Testing the Safety and Feasibility of HER2 CAR T Cells in Patients with Recurrent or Refractory Ependymoma

Inclusion Criteria

• INCLUSION CRITERIA FOR SCREENING
• Patient must have a diagnosis of ependymoma that is recurrent or progressive. All tumors must have histologic verification either at the time of diagnosis or recurrence.
• Patient must have received standard of care therapy including maximal safe surgical resection followed by local adjuvant radiation therapy at the time of reservation for screening.
• Patient must have adequate pre-trial tumor material available to determine HER2 status. Tumor tissue from the most recent resection or biopsy of recurrent disease is preferred. If unavailable, tumor tissue from prior recurrences or from the time of initial diagnosis is acceptable. * One exception will be patients who have previously received HER2-directed therapy (including but not limited to trastuzumab); these patients will need evaluation of tumor HER2 status after stopping treatment due to the possibility of HER2 downregulation or loss. * Tumor biopsy will not be performed for the purpose of HER2 screening. Patients will not be eligible for screening on PBTC-059 if pre-trial tumor tissue is not available or inadequate for HER2 testing. Tumor screening by immunohistochemistry (IHC) will be done centrally using the testing method validated at Texas Children’s Hospital. Sample for screening should be shipped within 7 days of reservation for screening in Oncology Patient Enrollment Network (OPEN).
• Patients that are known to be human immunodeficiency virus (HIV)-positive are ineligible due to the unknown safety and efficacy of infusing these patients with CAR T cells genetically modified using retroviral vectors. Additionally, the immunosuppression used for treatment in this study will pose an unacceptable risk.
• Patient must be >= 1 but =< 21 years of age at the time of screening consent.
• The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age- and developmentally appropriate assent should be obtained as required by institutional guidelines.
• Patients who are screened for this trial should be reasonably anticipated to meet the eligibility criteria for procurement and eligibility criteria for treatment described below if their tumor is HER2-positive.
• INCLUSION CRITERIA FOR PROCUREMENT
• Patient must have been screened and determined to have a diagnosis of a HER2-positive recurrent or progressive ependymoma.
• Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for =< 16 years of age) assessed within one week of procurement must be >= 60%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score provided the neurological deficit is stable.
• Patients must have received their last dose of cytotoxic chemotherapy >= 14 days preceding the date of procurement
• Peripheral absolute neutrophil count (ANC) >= 1.0 x 10^9 cells/L (within 3 days prior to each procurement)
• Platelet count >= 75 x 10^9 cells/L (within 3 days prior to each procurement) (unsupported, defined as no platelet transfusion within 4 days)
• Hemoglobin >= 8 g/dL (within 3 days prior to each procurement) (may receive red blood cell transfusions)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) for age (within 3 days prior to each procurement)
• Alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) and aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) =< 5 x institutional upper limit of normal (ULN) for age (within 3 days prior to each procurement)
• Serum creatinine < 1.5 x institutional upper limit of normal for age and gender (within 3 days prior to each procurement). Patients that do not meet the criteria but have a 24-hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible
• Oxygen saturation as measured by pulse oximetry is >= 93% on room air (within 3 days prior to each procurement)
• Patients who are receiving systemic corticosteroids must be on a stable or decreasing dose for at least two weeks prior to procurement, and corticosteroid dose must be less than or equal to dexamethasone 0.75 mg/m^2/day (or equivalent). Use of topical, ocular, intranasal, or inhaled corticosteroids are permitted.
• The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age- and developmentally appropriate assent should be obtained as required by institutional guidelines
• Patients who have undergone procurement for this trial should be reasonably anticipated to meet the eligibility criteria for treatment described below and to begin treatment within 180 days from the date of procurement.
• INCLUSION CRITERIA FOR TREATMENT
• Patients with a histologically confirmed diagnosis of HER2 positive ependymoma that is recurrent or progressive. Histologic verification may be from time of diagnosis or time of recurrence. In cases where there is question of recurrence, histologic verification, or verification of progression on follow up imaging is required prior to initiating treatment.
• Phase I (Stratum 1) * Patients must have evaluable disease in the central nervous system to be eligible. Evaluable disease includes either measurable OR non-measurable disease, defined as follows: ** Measurable disease (enhancing or non-enhancing tumor): *** At least 1 cm, or *** At least two times (in both perpendicular diameters) the magnetic resonance imaging (MRI) slice thickness, plus the interslice gap. ** Non-measurable disease (tumor that is too small to be accurately measured): *** Less than 1 cm in at least one perpendicular dimension, or *** Less than two times the MRI slice thickness, plus the interslice gap. *** No tumor visible on imaging but presence of malignant cells on cytologic examination of cerebrospinal fluid (CSF). ****Note: Leptomeningeal disease is considered non-measurable but evaluable.
• Surgical Study (Stratum 2): Patients with measurable disease in whom tumor resection is clinically indicated and feasible after the CAR T cell infusion.
• Patient must be >= 1 but =< 25 years of age at the start of treatment.
• The patient must have, at a minimum, one prescribed dose of the cryopreserved, autologous HER2 CAR T cell product available for infusion.
• Prior Anti-neoplastic Therapy * Cytotoxic chemotherapy: Patients must not have received cytotoxic chemotherapy for at least 28 days prior to the start of treatment and must have recovered from the acute treatment related toxicities (defined as =< grade 1 if not defined in eligibility criteria; excludes alopecia) prior to the start of treatment. * Biological, targeted, or investigational agents (anti-neoplastic): Patients must have a period of at least 28 days from the last receipt of said drug and all acute toxic effects must have resolved or recovered to grade 1 prior to the start of treatment. ** For agents that have known acute adverse events occurring beyond 28 days after administration, this period must be extended beyond the time during which adverse events are known to occur. * Monoclonal antibodies, checkpoint inhibitors, and other agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent >= 28 days prior to the start of treatment. * Adoptive cellular therapies: Patient must have recovered from any acute toxicity potentially related to the cellular product and received their last dose of the cellular product at least 90 days prior to the start of treatment. (Note: Patients who have previously received an adoptive cellular therapy may continue long-term follow up evaluations per the prior study’s evaluation schedule as needed for assessment of long-term toxicities including genotoxicity.) * Radiation: Patients must have had their last fraction of: ** Craniospinal irradiation, whole brain radiation, or radiation to > 50% of pelvis or spine >= 3 months prior to enrollment (90 days) prior to the start of treatment. ** Focal palliative irradiation to the tumor >= 42 days prior to the start of treatment. ** Patients who receive tumor-directed radiation (non-palliative) should have confirmed disease progression on imaging done at least 6 weeks after the completion of the last fraction of radiation. * Surgery: Patients must have not had tumor-directed surgery within 14 days prior to the start of treatment. Patients who have undergone surgery for other indications, including but not limited to shunt revision or ommaya placement, must have adequate wound healing and recovered from other acute effects from surgery. One exception is the placement of a central venous access device which will be allowed at any time point until treatment initiation on the study.
• Patients must be off all colony-forming growth factor(s) for at least 7 days prior to the start of treatment (e.g., filgrastim, sargramostim, or erythropoietin). Fourteen (14) days must have elapsed if the patient received a long-acting formulation (e.g., PEG-filgrastim).
• Patients who are receiving systemic corticosteroids must be on a stable or decreasing dose for at least 14 days prior to the start of treatment, and corticosteroid dose must be less than or equal to dexamethasone 0.5 mg/m^2/day (or equivalent) during the 14 days prior to the start of treatment. Use of topical, ocular, intranasal, or inhaled corticosteroids are permitted.
• Neurologic Status * In patients with neurological deficits, deficits should be stable for a minimum of 7 days prior to the start of treatment. A baseline detailed neurological exam should clearly document the neurological status of the patient prior to the start of treatment. * In patients with seizure disorders, seizures must be well controlled prior to the start of treatment.
• Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for =< 16 years of age) assessed within one week prior to the start of treatment must be >= 60%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Patients must have adequate organ and bone marrow function as defined above
• Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study.
• The patient or parent/guardian can understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Age and developmentally appropriate assent should be obtained as required by institutional guidelines

