A Study Evaluating the Safety and Efficacy of Brexucabtagene Autoleucel (KTE-X19) in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ZUMA-3)

Kite, A Gilead Company125 enrolled

Overview

The primary objectives of this study are to determine the safety and efficacy of brexucabtagene autoleucel (KTE-X19) in adult participants with relapsed/refractory (r/r) B-precursor acute lymphoblastic leukemia (ALL).

Bridging therapy could be administered at the discretion of the investigator and is recommended for participants with high disease burden at baseline (M3 marrow \[\> 25% leukemic blasts\] or ≥ 1,000 blasts/mm\^3 in the peripheral circulation) to control participant's disease prior to conditioning chemotherapy. Bridging therapy includes: Attenuated VAD: Vincristine non-liposomal (1-2 mg IV weekly) or liposomal (2.25 mg/m\^2 IV weekly), and dexamethasone 20-40 mg IV or oral administration (PO) daily x 3-4 days per week. Optional doxorubicin 50 mg/m\^2 IV x 1 (first week only). Mercaptopurine (6-MP): 50-75 mg/m\^2/day by mouth (administer at bedtime on an empty stomach to improve absorption). Hydroxyurea: Doses titrated between 15-50 mg/kg/day (rounded to the nearest 500 mg capsule and given as a single daily oral dose on a continuous basis). DOMP: Dexamethasone 6 mg/m\^2/day PO (or IV) divided twice daily (BID) Days 1-5, vincristine 1.5 mg/m\^2 (maximum dose 2 mg) IV on Day 1, methotrexate 20 mg/m\^2 PO weekly, 6-MP 50- 75mg/m\^2/day PO daily. Attenuated FLAG/FLAG-IDA: fludarabine 30 mg/m\^2 IV days 1-2, cytarabine 2 g/m\^2 IV days 1-2, G-CSF 5 μg/kg subcutaneously (SC) or IV starts on Day 3 and can continue until day before the start of conditioning chemotherapy. With or without idarubicin 6 mg/m\^2 IV Days 1-2. Mini-hyper CVAD (courses A and/or B): * Course A: Cyclophosphamide 150 mg/m\^2 every 12 hours x 3 days, dexamethasone 20 mg/d IV or PO daily Days 1-4 and 11-14, vincristine 2 mg IV x 1 * Course B: Methotrexate 250 mg/m\^2 IV over 24 hours on Day 1,cytarabine 0.5 g/m\^2 IV every 12 hours x 4 doses on Days 2 and 3. After completion of the Month 24 visit, subjects who received an infusion of KTE-X19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

125

Conditions

Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

Interventions

brexucabtagene autoleucelBIOLOGICAL

A single infusion of brexucabtagene autoleucel CAR transduced autologous T cells administered intravenously.

CyclophosphamideDRUG

Administered intravenously.

FludarabineDRUG

Administered intravenously.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: 1. Relapsed or refractory B-precursor ALL defined as one of the following: * Primary refractory disease * First relapse if first remission ≤ 12 months * Relapsed or refractory disease after 2 or more lines of systemic therapy * Relapsed or refractory disease after allogeneic transplant provided individuals is at least 100 days from stem cell transplant at the time of enrollment 2. Morphological disease in the bone marrow (≥ 5% blasts) 3. Individuals with Philadelphia chromosome positive (Ph+) disease are eligible if they are intolerant to tyrosine kinase inhibitor (TKI) therapy, or if they have relapsed/refractory disease despite treatment with at least 2 different TKIs 4. Eastern cooperative oncology group (ECOG) performance status of 0 or 1 5. Adequate renal, hepatic, pulmonary and cardiac function defined as: * Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 cc/min * Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 x 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, and no clinically significant arrhythmias * Baseline oxygen saturation \> 92% on room air 6. In individuals previously treated with blinatumomab, cluster of differentiation 19 (CD19) tumor expression in bone marrow or peripheral blood. Key Exclusion Criteria: 1. Diagnosis of Burkitt's leukemia/lymphoma according to World Health Organization (WHO) classification or chronic myelogenous leukemia lymphoid blast crisis 2. History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years 3. Isolated extramedullary disease 4. Central nervous system (CNS) abnormalities * Presence of CNS-3 disease or CNS-2 disease with neurological changes * History or presence of any CNS disorder such as a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement 5. History of concomitant genetic syndrome such as Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome or any other known bone marrow failure syndrome 6. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment 7. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment. 8. Primary immunodeficiency 9. Known infection with human immunodeficiency virus (HIV), hepatitis B (HBsAg positive) or hepatitis C virus. 10. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. 11. Prior medication: * Salvage chemotherapy including TKIs for Ph+ ALL within 1 week prior to enrollment * Prior CD19 directed therapy other than blinatumomab * Treatment with alemtuzumab within 6 months prior to leukapheresis, or treatment with clofarabine or cladribine within 3 months prior to leukapheresis * Donor lymphocyte infusion (DLI) within 28 days prior to enrollment * Any drug used for graft-versus-host disease (GVHD) within 4 weeks prior to enrollment * At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy prior to enrollment * Corticosteroid therapy for 7 days prior to enrollment 12. Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Ommaya reservoirs and dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted 13. Acute GVHD grade II-IV by Glucksberg criteria or severity B-D by International Bone Marrow Transplant Registry (IBMTR) index; acute or chronic GVHD requiring systemic treatment within 4 weeks prior to enrollment 14. Live vaccine ≤ 4 weeks prior to enrollment 15. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential 16. Individuals of both genders of child-bearing potential who are not willing to practice birth control from the time of consent through 6 months after the completion of brexucabtagene autoleucel (KTE-X19) 17. In the investigators judgment, the individuals is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation 18. History of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Locations (33)

