HER2-CAR T Cells in Treating Patients With Recurrent Brain or Leptomeningeal Metastases
HER2-CAR T Cells in Treating Patients With Recurrent Brain or Leptomeningeal Metastases
This phase I trial studies the side effects and best dose of HER2-CAR T cells in treating
 patients with cancer that has spread to the brain or leptomeninges and has come back
 (recurrent). HER2-CAR T cells delivered into the ventricles of the brain may recognize and
 kill tumor cells.
PRIMARY OBJECTIVES:

 I. Determine the safety and recommended phase 2 dosing (RP2D) of intraventricularly
 administered memory-enriched autologous HER2(EQ)BBzeta/CD19t+ T cells (HER2-chimeric antigen
 receptor [CAR] T cells) - either HER2(EQ)BBzeta/CD19t+ TCM in Arm 1, or HER2(EQ)BBzeta/CD19t+
 TN/MEM in Arm 2 - in participants with brain and/or leptomeningeal metastases from HER2
 positive cancers.

 SECONDARY OBJECTIVES:

 I. Assess cerebrospinal fluid (CSF) and peripheral blood for HER2-CAR T cell persistence and
 endogenous immune system activation.

 II. Describe changes in cytokine levels in the CSF and peripheral blood. III. Describe
 changes in circulating tumor cells in the CSF.

 IV. In study participants who complete at least the first three cycles of HER2-CAR T cell
 infusions:

 IVa. Describe the CNS clinical benefit defined as disease response rate based on Response
 Assessment in Neuro-Oncology Criteria (RANO) criteria (stable disease [SD], partial response
 [PR], or complete response [CR] in the brain).

 IVb. Describe the systemic clinical benefit based on Response Evaluation Criteria in Solid
 Tumors (RECIST) criteria.

 IVc. Estimate the median central nervous system (CNS) progression-free and overall survival
 rates (mPFS and mOS), (newly diagnosed versus recurrent metastases).

 V. In study participants who undergo tumor resection or biopsy during or after study
 treatment or upon autopsy, evaluate the tumor micro-environment for:

 Va. HER2-CAR T cell persistence. Vb. Immune cell subsets. Vc. Cytokine levels. Vd. HER2
 antigen expression levels. VI. Use biomathematical modeling of tumor growth to evaluate
 benefit of treatment.

 OUTLINE: This is a dose-escalation study.

 Patients receive HER2-CAR T cells via intraventricular administration over 5 minutes once
 weekly for 3 doses in the absence of disease progression or unacceptable toxicity. If
 patients continue to meet all eligibility criteria, they may receive additional cycles of
 HER2-CAR T cells at principal investigator's discretion.

 After completion of study treatment, participants are followed up at 4 weeks, 3, 6, 8, 10,
 and 12 months, and then for up to 15 years.
Inclusion Criteria:

 -  SCREENING: Participant has treated brain and/or leptomeningeal metastases that has not
 recurred OR

 -  Such participants are eligible to enroll in the study and undergo leukapheresis,
 but they cannot start treatment with HER2-CAR T cells until there is evidence of
 tumor progression/recurrence

 -  SCREENING: Participant has recurrent brain metastases after radiation therapy OR

 -  SCREENING: Participant has recurrent leptomeningeal metastases after intrathecal
 chemotherapy OR

 -  SCREENING: Participant has untreated brain or leptomeningeal metastases and refuses to
 undergo radiation and/or intrathecal chemotherapy

 -  Note: Participants with leptomeningeal metastasis (diagnosed by positive CSF
 cytology or characteristic findings on brain or spine magnetic resonance imaging
 [MRI]) may have concomitant brain metastases, but having both is not required

 -  SCREENING: Participant must have a Karnofsky performance status (KPS) >= 70

 -  SCREENING: Participant must have a life expectancy of >= 8 weeks

 -  SCREENING: The effects of HER2-CAR T cells on a developing fetus are unknown. For this
 reason, women of child-bearing potential must have negative serum pregnancy test and
 agree to use a reliable form of birth control prior to study entry and for at least
 two months following duration of study participation. Male research participants must
 agree to use a reliable form of birth control and not donate sperm during the study
 and for at least six months afterwards