Exclusion Criteria

• EXCLUSION CRITERIA FOR PROCUREMENT
• Patients who are known to be HIV-positive are ineligible due to the unknown safety and efficacy of infusing these patients with CAR T cells genetically modified using retroviral vectors. Additionally, the immunosuppression used for treatment in this study will pose an unacceptable risk
• EXCLUSION CRITERIA FOR TREATMENT
• Patients with Bulky Tumors on Imaging Studies * Bulky tumors will be defined as those: ** > 6 cm in single maximum dimension, or ** tumor causing uncal herniation or mass effect leading to midline shift with or without symptoms or signs of impending herniation or ** Active obstruction to CSF flow.
• Infratentorial tumors with symptoms or signs arising from brain stem involvement by the tumor. * Patients with stable cranial nerve deficit(s) secondary to prior surgery or a treated tumor will not be excluded.
• Surgical study (Stratum 2): Patients who have urgent need for surgical resection of tumor
• Pregnant women or nursing mothers are excluded from this study. * Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the start of treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. * Pregnant or breast-feeding women are excluded from this study because there is an unknown but potential risk of adverse events to the fetus or the nursing infant with the use of T cells genetically modified to express HER2 CAR. Pre-clinical studies in mice demonstrate the target antigen HER2 is necessary for normal fetal development of cardiac trabeculae, cranial sensory ganglia, and motor neuron development. Additionally, the lymphodepleting chemotherapy drugs fludarabine and cyclophosphamide are both Pregnancy Class D drugs.
• * Patients with active autoimmune disease, documented history of autoimmune disease/syndrome, or any other condition that requires ongoing systemic steroids or systemic immunosuppressive agents, except ** Patients with vitiligo or resolved asthma/atopy ** Patients with hypothyroidism stable on hormone replacement or Sjogren’s syndrome ** Patients requiring physiologic doses of corticosteroids (up to 0.5 mg/m^2/day dexamethasone equivalent)
• History of or ongoing pneumonitis or significant interstitial lung disease
• Ongoing or active uncontrolled infection
• Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator, would compromise the patient’s ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
• Patients with any of the following cardiac diseases * New York Heart Association (NYHA) functional class III or IV * Clinically significant cardiac arrhythmia including, but not limited to, Torsade de pointes or requiring a pacemaker * Left ventricular ejection fraction below 50% as determined by echocardiography (ECHO)
• Known HIV positivity * HIV-positive patients are ineligible due to the unknown safety and efficacy of infusing these patients with CAR T cells genetically modified using retroviral vectors. Additionally, the immunosuppression used for treatment in this study will pose an unacceptable risk.
• Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible.
• Patients who have received the last vaccination of a live vaccine =< 30 days prior to the start of treatment are ineligible. * Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines and must meet timeline for live vaccine.
• Herbal preparations/medications (except for vitamins) including, but not limited to: St. John’s wort, Kava, ephedra (ma huang), ginkgo biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh, and ginseng. Patients should stop using all herbal medications and dietary supplements at least 7 days prior to the start of treatment.
• Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions.
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition (murine protein-containing products, Dimethyl Sulfoxide [DMSO], or dextran 40).