Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Dermatologic Agents

Antibodies

Antibodies, Monoclonal

Nivolumab

Ipilimumab

Immunoglobulins

Isotretinoin

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over 90 minutes on day -14. Patients then receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/intracranital ICT) every week and nivolumab IV over 30 minutes every other week. Treatment repeats weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may receive additional CAR T cells weekly and nivolumab IV every other week or monthly at the discretion of the principal investigator and oncologist.

Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every week and nivolumab IV over 30 minutes every other week. Treatment repeats weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may receive additional CAR T cells weekly and nivolumab IV every other week or monthly at the discretion of the principal investigator and oncologist.

Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every week. Treatment repeats weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may receive additional CAR T cells weekly at the discretion of the principal investigator and oncologist.

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

Quality-of-Life Assessment

Questionnaire Administration

Behnam Badie

This phase I trial studies the side effects and how well IL13Ralpha2-CAR T cells work when given alone or together with nivolumab and ipilimumab in treating patients with glioblastoma that has come back (recurrent) or does not respond to treatment (refractory). Biological therapies, such as IL13Ralpha2-CAR T cells, use substances made from living organisms that may attack specific glioma cells and stop them from growing or kill them. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving IL13Ralpha2-CAR T cells and nivolumab together may work better in treating patients with glioblastoma.

PRIMARY OBJECTIVES:

I. To examine and describe the safety and feasibility of nivolumab plus ipilimumab as neoadjuvant therapy. (Arm 1) II. To examine and describe the safety and feasibility of IL13Ralpha2-CAR T cell plus nivolumab as adjuvant therapy. (Arms 1 and 2) III. To provide IL13Rα2-CAR T cell therapy for subjects who are unable to wait for randomization into Arms 1 and 2. This arm will provide additional safety data provided in COH IRB 13384 for the set dose schedule. (Arm 3) III. In arms determined to be safe and feasible, a selection design based on two Southwest Oncology Group (SWOG) two stage designs will be used to assess which arm(s) goes on for further study based on survival rate at 9 months.

SECONDARY OBJECTIVES:

I. Describe persistence, expansion and phenotype of endogenous and IL13Ralpha2-CAR CAR T cells in tumor cyst fluid (TCF), peripheral blood (PB), and cerebral spinal fluid (CSF).

II. Describe cytokine levels (PB, TCF, CSF) over the study period for each arm. (Arm 1 or Arm 2).

III. Estimate disease response rates. IV. Estimate time to progression. V. Estimate median overall survival (OS).

VI. In study participants who have completed the adjuvant dose-limiting toxicity (DLT) period:

VIa. 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-Core (QLQ-C)30 and EORTC QLQ Brain Cancer Patients (BN-20) survey scale, domain and item scores during and post treatment.

VIb. Assess if the area under the curve (AUC) for CD3 T cells, IFNgamma and IP-10 for the DLT period is greater in one arm versus (vs.) the other.

VII. In study participants who undergo an additional biopsy/resection or autopsy:

VIIa. Evaluate CAR T cell persistence in the tumor tissue and the location of the CAR T cells with respect to the injection, and VIIb. Evaluate IL13Ralpha2 antigen and PD-L1 levels on tumor tissue pre and post CAR T cell therapy.

VIII. Use biomathematical modeling of tumor growth to evaluate benefit of treatment.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over 90 minutes on day -14. Patients then receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (intracranial intraventricular \[ICV\]/intracranial intratumoral \[ICT\]) every week and nivolumab IV over 30 minutes every other week. Treatment repeats weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may receive additional CAR T cells weekly and nivolumab IV every other week or monthly at the discretion of the principal investigator and oncologist.

ARM II: Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every week and nivolumab IV over 30 minutes every other week. Treatment repeats weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may receive additional CAR T cells weekly and nivolumab IV every other week or monthly at the discretion of the principal investigator and oncologist.

ARM III: Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (intracranial intraventricular \[ICV\]/intracranial intratumoral \[ICT\]) every week. Treatment repeats weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4, patients may receive additional CAR T cells weekly at the discretion of the principal investigator and oncologist.

After completion of study treatment, patients are followed up at 30 days, 3, 6, and 12 months, and then annually for 15 years.

