Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Recurrence

Glioma

Disease Progression

Diffuse Intrinsic Pontine Glioma

Disease Attributes

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Brain Stem Neoplasms

Infratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Neuroepithelioma

Cardiotonic Agents

All Drugs and Chemicals

Antineoplastic Agents

Dopamine

TIC10 compound

GDC-0084

Sympathomimetics

Dopamine Agents

Neurotransmitter Agents

Protective Agents

Enzyme Inhibitors

Patients may receive a safety lead in of ONC201. During the trial validation phase, patients without prior biopsy receive ONC201 PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 PO weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO daily (QD). Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity

Patients may receive a safety lead in of ONC201. During the trial validation phase, patients without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity

Patients may receive a safety lead in of ONC201. During trial validation phase, patients without prior biopsy receive paxalisib PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive paxalisib PO daily during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity

ONC201

Radiation Therapy

Paxalisib

Kelly Hitchner

Girish Dhall, MD

Tom Davidson, MD

Megan Paul, MD

PNOC022@ucsf.edu

Sabine Mueller, MD, PhD

Lindsay Kilburn

Kenneth Cohen, MD

Susan Chi, MD

Carl Koschmann, MD

Anne Bendel

Andrew Cluster, MD

Derek Hanson, MD

Sharon Gardner, MD

Laura Gorski, BSN, RN, CPN, OCN

Kate Hogan, MS

Daniel Landi, MD

Matthew Miller, MD

Christoper Park, MD

Cassie Kline, MD

Nicholas Whipple, MD

Erin Crotty, MD

Jasper van der Lugt, MD, PhD

Raoull Hoogendijk

This phase II trial determines if the combination of ONC201 with different drugs, panobinostat or paxalisib, is effective for treating patients with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for patients with DMGs, and there are few treatment options. ONC201, panobinostat, and paxalisib are all enzyme inhibitors that may stop the growth of tumor cells by clocking some of the enzymes needed for cell growth. This phase II trial assesses different combinations of these drugs for the treatment of DMGs.

OUTLINE:

Participants will be randomized at study entry to one of the three study arms and subsequently will be included in one to three phases, and one of 3 cohorts depending on their stage of disease and prior treatment.

PRIMARY OBJECTIVES:

I. To assess efficacy of combination therapy with ONC201 (ONC201) and novel agent in participants with DMG based on median progression-free survival at 6 months (PFS6) (Cohorts 1 and 2).

II. To assess efficacy of combination therapy with ONC201 and novel agent in participants with recurrent DMG based on overall survival at 7 months (OS7) (Cohort 3).

EXPLORATORY OBJECTIVES:

I. To confirm blood brain barrier (BBB) penetration of ONC201 in DMGs by measuring the concentration of ONC201 in tumor tissue (All cohorts; target validation phase).

II. To confirm BBB penetration of novel agents in DMGs by measuring the concentration of drug (or metabolite) in tumor tissue (All cohorts; target validation phase).

III. To assess changes in immune cell infiltration in DMG tumor tissue after 1 or 2 doses of ONC201 (All cohorts; target validation phase).

IV. To assess correlation of intratumoral concentration of ONC201 with clinical outcome (All cohorts; target validation phase).

V. To assess correlation of intratumoral drug concentration of novel agents with clinical outcome. (All cohorts; target validation phase).

VI. To assess if intratumoral ONC201 concentrations differ in irradiated versus nonirradiated tumor tissue. (All cohorts; target validation phase).

VII. To assess if intratumoral concentrations of novel agents differ in irradiated versus nonirradiated tumor tissue. (All cohorts; target validation phase).

VIII. To assess tumor tissue biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts; target validation phase).

IX. To assess efficacy of combination therapy ONC201 and novel agent based on overall survival at 12 months (OS12). (All cohorts; maintenance combinations).

X. To assess toxicity of combination therapy ONC201 and novel agents. (All cohorts; maintenance combinations).

XI. To assess the toxicity of weekly ONC201 in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase).

XII. To assess the toxicity of twice weekly ONC201 in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase).

XIII. To assess the toxicity of novel agents in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase).

XIV. To assess the toxicity of weekly ONC201 in combination with re-irradiation after progression. (Cohort 3).

XV. To assess the toxicity of twice weekly ONC201 in combination with re-irradiation therapy after progression. (Cohort 3).

XVI. To assess the toxicity of novel agents in combination with re-irradiation after progression. (Cohort 3).

XVII. To assess the toxicity of ONC201 in combination with novel agents in participants after re-irradiation after progression. (Cohort 3).

XVIII. To assess cerebrospinal fluid (CSF) biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases).

XIX. To assess levels of circulating tumor deoxyribonucleic acid (ctDNA) in the context of imaging response criteria and clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases).

XX. To assess single cell ribonucleic acid (RNA) sequencing in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases).

XXI. To assess microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistics.

XXII. To assess Health-Related Quality of Life (HRQOL) and cognitive measures. (All cohorts/phases).

XXIII. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures. (All cohorts/phases).

COHORT DESCRIPTIONS:

COHORTS 1A \& 2A ( Target Validation cohorts); Includes newly diagnosed participants that have not yet undergone tumor tissue collection. Cohort 1A will include participants with DMG who have not yet completed radiation therapy and Cohort 2A will include participants with DMG who have completed radiation therapy.

COHORTS 1B \& 2B: Includes newly-diagnosed participants who have already undergone tumor tissue collection. Cohort 1B will include participants with DMG who have not yet completed radiation therapy and Cohort 2B will include participants with DMG who have completed radiation therapy.

COHORTS 3A \& 3B: Includes participants with progressive DMG. Cohort 3A will include participants planned for standard of care (SOC) tumor tissue collection. Cohort 3B will include participants not planned for SOC tumor tissue collection. The nomenclature will delineate participants previously enrolled in Cohorts 1 or 2.

TREATMENT ARM DESCRIPTIONS:

ARM 2: During the trial validation phase, patients without prior biopsy receive ONC201 PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 PO weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO daily (QD). Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity.

ARM 4: During the trial validation phase, patients without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity.

ARM 6: During trial validation phase, patients without prior biopsy receive paxalisib PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive paxalisib PO daily during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity.

After completion of study treatment, patient are followed every 12 months.

Combination Therapy for the Treatment of Diffuse Midline Gliomas

A Combination Therapy Trial Using an Adaptive Platform Design for Children and Young Adults With Diffuse Midline Gliomas (DMGs) Including Diffuse Intrinsic Pontine Gliomas (DIPGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression

Individual participant data after de-identification.

Percentage of participants alive and free from progression at 6 months after the initiation of the combination of the backbone (i.e., ONC201) with a novel agent given in the maintenance phase of therapy. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis.

OS7 is defined as the percentage of participants alive at 7 months after the initiation of the combination of the backbone (i.e., ONC201) with a novel agent given in the maintenance phase of therapy. The primary analysis for OS7 is based on the ITT population, according to treatment arm assignment. OS7 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown survival status at 7 months are considered failures (i.e., dead) for the OS7 analysis.

The Chad-Tough Defeat DIPG Foundation

Mithil Prasad Foundation

Storm the Heavens Fund

National Institute of Neurological Disorders and Stroke (NINDS)

University of California, San Francisco

Principal Investigator

Glioblastoma

Astrocytoma

Amino Acids

Fluorides

Radiopharmaceuticals

Tyrosine

Participants with intracranial neoplasms (glial or metastatic disease) with concern for recurrence or progression on conventional imaging (e.g., MRI) will receive F-18 fluoroethyltyrosine (FET) injected intravenously over approximately 1 minute and receive a single PET image lasting up to 40 minutes. Repeat FET PET will be offered to adult patients.

Participants with suspected glial neoplasms (Grade 2-4) planning to undergo a non-investigational biopsy or surgery prior to non-investigational, primary treatment (radiation therapy and/or surgery) will receive F-18 fluoroethyltyrosine (FET) injected intravenously over approximately 1 minute and receive a single PET image lasting up to 40 minutes. Repeat FET PET will be offered to adult patients.

Patients given an injected dose of 4 to 7 millicurie (mCi) of FET per scan. The radiopharmaceutical will be administered while the patient is in the PET scanner

F-18 Fluoroethyltyrosine (FET)

All patients receive single PET imaging lasting for 40 minutes. Acquired PET data will be reconstructed so that three time points are created: (1) Perfusion: 60-second acquisition that starts immediately when activity is noted in the field of view, (2) Equilibrium: 10-minute acquisition acquired between 10 and 20 minutes after injection, and (3) Washout: 10-minute acquisition acquired between 30 and 40 minutes after injection. A repeat PET image will be offered to adult patients.

Positron Emission Tomography (PET)

Thomas A Hope, MD

This phase II trial studies how well F-18 fluoroethyltyrosine (fluoroethyltyrosine) works in detecting tumors in participants with intracranial tumors that have come back. FET accumulates in malignant cells within intracranial neoplasms and can be used to detect recurrent disease and characterize the grade of glial neoplasms. Imaging agents such as FET can help oncologist to see the tumor better during a positron emission tomography (PET) scan.

PRIMARY OBJECTIVES:

I. To determine if F-18 fluoroethyltyrosine (FET) PET can differentiate between benign treatment-related changes and recurrence in comparison to pathology in population 1 with recurrent metastatic disease and high-grade gliomas.

II. To determine if FET PET can accurately differentiate between low-grade and high-grade gliomas in population 2.

SECONDARY OBJECTIVES:

I. To determine if FET PET can differentiate between benign treatment-related changes and recurrence in comparison to pathology or imaging follow-up in population 1.

II. To determine if FET PET can differentiate between benign treatment-related changes and recurrence in comparison to pathology in population 1 with recurrent low-grade gliomas.

OUTLINE:

Participants receive F-18 fluoroethyltyrosine intravenously (IV) over approximately 1 minute and undergo PET over 40 minutes. After completion of study treatment, participants are followed up periodically.

Fluoroethyltyrosine for Evaluation of Intracranial Neoplasms

Fluoroethyltyrosine for the Evaluation of Intracranial Neoplasm

Radiologists will classify lesions as having recurrent disease or not having recurrent disease. True Positives (TP) are defined as an FET PET read positive for tumor and pathology/follow-up demonstrates tumor recurrence in at least one biopsy sample, False positives (FP) are defined as an FET PET read positive for tumor and pathology/follow-up demonstrates negative tumor recurrence in all of the biopsy samples, True negatives (TN) are defined as an FET PET read as negative for tumor and pathology/follow-up also negative tumor recurrence in all of the biopsy samples and a false negative (FN) is defined as an FET PET read as negative for tumor and pathology/follow-up demonstrates tumor recurrence in at least one biopsy sample. Misclassification rate = \[FP+FN)\]/\[FP+FN+TP+TN\]

Readers will have access only to FET PET images for participants with suspected glial neoplasms (Grade 2-4) planning to undergo biopsy or surgery prior to primary treatment during evaluation and will grade the lesions in a binary fashion as having Grade II glial neoplasms or having Grade III/IV glial neoplasms. True positive (TP2): FET PET read as positive for Grade III/IV neoplasm, pathology demonstrates Grade III/IV neoplasm. False positive (FP2): FET PET read as positive for Grade III/IV neoplasm, pathology demonstrates Grade II neoplasm. True negative (TN2): FET PET read as positive for Grade II neoplasm, pathology demonstrates Grade II neoplasm. False negative (FN2): FET PET read as positive for Grade II neoplasm, pathology demonstrates Grade III/IV neoplasm. Misclassification rate = \[FP2+FN2\]/\[FP2+FN2+TP2+TN2\]

Participants with available histology (performed within 4 weeks of FET scans) or follow-up imaging (performed within 6 months of FET scan) will be included and a composite truth standard for recurrence or treatment-related changes will be evaluated for each case. In the absence of pathology, the composite truth standard will use available clinical information to make a determination. Positive for tumor recurrence on follow-up imaging will be based on Response assessment in neuro-oncology criteria (RANO) criteria reads. Follow-up imaging has to be performed within six months of the FET PET imaging study to be considered for evaluation. Additionally, the composite truth standard may consider tumor board notes and subsequent management of the patient to make a determination.

Low-grade glioma is defined by low uptake of FET. Radiologists will classify lesions based on imaging as either having recurrent disease or not having recurrent disease. True Positives (TP1L) are defined as an FET PET read positive for low-grade tumor and pathology/follow-up demonstrates low-grade tumor recurrence in at least one biopsy sample, False positives (FP1L) are defined as an FET PET read positive for low grade tumor recurrence and pathology/follow-up demonstrates negative low-grade tumor recurrence in all of the biopsy samples, True negatives (TN1L) are defined as an FET PET read as negative for low-grade tumor recurrence and pathology/follow-up also negative for low grade tumor recurrence in all of the biopsy samples and a false negative (FN1L) is defined as an FET PET read as negative for low grade tumor recurrence and pathology/follow-up demonstrates low grade tumor recurrence in at least one biopsy sample. Misclassification rate = \[FP1L+FN1L)\]/\[FP1L+FN1L+TP1L+TN1L\]

Fleiss' kappa statistic will be used to determine the agreement between the assessment of FET-PET tumor targeting (tracer uptake in target lesion: yes/ no), as assessed by three independent blinded readers. Scores range from 0 to 1 with higher scores indicating a great degree of agreement

Cohen's kappa statistics will be used to determine the reproducibility of the assessment by individual readers when analyzing the same data repeatedly and measures the agreement between two raters who each classify items into mutually exclusive categories.

Thomas Hope

Assistant Professor

Dermatologic Agents

Isotretinoin

CLOSED TO ACCRUAL 03/02/2018.

Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions.

Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intracavitary catheter over 5-10 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients 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

Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intraventricular catheter over 5-10 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available.

Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

Patients receive IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ Tn/mem via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

Given via intratumoral or intraventricular catheter

IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells

Given via intratumoral, intracavitary, or intraventricular catheter

IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes

Laboratory Biomarker Analysis

Magnetic Resonance Imaging

Magnetic Resonance Spectroscopic Imaging

Quality-of-Life Assessment

Behnam Badie

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.

PRIMARY OBJECTIVES:

I. To assess the feasibility and safety of cellular immunotherapy utilizing ex vivo expanded autologous memory-enriched T cells that are genetically modified using a self-inactivating (SIN) lentiviral vector to express an interleukin 13 receptor alpha 2 (IL13R alpha 2)-specific, hinge-optimized, 41BB-costimulatory chimeric antigen receptor (CAR), as well as a truncated human cluster of differentiation 19 (CD19) for participants with recurrent/refractory malignant glioma in one of the following ways: stratum 1 (intratumoral delivery of IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ central memory T cells \[Tcm\]) (IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes), stratum 2 (intracavitary delivery of IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ Tcm, stratum 3 (intraventricular delivery of IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ Tcm), stratum 4 (dual delivery \[both intratumoral and intraventricular\] of IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ Tcm), or stratum 5 (dual delivery of IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ naive and memory T cells \[Tn/mem\]).

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 IIIa. Estimate the six month progression free survival rate. IIIb. Estimate disease response rates. IIIc. Estimate median overall survival.

IV. In research participants who receive intraventricular infusions after progressing following intratumoral/intracranial infusions (stratum 1 or 2):

IVa. Estimate disease response. IVb. Describe CAR T cell and endogenous immune populations, as well as cytokine and microenvironment profiles (cerebral spinal fluid \[CSF\], cyst fluid, peripheral blood) considering post progression therapy(ies), if applicable.

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 research participants who undergo a second resection or autopsy:

VIa. To evaluate CAR T cell persistence in the tumor micro-environment and the location of the CAR T cells with respect to the injection.

VII. To evaluate IL13R alpha 2 antigen expression levels pre and post CAR T cell therapy.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 5 strata.

STRATUM I (Intratumoral delivery) CLOSED TO ACCRUAL 03/02/2018: Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions.

STRATUM II (Intracavitary delivery): Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intracavitary catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients 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.

STRATUM III (Intraventricular delivery): Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available.

