Genetically Modified Neural Stem Cells, Flucytosine, and Leucovorin for Treating Patients With Recurrent High-Grade Gliomas

• Sponsor: City of Hope Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02015819
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 16
• Location: 1
• Arm: 1
• Actual Duration (Months): 36
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor; Anaplastic Oligoastrocytoma	Biological: E. coli CD-expressing genetically modified neural stem cells; Drug: flucytosine; Drug: leucovorin calcium; Other: pharmacological study; Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

2. 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:

1. To assess for possible development of NSC immunogenicity (anti-NSC T cell and/or antibody response) with repeat doses of NSCs.

2. To characterize the relationship between intracerebral and systemic concentrations of 5-FC and 5-FU at the maximum tolerated dose/maximum feasible dose level.

3. To describe the clinical benefit (defined as stable disease, partial response, or complete response) of this treatment regimen.

4. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Study of Cytosine Deaminase-Expressing Neural Stem Cells in Combination With Oral 5-Fluorocytosine and Leucovorin for the Treatment of Recurrent High-Grade Gliomas
• Actual Study Start Date: Oct 7, 2014
• Actual Primary Completion Date: Oct 7, 2017
• Actual Study Completion Date: Oct 7, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (neural stem cells, flucytosine, leucovorin) 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. 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. Dose escalation used the following dose levels: Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg) Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg) Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis

Biological: E. coli CD-expressing genetically modified neural stem cells; Given intracranially; Other Names: HB1.F3.CD neural stem cells ; Drug: flucytosine; Given orally; Other Names: 5-FC 5-fluorocytosine Ro 2-9915 ; Drug: leucovorin calcium; Given orally; Other Names: CF CFR LV ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Medical Center	Duarte	California	United States	91010

Sponsors and Collaborators

• City of Hope Medical Center
• National Cancer Institute (NCI)

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 4, 2020

More Information

Publications

None provided.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT02015819
• Other Study ID Numbers: 13401; NCI-2013-02346; 13401; FD-R-004816
• First Posted: Dec 19, 2013
• Last Update Posted: Oct 20, 2021
• Last Verified: Sep 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Glioblastoma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Recurrence; Leucovorin; Flucytosine; Calcium; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)	Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)	Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)	Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
Arm/Group Description	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.	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.	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.	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. They will 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.
Period Title: Overall Study
STARTED	3	3	3	7
COMPLETED	3	3	3	6
NOT COMPLETED	0	0	0	1

Baseline Characteristics

Arm/Group Title	Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)	Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)	Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)	Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis	Total
Arm/Group Description	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	3	3	3	7	16
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59	40	57	58	57
Sex: Female, Male (Count of Participants)
Female	2 66.7%	0 0%	1 33.3%	0 0%	3 18.8%
Male	1 33.3%	3 100%	2 66.7%	7 100%	13 81.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	2 66.7%	2 28.6%	4 25%
Not Hispanic or Latino	3 100%	3 100%	1 33.3%	5 71.4%	12 75%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 33.3%	0 0%	0 0%	0 0%	1 6.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 33.3%	0 0%	0 0%	1 6.3%
White	2 66.7%	2 66.7%	3 100%	7 100%	14 87.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%	3 100%	3 100%	7 100%	16 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD)
Description	Number of DLTs per dose level and the MTD/MFD.
Time Frame	Day 28 of course 1

Outcome Measure Data

Analysis Population Description

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/Group Title	Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg)	Dose Level 2: (NSC 1x10^8 and 5-FC 37.5 mg/kg)	Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)	Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg + Leucovorin + Microdialysis
Arm/Group Description	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.	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.	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.	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.
Measure Participants	3	3	3	6
Count of Participants [Participants]	0 0%	0 0%	0 0%	1 14.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dose Level 1: (NSC 5x10^7 and 5-FC 37.5 mg/kg), Dose Level 2: (NSC 1x10^8 and 5-FC 37.5 mg/kg), Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg), Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg + Leucovorin + Microdialysis
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		MFD was determined to be 1.5x10^8 in combination with oral 5-FC 37.5 mg/kg and leucovorin 25 mg every 6 hours for 7 days.