IL13Ra2-CAR T Cells With or Without Nivolumab and Ipilimumab in Treating Patients With GBM

A Phase 1 Study to Evaluate IL13Rα2-Targeted Chimeric Antigen Receptor (CAR) T Cells Combined With Checkpoint Inhibition for Patients With Resectable Recurrent Glioblastoma

Will assess dose limiting toxicity and all toxicities. Toxicity is the primary endpoint and will be assessed using the National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Rates and associated 95% Clopper and Pearson binomial confidence limits (95% confidence interval \[CI\]) will be estimated for participants' experiencing dose limiting toxicity (DLT) during neoadjuvant treatment period (DLT period 1), during adjuvant treatment period (DLT period 2), neo-adjuvant and adjuvant feasibility, as well as survival at 9 months. All toxicities and side effects will be summarized in tables by dose, time period, organ, and severity.

A toxicity that causes side effects that are serious enough to prevent an increase in dose or level of that treatment.

As measured by the ability of patients receive ipilimumab/nivolumab (\> 80% of the assigned doses) and undergo undergo surgery so that they can go on to receive the first dose of CAR T cells.

Defined as the ability of patients to complete 4 cycles of CAR T infusions (\> 80% of the assigned dose) and 2 doses of nivolumab.

The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive.

Will assess chimeric antigen receptor (CAR) T and endogenous T cell levels and phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebral spinal fluid (CSF) (absolute number per ul by flow). Statistical and graphical methods will be used to describe persistence and expansion.

Statistical and graphical methods will be used to describe persistence and expansion.

By Response Assessment in Neuro-Oncology (RANO) criteria with the need for Avastin as an additional indicator of progression.

Progression is defined by RANO with the need for Avastin as an additional indicator of progression.

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

Will 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 Quality of Life Questionnaire Core 30 and the domain scale and items scores from the Quality of Life Questionnaire Brian Tumor Patients 20. Will be estimated for each treatment arm.

A two-tailed two-sample Students T test with a 0.05 level of significance will be used to determine if the AUCs over the adjuvant treatment DLT period (DLT period 2) for CD3, IFNgamma, and IP-10 are higher in one arm over the other.

Will assess perfusion and growth parameters based on serial brain magnetic resonance imaging (MRI)s.

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

National Cancer Institute (NCI)

City of Hope Medical Center

Nervous System Diseases

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Bevacizumab

Carboplatin

Temozolomide

Lomustine

Dianhydrogalactitol

Antineoplastic Agents, Alkylating

Alkylating Agents

Up to 120 eligible patients will be randomized to receive VAL-083.

Up to 60 patients will be randomized to receive "Investigator's choice of salvage therapy" temozolomide, lomustine, or carboplatin

VAL-083 given by intravenous infusion at a dose 40 mg/m2 IV on days 1, 2, and 3 of a 21-day treatment-cycle, for up to 12, 21-day treatment cycles

VAL-083, Dianhydrogalactitol

The product label for temozolomide (Temodar®) provides the following dosing information.

Newly Diagnosed GBM: 75 mg/m2 for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days 1-5 of a 28-day cycle of Temodar® for 6 cycles.

Refractory Anaplastic Astrocytoma: Initial dose 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle.

Physician's Choice of Salvage Therapy - temozolomide

The product label for lomustine (CeeNu; lomustine; CCNU) provides the following dosing information.

The recommended dose of lomustine in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m2 as a single oral dose every 6 weeks In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2 every 6 weeks.

Physician's Choice of Salvage Therapy - lomustine

The product label for (Paraplatin) carboplatin Injection provides the following dosing information.

As a single agent at a dosage of 360mg/m2 IV on day 1 every 28 days Alternatively, the carboplatin dose may be calculated by the Calvert formula below Calvert formula for carboplatin dosing: Total Dose (mg) = (target AUC) x (GFR + 25), where AUC = area under the curve and GFR = glomerular filtration rate.

Physician's Choice of Salvage Therapy - carboplatin

Nicholas Butowski, M.D.

This is an adaptive design, randomized controlled, Phase 3 clinical trial in patients with glioblastoma multiforme (GBM) or gliosarcoma (GS), previously treated with surgery (if appropriate), standard of care chemo-radiation with temozolomide, +/- adjuvant temozolomide, and bevacizumab and now has progressive disease during or after bevacizumab.

A total of up to 180 eligible patients with recurrent/progressive GBM or GS will be randomized to receive either the investigational drug (VAL-083) or "Investigator's choice of salvage therapy" as a contemporaneous control, in a 2:1 fashion. Up to 120 eligible patients will be randomized to receive VAL-083 at 40 mg/m2 IV on days 1, 2, and 3 of a 21-day treatment-cycle, for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation. Up to 60 patients will be randomized to receive "Investigator's choice of salvage therapy", limited to temozolomide, lomustine, or carboplatin, until they fulfill one of the criteria for study discontinuation. The dose level for Investigator's choice salvage therapy (temozolomide, lomustine, or carboplatin), will be in accordance with the product label or institutional guidelines.

