-item supplement questionnaire that was specifically developed to assess HRQoL in participants with low-grade non-Hodgkin lymphomas (such as follicular lymphoma). The NHL-LG20 includes multi-item scales of symptom burden, physical condition/fatigue, worries/fears on health and functioning, and emotional impact; and is administered in conjunction with the EORTC QLQ-C30. Each scale is measured from 0 to 100 after a linear transformation. Higher scores for functional scales and for the global health status or global HRQoL scales indicate a higher level of functioning and a better HRQoL, whereas higher scores in symptom scales represent a higher level of symptoms. | Baseline, up to 5 years | 
| Changes From Baseline in the European Quality of Life Five Dimensions Five Levels Scale (EQ-5D-5L) | The EQ-5D-5L questionnaire is a generic measure of health status that provides a simple descriptive profile and a single index value. The EQ-5D-5L comprises 2 components: a questionnaire covering 5 dimensions and a tariff of values based upon direct valuations of health states using a visual analog scale (VAS). Rating gets recorded on a vertical VAS in which the endpoints are labeled best imaginable health state is 100 (on the top) and worst imaginable health state is 0 (on the bottom). Higher scores of EQ VAS indicate better health. | Baseline, up to 5 years | 
| Changes From Baseline in the Visual Analog Scale (VAS) Scores | The EQ-5D-5L VAS is a 20-cm VAS for recording self-rated current HRQoL state and is used to describe the participants health status on the day of the assessment. The EQ-5D-5L VAS score is recorded by each participant for his or her current HRQoL state and scored 0 (the worst health you can imagine) to 100 (the best health you can imagine). Higher scores indicate better health. | Baseline, up to 5 years |