Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Adults With Refractory Large B-cell Lymphoma

NCT03704298 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: KTE-C19-111
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 5

Brief Summary

The primary objectives of this study are: Phase 1: To evaluate the safety of axicabtagene ciloleucel in combination with utomilumab and to identify the most appropriate dose and timing of utomilumab to carry forward into Phase 2 Phase 2: To evaluate the efficacy of axicabtagene ciloleucel and utomilumab as measured by complete response rate in participants with refractory large B-cell lymphoma

Conditions

Relapsed/Refractory Large B-cell Lymphoma

Outcome Measures

Primary Outcomes (2)

• Phase 1: Percentage of Participants Experiencing Adverse Events Defined as Dose Limiting Toxicities (DLTs)

  DLTs are study drug-related events with onset within first 28 days following infusion of axicabtagene ciloleucel or utomilumab: * Grade (GR) 4 hematologic toxicity lasting more than 30 days (except lymphopenia or B-cell aplasia) * All study drug-related GR 3 lasting for \> 7 days or 4 non-hematologic toxicities regardless of duration (except: aphasia/dysphasia or confusion/cognitive disturbance which resolves to at least GR 1 within 2 weeks or baseline within 4 weeks, fever of any grade, immediate study drug-related hypersensitivity reactions within 2 hours of drug infusion that are reversible to grade 2 or less within 24 hours, renal toxicity which requires dialysis for ≤ 7 days, intubation for airway protection if ≤ 7 days, tumor lysis syndrome, grade 3 liver function test elevation, provided there is resolution to ≤ GR 2 within 14 days, grade 4 transient serum hepatic enzyme abnormalities provided there is resolution to ≤ GR 3 within \< 72 hours, grade 3 nausea and/or anorexia).

  Up to 28 days

• Phase 2: Complete Response (CR) Rate

  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.

  Up to 1 year

Secondary Outcomes (9)

• Phase 1 and Phase 2: Objective Response Rate (ORR)

  From first infusion date of axicabtagene ciloleucel until first occurrence of CR or PR (maximum duration: 42.6 months)

• Phase 1 and Phase 2: Duration of Response (DOR)

  From first documentation of CR or PR until first occurrence of PD or death from any cause or up to last date known alive in the study (maximum duration: 42.6 months)

• Phase 1 and Phase 2: Progression Free Survival (PFS)

  From first infusion date of axicabtagene ciloleucel to the date of PD or death from any cause or up to last date known alive in the study (maximum duration: 43.5 months)

• Phase 1 and Phase 2: Overall Survival (OS)

  From first infusion date of axicabtagene ciloleucel to date of death from any cause or up to last date known alive in the study (maximum duration: 43.5 months)

• Phase 1 and Phase 2: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)

  From first dose up to 30 days post last dose (maximum duration: 23.0 months)

Study Arms (6)

Phase 1: Cohort 1: Axicabtagene Ciloleucel + Utomilumab 10 mg

EXPERIMENTAL

Participants will receive cyclophosphamide 500 mg/m\^2/day intravenously (IV) and fludarabine 30 mg/m\^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10\^6 anti-cluster of differentiation (CD) 19 chimeric antigen receptor (CAR) transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10\^8 anti-CD19 CAR T cells will be administered. Participants also will receive utomilumab 10 mg on Day 1, IV infusion, once every 4 weeks (Q4W) for 6 months or until progressive disease, whichever came first.

Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Axicabtagene Ciloleucel; Biological: Utomilumab

Phase 1: Cohort 2: Axicabtagene Ciloleucel + Utomilumab 30 mg

EXPERIMENTAL

Participants will receive cyclophosphamide 500 mg/m\^2/day IV and fludarabine 30 mg/m\^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10\^6 anti-CD19 CAR transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10\^8 anti-CD19 CAR T cells will be administered. Participants also will receive utomilumab 30 mg on Day 1, IV infusion, Q4W for 6 months or until progressive disease, whichever came first.

Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Axicabtagene Ciloleucel; Biological: Utomilumab

Phase 1: Cohort 3: Axicabtagene Ciloleucel + Utomilumab 100 mg

EXPERIMENTAL

Participants will receive cyclophosphamide 500 mg/m\^2/day IV and fludarabine 30 mg/m\^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10\^6 anti-CD19 CAR transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10\^8 anti-CD19 CAR T cells will be administered. Participants also will receive utomilumab 100 mg on Day 1, IV infusion, Q4W for 6 months or until progressive disease, whichever came first.

Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Axicabtagene Ciloleucel; Biological: Utomilumab

Phase 1: Cohort 4: Axicabtagene Ciloleucel + Utomilumab 200 mg

EXPERIMENTAL

Participants will receive cyclophosphamide 500 mg/m\^2/day IV and fludarabine 30 mg/m\^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10\^6 anti-CD19 CAR transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10\^8 anti-CD19 CAR T cells will be administered. Participants also will receive utomilumab 200 mg on Day 1, IV infusion, Q4W for 6 months or until progressive disease, whichever came first.

Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Axicabtagene Ciloleucel; Biological: Utomilumab

Phase 1: Cohort 5: Axicabtagene Ciloleucel + Utomilumab 400 mg

EXPERIMENTAL

Participants will receive cyclophosphamide 500 mg/m\^2/day IV and fludarabine 30 mg/m\^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel administered as a single IV infusion at a target dose of 2 x 10\^6 anti-CD19 CAR transduced autologous T cells/kg on Day 0. For participants weighing ≥ 100 kg, a maximum flat dose of axicabtagene ciloleucel at 2 x 10\^8 anti-CD19 CAR T cells will be administered. Participants also will receive utomilumab 400 mg on Day 1, IV infusion, Q4W for 6 months or until progressive disease, whichever came first. However, as the study was early terminated, no participants were enrolled in Cohort 5 of the study.

Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Axicabtagene Ciloleucel; Biological: Utomilumab

Phase 2: Axicabtagene Ciloleucel + Utomilumab

EXPERIMENTAL

Participants will receive cyclophosphamide 500 mg/m\^2/day IV and fludarabine 30 mg/m\^2/day IV conditioning chemotherapy for 3 days followed by axicabtagene ciloleucel and utomilumab based on the dose and schedule selected to move forward from the Phase 1 portion of the study as recommended by the internal safety review team. However, as the study was early terminated, no participants were enrolled in Phase 2 of the study.

Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Axicabtagene Ciloleucel; Biological: Utomilumab

Interventions

Cyclophosphamide DRUG

Administered according to package insert

Phase 1: Cohort 1: Axicabtagene Ciloleucel + Utomilumab 10 mg; Phase 1: Cohort 2: Axicabtagene Ciloleucel + Utomilumab 30 mg; Phase 1: Cohort 3: Axicabtagene Ciloleucel + Utomilumab 100 mg; Phase 1: Cohort 4: Axicabtagene Ciloleucel + Utomilumab 200 mg; Phase 1: Cohort 5: Axicabtagene Ciloleucel + Utomilumab 400 mg; Phase 2: Axicabtagene Ciloleucel + Utomilumab

Fludarabine DRUG

Administered according to package insert

Phase 1: Cohort 1: Axicabtagene Ciloleucel + Utomilumab 10 mg; Phase 1: Cohort 2: Axicabtagene Ciloleucel + Utomilumab 30 mg; Phase 1: Cohort 3: Axicabtagene Ciloleucel + Utomilumab 100 mg; Phase 1: Cohort 4: Axicabtagene Ciloleucel + Utomilumab 200 mg; Phase 1: Cohort 5: Axicabtagene Ciloleucel + Utomilumab 400 mg; Phase 2: Axicabtagene Ciloleucel + Utomilumab

Axicabtagene Ciloleucel BIOLOGICAL

A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously

Also known as: Yescarta®

Phase 1: Cohort 1: Axicabtagene Ciloleucel + Utomilumab 10 mg; Phase 1: Cohort 2: Axicabtagene Ciloleucel + Utomilumab 30 mg; Phase 1: Cohort 3: Axicabtagene Ciloleucel + Utomilumab 100 mg; Phase 1: Cohort 4: Axicabtagene Ciloleucel + Utomilumab 200 mg; Phase 1: Cohort 5: Axicabtagene Ciloleucel + Utomilumab 400 mg; Phase 2: Axicabtagene Ciloleucel + Utomilumab