2. Primary Outcome

Title	Number of Participants With Mechanical Issues With Repeat Administrations of NSCs Via Rickham
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)	Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)	Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)	Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
Arm/Group Description	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.	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.	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.	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.
Measure Participants	3	3	3	7
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

3. Secondary Outcome

Title	Number of Participants Developing Antibodies Against NSCs
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)	Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)	Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)	Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
Arm/Group Description	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.	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.	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.	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.
Measure Participants	3	3	3	5
Count of Participants [Participants]	0 0%	2 66.7%	0 0%	1 14.3%

4. Secondary Outcome

Title	Average Steady State Levels of 5-FC and 5-FU in the Brain
Description	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.

Outcome Measure Data

Analysis Population Description

Only participants in dose level 4 received intracerebral microdialysis and are included in this analysis

Arm/Group Title	Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
Arm/Group Description	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. They will 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.
Measure Participants	7
average steady state levels of 5-FC in the brain	213 (58)
average steady state levels of 5-FU in the brain	0.03 (0.01)

5. Secondary Outcome

Title	Average Steady State Levels of 5-FC Concentrations in Plasma
Description	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

Outcome Measure Data

Analysis Population Description

Only participants in dose level 4 received intracerebral microdialysis and are included in this analysis

Arm/Group Title	Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
Arm/Group Description	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. They will 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.
Measure Participants	7
Mean (Standard Error) [µmol/L]	748 (218)

6. Secondary Outcome

Title	Comparison of 5-FC in the Brain to 5-FC in the Plasma
Description	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.

Outcome Measure Data

Analysis Population Description

Only participants in dose level 4 received intracerebral microdialysis and are included in this analysis

Arm/Group Title	Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
Arm/Group Description	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. They will 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.
Measure Participants	7
Mean (Standard Error) [ratio]	29 (21)

7. Secondary Outcome

Title	Summary of Tumor Response Using the Response Assessment in Neuro-Oncology (RANO) Criteria
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)	Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)	Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)	Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
Arm/Group Description	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.	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.	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.	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.
Measure Participants	3	3	3	7
Stable Disease	2 66.7%	0 0%	0 0%	1 14.3%
Progressive Disease	1 33.3%	3 100%	3 100%	4 57.1%
Ineligible for Disease Response	0 0%	0 0%	0 0%	2 28.6%

