Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma

Overview

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

Full Title of Study: “A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma”

Study Type

  • Study Type: Interventional
  • Study Design
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: August 2020

Interventions

  • Biological: Axicabtagene Ciloleucel
    • A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg.
  • Drug: Fludarabine
    • Administered according to package insert
  • Drug: Cyclophosphamide
    • Administered according to package insert

Arms, Groups and Cohorts

  • Experimental: Axicabtagene Ciloleucel
    • A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, axicabtagene ciloleucel.

Clinical Trial Outcome Measures

Primary Measures

  • Phase 1 Study: Percentage of Participants Experiencing Adverse Events defined as Dose Limiting Toxicities (DLTs)
    • Time Frame: Up to 30 Days
    • Dose-limiting toxicity is defined as protocol-defined axicabtagene ciloleucel related events with onset within the first 30 days following axicabtagene ciloleucel infusion.
  • Phase 2 Pivotal Study: Overall Response Rate (ORR)
    • Time Frame: Up to 12 months
    • ORR is defined as the incidence of either a complete response (CR) or a partial response (PR) per the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma as determined by the study investigators.
  • Phase 2 Safety Management Study: Incidence and Severity of CRS and Neurologic Toxicities
    • Time Frame: Up to 12 months

Secondary Measures

  • Duration of Response (DOR)
    • Time Frame: Up to 12 months
    • Among participants who experience an objective response, DOR is defined as the date of their first objective response (which is subsequently confirmed) to disease progression per the revised IWG Response Criteria for Malignant Lymphoma or death regardless of cause.
  • Phase 1 Study: ORR
    • Time Frame: Up to 12 months
    • ORR is defined as the incidence of either a complete response (CR) or a partial response (PR) per the revised IWG Response Criteria for Malignant Lymphoma as determined as determined by the study investigators.
  • Phase 2 Study: ORR per Independent Radiological Review Committee (IRRC)
    • Time Frame: Up to 12 months
    • ORR is defined as the incidence of either a complete response (CR) or a partial response (PR) per the IRRC.
  • Progression-Free Survival (PFS)
    • Time Frame: Up to 12 months
    • PFS is defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per the revised IWG Response Criteria for Malignant Lymphoma or death from any cause.
  • Overall Survival (OS)
    • Time Frame: Up to 24 months
    • OS is defined as the time from axicabtagene ciloleucel infusion to the date of death.
  • Percentage of Participants Experiencing Adverse Events
    • Time Frame: Up to 12 months
  • Percentage of Participants Experiencing Clinically Significant Changes in Safety Lab Values
    • Time Frame: Up to 12 months
  • Percentage of Participants with Anti-Axicabtagene Ciloleucel Antibodies
    • Time Frame: Up to 12 months
  • Pharmacokinetics (Levels of Anti-CD19 CAR T Cells in Blood)
    • Time Frame: Up to 2 years
  • Pharmacodynamics (Levels of Cytokines in Serum)
    • Time Frame: Up to 12 months
  • Phase 2 Safety Management Study: ORR
    • Time Frame: Up to 12 months
    • ORR is defined as the incidence of either a complete response (CR) or a partial response (PR) per the revised IWG Response Criteria for Malignant Lymphoma as determined by study investigators.
  • Phase 2 Safety Management Study: Changes Over Time in the European Quality of Life Five Dimension Five Level Scale (EQ-5D)
    • Time Frame: Up to 5 years
    • The European Quality of Life Five Dimension Five Level Scale (EQ-5D) is a generic measure of health status that provides a simple descriptive profile and a single index value.
  • Phase 2 Safety Management Study: Changes Over Time in the Visual Analogue Scale (VAS) Score
    • Time Frame: Up to 5 years

Participating in This Clinical Trial

Key Inclusion Criteria

1. 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-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 IWG Response Criteria

5. Age 18 or older

6. Eastern cooperative oncology group (ECOG) performance status of 0 or 1

7. Absolute neutrophil count (ANC) ≥ 1000/uL

8. Absolute lymphocyte count ≥ 100/uL

9. Platelet count ≥ 75,000/uL

10. 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

11. 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.

12. Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and HGBCL after two systemic lines of therapy

Key Exclusion Criteria

1. 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 CAR therapy or other genetically modified T cell therapy

4. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment

5. History of 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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Kite, A Gilead Company
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Kite Study Director, Study Director, Kite, A Gilead Company

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