Patient case: 67-year-old male with esophageal cancer; genetic feature: EGFR

Clinical trial: Cellular Immunotherapy in Treating Patients With High-Risk Acute Lymphoblastic Leukemia

Summary: This phase I trial studies the side effects and best dose of cellular immunotherapy in treating patients with high-risk acute lymphoblastic leukemia. Placing a modified gene into white blood cells may help the body build an immune response to kill cancer cells.

Detailed description: PRIMARY OBJECTIVES: I. To examine the activity and safety of adoptive therapy using ex vivo expanded memory T cells that are enriched and genetically-modified to express a cluster of differentiation (CD)19-specific, hinge optimized, CD28-costimulatory chimeric antigen receptor (CAR) as well as a truncated human epithelial growth factor receptor (EGFR) (Arm 1: CD19R(EQ)28zeta/truncated human EGFR [EGFRt]+ central memory T cells [TCM]; Arm 2: CD19R(EQ)28zeta/EGFRt+ naive and memory T cells [TN/NEM]) shortly following a lymphodepleting preparative regimen for adults with poor prognosis CD19+ acute lymphoblastic leukemia (ALL).
  II. To determine the Phase II recommended dose (RP2D).
  SECONDARY OBJECTIVES: I. To study additional antitumor activity endpoints of CD19R(EQ)28zeta/EGFRt+ TCM and CD19R(EQ)28zeta/EGFRt+ TN/NEM. II. To explore the efficacy of infusional cetuximab to eliminate transferred CD19R(EQ)CD28zeta/EGFRt+ TCM and CD19R(EQ)28zeta/EGFRt+ TN/NEM.
  OUTLINE: This is a dose-escalation study.
  ARM I: Patients receive lymphodepleting regimen per treating physician's discretion 3-10 days before the T-cell infusion. Patients receive CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells IV over 15 minutes on day 0. Patients who have evidence of disease, whose tumor(s) continue to express the appropriate antigen target may receive an optional second infusion of CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells after 28 days.
  ARM II: Patients receive lymphodepleting regimen per treating physician's discretion 3-10 days before the T-cell infusion. Patients receive CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/nem-enriched T cells IV over 15 minutes on day 0. Patients who have evidence of disease, whose tumor(s) continue to express the appropriate antigen target may receive an optional second infusion of CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/nem-enriched T cells after 28 days.
  After completion of study treatment, patients are followed up at 24 hours, weekly for 1 month, monthly for 1 year, and then yearly for at least 15 years.

