Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Rituximab in Participants With Refractory Large B-Cell Lymphoma (ZUMA-14)

A Phase 2 Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Rituximab in Participants With Refractory Large B-Cell Lymphoma (ZUMA-14)

The primary objective of this study is to estimate the efficacy of axicabtagene ciloleucel in combination with rituximab, as measured by assessment of response rates in adult participants with relapsed/refractory large B-cell lymphoma.

Study Overview

• Status: Completed
• Conditions: Refractory Large B-cell Lymphoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Rituximab; Biological: Axicabtagene Ciloleucel

Detailed Description

Following at least 24 months of assessments after axicabtagene ciloleucel infusion, participants will be asked to rollover to a separate long-term follow-up study (Study KT-US-982-5968). Participants will complete the remainder of the 15-year follow-up assessments in the KT-US-982-5968 study.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
  • California
    • Duarte, California, United States, 91010-3012
      • City of Hope National Medical Center
    • Palo Alto, California, United States, 94305
      • Stanford Cancer Institute
    • Santa Monica, California, United States, 90404
      • UCLA Hematology/Oncology
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University Of Chicago Medical Center
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center, New York Presbyterian Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Austin, Texas, United States, 78704
      • St. David's South Austin Medical Center
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

• Histologically confirmed large B-cell lymphoma

• Chemotherapy-refractory disease, defined as one or more of the following:

  • No response to first-line therapy (primary refractory disease)
  • No response to second or greater lines of therapy OR
  • Refractory after autologous stem cell transplant (ASCT)
• At least 1 measureable lesion according to the Lugano Classification (Cheson 2014).

• Individuals must have received adequate prior therapy, including at a minimum:

  • Anti-CD20 monoclonal antibody
  • An anthracycline-containing chemotherapy regimen
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate renal, hepatic, pulmonary, and cardiac function

Key Exclusion Criteria:

• Known CD19 negative or CD20 negative tumor
• History of Richter's transformation of Chronic Lymphocytic Leukemia (CLL)
• Prior CAR therapy or other genetically modified T-cell therapy
• Prior organ transplantation including prior allogeneic stem cell transplant (SCT)
• Prior CD19 targeted therapy
• Clinically significant infection or cardiopulmonary disease
• Presence of any in-dwelling lines or drains (dedicated central venous access catheters allowed)
• History or presence of central nervous system (CNS) lymphoma or nonmalignant CNS disorder or cerebrospinal fluid (CSF) malignant cells or brain metastases
• History of autoimmune disease
• History of deep vein thrombosis (DVT) or pulmonary embolism (PE) within the last 6 months

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Axicabtagene Ciloleucel and Rituximab Combination; Participants will receive rituximab 375 mg/m^2, once on Day -5 along with conditioning chemotherapy (fludarabine 30 mg/m^2 over 30 minutes and cyclophosphamide 500 mg/m^2 over 60 minutes) once on Days -5 to -3, followed by axicabtagene ciloleucel 2 x 10^6 anti-cluster of differentiate 19 (CD19) chimeric antigen receptor (CAR) T cells/kg once on Day 0 and additional rituximab 375 mg/m^2 of 5 doses, once every 28 days starting from Day 21 up to Day 133.