In both study arms, interval medical histories, targeted physical exams, neurologic evaluations, complete blood counts, and other laboratory and safety assessments will be performed approximately every 21-days while receiving treatment. Tumor assessments are to be performed approximately every 42 ± 7 days while remaining on study. The study is estimated to last approximately 20 months.

This is an adaptive, randomized controlled, Phase 3 clinical trial in adult patients with histologically confirmed diagnosis of a recurrent glioblastoma multiforme (GBM) or gliosarcoma (GS), who have been previously treated with surgery (if appropriate), standard of care chemo-radiation with temozolomide, +/- adjuvant temozolomide, and bevacizumab and now have progressive disease during or after bevacizumab. Patients with prior low-grade glioma or anaplastic glioma are eligible, if histologic assessment demonstrates transformation to GBM or GS.

Treatment Groups: Eligible patients will be randomized to receive either the investigational drug (VAL-083) or "Investigator's choice of salvage therapy" as a contemporaneous control, in a 2:1 fashion. A total of up to 180 patients with recurrent/progressive GBM or GS will be enrolled; patients will be randomized to one of two treatment arms as follows:

Group 1: Up to 120 eligible patients will be randomized to receive VAL-083 at 40 mg/m2 IV on days 1, 2, and 3 of a 21-day treatment-cycle, for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation (death, intolerable toxicities, investigator's judgment, or withdrawal of consent). In patients who demonstrate response, stable disease or who continue therapy at the discretion of the investigator following initial progression and tolerate therapy, permission to continue treatment beyond 12 cycles will be considered but will require consent of the Sponsor. VAL-083 will be administered as an IV infusion over 30-60 minutes.

Group 2: Up to 60 patients will be randomized to receive "Investigator's choice of salvage therapy" until they fulfill one of the criteria for study discontinuation (death, intolerable toxicities, investigator's judgment, or withdrawal of consent). "Investigator's choice of salvage therapy" will be limited to the following: temozolomide, lomustine, or carboplatin. The dose level for Investigator's choice salvage therapy (temozolomide, lomustine, or carboplatin), will be in accordance with the product label or institutional guidelines.

In both arms, disease status will be evaluated with clinical and imaging evaluation. Baseline total tumor burden must be assessed by MRI within 2 weeks prior to randomization. For patients randomized to VAL-083, post-baseline tumor assessments are to be performed prior to every other 21-day cycle for VAL-083, i.e., prior to Cycles 3, 5, etc., while the patient is receiving VAL-083 treatment, and then approximately every 42 ± 7 days while remaining on study. For patients randomized to the Physician's choice salvage therapy arm, post-baseline tumor assessments are to be performed approximately every 42 ± 7 days while remaining on study, as long as the patient continues to demonstrate response or stable disease or comes off the study.

In both study arms, assessments will include interval medical histories, Karnofsky Performance Status, physical and neurological examinations, vital signs, weight, adverse events, hematology and serum biochemistry, pregnancy test (females), urinalysis, chest x-ray and EKG approximately every 21-days while receiving treatment, as well as MDASI-BT self-reporting assessment when MRI tumor measurements are performed.

In a subgroup of 60 study subjects receiving VAL-083, blood samples will be obtained to determine population pharmacokinetics at pre-dose Cycle 1 Day 1, then at post-infusion on Cycle 1 Day 1, Cycle 1 Day 3, Cycle 2 Day 1 and Cycle 3 (or Cycle 4) Day 1 (or Day 3) in accordance with the study subject's assigned sampling block. EKGs will be taken pre-dose and approximately 10 minutes post-infusion Cycle 1 Day 1, prior to the 15 min (15 ± 5 min) blood draw for PK assessment, as well as pre-dose and approximately 10 minutes post-infusion Cycle 1 Day 3, prior to the 15 min (15 ± 5 min) blood draw for PK.

In a separate sub-group of 15 study subjects receiving VAL-083, blood will be drawn from Cycle 1 Day 1 and Cycle 1 Day 3 of dosing for determination of plasma levels of VAL-083 over the first 6 hours after the end of infusion (i.e., 0.25, 0.5, 1, 2, 4 and 6 hr). Trough levels 24 hr after infusion will also be obtained in these subjects. EKGs will be taken pre-dose and approximately 10 minutes post-infusion Cycle 1 Day 1, prior to the 15 min (15 ± 5 min) blood draw for PK assessment, as well as pre-dose and approximately 10 minutes post-infusion Cycle 1 Day 3, prior to the 15 min (15 ± 5 min) blood draw for PK.