STRATUM IV (Dual delivery): Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

STRATUM V (Dual delivery): Patients receive IL13 \[EQ\]BBzeta/truncated CD19\[t\]+ Tn/mem via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

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.

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

Phase I Study of Cellular ImmunoTx Using Memory Enriched T Cells Lentivirally Transduced to Express an IL13Rα2-Specific, Hinge-Optimized, 41BB-Costimulatory Chimeric Receptor and a Truncated CD19 for Pts With Rec/Ref MaligGlioma

Will be graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0, the revised cytokine release syndrome grading system as well as the modified neurological grading system.

Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval) will be estimated for participants' experiencing DLTs at the recommended phase II dosing plan schedule.

Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and strata.

Descriptive statistics will be provided for brain inflammation (largest length of tumor) pre and post treatment.

Statistical and graphical methods will be used to describe the cytokine levels (cyst fluid, peripheral blood) over the study period.

Statistical and graphical methods will be used to describe the CAR T cell levels (cyst fluid, peripheral blood) over the study period.

Kaplan Meier methods will be used to estimate median PFS and graph the results.

Will be detected peripheral blood and cerebral spinal fluid.

Kaplan Meier methods will be used to estimate median overall survival and graph the results. OS will also be examined for all patients, as well as, separately for those that received initial treatment only and those that received intraventricular infusion following progression.

Estimate the mean and standard error for change from baseline during treatment and post treatment in the quality of life functioning scale, symptom scale and item scores from the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and the domain scale and items scores from the QLQ-brain neoplasm20.

In study participants that undergo a second resection or following autopsy, T cells numbers, location, and antigen levels will be described.

National Cancer Institute (NCI)

Food and Drug Administration (FDA)

City of Hope Medical Center

Oligodendroglioma

Gliosarcoma

Anaplastic Astrocytoma

Anaplastic Oligodendroglioma

Oligoastrocytoma

Anaplastic Oligoastrocytoma

Irinotecan

Camptothecin

Topoisomerase I Inhibitors

Patients receive carboxylesterase-expressing allogeneic neural stem cells intracranially over 1.5-4.5 hours on days 1 and 15 (day 1 only for patients at dose level 1) and irinotecan hydrochloride IV over 90 minutes on days 3 and 17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Carboxylesterase-expressing Allogeneic Neural Stem Cells

Irinotecan Hydrochloride

Pharmacological Study

Jana L Portnow

This phase I trial studies the side effects and best dose of carboxylesterase-expressing allogeneic neural stem cells when given together with irinotecan hydrochloride in treating patients with high-grade gliomas that have come back. Placing genetically modified neural stem cells into brain tumor cells may make the tumor more sensitive to irinotecan hydrochloride. Irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving carboxylesterase-expressing allogeneic neural stem cells and irinotecan hydrochloride may be a better treatment for high-grade gliomas.

PRIMARY OBJECTIVE:

I. To define the recommended phase II doses (RP2D) of intracranially administered carboxylesterase-expressing allogeneic neural stem cells (hCE1m6-NSCs) in combination with intravenous irinotecan in patients with recurrent high grade glioma.

SECONDARY OBJECTIVES:

I. To describe the relationship between hCE1m6-NSC dose and SN-38 (SN-38) concentrations in brain interstitium.

II. To characterize the relationship between intracerebral and systemic concentrations of irinotecan (irinotecan hydrochloride) and SN-38.

III. To investigate the biologic activity of hCE1m6 NSCs by comparing SN-38 concentrations in the brain after treatment with hCE1m6-NSCs and irinotecan versus irinotecan alone.

IV. To assess for possible development of adenovirally transduced neural stem cell (NSC) immunogenicity after first exposure and with repeat doses of NSCs.

V. To describe the clinical benefit (defined as stable disease, partial response, or complete response) in patients who receive treatment with repeat cycles of NSCs and irinotecan.

VI. To determine, at time of autopsy, the fate of the NSCs.

OUTLINE: This is a dose-escalation study of carboxylesterase-expressing allogeneic neural stem cells.