Outcomes

Primary Outcomes

Phase 1: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)

DLT is drug-related events with onset within first 28 days following infusion: * Grade (GR) 4 hematologic toxicity lasting more than 30 days (except lymphopenia) if not attributable to underlying disease * All 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/baseline within 2 weeks or baseline within 4 weeks, fever GR 3/ 4, immediate hypersensitivity reactions within 2 hours of drug infusion that are reversible ≤ GR 2 within 24 hours, renal toxicity which requires dialysis for ≤ 7 days, intubation for airway protection if ≤ 7 days, tumor lysis syndrome, GR 3 liver function test elevation, provided there is resolution to ≤ GR 2 within 14 days, GR 4 transient serum hepatic enzyme abnormalities provided there is resolution to ≤ GR 3 within \< 72 hours, hypogammaglobulinemia GR 3/ 4 and GR 3 nausea and/or anorexia).

Time frame: First infusion date of brexucabtagene autoleucel up to 28 days. Participants were evaluated in specified period but GR4 hematologic toxicity (specified in description) having onset in this period were further observed for 30 days for confirmation

Phase 2: Overall Complete Remission (OCR) Rate (Complete Remission [CR]+ Complete Remission With Incomplete Hematologic Recovery [CRi]) as Assessed Per Independent Review

OCR rate:percentage of participants achieving CR+CRi.CR: ≤5% blasts by morphology in bone marrow(BM);absolute neutrophil count(ANC)≥1000/microliters (μL) and platelets(Plt) ≥100000/μL in peripheral blood(PB);central nervous system extramedullary disease(CNS EMD) of CNS-1(no detectable leukemia in cerebrospinal fluid\[CSF\]);Non-CNS baselineEMD:if present(images shows CR),if no(images not needed),if performed shows negative positron emission tomography(PET) baseline,baseline lesions shows CR as disappearance of measurable and nonmeasurable nodal lesions(Nodal masses \>1.5 cm in greatest transverse diameter\[GTD\] at baseline have regressed to ≤l.5 cm GTD,nodes that were 1.1 to 1.5 cm\[long axis\] and \>1.0 cm\[short axis\] have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size) and no new lesions.CRi:all CR criteria except in PB ANC≥1000/μL and Plt\<100000/μL or ANC\<1000/μL and Plt ≥100000/μL.95% confidence interval (CI) was calculated by Clopper-Pearson method.

Time frame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years

Data from ClinicalTrials.gov

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Secondary Outcomes

Phase 2: Minimum Residual Disease (MRD) Negative Remission Rate

MRD was assessed utilizing multicolor flow cytometry to detect residual cancerous cells with a sensitivity of 10\^-4. MRD negative remission was defined as MRD \< 10\^-4 threshold. Percentage of participants with MRD negative remission was reported. 95% CI was calculated by Clopper-Pearson method.

