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

Phase 1

Active, not recruiting

• Conditions: Recurrent Anaplastic Astrocytoma; Recurrent Anaplastic Oligoastrocytoma; Recurrent Malignant Glioma; Recurrent Glioblastoma; Recurrent WHO Grade III Glioma; Recurrent Gliosarcoma; Recurrent Anaplastic Oligodendroglioma
• Interventions: Biological: Carboxylesterase-expressing Allogeneic Neural Stem Cells; Drug: Irinotecan; Drug: Irinotecan Hydrochloride; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study

• Registration Number: NCT02192359
• Lead Sponsor: City of Hope Medical Center

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2014-07-15
• Study First Submitted QC: 2014-07-15
• Study First Posted: 2014-07-16
• Study Start: 2016-03-07
• Primary Completion: 2022-02-21
• Results First Submitted: 2023-12-28
• Status Verified: 2024-04
• Results First Submitted QC: 2024-04-09
• Last Update Submitted: 2024-04-09
• Results First Posted: 2024-04-29
• Last Update Posted: 2024-04-29
• Study Completion: 2024-12-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

• Patient must be able to understand and be willing to sign a written informed consent document
• Participant must be willing to comply with study and/or follow-up procedures
• Karnofsky performance status >= 70%
• Life expectancy of >= 3 months
• Histologically-confirmed diagnosis of a grade III or IV glioma (including glioblastoma, anaplastic astrocytoma, gliosarcoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma), or has a prior, histologically-confirmed, diagnosis of a grade II glioma and now has radiographic findings consistent with a high-grade glioma (grade III or IV)
• Imaging studies show evidence of recurrent tumor(s); if a patient is going to be enrolled to dose level two or higher, the patient must have a component of supratentorial disease (so as to enable placement of a Rickham reservoir/catheter) that is amenable to resection or biopsy
• High-grade glioma has recurred or progressed after prior treatment with brain radiation and temozolomide
• Participant must be in need of a craniotomy for tumor resection or a stereotactic brain biopsy for the purpose of diagnosis or differentiating between tumor progression versus treatment-induced effects following radiation therapy +/- chemotherapy
• Based on the neurosurgeon?s judgment, there is no anticipated physical connection between the post-resection tumor cavity and the cerebral ventricles
• Neurosurgeon finds the prospective participant is able to undergo neurosurgery
• Any number of prior therapies is permitted; from the start of study treatment, the following time periods must have elapsed: 6 weeks from nitrosourea-containing chemotherapy, 4 weeks from non-nitrosourea-containing cytotoxic chemotherapy (except 23 days from last daily dose of temozolomide taken in a 5 of 28 day regimen), and 2 weeks from last dose of a targeted agent (except 4 weeks for bevacizumab); there is no time period requirement for prior radiation therapy
• Any clinically significant toxicity from prior therapy must have improved to grade 0 or grade 1
• Absolute neutrophil count (ANC) >= 1,500 cells/ul
• Platelets > 100,000 cells/ul
• Total bilirubin =< 2.0 mg/dl
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 4 times institutional upper limit of normal
• Serum creatinine =< 1.5 x the institutional upper limit of normal
• Homozygous negative for the UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT 1A1)*28 allele
• Absence anti-human leukocyte antigen (HLA) antibodies specific for HLA class I antigens expressed by the coagulation factor III (thromboplastin, tissue factor) (F3).cytosine deaminase (CD).carboxylesterase (CE) NSCs
• Negative serum pregnancy test (women of childbearing potential only)
• Agreement by females of childbearing potential and sexually active males to use an effective method of contraception while participating in this study; women of childbearing potential must have a negative pregnancy test < 2 weeks prior to registration

Read More

Exclusion Criteria

• Prior therapy with neural stem cells
• Use of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers including hepatic enzyme-inducing anticonvulsants (phenytoin, fosphenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine) within 2 weeks prior to start of study treatment
• Use of moderate to strong CYP3A4 inhibitors within 2 weeks prior to start of study treatment
• Use of drugs known to inhibit UGT1A1, such as atazanir, gemfibrozil, indinavir, or ketoconazole, within 2 weeks prior to start of study treatment
• Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids, such as systemic cyclosporine and tacrolimus; consult principal investigator for questions, including necessary washout period for the specific drug
• Flucytosine within 2 weeks prior to start of study treatment
• Use of herbal medications
• Current use (or planned use during the treatment period) of other investigational agents, or biological, chemotherapy, radiation or other anti-tumor therapy
• Patient has known human immunodeficiency virus (HIV) or hepatitis C infection; baseline testing for HIV or hepatitis C is not required
• Prospective participant is unable to undergo a magnetic resonance imaging (MRI) with contrast agent
• Known chronic or active viral infections of the central nervous system (CNS)
• Clinically significant uncontrolled illness
• Active infection requiring antibiotics
• Diagnosis of Gilbert?s disease
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan
• Known sensitivity to any of the products to be administered during dosing
• Any other active malignancy
• Pregnant women and women who are lactating
• Serious medical or psychiatric illness that could, in the investigator?s opinion, potentially interfere with the safety monitoring requirements and completion of treatment according to this protocol
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (hCE1m6-NSCs and irinotecan hydrochloride)	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 IV over 90 minutes on days 3 and 17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Treatment (hCE1m6-NSCs and irinotecan hydrochloride)	Pharmacological Study	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.
Treatment (hCE1m6-NSCs and irinotecan hydrochloride)	Laboratory Biomarker Analysis	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.
Treatment (hCE1m6-NSCs and irinotecan hydrochloride)	Irinotecan Hydrochloride	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.
Treatment (hCE1m6-NSCs and irinotecan hydrochloride)	Irinotecan	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Grade 3 or Higher Toxicity Profile Attributed to Irinotecan	Followed 30 days post treatment for all toxicities (min=33,max 142 days), up to 5 years for gene therapy toxicities	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.
Number of Participants Experiencing a Dose-limiting Toxicity (DLT)	28 days post first dose of NSC treatment on day 1, cycle 1	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
Number of Participants With Grade 3 or Higher Toxicity Profile Attributed to NSCs	Followed 30 days post treatment for all toxicities (min=33,max 142 days), up to 5 years for gene therapy toxicities	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.

Secondary Outcome Measures

Name	Time	Method
Median Ratio of SN-38 Area Under the Curve (AUC) to CPT-11 AUC in Plasma	Pre-dose, at 90 minutes (just prior to the end of the infusion), and then at 30 minutes, 1, 2, 4, 8, 24, and 48 hours after the end of the infusion after day 1, cycle 1	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.
Median Ratio of SN-38 AUC to CPT-11 AUC in the Brain	Pre-dose, at 90 minutes (just prior to the end of the infusion), and then at 30 minutes, 1, 2, 4, 8, 24, and 48 hours after the end of the infusion after day 1, cycle 1	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
Number of Participants With Clinical Benefit Defined by Response Assessment in Neuro-Oncology (RANO)	Until death or disease progression, a median of 2 months, up to 6 months	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.

Trial Locations

Locations (1)

City of Hope Medical Center; 🇺🇸 Duarte, California, United States