Study of KITE-363 or KITE-753 in Participants With Relapsed and/or Refractory B-cell Lymphoma

Study Overview
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Brief Summary
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The goal of this clinical study is to learn more about the safety and dosing of the study drugs, KITE-363 and KITE-753, in participants with relapsed and/or refractory B-cell lymphoma.

Detailed Description
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Eligible study participants who have received IP administration with either KITE-363 or KITE-753 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
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A Phase 1 Open-label, Multicenter Study Evaluating the Safety and Efficacy of KITE-363 or KITE-753, Autologous Anti-CD19/CD20 CAR T-cell Therapies, in Subjects With Relapsed and/or Refractory B-cell Lymphoma

Conditions
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Relapsed and/or Refractory B-cell Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: KITE-363
* Biological: KITE-753


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Relapsed and/or refractory B-cell lymphoma (R/R BCL). At least 1 measurable lesion. Adequate organ and bone marrow (BM) function. Key Exclusion Criteria: History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg, cervix, bladder, or breast) unless disease free and without anticancer therapy (with the exception of hormonal therapy in the case of breast cancer) for at least 3 years. History of Richter's transformation of chronic leukemic lymphoma, small lymphocytic lymphoma, or lymphoplasmacytic lymphoma. History of allogeneic stem cell transplant (allo-SCT). Auto-SCT within 6 weeks before the planned KITE-363 or KITE-753 infusion. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requires intravenous (IV) antimicrobials for management. Known history of human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) hepatitis B surface (HBs) antigen (HBsAg) positive infection, or hepatitis C (anti-hepatitis C virus [HCV] positive) infection. Individuals with detectable cerebrospinal fluid (CSF) malignant cells or brain metastases or a history of central nervous system (CNS) lymphoma, primary CNS lymphoma, or spinal epidural involvement. History or presence of a CNS disorder. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, active arrhythmia, New York Heart Association Class II or greater congestive heart failure or other clinically significant cardiac disease within the 6 months before enrollment. Primary immunodeficiency. History of autoimmune disease resulting in or requiring systemic immunosuppression and/or systemic disease-modifying agents within the last 2 years. History of non-line associated, clinically significant deep-vein thrombosis or pulmonary embolism requiring therapeutic anticoagulation within the 6 months before enrollment. Females of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Females who have undergone surgical sterilization or have been postmenopausal for at least 2 years are not considered to be of childbearing potential. 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KITE-363<br>Phase 1a (Dose Escalation): Participants with r/r large B-cell lymphoma will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single target starting dose of KITE-363 chimeric antigen receptor (CAR) transduced autologous T cells. Based on dose limiting toxicities (DLTs) observed in the first cohort, additional participants will be enrolled and administered escalating dose of KITE-363. Phase 1b (Dose Expansion): After completion of dose escalation, additional participants with r/r B-cell lymphoma across different disease indications will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single dose of KITE-363 at 1 or more dose-level deemed to be tolerable. | Drug: Cyclophosphamide<br>* Lymphodepleting chemotherapy administered intravenously<br>Drug: Fludarabine<br>* Lymphodepleting chemotherapy administered intravenously<br>Biological: KITE-363<br>* A single infusion of CAR-transduced autologous T cells administered intravenously<br>|
