Study Evaluating the Safety and Efficacy of KTE-C19 in Adult Participants With Refractory Aggressive Non-Hodgkin Lymphoma (ZUMA-1)

Gilead Sciences

Status and phase

Completed

Phase 2

Phase 1

Conditions

High Grade B-cell Lymphoma (HGBCL)

Refractory Diffuse Large B Cell Lymphoma (DLBCL)

Relapsed Diffuse Large B-Cell Lymphoma

Transformed Follicular Lymphoma (TFL)

Primary Mediastinal B-cell Lymphoma (PMBCL)

Treatments

Drug: Bendamustine

Drug: Levetiracetam

Drug: Cyclophosphamide

Drug: Fludarabine

Drug: Etoposide

Biological: Axicabtagene Ciloleucel

Drug: Doxorubicin

Drug: Gemcitabine

Drug: Dexamethasone

Drug: Prednisone

Drug: Tocilizumab

Drug: Oxaliplatin

Drug: Carboplatin

Drug: High-dose methylprednisolone

Drug: Vincristine

Drug: Methylprednisolone

Drug: Ifosfamide

Drug: Cisplatin

Drug: Rituximab

Study type

Interventional

Funder types

Industry

Identifiers

NCT02348216

2015-005007-86 (EudraCT Number)

KTE-C19-101

Details and patient eligibility

About

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.

Enrollment

307 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria

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)
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
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.
At least one measurable lesion per revised international working group (IWG Response Criteria
Eastern cooperative oncology group (ECOG) performance status of 0 or 1
Absolute neutrophil count (ANC) ≥ 1000/microliters (uL)
Absolute lymphocyte count ≥ 100/uL
Platelet count ≥ 75,000/uL
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
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.
Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and HGBCL after two systemic lines of therapy

Key Exclusion Criteria

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
History of allogeneic stem cell transplantation
Prior chimeric antigen receptor (CAR) therapy or other genetically modified T cell therapy
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
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
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
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.

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Sequential Assignment

Masking

None (Open label)

307 participants in 7 patient groups

Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy

Experimental group

Description:

Participants with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) will receive conditioning chemotherapy (fludarabine 30 mg/m\^2 intravenously \[IV\] over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel chimeric antigen receptor (CAR) transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of body weight (BW) on Day 0.

Treatment:

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Phase 2 (Pivotal Study): Cohort 1

Experimental group

Description:

Participants with refractory DLBCL will receive conditioning chemotherapy (fludarabine 30 mg/m\^2 IV over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0.

Treatment:

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Phase 2 (Pivotal Study): Cohort 2

Experimental group

Description:

Participants with refractory PMBCL or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m\^2 IV over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0.

Treatment:

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Phase 2 (Safety Management Study): Cohort 3

Experimental group

Description:

Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL will receive conditioning chemotherapy (fludarabine 30 mg/m\^2 IV over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0) and tocilizumab (8 mg/kg IV over 1 hour (not to exceed 800 mg)) on Day 2).

Treatment:

Drug: Tocilizumab

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Drug: Levetiracetam

Phase 2 (Safety Management Study): Cohort 4

Experimental group

Description:

Participants with r/r DLBCL,PMBCL,TFL,or high-grade B-cell lymphoma(HGBCL)after 2 systemic lines of therapy will receive optional bridging therapy(dexamethasone 20mg to 40mg,eitherorally or IV daily for 1 to 4 days or 1g/m\^2 of high-dose methylprednisolone(HDMP)for 3 days with rituximab at 375mg/m\^2 weekly for 3 weeks or bendamustine 90 mg/m\^2 on Days 1 and 2 and rituximab 375mg/m\^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m\^2 IV and cyclophosphamide 500mg/m\^2 IV)on Days -5,-4, and -3;followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW. Participants will receive a prophylactic regimen of levetiracetam(750 mg orally or IV twice daily(BID)starting on Day 0).Participants will receive tocilizumab(initiated on persistent Grade 1 cytokine release syndrome(CRS)for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).

Treatment:

Drug: Rituximab

Drug: High-dose methylprednisolone

Drug: Tocilizumab

Drug: Dexamethasone

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Drug: Bendamustine

Drug: Levetiracetam

Phase 2 (Safety Management Study): Cohort 5

Experimental group

Description:

Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy will receive debulking therapy (R-CHOP:rituximab 375mg/m\^2 D1,doxorubicin 50mg/m\^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m\^2 D1,vincristine 1.4 mg/m\^2 D1 or R-ICE:rituximab 375mg/ m\^2 D1,ifosfamide 5g/m\^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m\^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m\^2 D1,gemcitabine 1000mg/m\^2 D2,oxaliplatin 100mg/m\^2 D2 or R-GDP:rituximab 375mg/m\^2 D1 or D8,gemcitabine 1g/m\^2 D1 \& D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m\^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m\^2 IV and cyclophosphamide 500mg/m\^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants will also receive a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day.

Treatment:

Drug: Cisplatin

Drug: Rituximab

Drug: Ifosfamide

Drug: Vincristine

Drug: Carboplatin

Drug: Oxaliplatin

Drug: Prednisone

Drug: Gemcitabine

Drug: Doxorubicin

Drug: Etoposide

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Drug: Levetiracetam

Phase 2 (Safety Management Study): Cohort 6

Experimental group

Description:

Participants with r/r DLBCL,PMBCL,TFL orHGBCL after 2 systemic lines of therapy may receive bridging therapy(dexamethasone 20mg to 40mg,orally or IV daily for 1 to 4 days or 1g/m\^2 HDMP for 3 days with rituximab at 375mg/m\^2 weekly for 3 weeks or bendamustine 90 mg/m\^2 on Days 1 and 2 and rituximab 375mg/m\^2 on Day 1),conditioning chemotherapy(fludarabine 30mg/m\^2 IV and cyclophosphamide 500mg/m\^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0.Participants will also receive a prophylactic regimen of levetiracetam 750 mg orally or IV twice daily(BID)starting on Day 0)and corticosteroids(dexamethasone, 10 mg once daily on Days 0, 1, and 2).Participants will receive tocilizumab(initiated on persistent Grade 1 CRS for over 24 hours)and dexamethasone(persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity).

Treatment:

Drug: Rituximab

Drug: Methylprednisolone

Drug: High-dose methylprednisolone

Drug: Tocilizumab

Drug: Dexamethasone

Drug: Fludarabine

Biological: Axicabtagene Ciloleucel

Drug: Cyclophosphamide

Drug: Bendamustine

Drug: Levetiracetam

Trial documents