Clinical Trial 18816

Cancer Type: Malignant Hematology
Interventions:Atezolizumab (Tecentriq); Axicabtagene Ciloleucel (KTE-C19); KTE-C19; Not Applicable; cyclophosphamide; cytoxan (cyclophosphamide); fludarabine (Fludarabine phosphate)

Study Type: Treatment
Phase of Study: Phase I/II
Investigators:

  • Frederick Locke

Overview

Study Title

A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 in Combination with Atezolizumab in Subjects with Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Summary

The main purpose of this research study is to determine if the investigational products, KTE-C19 and Atezolizumab, when used concurrently and administered after participants receive a 3 day course of chemotherapy, is safe and effective in treating their disease.

Objective

The primary objective of phase 1 is to evaluate the safety of KTE-C19 and atezolizumab combination regimens. The primary objective of phase 2 is to evaluate the efficacy of KTE-C19 and atezolizumab, as measured by complete response rate in subjects with refractory diffuse large B-cell lymphoma (DLBCL). Secondary objectives will include assessing the safety and tolerability of KTE-C19 and atezolizumab and additional efficacy, biomarker, pharmacokinetic, and anti-therapeutic antibody endpoints.

Inclusion Criteria

  • Histologically proven Diffuse large B cell lymphoma (DLBCL) including the following types defined by World Health Organization (WHO) 2008: DLBCL not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly.
  • Chemotherapy-refractory disease, defined as one or more of the following: No response to first-line therapy (primary refractory disease); potential participants who are intolerant to first-line therapy chemotherapy are excluded; - OR - No response to second or greater lines of therapy - OR - Refractory post-autologous stem cell transplant(ASCT).
  • 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.
  • At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma (Cheson 2007). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
  • MRI of the brain showing no evidence of central nervous system (CNS) lymphoma.
  • At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the participant is planned for leukapheresis.
  • Age 18 years or older at the time of informed consent.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Adequate bone marrow, renal, hepatic, pulmonary and cardiac function.
  • Females of childbearing potential must have a negative serum or urine pregnancy test.

  • Exclusion Criteria

  • 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.
  • History of Richter's transformation of chronic lymphocytic leukemia (CLL).
  • Autologous stem cell transplant within 6 weeks of planned KTE-C19 infusion.
  • History of allogeneic stem cell transplantation..
  • Prior CD19 targeted therapy. Exception: Received KTE-C19 in this study and are eligible for re-treatment.
  • Prior treatment with PD-L1 inhibitor, PD-1 inhibitor, anti-CTLA4, anti-CD137, anti-OX40 or other immune checkpoint blockade or activator therapy. Exception: Received atezolizumab in this study and are eligible for re-treatment.
  • Treatment with systemic immunostimulatory agents within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to the first atezolizumab dose.
  • Prior chimeric antigen receptor therapy or other genetically modified T cell therapy.
  • History of severe, immediate hypersensitivity reaction attributed to aminoglycosides.
  • 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.
  • Known history of infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). If there is a positive history of treated hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or Nucleic Acid Testing.
  • Active tuberculosis.
  • Presence of any indwelling line or drain. Dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted.
  • Detectable cerebrospinal fluid malignant cells or known brain metastases, or history of cerebrospinal fluid malignant cells or brain metastases.
  • History or presence of non-malignant CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
  • Cardiac atrial or cardiac ventricular lymphoma involvement.
  • History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, NYHA Class II or greater congestive heart failure, or other clinically significant cardiac disease within 12 months of enrollment.
  • Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.
  • History of autoimmune disease. Exceptions: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone; or controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
  • History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest CT scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
  • History of deep vein thrombosis or pulmonary embolism within 6 months of enrollment.
  • Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
  • History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  • Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study.
  • Women who are pregnant or breastfeeding.
  • Potential participants of either sex not willing to practice birth control from the time of consent through 90 days after the last dose of completion of atezolizumab and at least 6 months since KTE-C19 infusion.
  • Unlikely to complete all protocol-required study visits or procedures.