Patients will be followed until death to ensure adequate power (90%) for the primary analysis.

Toxicity will be evaluated and documented using the NCI CTCAE version 4.

Quality of life will be evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT). This questionnaire will be completed by patients at baseline and at the time of each imaging evaluation, until progression.

The study is estimated to take approximately 20 months, including 18 months to enroll 180 patients and another 2 months to reach 125 events (deaths).

VAL-083 Phase 3 Study in Temozolomide-Avastin (Bevacizumab) Recurrent GBM

A Pivotal Randomized, Controlled Trial of VAL-083 in Patients With Recurrent Glioblastoma Who Have Failed Standard Temozolomide/Radiation Therapy and Bevacizumab (STAR-3)

The Clinical Study Report for this trial will be prepared upon completion of trial and provided to U.S. F.D.A. as required by applicable regulatory requirement(s). Each participating trial investigator will be provided a copy their patient data captured in the electronic data base for this trial. Data will include overall survival (OS), progression-free survival (PFS) at 6 months, median PFS, OS at 6 and 9 months, overall response rate (ORR), duration of response (DOR), disease control rate (DCR), occurrence of disease symptoms and evaluation of quality of life (QOL) measures during the progression-free period for VAL-083, compared to Investigator choice salvage therapy. Also, the safety and toxicity profile as well as pharmacokinetics of VAL-083 will be summarized.

Time from patient randomization to patient death

Time from patient randomization to first occurrence of disease progression (per RANO criteria) or death, whichever occurs first.

Time from the patient's first occurrence of a documented, objective response (confirmed Complete Response or Partial Response) until the time of relapse (per RANO criteria) or death from any cause

Time from patient randomization through 28 days following last study treatment received by patient. Safety will be assessed through summaries of AEs, changes in laboratory test results, ECGs, and changes in vital signs for all patients who receive any amount of VAL-083 or Physician's choice salvage therapy

Maximum observed plasma concentration of VAL-083 in a sub-group of 15 study subjects receiving VAL-083

Time of maximum observed plasma concentration of VAL-083 in a sub-group of 15 study subjects receiving VAL-083

Area under the concentration-time curve from pre-dose (time 0) to the time of the last quantifiable concentration of VAL-083 in plasma for a sub-group of 15 study subjects receiving VAL-083

Area under the concentration-time curve extrapolated to infinity for VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

Total oral body clearance at steady state for VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

AUMC/AUC for VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083, where AUMC is Area Under the Moment Curve

Volume of distribution during the terminal phase of VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

Terminal elimination rate constant determined by selection of at least 3 decreasing data points on the terminal phase of the concentration-time curve for VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

Terminal elimination half-life of VAL-083 in plasma of a sub-group of 15 study subjects receiving VAL-083

Evaluate patient quality of life from time of patient randomization to first occurrence of disease progression (per RANO criteria) or death, whichever occurs first.

DelMar Pharmaceuticals, Inc.

Disease Attributes

Temozolomide will be given to patients orally every 5 days with 23 days interval. The initial dose is 150 mg/m2 on the first day and 200 mg/m2 for the rest if no toxicity is seen. If 200 mg/m2 is toxic, the drug will return to 150 mg/m2 or will be stopped.

Temozolomide will be given to patients orally every 5 days with 23 days interval. The initial dose is 150 mg/m2 on the first day and 200 mg/m2 for the rest if no toxicity is seen. If 200 mg/m2 is toxic, the drug will return to 150 mg/m2 or will be stopped.

The B7-H3 CAR-T will be administrated via intratumoral or Intracerebroventricular injection through an Ommaya catheter in between Temozolomide cycles. Temozolomide treatment in the cycles of B7-H3 CAR-T treatment will be stopped.

Temozolomide is an FDA-approved drug that is given to patients

B7-H3-targeting CAR-T cells derived from patient own peripheral blood mononuclear cells will be given to patients via intracerebral injection though an Ommaya catheter

B7-H3 CAR-T

Jianmin Zhang, MD

Zhongzhou Su, MD

Feng Gao, MD

This is a randomized, parallel-arm, phase I/II study to evaluate the safety and efficacy of B7-H3 CAR-T in between Temozolomide cycles comparing to Temozolomide alone in treating patients with glioblastoma that has come back or does not respond to the standard treatment. The antigen B7-H3 is highly expressed in glioblastoma of a subset of patients. B7-H3 CAR-T, made from isolated patient peripheral blood mononuclear cells, can specifically attack patient glioblastoma cells that expressing B7-H3.