Eligibility: Inclusion Criteria:
  -  City of Hope (COH) pathology review confirms that research participant's diagnostic material is consistent with history of ALL with history of recurrence/progression/minimal residual disease (MRD) following prior therapy; additionally, CD19 positivity must be documented in a pathology report; however, it is not a requirement that the CD19 testing be performed by a COH pathologist; patients in second complete remission (CR2) or higher with history of CD19+ ALL on previous bone marrow biopsy are also eligible for the study
  -  Research participants with confirmed 1st or higher relapse of disease by morphology, cytogenetics or molecular, or research participants with refractory or residual disease
  * MRD will be defined in this protocol by presence of malignant cells at 0.01% or more by flow cytometry or polymerase chain reaction (PCR) analysis at the completion of initial remission induction therapy
  -  Karnofsky performance status (KPS) of >= 70%
  -  Life expectancy >= 16 weeks at time of enrollment
  -  Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
  -  All research participants must have the ability to understand and the willingness to sign a written informed consent
  -  Note: For research participants who do not speak English, a short form consent may be used with a COH certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated full consent in processed; however, the research participant is allowed to proceed with lymphodepletion and T cell infusion only after the translated full consent form is signed
  PROTOCOL-SPECIFIC CRITERIA:
  -  COH pathology review confirms that research participant's diagnostic material is consistent with ALL; additionally, CD19 positivity must be documented in a pathology report; however it is not a requirement that the CD19 testing be performed by a COH pathologist
  -  Negative serum pregnancy test for women of childbearing potential
  -  If a research participant has undergone prior allogeneic stem cell transplant (alloSCT), there must be documentation indicating that he/she does not have active graft versus host disease (GVHD)
  -  A pretreatment calculated creatinine clearance (absolute value) of >= 50 mL/minute
  -  Research participant must have a serum bilirubin =< 2.0 mg/dl; Note: in the event a participant has elevated levels of liver enzymes possibly related to underlying disease, the participant will still be considered eligible
  -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 times the institutional upper limits of normal; Note: in the event a patient has elevated levels of liver enzymes possibly related to underlying disease, the patient will still be considered eligible
  -  Ejection fraction measured by echocardiogram or multigated acquisition scan (MUGA) > 45% (within 6 weeks of time of screening)
  -  Diffusion capacity of the lung for carbon monoxide (DLCO) or forced expiratory volume in one second (FEV1) > 45% predicted
  ELIGIBILITY TO PROCEED WITH PBMC COLLECTION
  -  Research participant must have appropriate venous access
  -  If the research participant is undergoing leukapheresis, he/she must be at least 2 weeks from having received the last dose of immunosuppressant medications
  -  If a research participant has undergone prior alloSCT and is planning to undergo the leukapheresis, two months must have elapsed since allogeneic stem cell transplant to undergo PBMC collection for T cell manufacturing
  -  If the research participant is undergoing leukapheresis, the last dose of prior chemotherapy, immunotherapy or radiation must be at least 2 weeks before the leukapheresis procedure
  ELIGIBILITY TO UNDERGO LYMPHODEPLETION:
  -  Research participant's absolute leukemic blast count does not exceed 10,000 cells/uL
  -  Confirmed absence of central nervous system (CNS) disease
  -  Research participant has a released cryopreserved T cell product for T cell infusions on approximately day 0
  -  KPS >= 70%
  -  Non-hematological toxicity related to prior therapy must either have returned to =< grade 3, baseline, or deemed irreversible
  -  Participants of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 8 weeks after T cell infusion
  -  Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 90% or higher on room air
  -  Not requiring pressor support, no symptomatic cardiac arrhythmias, no acute coronary syndrome, or uncontrolled hypertension
  -  Preservation of renal function, serum creatinine did NOT increase by more than 2 fold above the normal reference range
  -  Total bilirubin =< 2.0 mg/dL
  -  ALT and AST =< 2.5 times the institutional upper limits of normal
  -  Research participants without clinically significant encephalopathy/new focal deficits
  -  No clinical evidence of uncontrolled active infectious process
  ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED T CELLS:
  -  Research participant has undergone lymphodepletion
  -  Pulmonary: Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 90% or higher on room air
  -  Cardiovascular: Not requiring pressor support, no symptomatic cardiac arrhythmias, no acute coronary syndrome, or uncontrolled hypertension
  -  Renal function: Preservation of renal function, serum creatinine did NOT increase by more than 2 fold above the normal reference range
  -  Liver function: Total bilirubin =< 2.0 mg/dL
  -  Liver function: ALT and AST =< 2.5 times the institutional upper limits of normal
  -  Research participant without clinically significant encephalopathy/new focal deficits
  -  Infectious diseases: No clinical evidence of uncontrolled active infectious process
  ELIGIBILITY CRITERIA TO UNDERGO OPTIONAL T CELL ABLATION:
  -  Research participant is scheduled for an alloSCT
  -  Research participant has >= 1% chimeric antigen receptor (CAR) modified T cells in the peripheral blood
  -  Pulmonary criteria: Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 90% or higher on room air
  -  Cardiovascular criteria: Not requiring pressor support, no symptomatic cardiac arrhythmias, no acute coronary syndrome, or uncontrolled hypertension
  -  Renal function criteria: Preservation of renal function, serum creatinine did NOT increase by more than 2 fold above the normal reference range
  -  Liver function criteria: Total bilirubin =< 2.0 mg/dL
  -  Liver function criteria: AST and ALT =< 2.5 times the institutional upper limits of normal
  -  Neurological: Research participant without clinically significant encephalopathy/new focal deficits
  -  Infectious diseases criteria: No clinical evidence of uncontrolled active infectious process
  Exclusion Criteria:
  -  Research participants with any uncontrolled illness including ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, poorly controlled pulmonary disease or psychiatric illness/social situations that would limit compliance with study requirements
  -  Research participants with known active hepatitis B or C infection; research participants who are human immunodeficiency virus (HIV) positive based on testing performed within 4 weeks of enrollment; research participants with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections
  -  Research participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
  -  Research participants with presence of other active malignancy. However, research participants with history of prior malignancy treated with curative intent and in complete remission are eligible
  -  Pregnant and lactating women
  -  Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I study
  -  Research participants with CNS involvement by leukemia, if deemed to be controlled and treatable by study team, at the time of enrollment are eligible; however, the CNS disease has to have been adequately treated with complete resolution of CNS leukemia confirmed by cerebral spinal fluid (CSF) analysis and imaging studies (if applicable) to be eligible to proceed with lymphodepletion
  -  History or presence of clinically relevant CNS pathology such as uncontrolled seizure disorder, stroke, severe brain injuries, dementia, cerebellar disease or psychosis
  -  Any known contraindications to cyclophosphamide, fludarabine, etoposide, cetuximab or tocilizumab
  -  Dependence on corticosteroids
  -  Defined as doses of corticosteroids of greater than or equal to 5 mg/day of prednisone or equivalent doses of other corticosteroids
  -  Note: topical and inhaled corticosteroids in standard doses and physiologic replacement for subjects with adrenal insufficiency are allowed
  -  Active autoimmune disease requiring systemic immunosuppressive therapy
  -  Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

Relevance to patient case: not relevant