Study Evaluating the Safety and Efficacy of KTE-C19 in Adult Participants With Refractory Aggressive Non-Hodgkin Lymphoma
Purpose
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.
Conditions
- Refractory Diffuse Large B Cell Lymphoma (DLBCL)
- Relapsed Diffuse Large B-Cell Lymphoma
- Transformed Follicular Lymphoma (TFL)
- Primary Mediastinal B-cell Lymphoma (PMBCL)
- High Grade B-cell Lymphoma (HGBCL)
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Sex
- All
- Accepts Healthy Volunteers
- No
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) 2. 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 3. 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. 4. At least one measurable lesion per revised international working group (IWG Response Criteria 5. Eastern cooperative oncology group (ECOG) performance status of 0 or 1 6. Absolute neutrophil count (ANC) ≥ 1000/microliters (uL) 7. Absolute lymphocyte count ≥ 100/uL 8. Platelet count ≥ 75,000/uL 9. 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 10. 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. 11. Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and HGBCL after two systemic lines of therapy
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 2. History of allogeneic stem cell transplantation 3. Prior chimeric antigen receptor (CAR) therapy or other genetically modified T cell therapy 4. 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 5. 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 6. 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 7. 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.
Study Design
- Phase
- Phase 1/Phase 2
- Study Type
- Interventional
- Allocation
- Non-Randomized
- Intervention Model
- Sequential Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
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Experimental Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy |
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. |
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Experimental Phase 2 (Pivotal Study): Cohort 1 |
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. |
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Experimental Phase 2 (Pivotal Study): Cohort 2 |
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. |
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Experimental Phase 2 (Safety Management Study): Cohort 3 |
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). |
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Experimental Phase 2 (Safety Management Study): Cohort 4 |
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). |
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Experimental Phase 2 (Safety Management Study): Cohort 5 |
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. |
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Experimental Phase 2 (Safety Management Study): Cohort 6 |
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). |
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More Details
- Status
- Completed
- Sponsor
- Kite, A Gilead Company