Background

* B7-H3 is expressed in 70% of patients with glioblastoma
* B7-H3 is not expressed in normal tissues especially not in central nervous system. Therefore, it is an attractive GBM target for CAR-T therapy
* The investigators constructed a retroviral vector encoding a chimeric antigen receptor (CAR) targeting B7-H3, which can mediate CAR transfer into patient T cells with high efficiency.

Objectives

* To evaluate the safety and tolerability intratumoral/intracerebroventricular injection of B7-H3 CAR-T when used in between Temozolomide cycles
* To compare the overall survival (OS) and progression-free survival (PFS) of R/R GBM patients treated with B7-H3 CAR-T in between Temozolomide cycles vs Temozolomide alone
* To access the pharmacokinetics and pharmacodynamics of B7-H3 CAR-T in between Temozolomide cycles

Design

* Experimental group: Patients autologous T cells are activated and transduced with retrovirus containing B7-H3 CAR. CAR-T cells are expanded ex vivo and infused back to patients via intratumoral or intracerebroventricular injection through an Ommaya catheter. 3 injections of CAR-T are planned at two different doses with 1-2 weeks intervals. The CAR-T injections occur in between Temozolomide (TMZ) cycles. Temozolomide treatment during the cycles of CAR-T injections will be stopped and resumed next cycle. Patients may receive additional CAR-T cycles at the discretion of the principal investigator and oncologist.
* Control group: Patients will receive regular cycles of Temozolomide treatment with 5 days of treatment and 23 days of interval.

B7-H3 CAR-T for Recurrent or Refractory Glioblastoma

B7-H3-Targeted Chimeric Antigen Receptor (CAR) T Cells in Treating Patients With Recurrent or Refractory Glioblastoma

The concentration of cytokines (IL-1, IL-2, IL-6, IL-10, TNF-α, IFN-γ) in PB and CSF

The chimeric antigen receptor (CAR) T and endogenous T cell levels and memory/effector phenotype detected in peripheral blood (PB), and cerebral spinal fluid (CSF) (absolute number per ul). Statistical and graphical methods will be used to describe persistence and expansion

Kaplan Meier methods will be used to estimate median OS

Number of Participants With Treatment-Related Adverse Events and Types of adverse events as Assessed by CTCAE v4.0

The highest dose of B7-H3 CAR-T that does not cause targeted dose-limiting toxicity

Kaplan Meier methods will be used to estimate median PFS. Progression is defined by Response Assessment in Neuro-Oncology (RANO) criteria

Peak Concentration (Cmax) of B7-H3 CAR-T in peripheral blood (PB) and cerebral spinal fluid (CSF)

Area under the concentration versus time curve (AUC) of B7-H3 CAR-T in peripheral blood (PB) and cerebral spinal fluid (CSF)

Objective Response Rate (ORR) will be assessed by comparison with baseline magnetic resonance imaging by RANO. Complete Response (CR) is disappearance of all measurable and non-measurable disease for at least 4 weeks. Partial Response (PR) is \>/= 50% decrease in lesions for at least 4 weeks. Duration of Response (DOR) is the time between the initial response to the treatment and subsequent disease progression.

Ningbo Yinzhou People's Hospital

Huizhou Municipal Central Hospital

BoYuan RunSheng Pharma (Hangzhou) Co., Ltd.

Second Affiliated Hospital, School of Medicine, Zhejiang University

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

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

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.

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.

Food and Drug Administration (FDA)

Patients will received regular cycles of Temozolomide treatment with 5 days of treatment and 23 days of interval. 3 infusions of B7-H3 CAR-T with 1-2 weeks of interval will be used in between cycles of Temozolomide treatment. Temozolomide treatment during B7-H3 CAR-T infusions will be stopped and resumed after CAR-T infusion.

The B7-H3 CAR-T will be administrated via intratumoral or Intracerebroventricular injection through an Ommaya catheter in between Temozolomide cycles. Temozolomide will be stopped during the infusion of B7-H3 CAR-T

This is a pilot phase I study to evaluate the safety and efficacy on B7-H3 CAR-T in between Temozolomide cycles in treating patients with glioblastoma that has come back or does not respond to the standard treatment. The antigen B7-H3 is highly expressed in glioblastoma of a subset of patients. B7-H3 CAR-T, made from isolated patient peripheral blood mononuclear cells, can specifically attack patient glioblastoma cells that expressing B7-H3.

