Clinical trial NCT01128218: A Study of the Specificity and Sensitivity of 5- Aminolevulinic Acid (ALA) Fluorescence in Malignant Brain Tumors
Official title: A Phase 1 and 2 Study of 5-aminolevulinic Acid (5-ALA) to Enhance Visualisation and Resection of Malignant Glial Tumors of the Brain
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Brain Neoplasms
Keywords: Brain Neoplasms
5-ALA
Aminolevulinic acid
Fluorescence
Gliomas
Glioblastoma
Surgery
Lead sponsor: Southern Illinois University
Sponsor class: OTHER
Collaborators: name: DUSA Pharmaceuticals, Inc.
First posted: 2010-05-21
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose escalation study
Primary purpose: TREATMENT

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.

Data collection will include measurement of dose-limiting toxicity, tumor fluorescence, and tumor density. Data analysis will evaluate toxicity, sensitivity, and specificity of 5-ALA.

Following completion of the phase 1 portion of this trial, an additional 14 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.

Detailed description: 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.

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, 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 19 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
* Tumor fluorescence assessed by neurosurgeon
* Tumor density from biopsies obtained by the neurosurgeon in will be assessed by neuropathology (Solid tumor, Tumor mixed infiltrating normal brain, No tumor)

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;

Following completion of the phase 1 portion of this trial, an additional 14 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.

Eligibility criteria: Inclusion Criteria:

* Patients must have clinically documented primary brain tumor for which resection is clinically indicated.
* 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 (Eastern Cooperative Oncology Group) performance status \<2 (Karnofsky \>60%)
* Normal organ and marrow function as defined below:

  * Leukocytes \> 3,000/mcL (microliter)
  * Absolute neutrophil count \> 1,500/mcL
  * Platelets \> 100,000/mcL
  * Total bilirubin within normal institutional limits AST (aspartate aminotransferase) (SGOT)/ALT (alanine transaminase) (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
* Agreement by women of child-bearing potential and men to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* 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

Primary outcomes:
measure: Establish a Safe Dose for Oral 5-ALA Administration
timeFrame: 6 months
measure: Determine the Sensitivity, Specificity, and Positive Predictive Value of 5-ALA Mediated Fluorescence for Malignant Glioma Tissue in the Brain.
timeFrame: Baseline
Secondary outcomes:
Other outcomes:
measure: Assess 5-ALA's Resulting Fluorescence for Distinguishing Tumor Within the Brain
timeFrame: Baseline
Locations:
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
Study officials:
affiliation: Southern Illinois University School of Medicine
name: Jeffrey W Cozzens, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.