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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion 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

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT01128218
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1/Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Southern Illinois University
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Jeffrey W Cozzens, MD
Principal Investigator Affiliation Southern Illinois University School of Medicine
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other, Industry
Overall Status Completed
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Brain Neoplasms
Study Website: View Trial Website
Additional Details

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.

Arms & Interventions

Arms

Experimental: Phase 1 Dose Level 1 (10mg/kg)

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

Experimental: Phase 1 Dose Level 2 (20mg/kg)

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

Experimental: Phase 1 Dose level 3 (30mg/kg)

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

Experimental: Phase 1 Dose level 4 (40mg/kg)

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

Experimental: Phase 1 Dose level 5 (50mg/kg)

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

Experimental: Phase 2 (40mg/kg)

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

Interventions

Drug: - 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

Contact a Trial Team

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Springfield, Illinois

Status

Address

Southern Illinois University School of Medicine

Springfield, Illinois, 62702