Clinical trial NCT02614066: 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)
Official title: A Phase 1/2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-X19 in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r ALL) (ZUMA-3)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2015-11-25
Enrollment: 125
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)
timeFrame: 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
measure: Phase 2: Overall Complete Remission (OCR) Rate (Complete Remission [CR]+ Complete Remission With Incomplete Hematologic Recovery [CRi]) as Assessed Per Independent Review
timeFrame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years
Secondary outcomes:
measure: Phase 2: Minimum Residual Disease (MRD) Negative Remission Rate
timeFrame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years
measure: Phase 2: Complete Remission (CR) Rate Per Independent Review
timeFrame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years
measure: Phase 2: Complete Remission With Incomplete Hematologic Recovery (CRi) Rate Per Independent Review
timeFrame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years
measure: Phase 2: Duration of Remission (DOR) Per Independent Review
timeFrame: From first CR or CRi (Phase 2) up to 3.7 years
measure: Phase 2: OCR Rate (CR + CRi) Per Investigator Review
timeFrame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 5 years
measure: Phase 2: Percentage of Participants With Allogeneic Stem Cell Transplant (Allo-SCT)
timeFrame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 5 years
measure: Phase 2: MRD Negative Remission Rate Among Complete Remission (CR) Participants
timeFrame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years
measure: Phase 2: MRD Negative Remission Rate Among Complete Remission With Incomplete Hematologic Recovery (CRi) Participants
timeFrame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years
measure: Phase 2: Overall Survival (OS)
timeFrame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 5 years
measure: Phase 2: Relapse-free Survival (RFS)
timeFrame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 3.7 years
measure: Phase 2: Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to 5 years
measure: Phase 2: Number of Participants Experiencing Laboratory Toxicity Grade 3 or Higher TEAEs Resulting From Increased Parameter Value
timeFrame: Up to 5 years
measure: Phase 2: Number of Participants Experiencing Laboratory Toxicity Grade 3 or Higher TEAEs Resulting From Decreased Parameter Value
timeFrame: Up to 5 years
measure: Phase 2: Percentage of Participants With Anti-KTE-X19 Antibodies
timeFrame: First infusion date of brexucabtagene autoleucel (Phase 2) up to 2.7 years
measure: Phase 2: Number of Participants With 5-Level European Quality of Life-5 Dimensions (EQ-5D-5L): Health Utility Index Scale
timeFrame: Baseline, Day 28, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, and Month 24
measure: Phase 2: EQ-5D Visual Analogue Scale (VAS) Score
timeFrame: Baseline, Day 28, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, and Month 24
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UC San Diego-Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles (UCLA)
state: California
city: Orange
country: United States
facility: University of California Irvine Medical Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Loyola University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: University of MD Greenbaum Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
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: New York
country: United States
facility: Mount Sinai Tisch Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: University of Rochester
state: New York
city: Nashville
country: United States
facility: Sarah Cannon
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor Charles A. Sammons Cancer Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Seattle
country: United States
facility: Seattle Cancer Center
state: Washington
city: Toronto
country: Canada
facility: University Health Network - Princess Margaret
state: Ontario
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Paris
country: France
facility: Hopital Saint Louis
city: Pessac
country: France
facility: Hopital Haut-Leveque
city: Rennes
country: France
facility: Hopital Pontchaillou - CHU de Rennes - Service d'Hematologie
city: Frankfurt
country: Germany
facility: Universitatsklinikum Frankfurt
city: München
country: Germany
facility: Klinikum der Universitat Munchen
city: Würzburg
country: Germany
facility: Universitaetsklinikum Wuerzburg
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
Study officials:
affiliation: Kite, A Gilead Company
name: Kite Study Director
role: STUDY_DIRECTOR
References:
citation: Oluwole OO, Shah BD, Baer MR, Bishop MR, Holmes H, Schiller GJ, et al. Outcomes of Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia Treated with Prior Blinatumomab in ZUMA-3, a Study of KTE-C19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy [Abstract S1569]. The 23rd European Hematology Association (EHA) Congress 2018 14-17 June; Stockholm, Sweden.
citation: Sabatino M, Choi K, Chiruvolu V, Better M. Production of Anti-CD19 CAR T Cells for ZUMA-3 and -4: Phase 1/2 Multicenter Studies Evaluating KTE-C19 in Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R ALL) [Abstract 711]. Blood 2016;128 (22):1227.
citation: Shah B, Castro J, Gokbuget N, Kersten MJ, Hagenbeek T, Wierda W, et al. ZUMA-3: A Phase 1/2 Multi-center Study Evaluating the Safety and Efficacy of KTE-C19 Anti-CD19 CAR T Cells in Adult Subjects with Relapsed/Refractory B Precursor Acute Lymphoblastic Leukemia (r/r ALL). European Society for Medical Oncology (ESMO) Congress 2016;Abstract 3713.
