Safety and Efficacy of KTE-C19 in Combination With Atezolizumab in Adults With Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Study Overview
=================
Brief Summary
-----------------
The primary objective of phase 1 is to evaluate the safety of KTE-C19 and atezolizumab combination regimens. The primary objective of phase 2 is to evaluate the efficacy of KTE-C19 and atezolizumab, as measured by complete response rate in participants with refractory diffuse large B-cell lymphoma (DLBCL). Subjects who received an infusion of KTE-C19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968

Official Title
-----------------
A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 in Combination With Atezolizumab in Subjects With Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Conditions
-----------------
Refractory Diffuse Large B Cell Lymphoma

Intervention / Treatment
-----------------
* Biological: KTE-C19
* Biological: Atezolizumab
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Histologically confirmed DLBCL Chemotherapy-refractory disease, defined as one or more of the following: Stable disease (duration of stable disease must be less than or equal to 6 months) or progressive disease as best response to most recent chemotherapy containing regimen Disease progression or recurrence less than or equal to 12 months of prior autologous stem cell transplantation (SCT) Individuals must have received adequate prior therapy including at a minimum: anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20-negative; and an anthracycline containing chemotherapy regimen At least one measurable lesion per revised International Working Group (IWG) Response Criteria Age 18 years or older Eastern cooperative oncology group (ECOG) performance status of 0 or 1 Adequate organ and bone marrow function All individuals or legally appointed representatives/caregivers, must personally sign and date the institutional review board (IRB)/independent ethics committee (IEC) approved consent form before initiating any study specific procedures or activities. Key Exclusion Criteria: History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years History of allogeneic stem cell transplantation Prior CAR therapy or other genetically modified T cell therapy Clinically significant active infection Known history of infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive) Individuals with detectable cerebrospinal fluid malignant cells or brain metastases or with a history of cerebrospinal fluid malignant cells or brain metastases History of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with central nervous system (CNS) involvement History of autoimmune disease. Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and participants with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed. Prior treatment with PD-L1 inhibitor, PD-1 inhibitor, anti-CTLA4, anti-CD137, anti-OX40 or other immune checkpoint blockade or activator therapy with the exception of Individuals who received atezolizumab in this study and are eligible for re-treatment Prior CD19 targeted therapy 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KTE-C19 + ATZ<br>Participants will receive conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide intravenous (IV) infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 chimeric antigen receptor (CAR) T cells/kg followed by 4 doses of atezolizumab (ATZ) (1200 mg/dose) IV infusion every 21 days. Treatment with ATZ will begin 21 days following KTE-C19 (Phase 1 Cohort 1), 14 days following KTE-C19 (Phase 1 Cohort 2), and 1 day following KTE-C19 (Phase 1, Cohort 3 & Phase 2). | Biological: KTE-C19<br>* A single infusion of KTE-C19 CAR-T cells administered intravenously<br>* Other names: Yescarta®;Biological: Atezolizumab<br>* Administered intravenously<br>Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Fludarabine<br>* Administered intravenously<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) | A DLT was defined as the following KTE-C19-related or ATZ-related events with an onset from immediately after the first ATZ infusion through 21 days after the first ATZ infusion: Grade 4 hematologic toxicity lasting > 30 days (except lymphopenia or B-cell aplasia); All KTE-C19- or ATZ-related Grade 3 non-hematologic toxicities lasting for > 7 days and all KTE-C19- or ATZ-related Grade 4 non-hematologic toxicities regardless of duration. | Baseline up to 21 days | 
| Phase 1 and 2: Complete Response Rate (CRR) | CRR was assessed based on the International Working Group Revised Response Criteria for Malignant Lymphoma (Cheson, 2007), and was defined as the percentage of participants achieving a complete response (CR) as assessed by the study investigators. CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and 2: Objective Response Rate (ORR) | ORR was assessed based on the International Working Group Revised Response Criteria for Malignant Lymphoma (Cheson, 2007), and was defined as the percentage of participants achieving a CR or partial response (PR) as assessed by the study investigators. CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined at least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. Participants who did not meet the criteria for objective response by the analysis cutoff date were considered non-responders. | From enrollment until first occurrence of CR or PR (up to approximately 2.5 years) | 