 -  SCREENING: Participant has a histologically confirmed cancer which is HER2+, defined
 as 3+ by immunohistochemistry (IHC) or gene amplification by fluorescence in situ
 hybridization (FISH)

 -  SCREENING: Participant must have the ability to understand and the willingness to sign
 a written informed consent

 -  ELIGIBILITY TO PROCEED WITH LEUKAPHERESIS: At least 2 weeks must have elapsed since
 the participant received his/her last dose of prior targeted agents, chemotherapy or
 radiation; at the PI's discretion, exception can be made for investigational agents
 that are delivered locally into the CSF

 -  ELIGIBILITY TO PROCEED WITH LEUKAPHERESIS: Research participant must not require more
 than 6 mg/day of dexamethasone (or the equivalent dose of another corticosteroid) on
 the day of leukapheresis

 -  ELIGIBILITY TO PROCEED WITH LEUKAPHERESIS: Participant must be willing to undergo
 placement of a catheter for central venous access if s/he does not have adequate
 peripheral venous access for collection of T cells

 -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Creatinine < 1.6 mg/dL

 -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: White blood cell (WBC) >
 2,000/uL (or absolute neutrophil count [ANC] > 1,000)

 -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Platelets >= 100,000/uL

 -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: International normalized
 ratio (INR) must be < 1.3

 -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Bilirubin < 1.5 mg/dL

 -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Alanine aminotransferase
 (ALT) and aspartate aminotransferase (AST) < 2.5 X upper limits of normal

 -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
 HER2-CAR T CELLS: Participant must be taking =< 6 mg/ day of dexamethasone (or the
 equivalent dose of another corticosteroid) during CAR T cell therapy

 -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
 HER2-CAR T CELLS: Participants agrees to stop treatment with chemotherapy or endocrine
 therapy during the first 3 cycles of the HER2-CAR T cell study

 -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
 HER2-CAR T CELLS: Participant does not have evidence of active infection and does not
 have a fever exceeding 38.5 degrees C; there is an absence of positive blood culture
 for bacteria, fungus, or virus within 48-hours prior to HER2-CAR T cell infusion
 and/or there aren't any indications of meningitis

 -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
 HER2-CAR T CELLS: WBC > 2,000/uL (or ANC > 1,000)

 -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
 HER2-CAR T CELLS: Platelets > 100,000/uL. However, if platelet level is between
 75,000-99,000/uL then HER2-CAR T-cell administration may proceed after platelet
 transfusion is given, and the post transfusion platelet count is >= 100,000/uL

 -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
 HER2-CAR T CELLS: Serum creatinine < 1.8 mg/dL

 -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
 HER2-CAR T CELLS: Serum total bilirubin or transaminases does not exceed 2 X upper
 limits of normal

 -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
 HER2-CAR T CELLS: 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 positive

 -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
 HER2-CAR T CELLS: Research participant does NOT have any known history of congestive
 heart failure (CHF) or cardiac symptoms consistent with New York Heart Association
 (NYHA) classification III-IV within 6 months prior to day 1 of protocol treatment,
 cardiomyopathy, myocarditis, myocardial infarction (MI), exposure to cardiotoxic
 medications or with clinical history suggestive of the above must have an
 electrocardiogram (EKG) and echocardiogram (ECHO) performed within 42 days prior to
 registration and as clinically indicated while on treatment

 -  If the research participant has new symptoms of congestive heart failure (CHF),
 cardiomyopathy, myocarditis, MI, or exposure to cardiotoxic medications, they
 already had a cardiac consultation, creatinine phosphokinase (CPK), and troponin
 testing at pre study deeming them fit for study participation

 -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
 HER2-CAR T CELLS: Participant has a released cryopreserved HER2-CAR T cell product

 -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: Participant must have at least 1 metastatic
 brain lesion (measurable disease per RANO-Brain Metastases [BM] is not required-i.e.,
 participant does not need to have at least 1 metastatic lesion >= 1 cm in longest
 dimension) that is new or increasing in size, or CSF cytology and/or radiographic
 findings consistent with leptomeningeal metastases

