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

NCT01128218 | Completed Phase 1 Results DMC

• 1 other identifier: COZ-SIU 10-002-1
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

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.

Conditions

Brain Neoplasms

Keywords

Brain Neoplasms; 5-ALA; Aminolevulinic acid; Fluorescence; Gliomas; Glioblastoma; Surgery

Outcome Measures

Primary Outcomes (2)

• 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

Other Outcomes (1)

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

  Baseline

Study Arms (6)

Phase 1 Dose Level 1 (10mg/kg)

EXPERIMENTAL

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

Drug: Tumor fluorescence

Phase 1 Dose Level 2 (20mg/kg)

EXPERIMENTAL

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

Drug: Tumor fluorescence

Phase 1 Dose level 3 (30mg/kg)

EXPERIMENTAL

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

Drug: Tumor fluorescence

Phase 1 Dose level 4 (40mg/kg)

EXPERIMENTAL

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

Drug: Tumor fluorescence

Phase 1 Dose level 5 (50mg/kg)

EXPERIMENTAL

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

Drug: Tumor fluorescence

Phase 2 (40mg/kg)

EXPERIMENTAL

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

Drug: Tumor fluorescence

Interventions

Tumor fluorescence 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

Also known as: 5-ALA, 5-aminolevulinic acid

Phase 1 Dose Level 1 (10mg/kg); Phase 1 Dose Level 2 (20mg/kg); Phase 1 Dose level 3 (30mg/kg); Phase 1 Dose level 4 (40mg/kg); Phase 1 Dose level 5 (50mg/kg); Phase 2 (40mg/kg)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Southern Illinois University: lead
• DUSA Pharmaceuticals, Inc.: collaborator

Study Sites (1)

Southern Illinois University School of Medicine

Springfield, Illinois, 62702, United States

Location

Related Publications (5)

• 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.

  PMID: 10555843 BACKGROUND

• 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.

  PMID: 18496181 BACKGROUND

• 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.

  PMID: 16648043 BACKGROUND

• 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.

  PMID: 19248665 BACKGROUND

• Cozzens JW, Lokaitis BC, Delfino K, Hoeft A, Moore BE, Fifer AS, Amin DV, Espinosa JA, Jones BA, Acakpo-Satchivi L. A Phase 2 Sensitivity and Selectivity Study of High-Dose 5-Aminolevulinic Acid in Adult Patients Undergoing Resection of a Newly Diagnosed or Recurrent Glioblastoma. Oper Neurosurg. 2024 Nov 11;29(1):71-79. doi: 10.1227/ons.0000000000001417.

  PMID: 39526779 DERIVED

Related Links

• Brain Cancer
• Cancer

MeSH Terms

Conditions

Brain Neoplasms; Glioma; Glioblastoma

Interventions

Aminolevulinic Acid

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Astrocytoma

Intervention Hierarchy (Ancestors)

Levulinic Acids; Keto Acids; Carboxylic Acids; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Barbara Lokaitis, BA, CCRP / Senior Clinical Research Coordinator
• Organization: SIU Medicine

blokaitis@siumed.edu

217.545.9737

Study Officials

• Jeffrey W Cozzens, MD

  Southern Illinois University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Dose escalation study

Study Record Dates

• First Submitted: May 13, 2010
• First Posted: May 21, 2010
• Study Start: March 1, 2011
• Primary Completion: February 1, 2021
• Study Completion: February 1, 2021
• Last Updated: November 30, 2023
• Results First Posted: November 30, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)