Neoplasms

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Glioma

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Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Dermatologic Agents

All Drugs and Chemicals

Aminolevulinic Acid

Photosensitizing Agents

Dose Level 1: Participants were given a one-time, single-dose administration of oral 10mg/kg Aminolevulinic Acid (5-ALA)

Dose Level 2: Participants were given a one-time, single-dose administration of oral 20mg/kg Aminolevulinic Acid (5-ALA)

Dose Level 3: Participants were given a one-time, single-dose administration of oral 30mg/kg Aminolevulinic Acid (5-ALA)

Dose Level 4: Participants were given a one-time, single-dose administration of oral 40mg/kg Aminolevulinic Acid (5-ALA)

Dose Level 5: Participants were given a one-time, single-dose administration of 50mg/kg Aminolevulinic Acid (5-ALA)

Phase 2: Participants were given a one-time, single-dose administration of 40mg/kg Aminolevulinic Acid (5-ALA)

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

Tumor fluorescence

Jeffrey W Cozzens, MD

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.

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.

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

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

Under blue light, the neurosurgeon will take two small biopsies per patient from areas identified as obvious tumor (fluorescent) and areas in the wall of the resection cavity that were judged to be normal (but possibly edematous), non-eloquent brain (non-fluorescent). 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.

Dose escalation from 10mg/kg to 50mg/kg to determine optimal 5-ALA dose

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.

DUSA Pharmaceuticals, Inc.

Southern Illinois University

Phase 1 Dose Level 1: Participants were given a one-time, single-dose administration of oral 10mg/kg Aminolevulinic Acid (5-ALA)

Phase 1, Dose Level 1 (10mg/kg)

Phase 1 Dose Level 2: Participants were given a one-time, single-dose administration of oral 20mg/kg Aminolevulinic Acid (5-ALA)

Phase 1, Dose Level 2 (20mg/kg)

Phase 1 Dose Level 3: Participants were given a one-time, single-dose administration of oral 30mg/kg Aminolevulinic Acid (5-ALA)

Phase 1, Dose Level 3 (30mg/kg)

Phase 1 Dose Level 4: Participants were given a one-time, single-dose administration of oral 40mg/kg Aminolevulinic Acid (5-ALA)

Phase 1, Dose Level 4 (40mg/kg)

Phase 1 Dose Level 5: Participants were given a one-time, single-dose administration of oral 50mg/kg Aminolevulinic Acid (5-ALA)

Phase 1, Dose Level 5 (50mg/kg)

Phase 2 Dose (40mg/kg): Participants were given a one-time, single-dose administration of oral 40mg/kg Aminolevulinic Acid (5-ALA)

Phase 2 (40mg/kg)

Phase 1 Dose Level 1 (10mg/kg)

Phase 1 Dose Level 2 (2omg/kg)

Phase 1 Dose Level 3 (30mg/kg)

Phase 1 Dose Level 4 (40mg/kg)

Phase 1 Dose Level 1: Participants were given a one-time, single-dose administration of oral 50mg/kg Aminolevulinic Acid (5-ALA)

Phase 1 Dose Level 5 (50mg/kg)

Phase 2: Participants were given a one-time, single-dose administration of oral 40mg/kg Aminolevulinic Acid (5-ALA)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Barbara Lokaitis, BA, CCRP / Senior Clinical Research Coordinator

Phase 1 Dose Level 2 (20mg/kg)

There were no dose limiting toxicities observed at any dose level arm. Therefore, the 40mg/kg dose was arbitrarily chosen for the phase 2 portion of the study.

Establish a Safe Dose for Oral 5-ALA Administration

Sensitivity

Specificity

Positive Predictive Value

Negative Predictive Value

A single arm in this open-label study where all patients are treated with the study drug - 5-aminolevulinic acid. Areas of the brain that are fluorescent and areas that are not fluorescent are evaluated for presence of tumor cells

Tumor fluorescence: Oral Phase 2 dose: 40mg/kg.

Phase 2 Dose Level 1 (40mg/kg)

Assessing sensitivity, specificity, positive predictive value, and negative predictive value in Phase 2 Study Population of N=14 Patients at 40 mg/kg Dose

Determine the Sensitivity, Specificity, and Positive Predictive Value of 5-ALA Mediated Fluorescence for Malignant Glioma Tissue in the Brain.

True Positives

True Negatives

False Positives

False Negatives

Phase 2 Study Population of N=14 Patients at 40 mg/kg Dose

Assess 5-ALA's Resulting Fluorescence for Distinguishing Tumor Within the Brain

Dose Level 1: Participants were given a one-time, single-dose administration of oral10mg/kg Aminolevulinic Acid (5-ALA)

Dose Level 5: Participants were given a one-time, single-dose administration of oral 50mg/kg Aminolevulinic Acid (5-ALA)

Phase 2 (40mg/kg): Participants were given a one-time, single-dose administration of oral 50mg/kg Aminolevulinic Acid (5-ALA)

Overall Study

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Micronutrients

Vitamins

Ascorbic Acid

Antioxidants

Protective Agents

Trace Elements

Vitamin C

Within 3 hours prior to surgery, patient will orally ingest \[or be given via Nasogastric (NG), Orogastric (OG), or Gastric tube (G-tube)\] 5-ALA/Gliolan®/5-Aminolevulinic acid mixed with sterile water (20mg/kg)

Within 3 hours prior to surgery, patient will orally ingest \[or be given via Nasogastric (NG), Orogastric (OG), or Gastric tube (G-tube)\] 1.5 Gm. placebo - ascorbic acid in 50 ml sterile water.