Background

* B7-H3 is expressed in 70% of patients with glioblastoma
* B7-H3 is not expressed in normal tissues especially not in central nervous system. Therefore, it is an attractive GBM target for CAR-T therapy
* The investigators constructed a retroviral vector encoding a chimeric antigen receptor (CAR) targeting B7-H3, which can mediate CAR transfer into patient T cells with high efficiency.

Objectives

* To evaluate the safety and tolerability intratumoral/intracerebroventricular injection of B7-H3 CAR-T when used in between Temozolomide cycles
* To compare the overall survival (OS) and progression-free survival (PFS) of R/R GBM patients treated with B7-H3 CAR-T in between Temozolomide cycles to the historical Temozolomide data
* To access the pharmacokinetics and pharmacodynamics of B7-H3 CAR-T in between Temozolomide cycles

Design

Patients autologous T cells are activated and transduced with retrovirus containing B7-H3 CAR. CAR-T cells are expanded ex vivo and infused back to patients via intratumoral or intracerebroventricular injection through an Ommaya catheter. 3 injections of CAR-T are planned at two different doses with 1-2 weeks intervals. The CAR-T injections occur in between Temozolomide (TMZ) cycles. Temozolomide treatment in the cycle of CAR-T injections will be stopped and resumed next cycle. Patients may receive additional CAR-T cycles at the discretion of the principal investigator and oncologist.

Pilot Study of B7-H3 CAR-T in Treating Patients With Recurrent and Refractory Glioblastoma

A Pilot Study of Chimeric Antigen Receptor (CAR) T Cells Targeting B7-H3 Antigen in Treating Patients With Recurrent and Refractory Glioblastoma

The chimeric antigen receptor positive (CAR+) T cell and memory/effector T cell percentages and cell counts detected in peripheral blood (PB), and cerebral spinal fluid (CSF). Statistical and graphical methods will be used to describe persistence and expansion

The highest dose of B7-H3 CAR-T that does not cause targeted dose limiting toxicity

Maintenance chemotherapy with TMZ will be administered at 150-200 mg/m2/day for 5 days in each 28-day cycle.And elemene injectable emulsion will be given for 80 -120 ml/day in each 14-day cycle or 21-day cycle.

Maintenance chemotherapy with TMZ will be administered at 150-200 mg/m2/day for 5 days in each 28-day cycle.

Elemene injectable emulsion will be given for 80 mg/day in each 14-day cycle.

Elemene

Maintenance chemotherapy with TMZ will be administered at 150 mg/m2/day for 5 days in each 28-day cycle.

This is a pilot phase I study to evaluate the safety and efficacy on elemene injectable emulsion in treating patients with glioblastoma. Elemene, isolated from the Chinese medicinal herb Curcuma wenyujin, was shown to exhibit antitumor activity in human and murine tumor cells in vitro and in vivo.Elemene injectable emulsion against malignant tumors was low. Therefore, the effect of Elemene injectable emulsion being used in clinical settings needs to be confirmed by further RCTs.

Background

* Elemene, isolated from the Chinese medicinal herb Curcuma wenyujin, was shown to exhibit antitumor activity in human and murine tumor cells in vitro and in vivo
* The study shows that the methodological quality of RCTs of Elemene injectable emulsion against malignant tumors was low. Therefore, the effect of Elemene injectable emulsion being used in clinical settings needs to be confirmed by further RCTs

Objectives

* To evaluate the safety of Elemene injectable emulsion to treat Refractory Glioblastoma with TMZ
* To evaluate the efficacy of Elemene injectable emulsion to treat Refractory Glioblastoma with TMZ

Design

This clinical trail is a randomized controlled trial.In control group,patients will receive TMZ-chemotherapy.In experimental group,patients will receive elemene injectable emulsion and TMZ-chemotherapy at the same time.

Pilot Study of Elemene in Treating Patients With Refractory Glioblastoma

A Pilot Study of Elemene Injectable Emulsion in Treating Patients With Refractory Glioblastoma

Kaplan Meier methods will be used to estimate median OS.

Kaplan Meier methods will be used to estimate median PFS. Progression is defined by Response Assessment in Neuro-Oncology (RANO) criteria.

Objective Response Rate (ORR) will be assessed by comparison with baseline magnetic resonance imaging by RANO.

Complete Response (CR) is disappearance of all measurable and non-measurable disease for at least 4 weeks.

Partial Response (PR) is ≥ 50% decrease in lesions for at least 4 weeks.

Duration of Response (DOR) is the time between the initial response to the treatment and subsequent disease progression.

Hangzhou Normal University

VAL-083 given by intravenous infusion with a starting dose of 1.5 mg/m2 IV. Escalating doses to be administered in sequential dose cohorts.

