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

Study Overview
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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.

Official Title
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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

Conditions
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Brain Neoplasms

Intervention / Treatment
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* Drug: Tumor fluorescence


Participation Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Level 1 (10mg/kg)<br>Dose Level 1: Participants were given a one-time, single-dose administration of oral 10mg/kg Aminolevulinic Acid (5-ALA) | Drug: Tumor fluorescence<br>* 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<br>* Other names: 5-aminolevulinic acid;|
| Experimental: Phase 1 Dose Level 2 (20mg/kg)<br>Dose Level 2: Participants were given a one-time, single-dose administration of oral 20mg/kg Aminolevulinic Acid (5-ALA) | Drug: Tumor fluorescence<br>* 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<br>* Other names: 5-aminolevulinic acid;|
| Experimental: Phase 1 Dose level 3 (30mg/kg)<br>Dose Level 3: Participants were given a one-time, single-dose administration of oral 30mg/kg Aminolevulinic Acid (5-ALA) | Drug: Tumor fluorescence<br>* 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<br>* Other names: 5-aminolevulinic acid;|
| Experimental: Phase 1 Dose level 4 (40mg/kg)<br>Dose Level 4: Participants were given a one-time, single-dose administration of oral 40mg/kg Aminolevulinic Acid (5-ALA) | Drug: Tumor fluorescence<br>* 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<br>* Other names: 5-aminolevulinic acid;|
| Experimental: Phase 1 Dose level 5 (50mg/kg)<br>Dose Level 5: Participants were given a one-time, single-dose administration of 50mg/kg Aminolevulinic Acid (5-ALA) | Drug: Tumor fluorescence<br>* 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<br>* Other names: 5-aminolevulinic acid;|
| Experimental: Phase 2 (40mg/kg)<br>Phase 2: Participants were given a one-time, single-dose administration of 40mg/kg Aminolevulinic Acid (5-ALA) | Drug: Tumor fluorescence<br>* 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<br>* Other names: 5-aminolevulinic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establish a Safe Dose for Oral 5-ALA Administration | Dose escalation from 10mg/kg to 50mg/kg to determine optimal 5-ALA dose | 6 months | 
| Determine the Sensitivity, Specificity, and Positive Predictive Value of 5-ALA Mediated Fluorescence for Malignant Glioma Tissue in the Brain. | The neurosurgeon will take two small biopsies per patient from areas identified as obvious tumor and areas in the wall of the resection cavity that were judged to be normal, non-eloquent brain. A neuropathologist will review all biopsy specimens, including those taken from the solid tumor. Pathologic confirmation of tumor type will be made by the study reference neuropathologist. We assessed 5-ALA's resulting fluorescence for distinguishing tumor within the brain, where True Positive: Fluorescence showing Tumor and Biopsy result Tumor False Positive: Fluorescence showing Tumor and Biopsy result No Tumor True Negative: No Fluorescence and Biopsy result No Tumor False Negative: No Fluorescence and Biopsy result Tumor These values represent the characteristics of 5-ALA aka its ability to distinguish tumor from non-tumor. From these parameters we determined sensitivity, specificity and the positive and negative predictive values. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain Neoplasms, 5-ALA, Aminolevulinic acid, Fluorescence, Gliomas, Glioblastoma, Surgery