Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioma

Glioblastoma

Astrocytoma

Oligodendroglioma

Gliosarcoma

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

Anaplastic Astrocytoma

Anaplastic Oligodendroglioma

Oligoastrocytoma

Anaplastic Oligoastrocytoma

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Irinotecan

Camptothecin

Topoisomerase I Inhibitors

Enzyme 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

Laboratory Biomarker Analysis

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.

National Cancer Institute (NCI)

City of Hope Medical Center

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.

Number of Participants With Clinical Benefit Defined by Response Assessment in Neuro-Oncology (RANO)

Overall Study

BIRC5 protein, human

Patients undergo standard of care surgical resection. Patients then receive NSC-CRAd-S-pk7 intracerebrally over 10 minutes QW for up to 4 doses in the absence of disease progression or unacceptable toxicity.

Neural Stem Cells-expressing CRAd-S-pk7

Resection

Jana L. Portnow

This phase I trial studies the effect of multiple doses of NSC-CRAd-S-pk7 in treating patients with high-grade gliomas that have come back (recurrent). NSC-CRAd-S-pk7 consists of neural stem cells that carry a virus, which can kill cancer cells. Giving multiple doses of NSC-CRAd-S-pk7 may kill more tumor cells.

PRIMARY OBJECTIVE:

I. Determine the recommended maximum tolerated number of cycles (MTC) of intracavitary (ICT) administered Neural Stem Cells-expressing CRAd-S-pk7 (NSCCRAd-S-pk7) for phase II testing based on dose-limiting toxicities (DLTs), the overall toxicity profile, and activity in patients with recurrent high-grade glioma (HGG).

SECONDARY OBJECTIVES:

I. Measure possible development of antibody and T cell responses to the neural stem cells (NSCs) and/or the oncolytic virus in cerebrospinal fluid (CSF), resection cavity fluid (when possible to obtain by aspiration before administering study agent through the ICT Rickham), and blood.

II. Evaluate the intracerebral biodistribution of NSC-CRAd-S-pk7 when permission to perform a brain autopsy on a study participant is given.

III. Identify the evidence of possible NSC migration outside of the brain, the presence of viral particles, and/or both in the CSF and blood.

IV. Estimate the rates of disease response using modified Response Assessment in Neuro-Oncology (RANO) criteria, progression-free survival at 6 months (PFS6months), overall survival at 9 months (OS9months), and median PFS and OS in the recurrent HGG patients, and estimate the rates of disease response, PFS6months, and OS9months for the cohort of 12 GBM patients at first or second recurrence who will be treated at the MTC.

V. Assess changes in HSPG and survivin expression in pre- and post-treatment tumor tissue samples treatment.

VI. Identify possible mechanisms of immune escape by analyzing immune cell population changes in the tumor microenvironment (TME) in pre- and post-treatment tumor tissue samples.

VII. Generate a biomathematical model to describe spatial temporal changes in tumor growth that may predict the effect of NSC-CRAd-S-pk7 on tumor response based on magnetic resonance imaging (MRI) measurements.

OUTLINE:

Patients undergo standard of care surgical resection. Patients then receive NSC-CRAd-S-pk7 intracerebrally over 10 minutes once weekly (QW) for up to 4 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 and 6 months, and then annually thereafter.

Multiple Doses of Neural Stem Cell Virotherapy (NSC-CRAd-S-pk7) for the Treatment of Recurrent High-Grade Gliomas

A Phase I Study of Multiple Doses of Neural Stem Cell-Based Oncolytic Virotherapy (NSC-CRAd-S-pk7) Administered Intracerebrally to Patients With Recurrent High-Grade Gliomas

Assessed using the Common Terminology Criteria for Adverse Events version 5.0.

Response Assessment in Neuro-Oncology Criteria will be used to assess response on brain magnetic resonance imaging in all study participants who receive at least 80% of the planned doses of study treatment. Disease response will be similarly assessed for the cohort of 12 glioblastoma (GBM) participants at first or second recurrence who will be treated at the maximum tolerated number of cycles (MTC).

Will estimate the rate 90% confidence interval (CI) for PFS at 6 months and use Kaplan Meier methods to estimate median PFS for all study participants as well as for the cohort of 12 GBM participants at first or second recurrence who will be treated at the MTC.

Will estimate the rate 90% CI for OS at 9 months and use Kaplan Meier methods to estimate median OS for all study participants as well as for the cohort of 12 GBM participants at first or second recurrence who will be treated at the MTC.

Changes in HSPG and survivin expression by immunohistochemistry IHC in pre- and post-treatment tissue to see if there is a relationship with disease response.

Changes in immune cell populations in the tumor microenvironment in pre- and posttreatment tumor tissue samples will be assessed by Vectra Spectral Imaging.

Develop a biomathematical model for predicting tumor response to study treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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
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

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