A Phase 1/2 interventional study of Tumor fluorescence in Brain Neoplasms, sponsored by Southern Illinois University. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-11-30.
Sponsored by Southern Illinois University · Phase 1/2, Interventional, and Treatment
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:
This trial will evaluate:
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.
1,960 studies on the registry are indexed under Brain Neoplasms; 516 are open to participants now.
This study's enrollment of 33 is below the median of 40 across 1,458 interventional studies indexed under Brain Neoplasms.
Browse Brain Neoplasms studies →Southern Illinois University is the lead sponsor of 28 studies on the registry; 2 are open to participants now.
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Normal organ and marrow function as defined below:
Exclusion Criteria:
Dose Level 1: Participants were given a one-time, single-dose administration of oral 10mg/kg Aminolevulinic Acid (5-ALA)
Drug: Tumor fluorescence
Dose Level 2: Participants were given a one-time, single-dose administration of oral 20mg/kg Aminolevulinic Acid (5-ALA)
Drug: Tumor fluorescence
Dose Level 3: Participants were given a one-time, single-dose administration of oral 30mg/kg Aminolevulinic Acid (5-ALA)
Drug: Tumor fluorescence
Dose Level 4: Participants were given a one-time, single-dose administration of oral 40mg/kg Aminolevulinic Acid (5-ALA)
Drug: Tumor fluorescence
Dose Level 5: Participants were given a one-time, single-dose administration of 50mg/kg Aminolevulinic Acid (5-ALA)
Drug: Tumor fluorescence
Phase 2: Participants were given a one-time, single-dose administration of 40mg/kg Aminolevulinic Acid (5-ALA)
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
Also known as: 5-ALA, 5-aminolevulinic acid
Establish a Safe Dose for Oral 5-ALA Administration
Dose escalation from 10mg/kg to 50mg/kg to determine optimal 5-ALA dose
Time frame: 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.
Time frame: Baseline
Assess 5-ALA's Resulting Fluorescence for Distinguishing Tumor Within 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.
Time frame: Baseline
| Milestone | 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) |
|---|---|---|---|---|---|---|
| Started | 3 | 3 | 3 | 4 | 6 | 14 |
| Completed | 3 | 3 | 3 | 4 | 6 | 14 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 |
Dose escalation from 10mg/kg to 50mg/kg to determine optimal 5-ALA dose
| Dose Limiting Toxicity | 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) |
|---|---|---|---|---|---|
| Establish a Safe Dose for Oral 5-ALA Administration | 0 | 0 | 0 | 0 | 0 |
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.
| Percentage | Phase 2 Dose Level 1 (40mg/kg) |
|---|---|
| Sensitivity | 63.64 |
| Specificity | 100 |
| Positive Predictive Value | 100 |
| Negative Predictive Value | 42.86 |
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.
| Biopsies | Phase 2 Dose Level 1 (40mg/kg) |
|---|---|
| True Positives | 14 |
| True Negatives | 6 |
| False Positives | 0 |
| False Negatives | 8 |
Collected over 6 years. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase 1, Dose Level 1 (10mg/kg) | 1/3 (33.3%) | 2/3 (66.7%) | 0/3 (0%) |
| Phase 1, Dose Level 2 (20mg/kg) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) |
| Phase 1, Dose Level 3 (30mg/kg) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) |
| Phase 1, Dose Level 4 (40mg/kg) | 0/4 (0%) | 0/4 (0%) | 0/4 (0%) |
| Phase 1, Dose Level 5 (50mg/kg) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) |
| Phase 2 (40mg/kg) | 0/14 (0%) | 2/14 (14.3%) | 0/14 (0%) |
| Event | 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) |
|---|---|---|---|---|---|---|
| deathCardiac disorders | 1/3 | 0/3 | 0/3 | 0/4 | 0/6 | 0/14 |
| scalp wound abscessInfections and infestations | 1/3 | 0/3 | 0/3 | 0/4 | 0/6 | 0/14 |
| severe cerebral edemaSurgical and medical procedures | 0/3 | 0/3 | 0/3 | 0/4 | 0/6 | 1/14 |
| partial seizureNervous system disorders | 0/3 | 0/3 | 0/3 | 0/4 | 0/6 | 1/14 |
| Age, Categorical(Participants) | 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 5 (50mg/kg) | Phase 2 (40mg/kg) | Total |
|---|---|---|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 1 | 2 | 3 | 1 | 6 | 6 | 19 |
| >=65 years | 2 | 1 | 0 | 3 | 0 | 8 | 14 |
| Age, Continuous(years) | 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 5 (50mg/kg) | Phase 2 (40mg/kg) | Total |
|---|---|---|---|---|---|---|---|
| Mean | 64 (32 to 87) | 61 (54 to 74) | 63 (62 to 67) | 71 (63 to 77) | 52.5 (44 to 62) | 56.36 (21 to 84) | 58.63 (21 to 87) |
| Sex: Female, Male(Participants) | 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 5 (50mg/kg) | Phase 2 (40mg/kg) | Total |
|---|---|---|---|---|---|---|---|
| Female | 3 | 1 | 0 | 1 | 3 | 8 | 16 |
| Male | 0 | 2 | 3 | 3 | 3 | 6 | 17 |
| Ethnicity (NIH/OMB)(Participants) | 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 5 (50mg/kg) | Phase 2 (40mg/kg) | Total |
|---|---|---|---|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
| Not Hispanic or Latino | 3 | 3 | 3 | 3 | 6 | 14 | 32 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | 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 5 (50mg/kg) | Phase 2 (40mg/kg) | Total |
|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 1 | 0 | 0 | 0 | 0 | 1 |
| White | 3 | 2 | 3 | 4 | 6 | 14 | 32 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Region of Enrollment(participants) | 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 5 (50mg/kg) | Phase 2 (40mg/kg) | Total |
|---|---|---|---|---|---|---|---|
| United States | 3 | 3 | 3 | 4 | 6 | 14 | 33 |
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Southern Illinois University