Patients receive carboxylesterase-expressing allogeneic neural stem cells intracranially over 1.5-4.5 hours on days 1 and 15 (day 1 only for patients at dose level 1) and irinotecan hydrochloride intravenously (IV) over 90 minutes on days 3 and 17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, 3 and 6 months, and then annually thereafter for a minimum of 15 years.

Carboxylesterase-Expressing Allogeneic Neural Stem Cells and Irinotecan Hydrochloride in Treating Patients With Recurrent High-Grade Gliomas

A Phase I Study of Intracranially Administered Carboxylesterase-Expressing Neural Stem Cells in Combination With Intravenous Irinotecan in Patients With Recurrent High-Grade Gliomas

Toxicities will be graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. A DLT is defined as an adverse event that is related to the administration of NSCs and/or irinotecan, occurs during the first treatment cycle and meets any of the following:

1. Received less than 80% of study treatments except due to CNS toxicity
2. Grade 4 thrombocytopenia or anemia or neutropenia lasting \> 7 days
3. Febrile neutropenia with ANC \< 0.5 x10\^9/L
4. Grade 3 central nervous system (CNS) disorder lasting \> 7 days not attributed to tumor or surgery and not present at baseline
5. Second occurrence of grade 3 CNS disorder not attributed to tumor or surgery and not present at baseline
6. Any grade 4 CNS disorder not attributed to tumor or surgery and not present at baseline
7. Grade 3 toxicity despite therapy lasting \> 7 days
8. Grade 3 toxicity resulting in study agent discontinuation
9. Grade 4 toxicity, except grade 4 diarrhea responding to therapy within 3 days

Grade 3 or higher toxicity profile as assessed by the NCI CTCAE version version 4.0. Toxicities reported are possibly, probably or definitely related to NSCs.

Grade 3 or higher toxicity profile as assessed by the NCI CTCAE version version 4.0. Toxicities reported are possibly, probably or definitely related to Irinotecan.

Pharmacokinetic data from patients who undergo intracerebral microdialysis will be summarized using descriptive statistics. hCE1m6-NSC dose and liposomal SN-38 concentrations in brain interstitium using microdialysis data from the patients treated with the initial neural stem cells (NSC) doses and from the patients in the cohort treated with the highest NSC dose. Ratios are reported as ratio x 100.

Pharmacokinetic data from patients who undergo intracerebral microdialysis will be summarized using descriptive statistics. hCE1m6-NSC dose and liposomal SN-38 concentrations in brain interstitium using microdialysis data from the patients treated with the initial neural stem cells (NSC) doses and from the patients in the cohort treated with the highest NSC dose. Ratio is reported as ratio x 100

Clinical benefit is defined by participants achieving stable disease (SD), partial response (PR), or complete response (CR).

CR: Complete disappearance of all enhancing disease (measurable and nonmeasureable) that is sustained for at least 4 weeks, stable or improved non-enhancing FLAIR/T2 lesions, no new lesions, off corticosteroids (physiologic replacement doses allowed), and neurologically stable or improved.

PR: ≥ 50% decrease of all measurable enhancing lesions, sustained for at least 4 weeks, no progression of non-measurable disease, stable or improved non-enhancing FLAIR/T2 lesions, no new lesions, corticosteroid dose stable or reduced (compared to baseline), and neurologically stable or improved.

SD: Does not qualify for CR, PR, or PD, stable non-enhancing FLAIR/T2 lesions, stable or reduced corticosteroids (compared to baseline), clinically stable.

Carboxylesterase-expressing Allogeneic Neural Stem Cells: Given intracranially, 5x10\^7 (1 dose)

Irinotecan: 180 mg/m2

Dose Level 1: 5x10^7 (1 Dose)

Carboxylesterase-expressing Allogeneic Neural Stem Cells: Given intracranially, 5x10\^7 (2 doses)

Irinotecan: 180 mg/m2

Dose Level 2: 5x10^7 (2 Doses)

Carboxylesterase-expressing Allogeneic Neural Stem Cells: Given intracranially, 1x10\^8 (2 doses)

Irinotecan: 180 mg/m2

Dose Level 3: 1x10^8 (2 Doses)

Carboxylesterase-expressing Allogeneic Neural Stem Cells: Given intracranially, 1.5x10\^8 (2 doses)

Irinotecan: 180 mg/m2

Dose Level 4: 1.5x10^8 (2 Doses)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Tumor Type

Dr. Jana Portnow

1 participant in each of dose levels 1, 3, and 4 was not evaluable for DLT because they were removed from the study due to adverse events not related to study treatment.