| Experimental: KITE-753<br>Phase 1a (Dose Escalation): Participants with r/r large B-cell lymphoma will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single target starting dose of KITE-753 chimeric antigen receptor (CAR) transduced autologous T cells. Based on dose limiting toxicities (DLTs) observed in the first cohort, additional participants will be enrolled and administered escalating dose of KITE-753. Phase 1b (Dose Expansion): After completion of dose escalation, additional participants with r/r B-cell lymphoma across different disease indications will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single dose of KITE-753 at 1 or more dose-level deemed to be tolerable. | Drug: Cyclophosphamide<br>* Lymphodepleting chemotherapy administered intravenously<br>Drug: Fludarabine<br>* Lymphodepleting chemotherapy administered intravenously<br>Biological: KITE-753<br>* A single infusion of CAR-transduced autologous T cells administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: Percentage of Participants Experiencing Adverse Events Defined as Dose-limiting Toxicities (DLTs) After the Infusion of KITE-363 or KITE-753 | DLTs are defined as the KITE-363-related or KITE-753-related events with onset within the first 28 days after the infusion of KITE-363 or KITE-753 respectively. | Up to 28 days | 
| Phase 1b: Objective Response Rate (ORR) for KITE-363 or KITE-753 | ORR is defined as the percentage of participants with a complete response (CR) or a partial response (PR) by the International Working Group (IWG) Lugano Response Criteria for Malignant Lymphoma (Cheson 2014) as determined by investigator assessment. | Up to 15 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Adverse Events (AEs) After the Infusion of KITE-363 or KITE-753 |  | Up to 15 years | 
| Percentage of Participants Experiencing Serious AEs (SAEs) After the Infusion of KITE-363 or KITE-753 |  | Up to 15 years | 
| Time To Next Treatment (TTNT) for KITE-363 or KITE-753 | TTNT is defined as the time from KITE-363 or KITE-753 infusion to the next anticancer treatment (including stem cell transplantation [SCT]) or death from any cause, whichever occurs first. | Up to 15 years | 
| Complete Response (CR) Rate for KITE-363 or KITE-753 | CR rate is defined as the incidence of a CR by the IWG Lugano Response Criteria for Malignant Lymphoma (Cheson 2014) as determined by investigator assessment. | Up to 15 years | 
| Duration of Response (DOR) for KITE-363 or KITE-753 | DOR is defined only for participants who experience an objective response and is the time from the first objective response to disease progression per the IWG Lugano Classification or death due to any cause, whichever occurs first. | Up to 15 years | 
| Progression-Free Survival (PFS) for KITE-363 or KITE-753 | PFS is defined as the time of KITE-363 or KITE-753 infusion to disease progression per IWG Lugano Response Criteria for Malignant Lymphoma (Cheson 2014) or death from any cause, whichever occurs first. | Up to 15 years | 
| Overall Survival (OS) for KITE-363 or KITE-753 | OS is defined as the time from KITE-363 or KITE-753 infusion to death from any cause. | Up to 15 years | 
| Percentage of Participants who Develop Antibodies to KITE-363 or KITE-753 Chimeric Antigen Receptor (CAR) T Cells |  | Enrollment; up to 12 months | 
| Levels of KITE-363 or KITE-753 CAR T Cells and Analytes (Including Cytokines) in the Blood |  | Up to 15 years | 
| Peak Serum Levels of Key Analytes Homeostatic/Proliferative Cytokines: Interleukin (IL)-2, IL-7, and IL-15 |  | Up to 3 months | 
| Peak Serum Levels of Key Analytes Inflammatory/Immune Modulating Cytokines: IFN-γ, IL-6, IL-10, IL-17, IL-1RA, Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF), and Tumor Necrosis Factor-Alpha (TNF-α) | IFN-γ=Interferon-Gamma, IL-1 Receptor Antagonist=IL-1RA | Up to 3 months | 
| Peak Serum Levels of Key Analytes Correlates of Acute Phase Response: C-Reactive Protein (CRP) |  | Up to 3 months | 
| Peak Serum Levels of Key Analytes Correlates of Acute Phase Response: Ferritin |  | Up to 3 months | 
| Peak Serum Levels of Key Analytes Correlates of Acute Phase Response: Soluble IL-2 Receptor Alpha (Sil-2Rα) |  | Up to 3 months | 
| Peak Serum Levels of Key Analytes Chemokines: IL-8, C-X-C Motif Chemokine Ligand-10 (CXCL-10), and Monocyte Chemotactic Protein-1 (MCP-1) |  | Up to 3 months | 
| Peak Serum Levels of Key Analytes Immune-Effector Molecules: Perforin, Granzyme A, and Granzyme B |  | Up to 3 months |