VAL-083 (Dianhydrogalactitol)

Howard A Burris, M.D.

Manish Patel, M.D.

Sani Kizilbash, M.D.

Gerald Falchook, M.D.

The purpose of this Phase 1/2, open-label, single-arm study is to determine the safety and the maximal tolerated dose (MTD) of VAL-083 in patients with recurrent malignant glioma. Pharmacokinetic (PK) properties will be explored and tumor responses to treatment will be evaluated.

Recurrent glial tumors of the brain continue to be one of the most challenging malignancies to treat. Median survival for patients with recurrent disease is approximately 6 months for glioblastoma multiforme. Bevacizumab is used for treatment of recurrent disease; however patients who fail bevacizumab do not have many treatment options.

Metastases to the brain are the most common intracranial tumors in adults and occur ten times more frequently than primary brain tumors. It is estimated that 8 - 10% of cancer patients may develop symptomatic metastatic tumors in the brain. Systemic therapy is rarely used for primary treatment of brain metastases because many tumors that metastasize to the brain are not chemosensitive or have been already heavily pretreated with potentially effective agents, and poor penetration through the blood brain barrier is an additional concern.

Dianhydrogalactitol (DAG) rapidly penetrates both the cerebrospinal fluid (CSF) and the blood-brain barrier and accumulates in brain tissue. Clinical study of DAG in patients with GBM or with progressive secondary brain tumors is warranted. Patients with secondary brain metastases were allowed to enroll into the current protocol in Cohorts 2 and 3; however, enrollment ceased with Amendment 5 and will not be continued beyond Cohort 3.

This study will utilize a standard 3 + 3 dose escalation design, until the MTD or the maximum specified dose has been reached. In Phase 2, additional patients with GBM will be treated at the MTD (or other selected optimum Phase 2 dose) to measure tumor responses to treatment.

Safety Study of VAL-083 in Patients With Recurrent Malignant Glioma

Open-label, Single Arm, Safety and Tolerability Dose Escalation Study of VAL-083 in Patients With Recurrent Malignant Glioma

The Clinical Study Report for this trial will be prepared and provided to U.S. F.D.A. as required by applicable regulatory requirement(s). Each participating trial investigator has been provided a copy their patient data captured in the electronic data base for this trial.

The determination of MTD will be based on analysis of tolerance data from the first cycle of therapy in each dose group.

Tumor assessment every other treatment cycle, as long as patient continues to demonstrate response or stable disease and tolerates therapy.

Plasma will be analyzed to estimate appropriate PK parameters (Cmax, Tmax, AUC, elimination half-life, drug clearance, mean residence time, and volume of distribution).

Newly diagnosed GBM patients who have completed chemoradiation treatment with temozolomide and received no subsequent maintenance temozolomide

The dosing regimen for patients will be VAL-083 (30 mg/m2) administered IV for 3 consecutive days at the beginning of every 21-day cycle. Patients will continue to receive VAL 083, for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation.

Barbara O'Brien, M.D.

The purpose of this phase 2, two arm, biomarker-driven study is to determine if treatment of O-6-methylguanine-DNA methyltransferase (MGMT) unmethylated glioblastoma with VAL-083 improves overall survival (OS), compared to historical control, in the adjuvant or recurrent setting.

Recurrent GBM is characterized by a dismal prognosis, with a median overall survival of 6.9 months. While a standard of care is established for the initial treatment of GBM - radiation with concurrent and adjuvant temozolomide chemotherapy - management of recurrent disease (NCCN, 2014) remains suboptimal. Treatment options include repeat surgery, re-irradiation, or chemotherapy (including experimental targeted therapies, biologic agents, and immunotherapies). Only a minority of patients has response to these treatments, and the resultant benefits in progression-free and overall survival are in the order of weeks to months.

Prognosis and response to therapy are known to be better in patients with a methylated MGMT promoter gene. Epigenetic silencing of MGMT by promoter methylation is an important factor in predicting outcome for patients with GBM treated with temozolomide. Approximately 66% of GBM tumors are MGMT unmethylated (high expression of MGMT), which through a MGMT repair mechanism, confers resistance to temozolomide, the standard chemotherapy treatment of GBM.

VAL-083, Dianhydrogalactitol (DAG), unlike temozolomide, is demonstrated to be active independent of MGMT resistance mechanisms, in vitro. Thus, it may provide a treatment option for those patients that are considered likely to be poor responders to temozolomide.

This is a non-comparative, two arm, biomarker-driven study with VAL-083 in GBM patients with either recurrent disease (Group 1) or newly diagnosed GBM patients requiring maintenance therapy after chemoradiation with temozolomide (Group 2).