Adverse Events

Time Frame	During and after treatment, up to 20 months
Arm/Group Title	Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)		Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)		Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)		Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
Arm/Group Description	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.		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.		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.		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. They will 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.
All Cause Mortality
	Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)		Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)		Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)		Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		3/3 (100%)		7/7 (100%)
Serious Adverse Events
	Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)		Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)		Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)		Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		1/3 (33.3%)		1/3 (33.3%)		4/7 (57.1%)
General disorders
Death	0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		1/7 (14.3%)
Fever	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Infections and infestations
Skin infection	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Brain abscess	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Wound infection	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Muscle weakness left-sided	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)
Pain in extremity	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Nervous system disorders
Seizure	1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)
Intracranial hemorrhage	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Psychiatric disorders
Confusion	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Vascular disorders
Hypertension	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Thromboembolic event	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Other (Not Including Serious) Adverse Events
	Dose Level 1 (NSC 5x10^7 and 5-FC 37.5 mg/kg)		Dose Level 2 (NSC 1x10^8 and 5-FC 37.5 mg/kg)		Dose Level 3 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg)		Dose Level 4 (NSC 1.5x10^8 and 5-FC 37.5 mg/kg) + Leucovorin + Microdialysis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		3/3 (100%)		7/7 (100%)
Blood and lymphatic system disorders
Anemia	2/3 (66.7%)		0/3 (0%)		2/3 (66.7%)		6/7 (85.7%)
Cardiac disorders
Sinus bradycardia	2/3 (66.7%)		1/3 (33.3%)		0/3 (0%)		4/7 (57.1%)
Sinus tachycardia	2/3 (66.7%)		2/3 (66.7%)		1/3 (33.3%)		4/7 (57.1%)
Premature ventricular contractions	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
tachypnea	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Endocrine disorders
Cushingoid	2/3 (66.7%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Eye disorders
Blurred vision	0/3 (0%)		0/3 (0%)		2/3 (66.7%)		0/7 (0%)
Dry eye	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/7 (14.3%)
Eye pain	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)
Floaters	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)
Gastrointestinal disorders
Abdominal distension	0/3 (0%)		2/3 (66.7%)		2/3 (66.7%)		2/7 (28.6%)
Abdominal pain	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		2/7 (28.6%)
Bloating	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/7 (28.6%)
Constipation	0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		5/7 (71.4%)
Diarrhea	1/3 (33.3%)		2/3 (66.7%)		1/3 (33.3%)		3/7 (42.9%)
Dry mouth	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Flatulence	1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)
Gastrointestinal pain	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)
Hemorrhoids	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)
Nausea	1/3 (33.3%)		3/3 (100%)		3/3 (100%)		3/7 (42.9%)
Oral pain	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/7 (28.6%)
Vomiting	1/3 (33.3%)		3/3 (100%)		1/3 (33.3%)		1/7 (14.3%)
Ulceration on Tongue	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)
mouth sores	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
General disorders
Chills	0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/7 (0%)
Edema face	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)
Fatigue	3/3 (100%)		3/3 (100%)		1/3 (33.3%)		4/7 (57.1%)
Fever	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Gait disturbance	2/3 (66.7%)		1/3 (33.3%)		2/3 (66.7%)		5/7 (71.4%)
Pain	1/3 (33.3%)		2/3 (66.7%)		1/3 (33.3%)		6/7 (85.7%)
Edema limbs	2/3 (66.7%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Localized edema	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)
Infections and infestations
Upper respiratory infection	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Mucosal infection	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Injury, poisoning and procedural complications
Bruising	1/3 (33.3%)		0/3 (0%)		2/3 (66.7%)		2/7 (28.6%)
Fall	2/3 (66.7%)		0/3 (0%)		0/3 (0%)		3/7 (42.9%)
numbness at surgical site	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
swelling, right side of forehead	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)
Investigations
Activated partial thromboplastin time prolonged	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Alanine aminotransferase increased	2/3 (66.7%)		0/3 (0%)		0/3 (0%)		2/7 (28.6%)
Alkaline phosphatase increased	0/3 (0%)		0/3 (0%)		0/3 (0%)		3/7 (42.9%)
Aspartate aminotransferase increased	2/3 (66.7%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Blood bilirubin increased	1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)
Cholesterol high	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
INR increased	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Lymphocyte count decreased	2/3 (66.7%)		1/3 (33.3%)		2/3 (66.7%)		6/7 (85.7%)
Platelet count decreased	2/3 (66.7%)		1/3 (33.3%)		2/3 (66.7%)		7/7 (100%)
Weight gain	2/3 (66.7%)		1/3 (33.3%)		0/3 (0%)		1/7 (14.3%)
Weight loss	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/7 (28.6%)