Following informed consent, within 3 hours prior to surgery, patient will orally ingest \[or be given via Nasogastric (NG), Orogastric (OG), or Gastric tube (G-tube)\] either (1) 5-ALA/Gliolan® mixed with sterile water (20mg/kg)

5-Aminolevulinic acid (ALA)

Placebo - ascorbic acid

Nader Sanai, MD

Gliomas are the most common primary brain tumor, yet remain a challenge to effectively treat. Mounting evidence suggests that survival improves with greater tumor removal, yet being able do a complete removal can be difficult due to the tumor's infiltrating nature. 5-aminolevulinic acid (5-ALA) is a natural compound that, when patients take it by mouth 3 hours before surgery, is selectively taken up by glioma cells and causes a red/pink fluorescence (glow) under a blue light that allows tumor margins to be seen during the course of surgery. While this compound is used as a standard-of-care agent in Europe, it remains under testing by the Food and Drug Administration (FDA). A recent clinical trial in Germany, however, has demonstrated a significant improvement in the rate of complete resection for certain brain tumors (65% vs. 34%).

The Barrow 5-ALA Intraoperative Confocal (BALANCE) Trial will measure the effect of 5-ALA on the amount of glioma tumor removal. To improve the usefulness of 5-ALA, a new special microscope fitted with a blue light, will be used to magnify microscopic fluorescence at the tumor margins. The investigators' hypothesis is that 5-ALA fluorescence with the use of the special microscope during surgery will greatly lower the amount of tumor left behind.

Gliomas are the most common primary brain tumor, yet are associated with a 12-14 month overall survival in the United States. Mounting evidence suggests that survival improves with greater extent of resection, yet achieving a complete radiographic resection is challenging due to the tumor's infiltrating nature. Oral 5-aminolevulinic acid (5-ALA/Gliolan®) is a natural compound that, when administered to patients within 3 hours prior to surgery, is selectively metabolized by glioma cells and induces a red/pink fluorescence under blue light that facilitates intraoperative identification of tumor margins. While this compound is used as a standard-of-care agent in Europe, it remains under examination by the Food and Drug Administration (FDA). A recent multicenter randomized, single-blind, controlled study in Germany demonstrated a significant improvement in the rate of complete resection for high-grade gliomas, as compared to conventional microneurosurgery (65% vs. 34%) (Stummer et al., Lancet Oncology 2006).

Patients with presumed newly-diagnosed glioma will be entered into the trial. On the basis of their expected extent of resection (low vs. high), they will be stratified in one of 2 groups - Group 1 (expected high extent or resection) or Group 2 (expected low extent of resection). Following stratification, patients with newly-diagnosed disease will be randomized to receive either study drug (5-ALA/Gliolan®) or placebo (ascorbic acid) prior to surgery. Those who have had previous biopsy only without further treatment will be eligible for randomization. Intraoperatively, 5-ALA/Gliolan® patients will undergo resection with combined fluorescence microscopy and confocal microscopy. Placebo patients will undergo resection with standard light microscopy. Postoperatively, patients will have an MRI scan with and without contrast within 48 hours of surgery. Subsequent analysis of each patient will include assessment of the primary endpoint, that is,volume of residual disease (VRD) by volumetrically quantifying the tumor before and after surgery using T1-weighted contrast-enhancement (high-grade gliomas) or T2-weighted hyperintensity (low-grade gliomas). Similarly, volumetric extent of resection will also be measured. Other secondary endpoints will include overall survival (OS), progression-free survival (PFS), and National Institute of Health Stroke Scale (NIHSS) (collected at baseline, 7-10 days post-op and at 6, 12, 18, and 24 months post op).

The Barrow 5-ALA Intraoperative Confocal (BALANCE) study will quantify the impact of 5-ALA/Gliolan(R) on low- and high-grade glioma extent of resection. To enhance the efficacy of 5-ALA/Gliolan(R), particularly for low-grade gliomas that fluoresce less vigorously due to their comparatively lower cellular metabolism, intraoperative confocal microscopy will be used to amplify microscopic fluorescence at the tumor margins. The investigators' hypothesis is that, for both low- and high-grade gliomas, 5-ALA/Gliolan(R) fluorescence in conjunction with intraoperative confocal microscopy will significantly lower the VRD.

Goals:

1. To determine the impact of intraoperative fluorescence and confocal microscopy on the volume of residual disease following resection of a newly-diagnosed glioma.

Sub-goals:

1. To assess the feasibility and utility of combining intraoperative fluorescence with confocal microscopy.
2. To determine the impact of this combined approach in improving volumetric extent of resection.
3. To determine the impact of this combined approach in improving overall survival and 6-month progression-free survival.

Fluorescence-guided Surgery for Low- and High-grade Gliomas

Barrow 5-ALA Intraoperative Confocal Evaluation Trial

Volumetric analysis of MRI contrast T1-weighted images (for low grade gliomas) will be compared to the preoperative sequences to calculate the volume of residual disease. Slice-by-slice assessment of pre- and postoperative tumor volume will be quantified by sequentially measuring the area of tumor on each slice and then integrating the combined measurements. This methodology has been previously reported (Sanai et al., Journal of Neurosurgery, 2010; Sanai et al, The New England Journal of Medicine, 2008)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of the Specificity and Sensitivity of 5- Aminolevulinic Acid (ALA) Fluorescence in Malignant Brain Tumors	NCT01128218	Brain Neoplasms	Tumor fluoresce...	18 Years -	Southern Illinois University
Fluorescence-guided Surgery for Low- and High-grade Gliomas	NCT01502280	Glioma	5-Aminolevulini... Placebo - ascor...	18 Years -	St. Joseph's Hospital and Medical Center, Phoenix
Fluorescence-guided Surgery for Low- and High-grade Gliomas	NCT01502280	Glioma	5-Aminolevulini... Placebo - ascor...	18 Years -	St. Joseph's Hospital and Medical Center, Phoenix

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