Genetically Modified Stem Cells and Irinotecan Hydrochloride in Treating Patients With Recurrent High-Grade Gliomas

• ClinicalTrials.gov Identifier: NCT02055196
• Recruitment Status: Withdrawn
• First Posted: February 5, 2014
• Last Update Posted: June 2, 2014
• Sponsor: City of Hope Medical Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): City of Hope Medical Center

Tracking Information

• First Submitted Date: January 30, 2014
• First Posted Date: February 5, 2014
• Last Update Posted Date: June 2, 2014
• Study Start Date: Not Provided
• Actual Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 3, 2014)

• Incidence of dose-limiting toxicity (DLT), graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: 6 weeks ]
  Tables will be created to summarize all toxicities and side effects by dose, course, organ severity (by NCI CTCAE version 4.0), and attribution. Rates and associated 95% Clopper Pearson confidence limits will be estimated for the DLT and clinical benefit at the MTD for cohort 1 and cohort 2 and in combination if the results are similar.
• Incidence of all attributable toxicities, graded according to NCI CTCAE version 4.0 [ Time Frame: Up to 15 years ]
  Tables will be created to summarize all toxicities and side effects by dose, course, organ severity (by NCI CTCAE version 4.0), and attribution.
• Biologic activity of the hCE1m6-NSCs through Cmax and AUC of irinotecan and SN-38 in dialysate and plasma [ Time Frame: Prior to the start of the irinotecan infusion and 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 on day 3 of week 1 ]
  Data from patients who undergo intracerebral microdialysis will be summarized using descriptive statistics and graphical methods.

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT02055196 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: February 3, 2014)

• Incidence of immunogenicity measured by the development of T cell responses and antibodies against the NSCs using TcR Vβ spectratyping, CD 107 degranulation assays, and flow cytometry [ Time Frame: Up to 15 years ]
  Results will be summarized in an exploratory fashion using descriptive statistics and graphical methods.
• NSC biodistribution in the brain via Feraheme-labeling of NSCs and MR imaging [ Time Frame: Up to 15 years ]
  Results will be summarized in an exploratory fashion using descriptive statistics and graphical methods.
• Clinical benefit measured by tumor response [ Time Frame: Up to 15 years ]
• NSC persistence at autopsy [ Time Frame: Up to 15 years ]
  Results will be summarized in an exploratory fashion using descriptive statistics and graphical methods.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Genetically Modified Stem Cells and Irinotecan Hydrochloride in Treating Patients With Recurrent High-Grade Gliomas
• Official Title: A Phase I Study of Intracranially Administered Carboxylesterase-Expressing Neural Stem Cells in Combination With Intravenous Irinotecan in Patients With Recurrent High-Grade Gliomas
• Brief Summary: This phase I trial studies the side effects and best dose of genetically modified stem cells when given together with irinotecan hydrochloride in treating patients with recurrent high-grade gliomas. Irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Placing a gene that has been created in the laboratory into neural stem cells and injecting it into the brain may help irinotecan hydrochloride kill more tumor cells once it reaches the brain.

Detailed Description

PRIMARY OBJECTIVES:

I. To define the recommend phase II doses of intracranially administered active modified human form of carboxylesterase (hCE1m6)- neuronal stem cells (NSCs) (carboxylesterase-expressing allogeneic neural stem cells) in combination with intravenous irinotecan (irinotecan hydrochloride).

II. To determine the biologic activity of the hCE1m6-NSCs by comparing SN-38 concentrations in the brain after treatment with hCE1m6-NSCs and irinotecan compared to irinotecan alone.

SECONDARY OBJECTIVES:

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

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

III. To assess for possible development of NSC immunogenicity after first exposure and with repeat doses of NSCs.

IV. To evaluate the intracerebral distribution of NSCs by using iron-labeling as a cellular tracker.

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 via intracerebral catheter on day 1 of week 1; weeks 1 and 3, weeks 1, 2, and 3; or weeks 1, 2, 3, and 4. Patients also receive irinotecan hydrochloride intravenously (IV) over 90 minutes on day 3 of week 1; weeks 1 and 3, weeks 1, 2, and 3; or weeks 1, 2, 3, and 4. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 15 years.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Adult Anaplastic Astrocytoma
• Adult Anaplastic Oligodendroglioma
• Adult Giant Cell Glioblastoma
• Adult Glioblastoma
• Adult Gliosarcoma
• Recurrent Adult Brain Tumor

Intervention

• Biological: carboxylesterase-expressing allogeneic neural stem cells
  Given via intracerebral catheter
  Other Name: hCE1m6-NSC
• Drug: irinotecan hydrochloride
  Given IV
  Other Names:

  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E
• Other: laboratory biomarker analysis
  Correlative studies

Study Arms

Experimental: Treatment (neuronal stem cells, irinotecan hydrochloride)

Patients receive carboxylesterase-expressing allogeneic neural stem cells via intracerebral catheter on day 1 of week 1; weeks 1 and 3, weeks 1, 2, and 3; or weeks 1, 2, 3, and 4. Patients also receive irinotecan hydrochloride IV over 90 minutes on day 3 of week 1; weeks 1 and 3, weeks 1, 2, and 3; or weeks 1, 2, 3, and 4. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

Interventions:

• Biological: carboxylesterase-expressing allogeneic neural stem cells
• Drug: irinotecan hydrochloride
• Other: laboratory biomarker analysis

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: May 30, 2014): 0
• Original Estimated Enrollment (submitted: February 3, 2014): 40
• Study Completion Date: Not Provided
• Actual Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patient has a prior, 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, supratentorial tumor(s)
• Patient's high-grade glioma has recurred or progressed after prior treatment with brain radiation and temozolomide
• Patient has a Karnofsky performance status of >= 70%
• Patient has a life expectancy of >= 3 months
• Female patients of childbearing potential and sexually-active male patients must agree 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
• PROTOCOL-SPECIFIC CRITERIA
• Patient 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
• Patients who will undergo tumor resection must have residual enhancing tumor (i.e. a gross total resection is not anticipated)
• Based on the neurosurgeon's judgment, there is no anticipated physical connection between the post-resection tumor cavity and the cerebral ventricles
• Absolute neutrophil count (ANC) of >= 1500 cells/mm^3
• Platelet count >= 100,000 cells/mm^3
• Total bilirubin =< 2.0 mg/dl
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 4 times the institutional upper limit of normal
• Serum creatinine =< the institutional upper limit of normal
• There is no limit to the number of prior therapies
• Patient must be able to understand and be willing to sign a written informed consent document
• INCLUSION CRITERIA FOR MTD COHORT 2
• Patient has a prior, histopathologically-confirmed diagnosis of glioblastoma
• Patient has not received any therapy for recurrent disease
• INCLUSION CRITERIA FOR PROCEEDING TO TREATMENT WITH IRINOTECAN DURING CYCLE 1
• A patient's daily total dose of dexamethasone must be =< 16 mg by day 3

Exclusion Criteria:

• Patient is homozygous or heterozygous for the UDP glycosyltransferase 1 family, polypeptide A1*28 allele (UGT 1A1*28) allele and/or has Gilbert's disease
• Patient must not be taking any cytochrome P450 3A4 (CYP3A4) hepatic enzyme-inducing anticonvulsants (phenytoin, fosphenytoin [Cerebyx], carbamazepine, phenobarbital, primidone, oxcarbazepine) or other moderate to strong CYP3A4 inhibitors or inducers for at least 2 weeks prior to start of study treatment
• Patient has anti-human leukocyte antigen (HLA) antibodies specific for HLA antigens expressed by the F3.CD.CE NSCs
• Patient has not recovered from any toxicity of prior therapies; an interval of at least 6 weeks must have elapsed since taking a nitrosourea-containing chemotherapy regimen, at least 4 weeks since completing a non-nitrosourea-containing cytotoxic chemotherapy regimen, and at least 2 weeks from taking the last dose of a targeted agent and the start of study treatment, with the exception of bevacizumab, where a wash out period of at least 4 weeks is required before starting study treatment
• Patient is taking flucytosine
• Patient is unable to undergo a magnetic resonance imaging (MRI)
• Patient has chronic or active viral infections of the central nervous system (CNS) or an uncontrolled illness
• Patient may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is participating in this study
• A patient with another active malignancy is ineligible for this study
• Non-compliance

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 64 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02055196
• Other Study ID Numbers: 13455; NCI-2014-00117 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 13455 ( Other Identifier: City of Hope Medical Center ); P30CA033572 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: City of Hope Medical Center
• Study Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jana Portnow; City of Hope Medical Center

• PRS Account: City of Hope Medical Center
• Verification Date: May 2014