White blood cell decreased	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/7 (28.6%)
Hemoglobin increased	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)
Metabolism and nutrition disorders
Anorexia	0/3 (0%)		2/3 (66.7%)		1/3 (33.3%)		3/7 (42.9%)
Dehydration	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Hyperglycemia	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Hypermagnesemia	2/3 (66.7%)		1/3 (33.3%)		0/3 (0%)		1/7 (14.3%)
Hypernatremia	1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		1/7 (14.3%)
Hypertriglyceridemia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Hypoalbuminemia	2/3 (66.7%)		1/3 (33.3%)		2/3 (66.7%)		5/7 (71.4%)
Hypocalcemia	2/3 (66.7%)		1/3 (33.3%)		0/3 (0%)		2/7 (28.6%)
Hypoglycemia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Hypokalemia	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)
Hyponatremia	2/3 (66.7%)		1/3 (33.3%)		3/3 (100%)		3/7 (42.9%)
Hypophosphatemia	1/3 (33.3%)		1/3 (33.3%)		2/3 (66.7%)		6/7 (85.7%)
Obesity	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Increased appetite	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)
Bone pain	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Kyphosis	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Neck pain	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)
Pain in extremity	2/3 (66.7%)		1/3 (33.3%)		1/3 (33.3%)		3/7 (42.9%)
Buttock pain	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)
Joint range of motion decreased	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)
Generalized muscle weakness	1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		2/7 (28.6%)
Muscle weakness lower limb	1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		3/7 (42.9%)
Muscle weakness left-sided	1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		3/7 (42.9%)
Muscle weakness right-sided	2/3 (66.7%)		0/3 (0%)		2/3 (66.7%)		1/7 (14.3%)
Joint range of motion decreased cervical spine	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/7 (14.3%)
Muscle weakness upper limb	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/7 (14.3%)
Nervous system disorders
Ataxia	1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		3/7 (42.9%)
Cerebrospinal fluid leakage	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)
Cognitive disturbance	0/3 (0%)		1/3 (33.3%)		3/3 (100%)		5/7 (71.4%)
Concentration impairment	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)
Dizziness	1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)
Dysarthria	1/3 (33.3%)		0/3 (0%)		2/3 (66.7%)		0/7 (0%)
Dysphasia	0/3 (0%)		0/3 (0%)		2/3 (66.7%)		3/7 (42.9%)
Headache	3/3 (100%)		3/3 (100%)		3/3 (100%)		7/7 (100%)
Hypersomnia	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		2/7 (28.6%)
Lethargy	0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		3/7 (42.9%)
Memory impairment	1/3 (33.3%)		2/3 (66.7%)		2/3 (66.7%)		4/7 (57.1%)
Paresthesia	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Peripheral sensory neuropathy	3/3 (100%)		0/3 (0%)		1/3 (33.3%)		2/7 (28.6%)
Seizure	2/3 (66.7%)		2/3 (66.7%)		1/3 (33.3%)		0/7 (0%)
Somnolence	1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		3/7 (42.9%)
Spasticity	1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)
Tremor	2/3 (66.7%)		0/3 (0%)		1/3 (33.3%)		2/7 (28.6%)
Facial muscle weakness	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Facial nerve disorder	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/7 (28.6%)
Left-sided balance/coordination problems	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
aphasia	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
hygroma	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
tightness/swelling at right side of brain	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Psychiatric disorders
Agitation	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)
Anxiety	0/3 (0%)		1/3 (33.3%)		3/3 (100%)		3/7 (42.9%)
Confusion	2/3 (66.7%)		1/3 (33.3%)		2/3 (66.7%)		4/7 (57.1%)
Depression	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)
Insomnia	1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		1/7 (14.3%)
Restlessness	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		2/7 (28.6%)
Emotional lability	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)
MOOD CHANGES	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)
frustration	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
impulsive	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Renal and urinary disorders
Proteinuria	0/3 (0%)		0/3 (0%)		0/3 (0%)		3/7 (42.9%)
Urinary frequency	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/7 (28.6%)
Urinary incontinence	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Urinary retention	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/7 (28.6%)
Respiratory, thoracic and mediastinal disorders
Cough	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		2/7 (28.6%)
Dyspnea	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)
Hiccups	0/3 (0%)		2/3 (66.7%)		1/3 (33.3%)		1/7 (14.3%)
Lung congestion	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Tachypnea	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
chest congestion	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Skin and subcutaneous tissue disorders
Dry skin	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)
Pruritus	1/3 (33.3%)		0/3 (0%)		2/3 (66.7%)		0/7 (0%)
Rash acneiform	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Rash maculo-papular	1/3 (33.3%)		0/3 (0%)		2/3 (66.7%)		0/7 (0%)
Skin ulceration	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Scalp pain	0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/7 (0%)
Skin sore	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
blisters	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
excoriation / rash at coccyx	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)
Vascular disorders
Hematoma	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)
Hypertension	3/3 (100%)		3/3 (100%)		2/3 (66.7%)		6/7 (85.7%)
Hypotension	3/3 (100%)		0/3 (0%)		2/3 (66.7%)		2/7 (28.6%)
Phlebitis	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)
Thromboembolic event	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.