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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Relapsed/Refractory Chronic Lymphocytic Leukemia and Relapsed/Refractory Small Lymphocytic Lymphoma

Intervention / Treatment
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* Biological: brexucabtagene autoleucel
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First Stage Cohort 1: 1 x 10^6 Anti-CD19 CAR T Cells/kg<br>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. | Biological: brexucabtagene autoleucel<br>* CAR-transduced autologous T cells administered intravenously<br>* Other names: KTE-X19;Drug: Fludarabine<br>* Administered intravenously<br>Drug: Cyclophosphamide<br>* Administered intravenously<br>|
| Experimental: First Stage Cohort 2: 2 x 10^6 Anti-CD19 CAR T Cells/kg<br>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. | Biological: brexucabtagene autoleucel<br>* CAR-transduced autologous T cells administered intravenously<br>* Other names: KTE-X19;Drug: Fludarabine<br>* Administered intravenously<br>Drug: Cyclophosphamide<br>* Administered intravenously<br>|
| Experimental: Second Stage Cohort 3: 1 x 10^6 Anti-CD19 CAR T Cells/kg<br>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. | Biological: brexucabtagene autoleucel<br>* CAR-transduced autologous T cells administered intravenously<br>* Other names: KTE-X19;Drug: Fludarabine<br>* Administered intravenously<br>Drug: Cyclophosphamide<br>* Administered intravenously<br>|
| Experimental: Second Stage Cohort 4A: 1 x 10^6 Anti-CD19 CAR T Cells/kg<br>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. | Biological: brexucabtagene autoleucel<br>* CAR-transduced autologous T cells administered intravenously<br>* Other names: KTE-X19;Drug: Fludarabine<br>* Administered intravenously<br>Drug: Cyclophosphamide<br>* Administered intravenously<br>|
| Experimental: Second Stage Cohort 4B: 2 x 10^6 Anti-CD19 CAR T Cells/kg<br>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. | Biological: brexucabtagene autoleucel<br>* CAR-transduced autologous T cells administered intravenously<br>* Other names: KTE-X19;Drug: Fludarabine<br>* Administered intravenously<br>Drug: Cyclophosphamide<br>* Administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Per Investigator Review Assessed by International Workshop on CLL (IWCLL) 2018 Criteria | 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. | First infusion date up to last follow up visit (maximum duration: 42 months) | 
| Percentage of Participants Experiencing 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 were defined as AEs with onset on or after the initiation of brexucabtagene autoleucel infusion. | First infusion date up to last follow up visit (maximum duration: 42 months) | 
| Peak Level of Anti-CD19 CAR T-Cells in Blood | Peak was defined as the maximum number of CAR T cells measured post-infusion. | First infusion date up to 3 months post-infusion (approximately 3 months) |