Time frame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years

Phase 2: Complete Remission (CR) Rate Per Independent Review

CR: ≤ 5% blasts by morphology in BM; ANC ≥ 1000/µL and Plt ≥ 100000/µL in PB; CNS EMD of CNS-1 (no detectable leukemia in CSF); Non-CNS EMD: if baseline EMD present (images must show CR), if no baseline EMD (then images not required), but if performed should show negative PET baseline, baseline lesions must show CR as disappearance of measurable and nonmeasurable nodal lesions (Nodal masses \> 1.5 cm in GTD at baseline must have regressed to ≤ l.5 cm GTD, nodes that were 1.1 to 1.5 cm \[long axis\] and \> 1.0 cm \[short axis\] must have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size) and no new lesions. Percentage of participants with CR was reported. 95% CI was calculated by Clopper-Pearson method.

Time frame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years

Phase 2: Complete Remission With Incomplete Hematologic Recovery (CRi) Rate Per Independent Review

CRi: ≤ 5% blasts by morphology in BM; ANC ≥ 1000/µL and Plt \< 100000/µL or ANC \< 1000/µL and Plt ≥ 100000/µL in PB; CNS EMD of CNS-1 (no detectable leukemia in CSF); Non-CNS EMD: if baseline EMD present (images must show CR), if no baseline EMD (then images not required), but if performed should show negative PET baseline, baseline lesions must show CR as disappearance of measurable and nonmeasurable nodal lesions (Nodal masses \> 1.5 cm in GTD at baseline must have regressed to ≤ l.5 cm GTD, nodes that were 1.1 to 1.5 cm \[long axis\] and \> 1.0 cm \[short axis\] must have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size, if tested) and no new lesions. Percentage of participants with CRi was reported. 95% CI was calculated by Clopper-Pearson method.

Time frame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years

Phase 2: Duration of Remission (DOR) Per Independent Review

DOR was defined as the time from first CR or CRi to relapse or any death in the absence of documented relapse. CR and CRi are defined in Outcome Measures 4 and 5. Relapse: ≤ 5% blasts by morphology in BM; or circulating leukemia present in PB; or CNS EMD of CNS-2 (detectable CSF blast cells in a sample of CSF with \< 5 white blood cells \[WBCs\] per mm\^3 with neurological changes) or CNS-3 (detectable CSF blast cells in a sample of CSF with ≥ 5 WBCs per mm\^3 with or without neurological changes); or progressive disease (PD): at least one of the following (≥ 50% increase from nadir in the sum of the products of at least two lymph nodes, or if a single node is involved at least a 50% increase in the product of the diameters of this one node; at least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis; ≥ 50% increase in size of splenic, hepatic or any other non-nodal lesion). Kaplan-Meier (KM) estimates was used for analyses.

Time frame: From first CR or CRi (Phase 2) up to 3.7 years

Phase 2: OCR Rate (CR + CRi) Per Investigator Review

OCR rate: percentage of participants achieving CR+CRi. CR: ≤ 5% blasts by morphology in BM; ANC ≥1000/µL and Plt ≥ 100000/µL in PB; CNS EMD of CNS-1 (no detectable leukemia in CSF); Non-CNS EMD: if baseline EMD present (images must show CR), if no baseline EMD (then images not required), but if performed should show negative PET baseline, baseline lesions must show CR as disappearance of measurable and nonmeasurable nodal lesions (Nodal masses \>1.5 cm in GTD at baseline must have regressed to ≤l.5 cm GTD, nodes that were 1.1 to 1.5 cm \[long axis\] and \>1.0 cm \[short axis\] must have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size, if tested) and no new lesions. CRi: all CR criteria except in PB ANC ≥1000/µL and Plt \<100000/µL or ANC \<1000/µL and Plt ≥100000/µL. 95% CI was calculated by Clopper-Pearson method.

Time frame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 5 years

Phase 2: Percentage of Participants With Allogeneic Stem Cell Transplant (Allo-SCT)

Time frame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 5 years

Phase 2: MRD Negative Remission Rate Among Complete Remission (CR) Participants

Percentage of participants with MRD negative remission among CR participants was reported. MRD was assessed utilizing multicolor flow cytometry to detect residual cancerous cells with a sensitivity of 10\^-4. MRD negative remission was defined as MRD \< 10\^-4 threshold. CR: ≤5% blasts by morphology in BM; ANC ≥ 1000/µL and Plt ≥ 100000/µL in PB; CNS EMD of CNS-1 (no detectable leukemia in CSF); Non-CNS EMD: if baseline EMD present (images must show CR), if no baseline EMD (then images not required), but if performed should show negative PET baseline, baseline lesions must show CR as disappearance of measurable and nonmeasurable nodal lesions (Nodal masses \> 1.5 cm in GTD at baseline must have regressed to ≤ l.5 cm GTD, nodes that were 1.1 to 1.5 cm \[long axis\] and \> 1.0 cm \[short axis\] must have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size) and no new lesions. 95% CI was calculated by Clopper-Pearson method.

