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)
Jason R. Westin
The goal of this clinical research study is to learn if the combination of KTE-C19 and atezolizumab can help to control diffuse large B-cell lymphoma (DLBCL) after you receive 3 days of fludarabine and cyclophosphamide. The safety of this drug combination will also be studied.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: Atezolizumab,Cyclophosphamide,Fludarabine,KTE-C19,MESNA
Treatment Location: Both at MD Anderson & Other Sites
Sponsor: Kite Pharma, Inc
The primary objective of phase 1 is to evaluate the safety of autologous T cells transduced with retroviral vector containing anti-CD19 CD28/CD3 zeta chimeric antigen receptor (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 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. Exploratory Endpoint(s) for phase 1 and 2 Objective response rate based on PD-L1 expression on tumor cells or infiltrating immune cells Investigation of potential biomarker development based on assessment of product cells, blood cells, tumor tissue at baseline and post-treatment, and the proposed actions of the investigational product Frequency of atezolizumab dose delays for ongoing acute toxicities following KTE-C19.
IRB Review and Approval Date: 10/11/2016
Recruitment Status: Open
Projected Accrual: 31
1) Histologically proven DLBCL including the following types defined by
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;
2) Chemotherapy-refractory disease, defined as one or more of the following: o No response to first-line therapy (primary refractory disease); subjects who are intolerant to first-line therapy chemotherapy are excluded: PD as best response to first-line therapy; SD as best response after at least 4 cycles of first-line therapy (e.g., 4 cycles of R-CHOP) with progressive disease within 6 months from last dose of therapy OR No response to second or greater lines of therapy: PD as best response to most recent therapy regimen; SD as best response after at least 2 cycles of last line of therapy with progressive disease within 6 months from last dose of therapy OR Refractory post-ASCT: Disease progression or relapsed </=12 months after ASCT (must have biopsy proven recurrence in relapsed subjects) if salvage therapy is given post-ASCT, the subject must have had no response to or relapsed after the last line of therapy
3) Subjects 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;
4) 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
5) MRI of the brain showing no evidence of CNS lymphoma
6) At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis
7) Age 18 years or older at the time of informed consent
8) Eastern cooperative oncology group (ECOG) performance status of 0 or 1
9) Adequate bone marrow, renal, hepatic, pulmonary and cardiac function defined as: ANC >/=1000/microL; Platelet count >/=75,000/microL; Absolute lymphocyte count >/=100/uL; Creatinine clearance (as estimated by Cockcroft Gault) >/=60 mL/min; Serum ALT/AST </=2.5 ULN; Total bilirubin </=1.5 mg/dl, except in subjects with Gilbert’s syndrome. Cardiac ejection fraction >/= 50%, no evidence of pericardial effusion as determined by an ECHO, and no clinically significant ECG findings; No clinically significant pleural effusion; Baseline oxygen saturation >92% on room air
10) Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential)
1) History of malignancy other than nonmelanoma skin cancer or carcinoma
in situ (e.g. cervix, bladder, breast) unless disease free for at least
2) History of Richter’s transformation of CLL
3) Autologous stem cell transplant within 6 weeks of planned KTE-C19 infusion
4) History of allogeneic stem cell transplantation
5) Prior CD19 targeted therapy with the exception of subjects who received KTE-C19 in this study and are eligible for re-treatment
6) Prior treatment with PD-L1 inhibitor, PD-1 inhibitor, anti-CTLA4, anti-CD137, anti-OX40 or other immune checkpoint blockade or activator therapy with the exception of subjects who received atezolizumab in this study and are eligible for re-treatment
7) Treatment with systemic immunostimulatory agents (including but not limited to interferon and IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to the first atezolizumab dose.
8) Prior chimeric antigen receptor therapy or other genetically modified T cell therapy
9) History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
10) 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.
11) 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 PCR and/or Nucleic Acid Testing.
12) Active tuberculosis.
13) Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube, indwelling foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted.
14) Subjects with detectable cerebrospinal fluid malignant cells or known brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases.
15) 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.
16) Subjects with cardiac atrial or cardiac ventricular lymphoma involvement.
17) History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, or other clinically significant cardiac disease within 12 months of enrollment.
18) Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.
19) History of autoimmune disease. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
20) History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 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.
21) History of deep vein thrombosis or pulmonary embolism within 6 months of enrollment
22) Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
23) History of severe immediate hypersensitivity reaction to any of the agents used in this study
24) 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
25) 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
26) Subjects of either sex who are 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
27) Any medical, psychological or social condition that may prevent the subject from participating in the study, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
Phase I/Phase II
Jason R. Westin
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