Patient case: 70-year-old male with melanoma; genetic feature: NF1 truncation

Clinical trial: Genetically Modified T-cells in Treating Patients With Recurrent or Refractory Malignant Glioma

Summary: This phase I trial studies the side effects and best dose of genetically modified T-cell immunotherapy in treating patients with malignant glioma that has come back (recurrent) or has not responded to therapy (refractory). A T cell is a type of immune cell that can recognize and kill abnormal cells in the body. T cells are taken from the patient's blood and a modified gene is placed into them in the laboratory and this may help them recognize and kill glioma cells. Genetically modified T-cells may also help the body build an immune response against the tumor cells.
  Funding Source - FDA OOPD

Detailed description: PRIMARY OBJECTIVES:
  I. To assess the feasibility and safety of intratumoral (stratum 1), intracavitary (stratum 2), intraventricular (stratum 3), or dual delivery (both intratumoral and intraventricular) (stratum 4) cellular immunotherapy utilizing ex vivo expanded autologous central memory T cells (TCM)-enriched T cells that are genetically modified using a self-inactivating (SIN) lentiviral vector to express a interleukin 13 receptor alpha 2 (IL13Rα2)-specific, hinge-optimized, 41BB-costimulatory chimeric antigen receptor (CAR), as well as a truncated human cluster of differentiation 19 (CD19) (IL13 [EQ]BBzeta/truncated CD19[t]+ TCM) (IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes), for research participants with recurrent/refractory malignant glioma.
  II. To determine maximum tolerated dose schedule (MTD) and a recommended phase II dosing plan (RP2D) for each stratum based on dose limiting toxicities (DLTs) and the full toxicity profile.
  SECONDARY OBJECTIVES:
  I. To assess the timing and extent of brain inflammation, as assessed by magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS), following T cell administration.
  II. To describe cytokine levels (cyst fluid, peripheral blood) over the study period.
  III. In research participants who receive the full schedule of three CAR+ T cell doses: estimate the six month progression free survival rate, disease response rates, and median overall survival.
  IV. In research participants who receive intraventricular infusions after progressing following intratumoral/intracranial infusions (stratum 1 or 2): estimate disease response rate and overall survival if the sample size is large enough.
  V. In research participants who receive at least one dose of CAR+ T cells estimate the mean change from baseline in quality of life using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and EORTC QLQ brain neoplasm (BN)-20 survey scale, domain and item scores during and post treatment.
  VI. For study participants who undergo a second resection or autopsy: To evaluate CAR+ T cell persistence in the tumor micro-environment and the location of the CAR+ T cells with respect to the injection site, and to evaluate IL13Ra2 antigen expression levels pre and post CAR+ T cell therapy.
  OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 4 strata.
  Patients receive IL13Rα2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral (stratum 1) or intracavitary (stratum 2) or intraventricular (stratum 3) or dual delivery (both intratumoral and intraventricular) (stratum 4) catheter over 5 minutes weekly for 3 weeks in the absence of disease progression. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as they continue to remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions.
  After completion of study treatment, patients are followed up at 4 weeks, 3, 6, 8, 10 and 12 months and then yearly for 15 years.

Eligibility: Inclusion Criteria:
  -  Participant has a prior histologically-confirmed diagnosis of a grade III or IV glioma, or has a prior histologically-confirmed diagnosis of a grade II glioma and now has radiographic progression consistent with a grade III or IV malignant glioma (MG) after completing standard therapy
  -  Radiographic evidence of progression/recurrence of the measurable disease more than 12 weeks after the end of the initial radiation therapy
  -  Karnofsky performance status (KPS) >= 60%
  -  Life expectancy > 4 weeks
  -  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
  -  COH Clinical Pathology confirms IL13R alpha 2+ tumor expression by immunohistochemistry (>= 20%, 1+)
  -  All research participants must have the ability to understand and the willingness to sign a written informed consent
  ELIGIBILITY TO PROCEED WITH PBMC COLLECTION:
  -  Research participant must not require more than 2 mg TID of Dexamethasone on the day of PBMC collection
  -  Research participant must have appropriate venous access
  -  At least 2 weeks must have elapsed since the research participant received his/her last dose of prior chemotherapy or radiation
  ELIGIBILITY TO PROCEED WITH RICKHAM PLACEMENT:
  -  Creatinine < 1.6 mg/dL
  -  White blood cell (WBC) > 2,000/dl
  -  Absolute neutrophil count (ANC) > 1,000
  -  Platelets >= 100,000/dl
  -  International normalized ratio (INR) < 1.3
  -  Bilirubin < 1.5 mg/dL
  -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2 x upper limits of normal
  -  An interval of at least 12 weeks must have elapsed since the completion of initial radiation therapy
  -  At least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen
  -  At least 23 days since the completion of Temodar and/or 4 weeks for any other non-nitrosourea-containing cytotoxic chemotherapy regimen; if a patient's most recent treatment was with a targeted agent only, and s/he has recovered from any toxicity of this targeted agent, then a waiting period of only 2 weeks is needed from the last dose and the start of study treatment, with the exception of bevacizumab where a wash out period of at least 4 weeks is required before starting study treatment
  ELIGIBILITY TO PROCEED WITH T CELL INFUSION:
  -  Research participant has a released cryopreserved T cell product
  -  Research participant does not require supplemental oxygen to keep saturation greater than 95% and/or does not have presence of any radiographic abnormalities on chest x-ray that are progressive
  -  Research participant does not require pressor support and/or does not have symptomatic cardiac arrhythmias
  -  Research participant does not have a fever exceeding 38.5° Celsius (C); there is an absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to T cell infusion and/or there aren't any indications of meningitis
  -  Serum total bilirubin does not exceed 2 x normal limit
  -  Transaminases does not exceed 2 x normal limit
  -  Serum creatinine =< 1.8 mg/dL
  -  Research participant does not have uncontrolled seizure activity following surgery prior to starting the first T cell dose
  -  Platelet count must be >= 100,000; however, if platelet level is between 75,000-99,000, then T-cell infusion may proceed after platelet transfusion is given and the post transfusion platelet count is >= 100,000
  -  Research participants must not require more than 2 mg thrice daily (TID) of dexamethasone during T cell therapy
  Exclusion Criteria:
  -  Research participant requires supplemental oxygen to keep saturation greater than 95% and the situation is not expected to resolve within 2 weeks
  -  Research participant requires pressor support and/or has symptomatic cardiac arrhythmias
  -  Research participant requires dialysis
  -  Research participant has uncontrolled seizure activity and/or clinically evident progressive encephalopathy
  -  Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I study; a legal guardian may substitute for the research participant
  -  Research participants with any non-malignant intercurrent illness which is either poorly controlled with currently available treatment, or which is of such severity that the investigators deem it unwise to enter the research participant on protocol shall be ineligible
  -  Research participants with any other active malignancies
  -  Research participants being treated for severe infection or who are recovering from major surgery are ineligible until recovery is deemed complete by the investigator
  -  Research participants with any uncontrolled illness including ongoing or active infection; research participants with known active hepatitis B or C infection; research participants who have tested positive for human immunodeficiency virus (HIV) within 4 weeks of enrollment; research participants with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections
  -  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