Time frame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years

Phase 2: MRD Negative Remission Rate Among Complete Remission With Incomplete Hematologic Recovery (CRi) Participants

Percentage of participants with MRD negative remission among CRi participants was reported. MRD was assessed utilizing multicolor flow cytometry to detect residual cancerous cells with a sensitivity of 10\^-4. MRD negative remission was defined as MRD \< 10\^-4 threshold. CRi: ≤ 5% blasts by morphology in BM; ANC ≥ 1000/µL and Plt \< 100000/µL or ANC \< 1000/µL and Plt ≥ 100000/µL in PB; CNS EMD of CNS-1 (no detectable leukemia in CSF); Non-CNS EMD: if baseline EMD present (images must show CR), if no baseline EMD (then images not required), but if performed should show negative PET baseline, baseline lesions must show CR as disappearance of measurable and nonmeasurable nodal lesions (Nodal masses \>1.5 cm in GTD at baseline must have regressed to ≤l.5 cm GTD, nodes that were 1.1 to 1.5 cm \[long axis\] and \>1.0 cm \[short axis\] must have decreased to 1.0 cm in their short axis, spleen and/or liver must be normal size) and no new lesions. 95% CI was calculated by Clopper-Pearson method.

Time frame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years

Phase 2: Overall Survival (OS)

OS was defined as the time from brexucabtagene autoleucel infusion to the date of death from any cause. Participants who had not died by the analysis data cutoff date were censored at their last contact date. KM estimates was used for analyses.

Time frame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 5 years

Phase 2: Relapse-free Survival (RFS)

RFS: time from brexucabtagene autoleucel infusion to date of disease relapse or death from any cause. Participants not meeting criteria for relapse by the analysis data cutoff date were censored at their last evaluable disease assessment date. Participants who had not achieved a CR or CRi at analysis data cutoff were evaluated as an RFS event at Day 0. CR and CRi are defined in Outcome Measures 4 and 5. Relapse is defined in Outcome Measure 6. KM estimates was used for analyses.

Time frame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years

Phase 2: Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs)

An AE was any untoward medical occurrence in a participant after brexucabtagene autoleucel infusion, which did not necessarily have a causal relationship with the treatment. An AE could therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. TEAEs included all AEs with onset on or after initiation of the brexucabtagene autoleucel infusion.

Time frame: Up to 5 years

Phase 2: Number of Participants Experiencing Laboratory Toxicity Grade 3 or Higher TEAEs Resulting From Increased Parameter Value

Grading categories are determined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening.

Time frame: Up to 5 years

Phase 2: Number of Participants Experiencing Laboratory Toxicity Grade 3 or Higher TEAEs Resulting From Decreased Parameter Value

Grading categories are determined by CTCAE version 4.03. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening.

Time frame: Up to 5 years

Phase 2: Percentage of Participants With Anti-KTE-X19 Antibodies

Time frame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 2.7 years

Phase 2: Number of Participants With 5-Level European Quality of Life-5 Dimensions (EQ-5D-5L): Health Utility Index Scale

The EQ-5D-5 levels(EQ-5D-5L)is a standardized measure of health status of the participant that provides a simple, generic measure of health for clinical and economic appraisal.It is a self-reported questionnaire used to assess the overall health status of participant scoring 5 dimensions of health: mobility,self-care,usual activities,pain/discomfort and anxiety/depression.Each dimension has 5 levels:no problems,slight problems,moderate problems,severe problems,and extreme problems.EQ-5D health states, defined by the EQ-5D descriptive system, are converted into a single summary index by a formula that attaches values (called QOL utilities)to each of the levels in each dimension.EQ-5D Summary Index values range from -0.11(worst health) to 1.00(perfect health).This decision results in a 1-digit number that shows the level for that dimension. The digits for 5 dimensions can be combined to 5-digit number that show the participant's health.Higher scores of EQ-5D-5L indicate better health.

Time frame: Baseline, Day 28, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, and Month 24

Phase 2: EQ-5D Visual Analogue Scale (VAS) Score

EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant. The EQ-5D is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The EQ-5D-VAS records the participant's self-rated health on a 20-cm vertical visual analogue scale and is asked to make a global assessment of their current state of health with 0 indicating the worst health they can imagine and 100 indicating the best health they can imagine. Higher scores indicated a better health state.

Time frame: Baseline, Day 28, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, and Month 24