Utomilumab BIOLOGICAL

Administered as an IV infusion

Phase 1: Cohort 1: Axicabtagene Ciloleucel + Utomilumab 10 mg; Phase 1: Cohort 2: Axicabtagene Ciloleucel + Utomilumab 30 mg; Phase 1: Cohort 3: Axicabtagene Ciloleucel + Utomilumab 100 mg; Phase 1: Cohort 4: Axicabtagene Ciloleucel + Utomilumab 200 mg; Phase 1: Cohort 5: Axicabtagene Ciloleucel + Utomilumab 400 mg; Phase 2: Axicabtagene Ciloleucel + Utomilumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically proven large B-cell lymphoma including the following types:
• Diffuse large B cell lymphoma (DLBCL) not otherwise specified Activated B cell / Germinal center B cell (ABC/GCB).
• High grade B-cell lymphoma (HGBCL) with or without MYC and BCL2 and/or BCL6 rearrangement.
• DLBCL arising from follicular lymphoma.
• T cell/histiocyte rich large B-cell lymphoma.
• DLBCL associated with chronic inflammation.
• Primary cutaneous DLBCL, leg type.
• Epstein-Barr virus (EBV) + DLBCL
• Relapsed or chemotherapy-refractory disease, defined as one or more of the following:
• No response to first-line therapy (primary refractory disease); individuals who are intolerant to first-line systemic chemotherapy are excluded
• Progressive disease (PD) as best response to first-line therapy.
• Stable disease (SD) as best response after at least 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP) with SD duration no longer than 6 months from last dose of therapy.
• No response to second or greater lines of therapy.
• PD as best response to most recent therapy regimen.
• SD as best response after at least 2 cycles of last line of therapy with SD duration no longer than 6 months from last dose of therapy OR

You may not qualify if:

• Histologically proven primary mediastinal B-cell lymphoma (PMBCL).
• History of Richter's transformation of chronic lymphocytic lymphoma (CLL).
• Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy.
• History of severe, immediate hypersensitivity reaction attributed to aminoglycosides.
• History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection. Individuals with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines or applicable country guidelines.
• Individuals with detectable cerebrospinal fluid malignant cells, brain metastases, or a history of CNS lymphoma.
• History or presence of CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
• Individuals with cardiac atrial or cardiac ventricular lymphoma involvement.
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
• Requirement for urgent therapy due to tumor mass effects (eg, blood vessel compression, bowel obstruction, or transmural gastric involvement.
• Primary immunodeficiency.
• History of autoimmune disease (eg, Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years. Individuals with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and individuals with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
• History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment
• Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
• Autologous stem cell transplant within 6 weeks of planned enrollment

Sponsors & Collaborators

• Kite, A Gilead Company: lead
• Pfizer: collaborator

Study Sites (5)

Stanford Cancer Institute

Palo Alto, California, 94305, United States

Location

UCLA Hematology/ Oncology

Santa Monica, California, 90404, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Related Publications (1)

• 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.

  PMID: 34515338 DERIVED

Related Links

• Gilead Clinical Trials Website

MeSH Terms

Conditions

Recurrence

Interventions

Cyclophosphamide; fludarabine; axicabtagene ciloleucel; utomilumab

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Medical Information
• Organization: Kite, A Gilead Company

medinfo@kitepharma.com

844-454-5483 (1-844-454-KITE)

Study Officials

• Kite Study Director

  Kite, A Gilead Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 10, 2018
• First Posted: October 12, 2018
• Study Start: November 20, 2018
• Primary Completion: May 7, 2021
• Study Completion: December 15, 2022
• Last Updated: June 28, 2024
• Results First Posted: June 28, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: 18 months after study completion
• Access Criteria: A secured external environment with username, password, and RSA code.

Locations

US (5)