A Study of the Specificity and Sensitivity of 5- Aminolevulinic Acid (ALA) Fluorescence in Malignant Brain Tumors

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

33 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-03-31

Study Completion Date

2021-02-28

Brief Summary

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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

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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.

Conditions

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Brain Neoplasms

Keywords

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Brain Neoplasms 5-ALA Aminolevulinic acid Fluorescence Gliomas Glioblastoma Surgery

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

SEQUENTIAL

Dose escalation study

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Intervention Type DRUG

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

Recommended oral dose of phase 1 will be used in phase 2

Interventions

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Tumor fluorescence

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

Recommended oral dose of phase 1 will be used in phase 2

Intervention Type DRUG

Other Intervention Names

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5-ALA 5-aminolevulinic acid

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Jeffrey W Cozzens, MD

Role: PRINCIPAL_INVESTIGATOR

Southern Illinois University School of Medicine

Locations

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Southern Illinois University School of Medicine

Springfield, Illinois, United States

Site Status

Countries

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United States

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

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COZ-SIU 10-002-1

Identifier Type: -

Identifier Source: org_study_id

A Study of the Specificity and Sensitivity of 5- Aminolevulinic Acid (ALA) Fluorescence in Malignant Brain Tumors

Study Results

Basic Information

Brief Summary

Detailed Description

Conditions

Keywords

Study Design

Study Groups

Phase 1 Dose Level 1 (10mg/kg)

Tumor fluorescence

Phase 1 Dose Level 2 (20mg/kg)

Tumor fluorescence

Phase 1 Dose level 3 (30mg/kg)

Tumor fluorescence

Phase 1 Dose level 4 (40mg/kg)

Tumor fluorescence

Phase 1 Dose level 5 (50mg/kg)

Tumor fluorescence

Phase 2 (40mg/kg)

Tumor fluorescence

Interventions

Tumor fluorescence

Other Intervention Names

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

Sponsors

DUSA Pharmaceuticals, Inc.

Southern Illinois University

Responsible Party

Principal Investigators

Jeffrey W Cozzens, MD

Locations

Southern Illinois University School of Medicine

Countries

References

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.

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.

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.

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

Related Links

Other Identifiers

COZ-SIU 10-002-1