Group 1: A total of up to 83 patients with recurrent/progressive GBM will be enrolled. This will include 35 patients treated at 40 mg/m2 and up to 48 patients treated at 30 mg/m2.

Group 2: Up to an additional 36 newly diagnosed GBM patients who have completed chemoradiation treatment with temozolomide and received no subsequent maintenance temozolomide will be enrolled.

Eligible patients will receive VAL-083 IV on days 1, 2, and 3, for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation (disease progression, death, intolerable toxicities, investigator's judgment, or withdrawal of consent). Disease status will be evaluated with clinical and MRI evaluation every other 21-day cycle, while the patient is receiving VAL-083 treatment, and then approximately every 42 ± 7 days while remaining on study. Symptom burden will be evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) completed by patients at baseline and at the time of each imaging evaluation.

Interval medical histories, targeted physical exams, neurologic evaluations, complete blood counts, and other laboratory and safety assessments will be performed approximately every 21-days. Blood samples will be taken at Cycle 1 Day 1 pre-dose, 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of iv infusion with VAL-083 to determine the PK profile and dose-exposure relationship of VAL-083.

Toxicity will be evaluated and documented using the NCI CTCAE version 4.

This study will take approximately 36 months to enroll.

Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Glioblastoma in the Adjuvant or Recurrent Setting

Phase 2 Study of VAL-083 Treatment for MGMT Unmethylated Bevacizumab-naïve Glioblastoma in the Adjuvant or Recurrent Setting

The Clinical Study Report for this trial will be prepared and provided to U.S. F.D.A. as required by applicable regulatory requirement(s). Each participating trial investigator will be provided a copy their patient data captured in the electronic data base for this trial.

Length of time from start of treatment (Day 1) until patient death

Time from start of treatment (Day 1) until to the first occurrence of progression or patient death, whichever occurs first

The median length of time from start of treatment (Day 1) until to the first occurrence of progression or patient death, whichever occurs first

The median length of time from start of treatment (Day 1) until patient death

Overall number of tumor complete response (CR) or partial response (PR) determined via MRI assessment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
IL13Ra2-CAR T Cells With or Without Nivolumab and Ipilimumab in Treating Patients With GBM	NCT04003649	Recurrent Gliob... Refractory Glio...	IL13Ralpha2-spe... Ipilimumab Nivolumab Quality-of-Life... Questionnaire A...	18 Years -	City of Hope Medical Center
VAL-083 Phase 3 Study in Temozolomide-Avastin (Bevacizumab) Recurrent GBM	NCT03149575	Glioblastoma Mu... Glioblastoma Glioma GBM Brain Cancer	VAL-083, Dianhy... Physician's Cho... Physician's Cho... Physician's Cho...	18 Years -	Kintara Therapeutics, Inc.
B7-H3 CAR-T for Recurrent or Refractory Glioblastoma	NCT04077866	Recurrent Gliob... Refractory Glio...	Temozolomide B7-H3 CAR-T	18 Years - 75 Years	Second Affiliated Hospital, School of Medicine, Zhejiang University
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
Pilot Study of B7-H3 CAR-T in Treating Patients With Recurrent and Refractory Glioblastoma	NCT04385173	Recurrent Gliob... Refractory Glio...	B7-H3 CAR-T Temozolomide	18 Years - 75 Years	Second Affiliated Hospital, School of Medicine, Zhejiang University
Pilot Study of Elemene in Treating Patients With Refractory Glioblastoma	NCT04674527	Refractory Glio...	Elemene Temozolomide	18 Years -	Second Affiliated Hospital, School of Medicine, Zhejiang University
IL13Ra2-CAR T Cells With or Without Nivolumab and Ipilimumab in Treating Patients With GBM	NCT04003649	Recurrent Gliob... Refractory Glio...	IL13Ralpha2-spe... Ipilimumab Nivolumab Quality-of-Life... Questionnaire A...	18 Years -	City of Hope Medical Center
Safety Study of VAL-083 in Patients With Recurrent Malignant Glioma	NCT01478178	Glioma Glioblastoma Glioblastoma Mu... GBM Brain Cancer	VAL-083 (Dianhy...	18 Years -	Kintara Therapeutics, Inc.
Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Glioblastoma in the Adjuvant or Recurrent Setting	NCT02717962	Glioma Glioblastoma Glioblastoma Mu... GBM Brain Cancer	VAL-083, Dianhy...	18 Years -	Kintara Therapeutics, Inc.

Spots Global Cancer Trial Database for refractory glioblastoma