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A Phase 1 and 2 Study of 5-aminolevulinic Acid (5-ALA) to Enhance Visualisation and Resection of Malignant Glial Tumors of the Brain

Phase 1/Phase 2
18 Years
Not Enrolling
Brain Neoplasms

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Trial Information

A Phase 1 and 2 Study of 5-aminolevulinic Acid (5-ALA) to Enhance Visualisation and Resection of Malignant Glial Tumors of the Brain

Specific Aims:

This study is intended to investigate the utility, safety and efficacy of 5-aminolevulinic
acid (5-ALA) induced brain tumor fluorescence during malignant brain tumor resection.
Specifically this study is intended to:

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

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

- 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.

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

Background and Significance:

There is a considerable body of literature that suggests that completeness of resection is a
positive factor for longer term survival in individuals with malignant glioma.
Unfortunately, it is often difficult to completely remove a malignant brain tumor because
during surgery it is sometimes very difficult to distinguish tumor from normal brain. It
would be very helpful if there would be some way to help the surgeon make this distinction.
Malignant glioma tumor cells (more so than normal cells) contain the biosynthetic pathways
to produce protoporphyrin from a naturally occurring amino acid, 5-aminolevulinic acid
(5-ALA). Protoporphyrin is the immediate precursor to hemoglobin (it is hemoglobin without
the iron atom) and is fluorescent under blue light. When exogenous 5-ALA is provided at
increased concentration, protoporphyrin concentration in the malignant cell increases at a
rate far greater than normal brain cells and renders the malignant cell fluorescent red
under blue light. This feature distinguishes the tumor cells from normal cells
intraoperatively and facilitates complete resection.

Recent studies in Germany have confirmed the utility of pre-operative oral 5-ALA and
intraoperative brain tumor fluorescence in aiding the resection of brain tumors in
individuals with malignant brain tumors. These studies have led to oral 5-ALA to be approved
for this indication by the European Medicines Agency (The European Medicines Agency comments
and approval can be found at:, but oral 5-ALA has not
been approved for this indication by the United States FDA. This proposal is a phase 1 and
phase 2 trial that will hopefully lead to FDA approval of oral 5-ALA for intra-operative
visualization of malignant brain tumors.

Experimental Plan and Methods:

In the phase 1 part of this proposed study, a minimum of 3 to a maximum of 18 patients will
be administered oral 5-ALA 4 hours prior to surgery in cohorts of 3 at five escalating doses
of 5-ALA (10, 20, 30, 40, or 50 mg/kg).

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

- 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.

Discussions statisticians have led to the development of a number of 2x2 tables and 3x3
tables of data analysis that will lead to establishment of the sensitivity and specificity
of fluorescence-guided brain tumor resection compared to conventional brain tumor resection

Inclusion Criteria:

- 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

- 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

Exclusion Criteria:

- Prior therapy is not an exclusion criterion

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Establish a safe dose for oral 5-ALA administration.

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Jeffrey W. Cozzens, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

NorthShore University HealthSystem


United States: Food and Drug Administration

Study ID:




Start Date:

September 2009

Completion Date:

January 2010

Related Keywords:

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