Drug: Cyclophosphamide; Administered according to package insert; Drug: Fludarabine; Administered according to package insert; Drug: Rituximab; Administered intravenously; Other Names: RITUXAN®; Biological: Axicabtagene Ciloleucel; A single infusion of CAR-transduced autologous T cells administered intravenously; Other Names: Yescarta®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR) Rate Per the International Working Group (IWG) Lugano Classification as Determined by Study Investigators	CR rate is defined as the incidence of a CR per the IWG Lugano Classification as determined by study investigators. CR rate: percentage of participants with CR [complete metabolic response (CMR); complete radiological response (CRR)]. CMR: positron emission tomography (PET) 5-point scale (5-PS) scores of 1 (no uptake above background), 2 (uptake ≤ mediastinum), 3 (uptake > mediastinum but ≤ liver) with/without a residual mass); no new lesions; and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow (BM). CRR: target nodes/nodal masses regressed to ≤ 1.5 cm in longest transverse diameter of lesion (LDi); no extralymphatic sites of disease; absent non-measured lesion (NMLs); organ enlargement regress to normal; no new sites; and bone marrow normal by morphology. 95% confidence interval (CI) was calculated by Clopper-Pearson method.	First infusion date up to maximum duration of 32.7 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs)	An AE is defined as any untoward medical occurrence in a clinical trial participant that does not necessarily have a relationship with study treatment or worsening of a pre-existing medical condition. TEAEs are any AEs with onset on or after axicabtagene ciloleucel infusion or worsening of a pre-existing medical condition that occurs on or after axicabtagene ciloleucel infusion.	First infusion date up to maximum duration of 27 months
Percentage of Participants Who Experienced Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Value	Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Laboratory parameters with only non-zero values are presented.	First infusion date up to maximum duration of 27 months
Objective Response Rate (ORR) Per the IWG Lugano Classification as Determined by Study Investigators	ORR: percentage of participants with CR [CMR;CRR] or PR [partial metabolic response (PMR); partial radiologic response (PRR)].CMR: PET 5PS scores of 1 (no uptake above background, 2 (uptake ≤ mediastinum), 3 (uptake > mediastinum but ≤ liver) with/without a residual mass; no new lesions; no evidence of FDG-avid disease in BM. CRR: target nodes/nodal masses regressed to ≤ 1.5 cm in LDi;no extralymphatic sites of disease;absent NMLs;organ enlargement regress to normal;no new sites;bone marrow morphology normal. PMR: scores 4 (uptake moderately > liver), 5 (uptake markedly > liver, new lesions) with reduced uptake compared with baseline and residual mass; no new lesions; responding disease at interim/residual disease at end of treatment (EOT). PRR: ≥ 50% decrease in sum of the product of perpendicular diameters (SPD) of up to 6 target measurable nodes and extra-nodal sites; absent/normal, regressed, but no increase of NMLs; spleen regressed by > 50% in length beyond normal; no new sites.	First infusion date up to maximum duration of 32.7 months
Duration of Response (DOR) Per the IWG Lugano Classification as Determined by Study Investigators	DOR is defined only for participants who experience an objective response and is the time from the first objective response to disease progression [progressive metabolic disease (PMD); progressive radiologic disease (PRD)] or death from any cause. Objective response is defined in outcome measure (OM) 4. PMD: scores 4 (uptake moderately > liver), 5 (uptake markedly > liver, new lesions) with increased uptake compared with baseline; new fluorodeoxyglucose (FDG)-avid foci consistent with lymphoma rather than another etiology; new or recurrent FDG-avid foci in bone marrow. PRD: LDi >1.5 cm; ≥ 50% increase from cross product of LDi and perpendicular diameter (PPD); increase in LDi or shortest axis perpendicular to the LDi (SDi) of 0.5 cm for lesions ≤1.5 cm and 1 cm for lesions >2 cm; spleen increased by >50% in length beyond normal; new or recurrent splenomegaly, bone marrow involvement; new lesions; progression of pre-existing lesions. Kaplan-Meier (KM) estimate of median was reported.	From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (up to approximately 32.7 months)
Progression-Free Survival (PFS) Per the IWG Lugano Classification as Determined by Study Investigators	PFS is defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression (PMD; PRD) or death from any cause. PMD: scores 4 (uptake moderately > liver), 5 (uptake markedly > liver, new lesions) with increased uptake compared with baseline; new FDG-avid foci consistent with lymphoma rather than another etiology; new or recurrent FDG-avid foci in bone marrow. PRD: LDi >1.5 cm; ≥ 50% increase from cross product of LDi and PPD; increase in LDi or SDi of 0.5 cm for lesions ≤1.5 cm and 1 cm for lesions >2 cm; spleen increased by >50% in length beyond normal; new or recurrent splenomegaly, bone marrow involvement; new lesions; progression of pre-existing lesions. KM estimate of median was reported.	First infusion date up to disease progression or death regardless of cause (up to approximately 32.7 months)
Overall Survival (OS)	OS is defined as the time from axicabtagene ciloleucel infusion to the date of death from any cause. KM estimate of median was reported.	First infusion date up to death regardless of cause (up to approximately 32.7 months)
Peak Level of Anti-CD19 CAR T Cells in Blood	Peak was defined as the maximum number of CAR T cells in blood measured after infusion.	Baseline (Day 0), post-infusion on Days 7, 14, 21, 28, 49, 105, 180, Months 9, 12, 15, 18, and 24
Level of Anti-CD19 CAR T Cells in Blood by Visit		Baseline (Day 0), post-infusion on Days 7, 14, 21, 28, 49, 105, 180, Months 9, 12, 15, 18, and 24
Area Under the Curve of CAR T Cells From Day 0 to Day 28 (AUC0-28)	AUC0-28 is defined as the area under curve in a plot of number of CAR T cells against scheduled visit from Day 0 to Day 28.	Baseline (Day 0), post-infusion on Days 7, 14, 21, and 28
Time to Peak Level of Anti-CD19 CAR T Cells in Blood	Time to peak was defined as the number of days from the date of the axicabtagene ciloleucel infusion to the date of peak level defined as the maximum number of CAR T cells in blood measured after infusion.	Baseline (Day 0), post-infusion on Days 7, 14, 21, 28, 49, 105, 180, Months 9, 12, 15, 18, and 24

Collaborators and Investigators

• Sponsor: Kite, A Gilead Company
• 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.

Helpful Links

• Gilead Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2019
• Primary Completion (Actual): January 30, 2023
• Study Completion (Actual): January 30, 2023

Study Registration Dates

• First Submitted: June 27, 2019
• First Submitted That Met QC Criteria: June 27, 2019
• First Posted (Actual): June 28, 2019

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 16, 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; 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; Cyclophosphamide; Rituximab; Fludarabine; Axicabtagene ciloleucel
• Other Study ID Numbers: KT-US-471-0114; 2019-004803-11 (EudraCT Number)

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.gileadclinicaltrials.com/transparency-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