citation: Shah B, Huynh V, Sender LS, Lee DW, Castro JE, Wierda WG, et al. High Rates of Minimal Residual Disease-Negative (MRD-) Complete Responses (CR) in Adult and Pediatric and Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL) Treated With KTE-C19 (Anti-CD19 Chimeric Antigen Receptor [CAR] T Cells): Preliminary Results of the ZUMA-3 and ZUMA-4 Trials. Blood 2016;128 (22):2803.
citation: Shah B, Stock W, Wierda W, Topp M, Kersten MJ, Houot R, et al. KTE-C19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T cell Therapy in Adult Patients (Pts) With Relapsed/ Refractory Acute Lymphoblastic Leukemia (R/R ALL) in the ZUMA-3 Trial: Preliminary Results of Novel Safety Interventions [Abstract ALL-025]. Clinical lymphoma, myeloma & leukemia 2017;17:S253.
citation: Shah B, Stock W, Wierda W, Topp MS, Kersten MJ, Houot R, et al. Preliminary Results of Novel Safety Interventions in Adult Patients (Pts) With Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL) in the ZUMA-3 Trial. European Society for Medical Oncology (ESMO) Congress 2017.
citation: Shah B, Wierda WG, Schiller GJ, Bishop MR, Castro JE, Sabatino M, et al. KTE-C19 Chimeric Antigen Receptor (CAR) T Cell Therapy in Adults with High-Burden Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL): Updated Results from Phase 1/2 of ZUMA-3 [Abstract P523]. The 22nd European Hematology Association (EHA) Congress 2017 22-25 June; Madrid, Spain.
citation: Shah BD, Bishop MR, Oluwole OO, Logan A, Baer MR, Donnellan WB, et al. End of Phase I Results of ZUMA-3, A Phase 1/2 Study of KTE-X19, Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Adult Patients (pts) with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL) [Abstract]. J Clin Oncol 2019;37 (15):7006.
citation: Shah BD, Bishop MR, Oluwole OO, Logan AC, Baer MR, Donnellan WB, et al. KTE-X19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia: End of Phase 1 Results of ZUMA-3 [Abstract PS945]. HemaSphere 2019;3 (S1):426.
citation: Shah BD, Oluwole OO, Baer MR, Bishop MR, Holmes H, Schiller GJ, et al. KTE-C19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Adult Patients with Relapsed/ Refractory Acute Lymphoblastic Leukemia (R/R ALL): Outcomes in Patients Who Were Treated with Prior Blinatumomab in ZUMA-3 [Abstract ALL-128]. Clinical lymphoma, myeloma & leukemia 2018;18 (Supplement 1):S184.
citation: Shah BD, Oluwole OO, Baer MR, Bishop MR, Holmes H, Schiller GJ, et al. Outcomes of Patients Treated With Prior Blinatumomab in ZUMA-3, a Study of KTE-C19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. ASCO; 2018 01-05 June; Chicago, IL.
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citation: Wierda WG, Bishop MR, Oluwole O, Logan AC, Baer MR, Donnellan WB, et al. Updated Phase 1 Results of Zuma-3: Kte-X19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia [Abstract 256]. Biol Blood Marrow Transplant 2019;25 (3):S185.
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citation: Shah BD, Bishop MR, Oluwole OO, Logan AC, Baer MR, Donnellan WB, O'Dwyer KM, Holmes H, Arellano ML, Ghobadi A, Pagel JM, Lin Y, Cassaday RD, Park JH, Abedi M, Castro JE, DeAngelo DJ, Malone AK, Mawad R, Schiller GJ, Rossi JM, Bot A, Shen T, Goyal L, Jain RK, Vezan R, Wierda WG. KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results. Blood. 2021 Jul 8;138(1):11-22. doi: 10.1182/blood.2020009098.
citation: Shah BD, Ghobadi A, Oluwole OO, Logan AC, Boissel N, Cassaday RD, Leguay T, Bishop MR, Topp MS, Tzachanis D, O'Dwyer KM, Arellano ML, Lin Y, Baer MR, Schiller GJ, Park JH, Subklewe M, Abedi M, Minnema MC, Wierda WG, DeAngelo DJ, Stiff P, Jeyakumar D, Feng C, Dong J, Shen T, Milletti F, Rossi JM, Vezan R, Masouleh BK, Houot R. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021 Aug 7;398(10299):491-502. doi: 10.1016/S0140-6736(21)01222-8. Epub 2021 Jun 4.
citation: Shah BD, Smith NJ, Feng C, Jeyakumar S, Castaigne JG, Faghmous I, Masouleh BK, Malone DC, Bishop MR. Cost-Effectiveness of KTE-X19 for Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in the United States. Adv Ther. 2022 Aug;39(8):3678-3695. doi: 10.1007/s12325-022-02201-6. Epub 2022 Jun 21.