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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02926833
Recruitment Status : Active, not recruiting
First Posted : October 6, 2016
Results First Posted : June 26, 2020
Last Update Posted : June 26, 2020
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Gilead Sciences ( Kite, A Gilead Company )

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).


Condition or disease Intervention/treatment Phase
Refractory Diffuse Large B Cell Lymphoma Biological: KTE-C19 Biological: Atezolizumab Drug: Cyclophosphamide Drug: Fludarabine Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : September 29, 2016
Actual Primary Completion Date : February 21, 2019
Estimated Study Completion Date : August 2033


Arm Intervention/treatment
Experimental: KTE-C19 + ATZ
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
A single infusion of KTE-C19 CAR-T cells administered intravenously
Other Name: Axicabtagene ciloleucel

Biological: Atezolizumab
Administered intravenously

Drug: Cyclophosphamide
Administered intravenously

Drug: Fludarabine
Administered intravenously




Primary Outcome Measures :
  1. Phase 1: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) [ Time Frame: Baseline up to 21 days ]
    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.

  2. Phase 1 and 2: Complete Response Rate (CRR) [ Time Frame: Month 6 ]
    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.


Secondary Outcome Measures :
  1. Phase 1 and 2: Objective Response Rate (ORR) [ Time Frame: From enrollment until first occurrence of CR or PR (up to approximately 2.5 years) ]
    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.

  2. Phase 1 and 2: Duration of Response (DOR) [ Time Frame: 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) ]
    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.

  3. Phase 1 and 2: Progression-Free Survival (PFS) [ Time Frame: From the date of first KTE-C19 infusion to disease progression or death regardless of cause (up to approximately 2.5 years ) ]
    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.

  4. Phase 1 and 2: Overall Survival (OS) [ Time Frame: From the date of first KTE-C19 infusion to the date of death regardless of cause (up to approximately 2.5 years) ]
    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.

  5. Phase 1 and 2: Percentage of Participants Experiencing Adverse Events (AEs) [ Time Frame: 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) ]
  6. Phase 1 and 2: Percentage of Participants With Serum Chemistry Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Values [ Time Frame: 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) ]
    ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase.

  7. Phase 1 and 2: Percentage of Participants With Serum Chemistry Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Values [ Time Frame: 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) ]
  8. Phase 1 and 2: Percentage of Participants With Hematology Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Values [ Time Frame: 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) ]
  9. Phase 1 and 2: Percentage of Participants With Hematology Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Values [ Time Frame: 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) ]
  10. Phase 1 and 2: Peak Anti-CD19 CAR T-Cell (KTE-C19) Level (Maximum Observed Plasma Concentration) in Blood [ Time Frame: 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 ]
  11. Phase 1 and 2: Percentage of Participants With Anti-KTE-C19 Antibodies [ Time Frame: Baseline up to approximately 2.5 years ]
  12. Phase 1 and 2: Atezolizumab Levels in Blood [ Time Frame: Days 1, 14, 21, 22, 35, 42, 43, 56, 63, 64, 77, 84, 154, and 174 ]
  13. Phase 1 and 2: Percentage of Participants With Anti-Atezolizumab Antibodies [ Time Frame: Baseline up to approximately 2.5 years ]
  14. Phase 1 and 2: Peak Serum Levels of C-Reactive Protein (CRP) in Blood [ Time Frame: 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 ]
  15. 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 [ Time Frame: 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 ]
  16. Phase 1 and 2: Peak Serum Levels of Ferritin in Blood [ Time Frame: 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 ]
  17. Phase 1 and 2: Peak Serum Levels of Interleukin-2 Receptor Alpha (IL-2Rα) in Blood [ Time Frame: 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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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-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 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 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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02926833


Locations
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United States, California
City of Hope
Duarte, California, United States, 91010
Stanford Cancer Center
Palo Alto, California, United States, 94305
United States, Florida
H Lee Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Kite, A Gilead Company
Genentech, Inc.
Investigators
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Study Director: Kite Study Director Kite, A Gilead Company
  Study Documents (Full-Text)

Documents provided by Gilead Sciences ( Kite, A Gilead Company ):
Study Protocol  [PDF] September 21, 2017
Statistical Analysis Plan  [PDF] June 25, 2018

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Responsible Party: Kite, A Gilead Company
ClinicalTrials.gov Identifier: NCT02926833    
Other Study ID Numbers: KTE-C19-106
First Posted: October 6, 2016    Key Record Dates
Results First Posted: June 26, 2020
Last Update Posted: June 26, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cyclophosphamide
Fludarabine
Atezolizumab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists