Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor, Anaplastic Oligoastrocytoma
Conditions
Brief summary
This phase I trial studies the side effects and determines the best dose of genetically modified neural stem cells and flucytosine when given together with leucovorin for treating patients with recurrent high-grade gliomas. Neural stem cells can travel to sites of tumor in the brain. The neural stem cells that are being used in this study were genetically modified express the enzyme cytosine deaminase (CD), which converts the prodrug flucytosine (5-FC) into the chemotherapy agent 5-fluorouracil (5-FU). Leucovorin may help 5-FU kill more tumor cells. The CD-expressing neural stem cells are administered directly into the brain. After giving the neural stem cells a few days to spread out and migrate to tumor cells, research participants take a 7 day course of oral 5-FC. (Depending on when a research participant enters the study, they may also be given leucovorin to take with the 5-FC.) When the 5-FC crosses into brain, the neural stem cells convert it into 5-FU, which diffuses out of the neural stem cells to preferentially kill rapidly dividing tumor cells while minimizing toxicity to healthy tissues. A Rickham catheter, placed at the time of surgery, will be used to administer additional doses of NSCs every two weeks, followed each time by a 7 day course of oral 5-FC (and possibly leucovorin). This neural stem cell-based anti-cancer strategy may be an effective treatment for high-grade gliomas. Funding Source - FDA OOPD
Detailed description
PRIMARY OBJECTIVES: I. To define the phase II recommended dose of intracerebrally administered cytosine deaminase (CD)-expressing neural stem cells (NSCs) in combination with oral 5-fluorocytosine (FC) (flucytosine) and leucovorin. II. To determine the feasibility of treating study patients with more than 1 dose of NSCs followed by 7-day courses of 5-FC and leucovorin. SECONDARY OBJECTIVES: I. To assess for possible development of NSC immunogenicity (anti-NSC T cell and/or antibody response) with repeat doses of NSCs. II. To characterize the relationship between intracerebral and systemic concentrations of 5-FC and 5-FU at the maximum tolerated dose/maximum feasible dose level. III. To describe the clinical benefit (defined as stable disease, partial response, or complete response) of this treatment regimen. IV. To determine, at time of autopsy, the fate of the NSCs. OUTLINE: This is dose-escalation study of CD-expressing genetically modified neural stem cells and flucytosine. Patients receive CD-expressing neural stem cells intracranially (IC) on days 1 and 15 and flucytosine orally (PO) every 6 hours on days 4-10 and 18-24. Depending on when a subject enters the study, they may also be given leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 30 days, 3 months, 6 months, 1 year, and then annually thereafter.
Interventions
Given intracranially
DRUGflucytosine
Given orally
DRUGleucovorin calcium
Given orally
OTHERpharmacological study
Correlative studies
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient has had a prior, histologically-confirmed, diagnosis of a grade III or IV glioma (including glioblastoma, anaplastic oligodendroglioma, or 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). The presence of infratentorial tumor is allowed as long as the patient also has supratentorial disease that is amenable to resection or biopsy. * 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 * The 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 * Based on the neurosurgeon's judgement, there is no anticipated physical connection between the post-resection tumor cavity and the cerebral ventricles * Absolute neutrophil count (ANC) \>= 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 * All subjects must have the ability to understand and the willingness to sign a written informed consent
Exclusion criteria
* Patient has anti-human leukocyte antigen (HLA) antibodies specific for HLA antigens expressed by the 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 (except temozolomide: only an interval of 23 days is required from the last dose administered when patient has been recently treated with the standard temozolomide regimen of daily for 5 days, repeated every 28 days) * At least 2 weeks from taking the last dose of targeted agent * At least 4 weeks from the last dose of bevacizumab * Patient is unable to undergo a magnetic resonance imaging (MRI) * Patient is allergic to 5-FC, leucovorin, or 5-FU * Patient has chronic or active viral infections of the central nervous system (CNS) * Patient has a coagulopathy or bleeding disorder * Patient has an uncontrolled illness including ongoing or active infection * Patient is receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy * Patient has had prior therapy with neural stem cells * Patient is pregnant or breast feeding; pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is participating in this study * Patient has another active malignancy * Non-compliance; a patient has a 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | Day 28 of course 1 | Number of DLTs per dose level and the MTD/MFD. |
| Number of Participants With Mechanical Issues With Repeat Administrations of NSCs Via Rickham | 28 days after last infusion of NSCs, up to 6 months total | Number of participants with mechanical issues with repeat administrations of NSCs via Rickham. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Steady State Levels of 5-FC Concentrations in Plasma | Samples were obtained prior to the first dose of 5-FC then every 30 minutes for 3 hours, additional samples at 4 and 6 hours after the morning doses on days 4, 5. On days 6, 7, 8 blood samples were collected just before morning dose and 90 minutes later | PK data from the patients who undergo intracerebral microdialysis (dose level 4) will be summarized using descriptive statistics. |
| Number of Participants Developing Antibodies Against NSCs | While receiving treatment, up to 6 months. | Development of a antibody response to the NSCs will be evaluated by flow cytometry. Data from assessing for possible development of NSC immunogenicity with repeat exposure will be presented in an exploratory fashion using descriptive statistics. |
| Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Up to 3 years post NSC infusion | Per RANO criteria: Complete Response (CR): Complete disappearance of all enhancing disease that is sustained for at least 4 weeks, stable or improved non-enhancing FLAIR/T2 lesions, no new lesions, off corticosteroids, and neurologically stable or improved. Partial Response (PR): \>= 50% decrease of all measurable enhancing lesions, sustained or at least 4 weeks, no progression of non-measurable disease, stable or improved non-enhancing FLAIR/T2 lesions, non new lesions, corticosteroid dose stable or reduced, and neurologically stable or improved. Stable Disease (SD): Dose not qualify for CR, PR, or PD, stable non-enhancing FLAIR/T2 lesions, stable or reduced corticosteroids, clinically stable. Progressive Disease (PD): \>=25% increase in enhancing lesion despite stable or increasing steroid dose, increase (significant) in non-enhancing T2/FLAIR lesions that is not attributable to other non-tumor causes, any new lesions, clinical deterioration |
| Comparison of 5-FC in the Brain to 5-FC in the Plasma | The ratio of average brain interstitial 5-FC and 5-FU concentrations to average plasma steady-state levels was calculated using all measured data. | PK data from the patients who undergo intracerebral microdialysis (dose level 4) will be summarized using the mean ratio of average brain interstitial 5-FC concentrations to the average steady-state plasma levels. |
| Average Steady State Levels of 5-FC and 5-FU in the Brain | Following the first dose of 5-FC, samples were collected every hour for 24 hours and then every 3 hours thereafter until the end of the 7-day course of 5-FC or until the microdialysis catheter stopped functioning. | Pharmacokinetic (PK) data from the patients who undergo intracerebral microdialysis (dose level 4) will be summarized using descriptive statistics. All summaries will be exploratory in spirit. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg) Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 3 |
| Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg) Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 3 |
| Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 3 |
| Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis Patients receive CD-expressing neural stem cells intracranially on days 1 and 15. Flucytosine is taken orally every 6 hours on days 4-10 and 18-24. Leucovorin orally every 6 hours on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 7 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Rickham catheter was misaligned | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg) | Total | Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis | Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) | Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg) |
|---|---|---|---|---|---|
| Age, Continuous | 59 years | 57 years | 58 years | 57 years | 40 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 4 Participants | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 12 Participants | 5 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 14 Participants | 7 Participants | 3 Participants | 2 Participants |
| Region of Enrollment United States | 3 participants | 16 participants | 7 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 13 Participants | 7 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 3 / 3 | 7 / 7 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 7 / 7 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 1 / 3 | 4 / 7 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD)
Number of DLTs per dose level and the MTD/MFD.
Time frame: Day 28 of course 1
Population: 1 participant in dose level 4 was unevaluable and had to be replaced after receiving the first dose of CD-NSCs due to the tip of the Rickham catheter migrating into the lateral ventricle.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg) | Number of Participants With Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
| Dose Level 2: (NSC 1x10^8 and 5-FC 37.5 mg/kg) | Number of Participants With Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
| Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) | Number of Participants With Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 0 Participants |
| Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg + Leucovorin + Microdialysis | Number of Participants With Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) | 1 Participants |
Primary
Number of Participants With Mechanical Issues With Repeat Administrations of NSCs Via Rickham
Number of participants with mechanical issues with repeat administrations of NSCs via Rickham.
Time frame: 28 days after last infusion of NSCs, up to 6 months total
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg) | Number of Participants With Mechanical Issues With Repeat Administrations of NSCs Via Rickham | 0 Participants |
| Dose Level 2: (NSC 1x10^8 and 5-FC 37.5 mg/kg) | Number of Participants With Mechanical Issues With Repeat Administrations of NSCs Via Rickham | 0 Participants |
| Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) | Number of Participants With Mechanical Issues With Repeat Administrations of NSCs Via Rickham | 0 Participants |
| Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg + Leucovorin + Microdialysis | Number of Participants With Mechanical Issues With Repeat Administrations of NSCs Via Rickham | 0 Participants |
Secondary
Average Steady State Levels of 5-FC and 5-FU in the Brain
Pharmacokinetic (PK) data from the patients who undergo intracerebral microdialysis (dose level 4) will be summarized using descriptive statistics. All summaries will be exploratory in spirit.
Time frame: Following the first dose of 5-FC, samples were collected every hour for 24 hours and then every 3 hours thereafter until the end of the 7-day course of 5-FC or until the microdialysis catheter stopped functioning.
Population: Only participants in dose level 4 received intracerebral microdialysis and are included in this analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg) | Average Steady State Levels of 5-FC and 5-FU in the Brain | average steady state levels of 5-FC in the brain | 213 µmol/L | Standard Deviation 58 |
| Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg) | Average Steady State Levels of 5-FC and 5-FU in the Brain | average steady state levels of 5-FU in the brain | 0.03 µmol/L | Standard Deviation 0.01 |
Secondary
Average Steady State Levels of 5-FC Concentrations in Plasma
PK data from the patients who undergo intracerebral microdialysis (dose level 4) will be summarized using descriptive statistics.
Time frame: Samples were obtained prior to the first dose of 5-FC then every 30 minutes for 3 hours, additional samples at 4 and 6 hours after the morning doses on days 4, 5. On days 6, 7, 8 blood samples were collected just before morning dose and 90 minutes later
Population: Only participants in dose level 4 received intracerebral microdialysis and are included in this analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg) | Average Steady State Levels of 5-FC Concentrations in Plasma | 748 µmol/L | Standard Error 218 |
Secondary
Comparison of 5-FC in the Brain to 5-FC in the Plasma
PK data from the patients who undergo intracerebral microdialysis (dose level 4) will be summarized using the mean ratio of average brain interstitial 5-FC concentrations to the average steady-state plasma levels.
Time frame: The ratio of average brain interstitial 5-FC and 5-FU concentrations to average plasma steady-state levels was calculated using all measured data.
Population: Only participants in dose level 4 received intracerebral microdialysis and are included in this analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg) | Comparison of 5-FC in the Brain to 5-FC in the Plasma | 29 ratio | Standard Error 21 |
Secondary
Number of Participants Developing Antibodies Against NSCs
Development of a antibody response to the NSCs will be evaluated by flow cytometry. Data from assessing for possible development of NSC immunogenicity with repeat exposure will be presented in an exploratory fashion using descriptive statistics.
Time frame: While receiving treatment, up to 6 months.
Population: 2 participants in dose level 4 were not assessed in this analysis because one participant only received one dose of CD-NSCs and the other we were unable to obtain post second CD-NSC dose serum sample to analyze.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg) | Number of Participants Developing Antibodies Against NSCs | 0 Participants |
| Dose Level 2: (NSC 1x10^8 and 5-FC 37.5 mg/kg) | Number of Participants Developing Antibodies Against NSCs | 2 Participants |
| Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) | Number of Participants Developing Antibodies Against NSCs | 0 Participants |
| Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg + Leucovorin + Microdialysis | Number of Participants Developing Antibodies Against NSCs | 1 Participants |
Secondary
Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria
Per RANO criteria: Complete Response (CR): Complete disappearance of all enhancing disease that is sustained for at least 4 weeks, stable or improved non-enhancing FLAIR/T2 lesions, no new lesions, off corticosteroids, and neurologically stable or improved. Partial Response (PR): \>= 50% decrease of all measurable enhancing lesions, sustained or at least 4 weeks, no progression of non-measurable disease, stable or improved non-enhancing FLAIR/T2 lesions, non new lesions, corticosteroid dose stable or reduced, and neurologically stable or improved. Stable Disease (SD): Dose not qualify for CR, PR, or PD, stable non-enhancing FLAIR/T2 lesions, stable or reduced corticosteroids, clinically stable. Progressive Disease (PD): \>=25% increase in enhancing lesion despite stable or increasing steroid dose, increase (significant) in non-enhancing T2/FLAIR lesions that is not attributable to other non-tumor causes, any new lesions, clinical deterioration
Time frame: Up to 3 years post NSC infusion
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg) | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Stable Disease | 2 Participants |
| Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg) | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Ineligible for Disease Response | 0 Participants |
| Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg) | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Progressive Disease | 1 Participants |
| Dose Level 2: (NSC 1x10^8 and 5-FC 37.5 mg/kg) | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Stable Disease | 0 Participants |
| Dose Level 2: (NSC 1x10^8 and 5-FC 37.5 mg/kg) | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Ineligible for Disease Response | 0 Participants |
| Dose Level 2: (NSC 1x10^8 and 5-FC 37.5 mg/kg) | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Progressive Disease | 3 Participants |
| Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Progressive Disease | 3 Participants |
| Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Stable Disease | 0 Participants |
| Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Ineligible for Disease Response | 0 Participants |
| Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg + Leucovorin + Microdialysis | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Stable Disease | 1 Participants |
| Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg + Leucovorin + Microdialysis | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Ineligible for Disease Response | 2 Participants |
| Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg + Leucovorin + Microdialysis | Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria | Progressive Disease | 4 Participants |