Number of Participants Experiencing a Dose-limiting Toxicity (DLT)

Number of Participants With Grade 3 or Higher Toxicity Profile Attributed to NSCs

Fatigue

Platelet count decreased

White blood cell decreased

Meningitis

Hypophosphatemia

Brain abscess

Catheter related infection

Number of Participants With Grade 3 or Higher Toxicity Profile Attributed to Irinotecan

All 4 participants in dose level 3 and one participant in dose level 4 did not have plasma samples collected.

Median Ratio of SN-38 Area Under the Curve (AUC) to CPT-11 AUC in Plasma

All 4 participants in dose level 3 did not have brain samples collected.

Median Ratio of SN-38 AUC to CPT-11 AUC in the Brain

1 participant in dose levels 1 and 3 and 2 is dose level 4 were unevaluable for response due to not receiving the full treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combination Therapy for the Treatment of Diffuse Midline Gliomas	NCT05009992	Diffuse Intrins... Diffuse Midline... Recurrent Diffu... Recurrent Diffu... Recurrent WHO G... WHO Grade III G...	ONC201 Radiation Thera... Paxalisib	2 Years - 39 Years	University of California, San Francisco
Fluoroethyltyrosine for Evaluation of Intracranial Neoplasms	NCT04044937	Intracranial Ne... Low Grade Gliom... Recurrent Gliob... Recurrent World... Recurrent WHO G...	F-18 Fluoroethy... Positron Emissi...	3 Years -	University of California, San Francisco
Genetically Modified T-cells in Treating Patients With Recurrent or Refractory Malignant Glioma	NCT02208362	Recurrent Gliob... Recurrent Malig... Recurrent WHO G... Recurrent WHO G... Refractory Glio... Refractory Mali... Refractory WHO ... Refractory WHO ...	IL13Ralpha2-spe... IL13Ralpha2-spe... Laboratory Biom... Magnetic Resona... Magnetic Resona... Quality-of-Life...	12 Years - 75 Years	City of Hope Medical Center
Carboxylesterase-Expressing Allogeneic Neural Stem Cells and Irinotecan Hydrochloride in Treating Patients With Recurrent High-Grade Gliomas	NCT02192359	Recurrent Anapl... Recurrent Anapl... Recurrent Anapl... Recurrent Gliob... Recurrent Glios... Recurrent Malig... Recurrent WHO G...	Carboxylesteras... Irinotecan Irinotecan Hydr... Laboratory Biom... Pharmacological...	18 Years - 69 Years	City of Hope Medical Center
BGB-290 and Temozolomide in Treating Patients With Recurrent Gliomas With IDH1/2 Mutations	NCT03914742	IDH1 Mutation IDH2 Mutation Recurrent Gliob... Recurrent WHO G... Recurrent WHO G...	PARP Inhibitor ... Temozolomide Therapeutic Con...	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Serial MR Imaging and MR Spectroscopic Imaging for the Characterization of Lower Grade Glioma	NCT04540107	Recurrent World... Recurrent WHO G... WHO Grade II Gl... WHO Grade III G...	Hyperpolarized ... Magnetic Resona... Magnetic Resona...	18 Years -	University of California, San Francisco
Multiple Doses of Neural Stem Cell Virotherapy (NSC-CRAd-S-pk7) for the Treatment of Recurrent High-Grade Gliomas	NCT05139056	Recurrent Anapl... Recurrent Anapl... Recurrent Anapl... Recurrent Gliob... Recurrent Glios... Recurrent Malig... Recurrent WHO G... Recurrent WHO G...	Neural Stem Cel... Resection	18 Years -	City of Hope Medical Center

Spots Global Cancer Trial Database for recurrent who grade iii glioma