| Phase 1 and 2: Duration of Response (DOR) | DOR for participants who experienced an objective response was defined as the date of their first confirmed objective response (CR or PR) to disease progression per the revised International Working Group Response Criteria for Malignant Lymphoma (Cheson, 2007) or death regardless of cause. CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined at least a 50% decrease in SPD of up to six of the largest dominant nodes or nodal masses. Disease progression was defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir. The Kaplan-Meier approach was used to estimate DOR. | From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (up to approximately 2.5 years) | 
| Phase 1 and 2: Progression-Free Survival (PFS) | PFS was defined as the time from the KTE-C19 infusion date to the date of disease progression per the revised International Working Group Response Criteria for Malignant Lymphoma (Cheson, 2007) or death from any cause. Disease progression was defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir. The Kaplan-Meier approach was used to estimate PFS. | From the date of first KTE-C19 infusion to disease progression or death regardless of cause (up to approximately 2.5 years ) | 
| Phase 1 and 2: Overall Survival (OS) | OS was defined as the time from KTE-C19 infusion to the date of death from any cause. The Kaplan-Meier approach was used to estimate OS. | From the date of first KTE-C19 infusion to the date of death regardless of cause (up to approximately 2.5 years) | 
| Phase 1 and 2: Percentage of Participants Experiencing Adverse Events (AEs) |  | Enrollment up to 30 days after completion of the final dose of atezolizumab, or 3 months after the KTE-C19 infusion, whichever was longer (up to approximately 2.5 years) | 
| Phase 1 and 2: Percentage of Participants With Serum Chemistry Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Values | ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase. | Enrollment up to 30 days after completion of the final dose of atezolizumab, or 3 months after the KTE-C19 infusion, whichever was longer (up to approximately 2.5 years) | 
| Phase 1 and 2: Percentage of Participants With Serum Chemistry Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Values |  | Enrollment up to 30 days after completion of the final dose of atezolizumab, or 3 months after the KTE-C19 infusion, whichever was longer (up to approximately 2.5 years) | 
| Phase 1 and 2: Percentage of Participants With Hematology Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Values |  | Enrollment up to 30 days after completion of the final dose of atezolizumab, or 3 months after the KTE-C19 infusion, whichever was longer (up to approximately 2.5 years) | 
| Phase 1 and 2: Percentage of Participants With Hematology Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Values |  | Enrollment up to 30 days after completion of the final dose of atezolizumab, or 3 months after the KTE-C19 infusion, whichever was longer (up to approximately 2.5 years) | 
| Phase 1 and 2: Peak Anti-CD19 CAR T-Cell (KTE-C19) Level (Maximum Observed Plasma Concentration) in Blood |  | Pre-infusion (Baseline); Post-infusion: Days 7 (Phase 2), 14, 22 (Phase 2), 28 (Phase 2; optional), 35 (Phase 1, Cohort 3; optional), 43, 49 (optional), 64, 69 (optional), 94; long-term follow-up: every 3 months from Month 6 to Month 18, and Month 24 | 
| Phase 1 and 2: Percentage of Participants With Anti-KTE-C19 Antibodies |  | Baseline up to approximately 2.5 years | 
| Phase 1 and 2: Atezolizumab Levels in Blood |  | Days 1, 14, 21, 22, 35, 42, 43, 56, 63, 64, 77, 84, 154, and 174 | 
| Phase 1 and 2: Percentage of Participants With Anti-Atezolizumab Antibodies |  | Baseline up to approximately 2.5 years | 
| Phase 1 and 2: Peak Serum Levels of C-Reactive Protein (CRP) in Blood |  | Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, and 14, and 22 , optional Day 28 (Phase 2) or Day 35 (Phase 1 Cohort 3), optional Day 49, optional Day 69, and Day 94 post-KTE-C19 infusion | 
| Phase 1 and 2: Peak Serum Levels of C-X-C Motif Chemokine 10 (CXCL10), Interferon-Gamma (IFN-γ), Interleukin-1 Receptor Antagonist (IL-1RA), Interleukin (IL)-2, IL-6, IL-8, IL-15, and Tumor Necrosis Factor-Alpha (TNF-α) in Blood |  | Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, and 14, and 22 , optional Day 28 (Phase 2) or Day 35 (Phase 1 Cohort 3), optional Day 49, optional Day 69, and Day 94 post-KTE-C19 infusion | 
| Phase 1 and 2: Peak Serum Levels of Ferritin in Blood |  | Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, and 14, and 22 , optional Day 28 (Phase 2) or Day 35 (Phase 1 Cohort 3), optional Day 49, optional Day 69, and Day 94 post-KTE-C19 infusion | 
| Phase 1 and 2: Peak Serum Levels of Interleukin-2 Receptor Alpha (IL-2Rα) in Blood |  | Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, and 14, and 22 , optional Day 28 (Phase 2) or Day 35 (Phase 1 Cohort 3), optional Day 49, optional Day 69, and Day 94 post-KTE-C19 infusion |