Study to Evaluate the Safety and Tolerability of Brexucabtagene Autoleucel (KTE-X19) in People With Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (ZUMA-8)

• ClinicalTrials.gov Identifier: NCT03624036
• Recruitment Status: Terminated
• First Posted: August 9, 2018
• Results First Posted: May 10, 2022
• Last Update Posted: November 18, 2023
• Sponsor: Kite, A Gilead Company
• Information provided by (Responsible Party): Gilead Sciences ( Kite, A Gilead Company )

Tracking Information

• First Submitted Date: August 7, 2018
• First Posted Date: August 9, 2018
• Results First Submitted Date: February 14, 2022
• Results First Posted Date: May 10, 2022
• Last Update Posted Date: November 18, 2023
• Actual Study Start Date: November 15, 2018
• Actual Primary Completion Date: February 12, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 6, 2022)

Number of Participants Experiencing Dose Limiting Toxicities (DLTs) [ Time Frame: First infusion date of brexucabtagene autoleucel up to 28 days. Participants were evaluated in specified period but Grade 4 hematologic toxicity (specified in description) having onset in this period were further observed for 30 days for confirmation. ]

DLTs refer to toxicities with onset experienced during the first 28 days of study treatment that have been judged to be clinically significant and related to study treatment. DLTs evaluated may include with some exceptions: All brexucabtagene autoleucel related Grade 3 non-hematologic toxicities lasting for more than 7 days, Grade 4 non-hematologic toxicities regardless of duration, and Grade 4 hematologic toxicity lasting more than 30 days if not attributable to underlying disease.

Original Primary Outcome Measures (submitted: August 7, 2018)

• Phase 1: Incidence of Dose-Limiting Toxicities (DLTs) [ Time Frame: Up to 28 days ]
  Dose-limiting toxicity is defined as protocol-defined KTE-C19-related events with onset within the first 28 days following KTE-C19 infusion.
• Phase 2: Objective Response Rate per Independent Review [ Time Frame: Up to 2 years ]
  Objective response rate is defined per the International Workshop on CLL (IWCLL) 2018 criteria.

Current Secondary Outcome Measures (submitted: October 31, 2023)

• Objective Response Rate (ORR) Per Investigator Review Assessed by International Workshop on CLL (IWCLL) 2018 Criteria [ Time Frame: First infusion date up to last follow up visit (maximum duration: 42 months) ]
  ORR was defined as percentage of participants achieving either complete response (CR), complete response with incomplete hematopoetic recovery (CRi) or partial response (PR). Criteria for CR: no lymphadenopathy >1.5 cm or hepatomegaly/splenomegaly, lymphocytes <4000/microliters (μL), bone marrow sample must be normocellular with 30% lymphocytes and no B-lymphoid nodules, platelets ≥100,000/µL, hemoglobin ≥11 grams per deciliter (g/dL). CRi: All CR criteria were met except with platelet count <100,000/μL, hemoglobin <11 g/dL or neutrophil count <500/μL. PR: ≥1 of these: ≥50% decrease in lymphocytes, lymphadenopathy, size of liver and spleen, 50% decrease in bone marrow infiltrates; and ≥1 of these: platelets ≥100,000/µL or ≥50% increase from Baseline, hemoglobin ≥11 g/dL or ≥50% increase from Baseline. Participants who did not meet criteria were considered nonresponders. 95% confidence interval (CI) was calculated by Clopper-Pearson method.
• Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) [ Time Frame: First infusion date up to last follow up visit (maximum duration: 42 months) ]
  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 were defined as AEs with onset on or after the initiation of brexucabtagene autoleucel infusion.
• Peak Level of Anti-CD19 CAR T-Cells in Blood [ Time Frame: First infusion date up to 3 months post-infusion (approximately 3 months) ]
  Peak was defined as the maximum number of CAR T cells measured post-infusion.

Original Secondary Outcome Measures (submitted: August 7, 2018)

