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:
http://www.emea.europa.eu/humandocs/PDFs/EPAR/gliolan/H-744-en6.pdf), 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; i.e., nausea, vomiting, liver function, photo-sensitivity,
survival

- 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:

- single dose toxicity of oral 5-ALA given pre-operatively;

- 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;

- 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;

- 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
techniques.