Study of Safety and Efficacy of KTE-C19 in Combination With Atezolizumab in Adults With Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (ZUMA-6)

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)

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).

Participants 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 (NCT05041309).

Study Overview

• Status: Completed
• Conditions: Refractory Diffuse Large B Cell Lymphoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Biological: KTE-C19; Biological: Atezolizumab

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Palo Alto, California, United States, 94305
      • Stanford Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612
      • H Lee Moffitt Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Histologically confirmed DLBCL

2. 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)

3. Individuals must have received adequate prior therapy including at a minimum:

   • Anti-cluster of differentiate 20 (anti-CD20) monoclonal antibody unless investigator determines that tumor is CD20-negative; and
   • an anthracycline containing chemotherapy regimen
4. At least one measurable lesion per revised International Working Group (IWG) Response Criteria
5. Age 18 years or older
6. Eastern cooperative oncology group (ECOG) performance status of 0 or 1
7. Adequate organ and bone marrow function
8. 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:

1. 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
2. History of allogeneic stem cell transplantation
3. Prior CAR therapy or other genetically modified T cell therapy
4. Clinically significant active infection
5. Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive)
6. Individuals with detectable cerebrospinal fluid malignant cells or brain metastases or with a history of cerebrospinal fluid malignant cells or brain metastases
7. History of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with central nervous system (CNS) involvement
8. 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.
9. 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.
10. Prior treatment with Programmed Cell Death Ligand 1 (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
11. Prior CD19 targeted therapy

Note: Other protocol defined Inclusion/Exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 Cohort 1: KTE-C19 + ATZ (After 21 Days of KTE-C19); Participants received 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, beginning 21 days following KTE-C19.	Drug: Cyclophosphamide; Administered intravenously; Drug: Fludarabine; Administered intravenously; Biological: KTE-C19; A single infusion of KTE-C19 CAR-T cells administered intravenously; Other Names: Yescarta®; Axicabtagene ciloleucel; Biological: Atezolizumab; Administered intravenously
Experimental: Phase 1 Cohort 2: KTE-C19 + ATZ (After 14 Days of KTE-C19); Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 14 days following KTE-C19.	Drug: Cyclophosphamide; Administered intravenously; Drug: Fludarabine; Administered intravenously; Biological: KTE-C19; A single infusion of KTE-C19 CAR-T cells administered intravenously; Other Names: Yescarta®; Axicabtagene ciloleucel; Biological: Atezolizumab; Administered intravenously
Experimental: Phase 1 Cohort 3: KTE-C19 + ATZ (After 1 Day of KTE-C19); Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19.	Drug: Cyclophosphamide; Administered intravenously; Drug: Fludarabine; Administered intravenously; Biological: KTE-C19; A single infusion of KTE-C19 CAR-T cells administered intravenously; Other Names: Yescarta®; Axicabtagene ciloleucel; Biological: Atezolizumab; Administered intravenously
Experimental: Phase 2: KTE-C19 + ATZ (After 1 Day of KTE-C19); Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19.	Drug: Cyclophosphamide; Administered intravenously; Drug: Fludarabine; Administered intravenously; Biological: KTE-C19; A single infusion of KTE-C19 CAR-T cells administered intravenously; Other Names: Yescarta®; Axicabtagene ciloleucel; Biological: Atezolizumab; Administered intravenously

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.	From enrollment until first occurrence of CR or PR (maximum duration: 6.2 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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: Atezolizumab Levels in Blood		Days 1, 14, 21, 22, 35, 42, 43, 56, 63, 64, 77, 84, 154, and 174
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
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 (maximum duration: 6.2 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 (maximum duration: 6.2 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 (maximum duration: 6.2 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 (maximum duration: 6.2 years)
Phase 1 and 2: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)	An adverse event was defined as any untoward medical occurrence in a clinical trial participant. The event did not necessarily have a relationship with study treatment. Adverse events included worsening of a pre-existing medical condition. Worsening indicated that the pre-existing medical condition had increased in severity, frequency, and/or duration or had an association with a worse outcome. A pre-existing condition that had not worsened during the study or involved an intervention such as elective cosmetic surgery or a medical procedure while in study, was not considered an adverse event. TEAEs included all AEs with onset on or after initiation of axicabtagene ciloleucel.	Up to 1.8 years
Phase 1 and 2: Percentage of Participants With Serum Chemistry Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Values	Post axicabtagene ciloleucel infusion lab toxicities were reported. It included lab toxicities observed on or after the axicabtagene ciloleucel infusion date. ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase.	Up to 1.8 years
Phase 1 and 2: Percentage of Participants With Serum Chemistry Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Values	Post axicabtagene ciloleucel infusion lab toxicities were reported. It included lab toxicities observed on or after the axicabtagene ciloleucel infusion date.	Up to 1.8 years
Phase 1 and 2: Percentage of Participants With Hematology Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Values	Post axicabtagene ciloleucel infusion lab toxicities were reported. It included lab toxicities observed on or after the axicabtagene ciloleucel infusion date.	Up to 1.8 years
Phase 1 and 2: Percentage of Participants With Hematology Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Values	Post axicabtagene ciloleucel infusion lab toxicities were reported. It included lab toxicities observed on or after the axicabtagene ciloleucel infusion date.	Up to 1.8 years
Phase 1 and 2: Percentage of Participants With Anti-KTE-C19 Antibodies		Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, 14, 22 , 28, Day 35, 49, 69, and 94 post-KTE-C19 infusion
Phase 1 and 2: Percentage of Participants With Anti-Atezolizumab Antibodies		Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, 14, 22 , 28, Day 35, 49, 69, and 94 post-KTE-C19 infusion

Collaborators and Investigators

• Sponsor: Kite, A Gilead Company
• Collaborators: Genentech, Inc.
• Investigators: Study Director: Kite Study Director, Kite, A Gilead Company

Publications and helpful links

General Publications

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
• Jacobson CA, Locke FL, Miklos DB, Herrera AF, Westin JR, Lee J, et al. End of Phase 1 results for ZUMA-6: Axicabtagene ciloleucel (axi-cel) in combination with atezolizumab for the treatment of patients with refractory diffuse large B cell lymphoma. Presented at ASH, 2018.
• Locke FL, Westin JR, Miklos DB, Herrera AF, Jacobson CA, Lee J, et al. Phase 1 results from ZUMA-6: Axicabtagene ciloleucel (axi-cel; KTE-C19) in combination with atezolizumab for the treatment of patients with refractory diffuse large B cell lymphoma. Presented at ASH, 2018, presentation #2628.

Helpful Links

• Gilead Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2016
• Primary Completion (Actual): January 12, 2023
• Study Completion (Actual): January 12, 2023

Study Registration Dates

• First Submitted: October 5, 2016
• First Submitted That Met QC Criteria: October 5, 2016
• First Posted (Estimated): October 6, 2016

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Cyclophosphamide; Fludarabine; Atezolizumab; Axicabtagene ciloleucel
• Other Study ID Numbers: KTE-C19-106

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy
• IPD Sharing Time Frame: 18 months after study completion
• IPD Sharing Access Criteria: A secured external environment with username, password, and RSA code.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No