Clinical trial NCT02926833: Study of Safety and Efficacy of KTE-C19 in Combination With Atezolizumab in Adults With Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Refractory Diffuse Large B Cell Lymphoma
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
Collaborators: name: Genentech, Inc.
First posted: 2016-10-06
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: This study uses a single group design. The arms reported in the Arms and Intervention section are based on the atezolizumab dosing schedule in the 4 Cohorts.
Primary purpose: TREATMENT

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).

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).


Eligibility 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-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

Primary outcomes:
measure: Phase 1: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs)
timeFrame: Baseline up to 21 days
measure: Phase 1 and 2: Complete Response Rate (CRR)
timeFrame: From enrollment until first occurrence of CR or PR (maximum duration: 6.2 years)
Secondary outcomes:
measure: Phase 1 and 2: Objective Response Rate (ORR)
timeFrame: From enrollment until first occurrence of CR or PR (maximum duration: 6.2 years)
measure: Phase 1 and 2: Duration of Response (DOR)
timeFrame: From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (maximum duration: 6.2 years)
measure: Phase 1 and 2: Progression-Free Survival (PFS)
timeFrame: From the date of first KTE-C19 infusion to disease progression or death regardless of cause (maximum duration: 6.2 years)
measure: Phase 1 and 2: Overall Survival (OS)
timeFrame: From the date of first KTE-C19 infusion to the date of death regardless of cause (maximum duration: 6.2 years)
measure: Phase 1 and 2: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Up to 1.8 years
measure: Phase 1 and 2: Percentage of Participants With Serum Chemistry Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Values
timeFrame: Up to 1.8 years
measure: Phase 1 and 2: Percentage of Participants With Serum Chemistry Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Values
timeFrame: Up to 1.8 years
measure: Phase 1 and 2: Percentage of Participants With Hematology Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Values
timeFrame: Up to 1.8 years
measure: Phase 1 and 2: Percentage of Participants With Hematology Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Values
timeFrame: Up to 1.8 years
measure: Phase 1 and 2: Peak Anti-CD19 CAR T-Cell (KTE-C19) Level (Maximum Observed Plasma Concentration) in Blood
timeFrame: 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
measure: Phase 1 and 2: Percentage of Participants With Anti-KTE-C19 Antibodies
timeFrame: 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
measure: Phase 1 and 2: Atezolizumab Levels in Blood
timeFrame: Days 1, 14, 21, 22, 35, 42, 43, 56, 63, 64, 77, 84, 154, and 174
measure: Phase 1 and 2: Percentage of Participants With Anti-Atezolizumab Antibodies
timeFrame: 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
measure: Phase 1 and 2: Peak Serum Levels of C-Reactive Protein (CRP) in Blood
timeFrame: 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
measure: 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
timeFrame: 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
measure: Phase 1 and 2: Peak Serum Levels of Ferritin in Blood
timeFrame: 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
measure: Phase 1 and 2: Peak Serum Levels of Interleukin-2 Receptor Alpha (IL-2Rα) in Blood
timeFrame: 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
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center
state: Florida
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Kite, A Gilead Company
name: Kite Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.