A Study of the Specificity and Sensitivity of 5-ALA Fluorescence in Malignant Brain Tumors

NCT00977795 | Withdrawn Phase 1 DMC

• 1 other identifier: EH09-377
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Extent of resection is a very important prognostic factor affecting survival in individuals diagnosed with a malignant glioma. However, the infiltrative nature of the malignant glioma tumor cells produces indistinct borders between normal and malignant tissues, and the lack of easily identifiable tumor margins confounds attempts at total resection. The investigators propose to identify the borders of malignant gliomas intraoperatively using oral 5-aminolevulinic Acid (5-ALA) which results in fluorescence of the malignant cells and thereby provide an opportunity for more complete tumor resection. When exogenous 5-ALA is provided at increased concentration the tumor cells will become fluorescent under ultraviolet light. This feature identifies the tumor cells intraoperatively and facilitates complete resection. The following data will be collected:

• Dose-limiting toxicity data
• Tumor fluorescence assessed by neurosurgeon (0 to +++) in three distinct areas of fluorescence (Strong fluorescence, Weak fluorescence, No fluorescence)
• Tumor density from biopsies obtained by the neurosurgeon in the same three distinct areas of fluorescence and assessed by neuropathology (Solid tumor, Tumor mixed infiltrating normal brain, No tumor)
• Neurosurgeon's intra-operative estimate of residual tumor
• Neuroradiologist's estimate of post-operative residual tumor on MRI
• Time to progression by MRI
• Survival (time to progression, one year survival rate and total survival This trial will evaluate:
• The toxicity of a single dose of oral 5-ALA given pre-operatively.
• The sensitivity and specificity of 5-ALA - Protoporphyrin IX (Pp IX) as an intraoperative fluorescent detection agent and aid for resection of tumor tissue remaining in the walls of the resection cavity of primary and recurrent malignant brain tumors.
• The relationship of the neurosurgeon's estimate of the extent of malignant glioma resection (as guided by tumor fluorescence) to the actual extent of resection determined by post-operative imaging.
• The time-to-progression, one year survival rate and total survival as a function of the extent of resection. Following completion of the phase 1 portion of this trial, an additional 15 subjects will be entered at the recommended phase 2 dose level in order to further define the above parameters at the recommended phase 2 dose level.

Conditions

Brain Neoplasms

Keywords

Brain Neoplasms; 5-ALA; Aminolevulinic acid; Fluorescence; Gliomas; Glioblastoma; Surgery

Outcome Measures

Primary Outcomes (1)

• Establish a safe dose for oral 5-ALA administration.

  6 months

Secondary Outcomes (3)

• Determine the sensitivity and specificity of 5-ALA mediated fluorescence for malignant glioma tissue in the brain

  24 months

• Compare the neurosurgeon's intra-operative estimate of the extent of malignant glioma resection (as guided by tumor fluorescence) with the actual extent of resection determined by post-operative imaging

  24 months

• Compare time-to-progression and survival to that in comparable cases performed without the aid of 5-ALA

  24 months

Study Arms (1)

Tumor fluorescence

EXPERIMENTAL

A single arm in this open-label study where all patients are treated with the study drug. Areas of the brain that are fluorescent and areas that are not fluorescent are evaluated for presence of tumor cells

Drug: 5-aminolevulinic acid

Interventions

5-aminolevulinic acid DRUG

oral doses in phase 1 study of 10mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg and 50 mg/kg

Also known as: 5-ALA, aminolevulinic acid

Tumor fluorescence

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have clinically documented primary brain tumor for which resection is clinically indicated. The anticipated histology at resection should include: Anaplastic astrocytoma (10002224), Astrocytoma malignant NOS (10003572), Brain stem glioma (10006143), Ependymoma (10014967), Ependymoma malignant (10014968), Glioblastoma (10018336), Glioblastoma multiforme (10018337), Gliosarcoma (10018340), Anaplastic oligodendroglioma (10026659), Oligodendroglioma (10030286), Medulloblastoma (10027107), Mixed astrocytoma-ependymoma (10027743), Miscellaneous CNS primary tumor (10007959), Supratentorial primitive neuroectodermal tumor (10056672)
• Prior therapy is not a consideration in protocol entry
• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of 5-ALA in patients \<18 years of age, children are excluded from this study but will be eligible for future pediatric phase 1 single-agent trials
• ECOG performance status \<2 (Karnofsky \>60%)
• Life expectancy is not a consideration for protocol entry
• Patients must have normal organ and marrow function as defined below:
• Leukocytes \> 3,000/mcL
• Absolute neutrophil count \> 1,500/mcL
• Platelets \> 100,000/mcL
• Total bilirubin within normal institutional limits
• AST (SGOT)/ALT (SGPT) \< 2.5 X institutional upper limit of normal
• Creatinine within normal institutional limits, OR
• Creatinine clearance \> 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
• The effects of 5-ALA on the developing human fetus are unknown. 5-ALA has unknown teratogenic or abortifacient effects. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document

You may not qualify if:

• Patients may not be receiving any other investigational agents at the time of entry into the study
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-ALA
• Personal or family history of porphyrias
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because 5-ALA is of unknown teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with 5-ALA, breastfeeding should be discontinued if the mother is treated with 5-ALA

Sponsors & Collaborators

• Endeavor Health: lead

Related Publications (4)

• Keles GE, Anderson B, Berger MS. The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere. Surg Neurol. 1999 Oct;52(4):371-9. doi: 10.1016/s0090-3019(99)00103-2.

  PMID: 10555843 BACKGROUND

• Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery. 2008 Apr;62(4):753-64; discussion 264-6. doi: 10.1227/01.neu.0000318159.21731.cf.

  PMID: 18496181 BACKGROUND

• Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ; ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006 May;7(5):392-401. doi: 10.1016/S1470-2045(06)70665-9.

  PMID: 16648043 BACKGROUND

• Tonn JC, Stummer W. Fluorescence-guided resection of malignant gliomas using 5-aminolevulinic acid: practical use, risks, and pitfalls. Clin Neurosurg. 2008;55:20-6. No abstract available.

  PMID: 19248665 BACKGROUND

MeSH Terms

Conditions

Brain Neoplasms; Glioma; Glioblastoma

Interventions

Aminolevulinic Acid

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Astrocytoma

Intervention Hierarchy (Ancestors)

Levulinic Acids; Keto Acids; Carboxylic Acids; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Jeffrey W. Cozzens, M.D.

  Endeavor Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 15, 2009
• First Posted: September 16, 2009
• Study Start: September 1, 2009
• Primary Completion: January 1, 2010
• Study Completion: January 1, 2010
• Last Updated: September 10, 2019

Record last verified: 2019-09