 -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: Participants whose brain metastases have been
 treated with whole brain radiation (WBRT) or stereotactic radiosurgery (SRS):
 previously radiated metastases must have >= 20% increase in longest diameter that is
 also >= 5 mm absolute increase from prior brain MRI or histopathologically proven
 recurrent tumor. Otherwise, new or not previously radiated lesions must be present

 -  Note: Participants who have undergone local therapy (surgical resection or
 biopsy, or SRS), must have recovered from all acute side effects before starting
 treatment with HER2-CAR T cells

 -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: If a participant with brain metastases does
 not meet the above criteria, but there is still concern by the study team that changes
 in an enhancing brain lesion seen on brain MRI could be due to tumor progression, then
 the participant can undergo resection or biopsy of the lesion(s) to distinguish
 between tumor progression versus radiation necrosis. If there is histopathological
 evidence of tumor progression, then the participant can proceed with study treatment

 -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: Research participant does not have
 uncontrolled seizure following surgery prior to starting the first CAR T cell dose

 -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: Participants must have recovered from
 toxicity (=< grade 1) of prior therapy (excluding alopecia and peripheral neuropathy)

 -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: Wash-out requirements (standard or
 investigational). The required waiting period between the last dose of the most recent
 chemotherapy agent(s) and first dose of HER2-CAR T cells is:

 -  Four weeks for a cytotoxic chemotherapy, except for capecitabine, which will only
 require a 1 week waiting period from the last dose (on a dosing schedule of bid x
 14 days, then off x 7 days);

 -  At least 6 weeks must have passed since the completion of a
 nitrosourea-containing chemotherapy regimen;

 -  At least four half-lives for a targeted agent

 Exclusion Criteria:

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Research participant requires supplemental
 oxygen to keep saturation greater than 95% and the situation is not expected to
 resolve within 2 weeks

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Research participants with a known history of
 congestive heart failure (CHF) or cardiac symptoms consistent with NYHA classification
 III-IV within 6 months prior to day 1 of protocol treatment, cardiomyopathy,
 myocarditis, myocardial infarction (MI), exposure to cardiotoxic medications or with
 clinical history suggestive of the above must have an EKG and echocardiogram (ECHO)
 performed within 42 days prior to registration and as clinically indicated while on
 treatment.

 -  Research participants with new symptoms of CHF, cardiomyopathy, myocarditis, MI,
 or exposure to cardiotoxic medications must have a cardiac consultation,
 creatinine phosphokinase (CPK), and troponin testing at pre study and as
 clinically indicated

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Research participant requires dialysis

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Research participant has uncontrolled seizure
 activity and/or clinically evident progressive encephalopathy

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Failure of research participant to understand
 the basic elements of the protocol and/or the risks/benefits of participating in this
 phase 1 study. A legal guardian may substitute for the research participant

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is unwilling to stop treatment
 with chemotherapy or endocrine therapy during the first 3 cycles of the HER2-CAR T
 cell study

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has a coagulopathy or bleeding
 disorder or cannot safely discontinue anticoagulation prior to placement of a Rickham
 reservoir

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has a chronic or active viral
 infection of the CNS

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has any uncontrolled illness,
 including ongoing or active infection; participant has known active hepatitis B or C
 infection; participants with any signs or symptoms of active infection, positive blood
 cultures or radiological evidence of infections

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is human immunodeficiency virus
 (HIV) seropositive based on testing performed within 4 weeks of screening

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has an autoimmune disease

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has another active malignancy

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participants with lung metastases (exception
 may be allowed per principal investigator [PI] discretion for participants that are
 not symptomatic from their lung metastases)

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is unable to undergo a brain MRI

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is breast feeding. Because there
 is an unknown but potential risk for adverse events in nursing infants secondary to
 treatment of the mother with HER2-CAR T cells, breastfeeding should be discontinued if
 the mother wants to participate in this study

 -  EXCLUSION CRITERIA FOR STUDY SCREENING: Patient has a serious medical or psychiatric
 illness that could, in the investigator's opinion, potentially interfere with the
 safety monitoring requirements and completion of treatment according to this protocol