Clinical trial NCT02348216: Study Evaluating the Safety and Efficacy of KTE-C19 in Adult Participants With Refractory Aggressive Non-Hodgkin Lymphoma
Official title: A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Relapsed Diffuse Large B-Cell Lymphoma
Transformed Follicular Lymphoma (TFL)
Primary Mediastinal B-cell Lymphoma (PMBCL)
High Grade B-cell Lymphoma (HGBCL)
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2015-01-28
Enrollment: 307
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study will be separated into 3 distinct phases designated as the Phase 1 study, Phase 2 pivotal study (Cohort 1 and Cohort 2), and Phase 2 safety management study (Cohort 3 and Cohort 4, Cohort 5 and Cohort 6).

The primary objectives of this study are:

* Phase 1 Study: Evaluate the safety of axicabtagene ciloleucel regimens
* Phase 2 Pivotal Study; Evaluate the efficacy of axicabtagene ciloleucel
* Phase 2 Safety Management Study: Assess the impact of prophylactic regimens or earlier interventions on the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities

Subjects 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.


Eligibility criteria: Key Inclusion Criteria

1. Histologically confirmed:

   * Diffuse Large B Cell Lymphoma (DLBCL)
   * Primary Mediastinal Large B Cell Lymphoma (PMBCL)
   * Transformation Follicular Lymphoma (TFL)
   * High grade B-cell lymphoma (HGBCL)
2. Chemotherapy-refractory disease, defined as one of more of the following:

   * No response to last line of therapy i. Progressive disease (PD) as best response to most recent therapy regimen ii. Stable disease (SD) as best response to most recent therapy with duration no longer than 6 month from last dose of therapy OR
   * Refractory post-autologous stem cell transplant (ASCT) i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy proven recurrence in relapsed individuals) ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy
3. Individuals must have received adequate prior therapy including at a minimum:

   * Anti-cluster of differentiate 20 (CD20) monoclonal antibody unless investigator determines that tumor is CD20-negative and
   * an anthracycline containing chemotherapy regimen
   * for individual with transformed FL must have chemorefractory disease after transformation to DLBCL.
4. At least one measurable lesion per revised international working group (IWG Response Criteria
5. Eastern cooperative oncology group (ECOG) performance status of 0 or 1
6. Absolute neutrophil count (ANC) ≥ 1000/microliters (uL)
7. Absolute lymphocyte count ≥ 100/uL
8. Platelet count ≥ 75,000/uL
9. Adequate renal, hepatic, pulmonary and cardiac function defined as:

   * Creatinine clearance (as estimated by Cockcroft Gault) \> 60 mL/min
   * Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \< 2.5 upper limit of normal (ULN)
   * Total bilirubin \< 1.5 mg/dL, except in individuals with Gilbert's syndrome
   * Cardiac ejection fraction \>50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant pleural effusion
   * Baseline oxygen saturation \>92% on room air
10. 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.
11. Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and HGBCL after two systemic lines of therapy

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 chimeric antigen receptor (CAR) therapy or other genetically modified T cell therapy
4. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment
5. 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
6. Individuals with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma, cerebrospinal fluid malignant cells or brain metastases
7. History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement

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

Primary outcomes:
measure: Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs)
timeFrame: First infusion date of axicabtagene ciloleucel up to 30 days
measure: Phase 2 Pivotal Study (Cohorts 1 and 2): Overall Response Rate (ORR) as Assessed by Investigator Per Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma
timeFrame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7 years)
measure: Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades
timeFrame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 6.8 years)
measure: Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
timeFrame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 5.4 years)
measure: Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
timeFrame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.4 years)
measure: Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
timeFrame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.1 years)
Secondary outcomes:
measure: Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma
timeFrame: First OR to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively)
measure: Phase 1 Study: ORR as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma
timeFrame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months)
measure: Phase 2 Pivotal Study (Cohorts 1 and 2): ORR Per Independent Radiological Review Committee (IRRC)
timeFrame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years)
measure: Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator Per the Revised IWG Response Criteria for Malignant Lymphoma
timeFrame: First infusion date of axicabtagene ciloleucel to last follow-up visit (maximum duration: 6.8, 5.4, 4.4, 4.1 years for Cohorts 3, 4, 5, and 6 respectively)
measure: Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma
timeFrame: First infusion date of axicabtagene ciloleucel to disease progression or death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively)
measure: Phase 2: Overall Survival (OS)
timeFrame: First infusion date of axicabtagene ciloleucel to the date of death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively)
measure: Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC Per Cheson 2007
timeFrame: First objective response up to the data cutoff date of 11 August 2018 (maximum: 2.7 years)
measure: Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007
timeFrame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years)
measure: Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC Per Cheson 2007
timeFrame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years)
measure: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
timeFrame: First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years)
measure: Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs
timeFrame: First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years)
measure: Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies
timeFrame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively)
measure: Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood
timeFrame: Baseline up to Month 60 (for Phase 1 and Phase 2 Cohorts 1, 2, and 3); Baseline up to Month 24 (for Phase 2 Cohorts 4, 5, and 6)
measure: Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3)
timeFrame: Baseline up to Month 3
measure: Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6)
timeFrame: Baseline up to Month 3
measure: Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6)
timeFrame: Baseline up to Month 3
measure: Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum
timeFrame: Baseline up to Month 3
measure: Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2)
timeFrame: Baseline up to Month 3
measure: Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3)
timeFrame: Baseline up to Month 3
measure: Percentage of Participants With Positive Replication Competent Retrovirus (RCR)
timeFrame: Day 0 (pre-infusion) up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively)
measure: Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score
timeFrame: Baseline, Week 4, Month 3, and Month 6
measure: Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score
timeFrame: Baseline, Week 4, Month 3, and Month 6
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: La Jolla
country: United States
facility: University of California San Diego (UCSD)
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Santa Monica
country: United States
facility: University of California Los Angeles (UCLA)
state: California
city: Denver
country: United States
facility: Sarah Cannon - Denver
state: Colorado
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic - Taussig Cancer Institute
state: Ohio
city: Nashville
country: United States
facility: Sarah Cannon - Tennesee
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Sarah Cannon-Methodist Healthcare System - San Antonio
state: Texas
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret
state: Ontario
city: Paris
country: France
facility: Hopital Saint Louis
city: Pessac
country: France
facility: Hopital Haut-Leveque
city: Rennes
country: France
facility: CHU de Rennes
city: Dresden
country: Germany
facility: Universitätsklinik Dresden
city: Essen
country: Germany
facility: University Hospital of Essen
city: Würzburg
country: Germany
facility: Universitaetsklinikum Wuerzburg
city: Tel Aviv
country: Israel
facility: Tel Aviv Souraski Medical Center
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: Kite, A Gilead Company
name: Kite Study Director
role: STUDY_DIRECTOR
References:
citation: Topp MS, van Meerten T, Wermke M et al. Preliminary Results of Earlier Steroid Use with Axicabtagene Ciloleucel in Patients With Relapsed/Refractory Large B Cell Lymphoma. Poster presented at the American Society of Presented at: American Society of Clinical Oncology Annual Meeting. May 31-June 4, 2019; Chicago, Illinois; Abstract 7558.
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