• Complete Response (CR/CRi) Rate per Independent Review [ Time Frame: Up to 15 years ]
  Complete response rate is defined per the IWCLL 2018 criteria.
• Objective Response Rate (ORR) per Investigator Review [ Time Frame: Up to 15 years ]
  Objective response rate is defined per the IWCLL 2018 criteria.
• Complete Response Rate (CR/CRi) per Investigator Review [ Time Frame: Up to 15 years ]
  Complete response rate is defined per the IWCLL 2018 criteria.
• Minimal Residual Disease Negative (MRD-) Rate [ Time Frame: Up to 15 years ]
  MRD- rate is defined per the IWCLL 2018 criteria.
• Incidence of MRD- Among Participants who have Achieved CR or CRi [ Time Frame: Up to 15 years ]
• Duration of Response (DOR) [ Time Frame: Up to 15 years ]
  DOR is defined as the time from first objective response to relapse or death.
• Progression-Free Survival (PFS) [ Time Frame: Up to 15 years ]
  PFS is defined as the time from the KTE-C19 infusion date to the date of disease progression or death from any cause.
• Overall Survival [ Time Frame: Up to 15 years ]
  Overall survival is defined as the time from the KTE-C19 infusion to the date of death from any cause.
• Incidence of Adverse Events (AEs) [ Time Frame: Up to 15 years ]
• Percentage of Participants Experiencing Clinically Significant Changes in Laboratory Values [ Time Frame: Up to 15 years ]
• Phase 2: Change from Baseline in European Quality of Life Five Dimension Five Level Scale (EQ-5D) [ Time Frame: Baseline and up to 15 years ]
  The European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L) is a generic measure of health status that provides a simple descriptive profile and a single index value.
• Phase 2: Change from Baseline in Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) [ Time Frame: Baseline and up to 15 years ]
  The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) is a valid, reliable, and efficient measure of leukemia-specific health-related quality of life for acute and chronic disease. It was developed to assess symptoms (eg, fevers, chills, night sweats, nodal swelling, fatigue) specifically relevant to participants with leukemia.
• Phase 1: Objective Response Rate per Independent Review [ Time Frame: Up to 15 years ]
  Objective response rate is defined per the IWCLL 2018 criteria.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Evaluate the Safety and Tolerability of Brexucabtagene Autoleucel (KTE-X19) in People With Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
• Official Title: A Phase 1 Multicenter Study Evaluating the Safety and Tolerability of KTE-X19 in Adult Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Brief Summary

The primary objective of this study is to evaluate the safety and tolerability of brexucabtagene autoleucel (KTE-X19) in adults with relapsed/refractory chronic lymphocytic leukemia (r/r CLL) and small lymphocytic lymphoma (r/r SLL) who have received at least 2 prior lines of treatment, one of which must include a Bruton's tyrosine kinase (BTK) inhibitor.

After the end of KTE-C19-108, participants who received an infusion of brexucabtagene autoleucel will complete the remainder of the 15-year follow-up assessments in a separate Long-term Follow-up study, KT-US-982-5968 (NCT05041309).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Relapsed/Refractory Chronic Lymphocytic Leukemia and Relapsed/Refractory Small Lymphocytic Lymphoma

Intervention

• Biological: brexucabtagene autoleucel
  CAR-transduced autologous T cells administered intravenously
  Other Name: KTE-X19
• Drug: Fludarabine
  Administered intravenously
• Drug: Cyclophosphamide
  Administered intravenously

Study Arms

• Experimental: First Stage Cohort 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg
  Participants with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) will receive conditioning chemotherapy (fludarabine 30 mg/m^2/day over 30 minutes and cyclophosphamide 500 mg/m^2/day over 30-60 minutes) on Days -5 to -3 with 2 rest days, followed by single infusion of brexucabtagene autoleucel 1 x 10^6 anti-cluster of differentiate 19 (CD19) chimeric antigen receptor (CAR) T cells/kg on Day 0.
  Interventions:

  • Biological: brexucabtagene autoleucel
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
• Experimental: First Stage Cohort 2: 2 x 10^6 Anti-CD19 CAR T Cells/kg
  Participants with r/r CLL will receive conditioning chemotherapy (fludarabine 30 mg/m^2/day over 30 minutes and cyclophosphamide 500 mg/m^2/day over 30-60 minutes) on Days -5 to -3 with 2 rest days, followed by single infusion of brexucabtagene autoleucel 2 x 10^6 anti-CD19 CAR T cells/kg on Day 0.
  Interventions:

  • Biological: brexucabtagene autoleucel
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
• Experimental: Second Stage Cohort 3: 1 x 10^6 Anti-CD19 CAR T Cells/kg
  Participants with r/r CLL and small lymphocytic lymphoma (SLL) with ≤1% malignant cells in peripheral blood or absolute lymphocyte count (ALC) < 5,000 cells/μL will receive conditioning chemotherapy (fludarabine 30 mg/m^2/day over 30 minutes and cyclophosphamide 500 mg/m^2/day over 30-60 minutes) on Days -5 to -3 with 2 rest days, followed by single infusion of brexucabtagene autoleucel 1 x 10^6 anti-CD19 CAR T cells/kg on Day 0.
  Interventions:

  • Biological: brexucabtagene autoleucel
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
• Experimental: Second Stage Cohort 4A: 1 x 10^6 Anti-CD19 CAR T Cells/kg
  Participants with r/r CLL who previously received two lines of therapy along with ibrutinib with or without anti CD20 antibodies, B-cell lymphoma 2 (BCL-2) and Phosphoinositide 3-kinase (PI3k) inhibitors will receive ibrutinib up to 30 hours prior to leukapheresis along with conditioning chemotherapy (fludarabine 30 mg/m^2/day over 30 minutes and cyclophosphamide 500 mg/m^2/day over 30-60 minutes) on Days -5 to -3 with 2 rest days, followed by single infusion of brexucabtagene autoleucel 1 x 10^6 anti-CD19 CAR T cells/kg on Day 0.
  Interventions:

  • Biological: brexucabtagene autoleucel
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
• Experimental: Second Stage Cohort 4B: 2 x 10^6 Anti-CD19 CAR T Cells/kg

  Participants with r/r CLL who previously received two lines of therapy along with ibrutinib with or without anti CD20 antibodies, BCL-2 and PI3k inhibitors will receive ibrutinib up to 30 hours prior to leukapheresis along with conditioning chemotherapy (fludarabine 30 mg/m^2/day over 30 minutes and cyclophosphamide 500 mg/m^2/day over 30-60 minutes) on Days -5 to -3 with 2 rest days, followed by single infusion of brexucabtagene autoleucel 2 x 10^6 anti-CD19 CAR T cells/kg on Day 0.

  Upon completion of Cohort 4A, it was determined not to enroll participants in Cohort 4B.

  Interventions:

  • Biological: brexucabtagene autoleucel
  • Drug: Fludarabine
  • Drug: Cyclophosphamide

• Publications *: Davids MS, Kenderian SS, Flinn IW, Hill BT, Maris M, Ghia P, et al. ZUMA-8: A Phase 1 Study of KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy, in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia. Blood. 2022;140:7454-6.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 18, 2021): 16
• Original Estimated Enrollment (submitted: August 7, 2018): 108
• Actual Study Completion Date: November 18, 2022
• Actual Primary Completion Date: February 12, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Documentation of relapsed or refractory CLL and SLL; must have received at least 2 prior lines of treatment, one of which must include a Bruton's tyrosine kinase (BTK) inhibitor.

  • Cohort 1 and 2: Participants with r/r CLL who have received at least 2 prior lines of treatment, one of which must include a BTK inhibitor.
  • Cohort 3: Participants with r/r CLL and SLL must present with ≤ 1% circulating tumor cells in peripheral blood or absolute lymphocyte count (ALC) < 5000 cells/μL. Participants must have received at least 2 prior lines of treatment, one of which must include a BTK inhibitor.
  • Cohort 4: Participants with r/r CLL who have received at least 2 prior lines of treatment and must have received ibrutinib as a single agent or in comibation with anti-cluster of differentiate 20 (CD20) antibodies, B-cell lymphoma 2 (BCL-2) inhibitors, and phosphoinositide 3-kinase inhibitor (PI3k) inhibitors for at least 6 months as the last line of therapy prior to screening. Ibrutinib administration will continue up to 30 hours prior to leukapheresis. In case of treatment interruption with ibrutinib, the principal investigator should reach out to the medical monitor to discuss.
• An indication for treatment per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria and radiographically measurable disease (at least 1 lesion > 1.5 cm in diameter)

• Adequate hematologic function as indicated by:

  • Platelet count ≥ 50 × 10^9/L
  • Neutrophil count ≥ 0.5 × 10^9/L
  • Hemoglobin ≥ 8 g/dL unless lower values are attributable to CLL

• Adequate renal, hepatic, cardiac and pulmonary function defined as:

  • Creatinine clearance (as estimated by Cockcroft-Gault) ≥ 60 mL/min
  • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN)
  • Total bilirubin ≤ 1.5 mg/dL unless participant has Gilbert's syndrome
  • Left ventricular ejection fraction (LVEF) ≥ 50%, no evidence of pericardial effusion, no New York Heart Association (NYHA) class III or IV functional classification, no clinically significant arrhythmias
  • No clinically significant pleural effusion
  • Baseline oxygen saturation > 92% on room air
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy or BTKi (ibrutinib or acalabrutinib) at the time the participant is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy. At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the participant is planned for leukapheresis (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists)

Key Exclusion Criteria:

• A history of treatment including any of the following:

  • Prior cluster of differentiate 19 (CD19) directed therapy
  • Prior allogeneic hematopoietic stem cell transplant (SCT) or donor lymphocyte infusion (DLI) within 6 months prior to enrollment
• History of autoimmune disease resulting in end-organ injury unless attributable to CLL (eg, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA))
• Diagnosis of Richter's transformation or a history of malignancy other than non-melanoma skin cancer or carcinoma in situ (eg, skin, cervix, bladder, breast), superficial bladder cancer, asymptomatic localized low grade prostate cancer for which watch-and-wait approach is standard of care, or any other cancer that has been in remission for > 3 years prior to enrollment
• History of severe hypersensitivity reaction attributed to aminoglycosides

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy, United States
• Removed Location Countries: Germany, Spain

Administrative Information

• NCT Number: NCT03624036
• Other Study ID Numbers: KTE-C19-108; 2018-001923-38 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Gilead Sciences ( Kite, A Gilead Company )
• Original Responsible Party: Same as current
• Current Study Sponsor: Kite, A Gilead Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Kite Study Director; Kite, A Gilead Company

• PRS Account: Gilead Sciences
• Verification Date: October 2023