Erythroplakia, Leukoplakia
Conditions
Brief summary
Oral leukoplakia within the mouth is a visible white patch which can develop into cancer if not treated. There is no good treatment for these lesions, apart from surgery which is associated with significant side effects and physical deformation of the treated area. The investigators hypothesized that photodynamic therapy can be used safely and effectively to induce significant regression of oral leukoplakia.
Detailed description
This is a combined Phase I/II non-randomized prospective study designed to determine the safety and assess the clinical efficacy of PDT in the treatment of oral leukeplekia with 5-ALA and 585-nm PDL with 1.5 ms pulse time. In the first part of the study we determined the maximum tolerated dose (MTD) of the PDL radiant exposure in combination with 5-ALA. In the second phase of the study, this dose is used to treat subjects at the MTD in order to determine the efficacy of the treatment by documenting the regression of the treated lesions.
Interventions
DEVICEPDL-585, ScleroPLUS laser
PDT Treatment; emits light with 585 nm wavelength in pulses of 1.5 milliseconds in sections of 5 mm diameter to target the lesion and surrounding tissue
DRUG5-Aminolevulinic Acid (Levulan KerastickTM)
Topically administered; incubation time 60-180 minutes; single dose (345 mg of active 5-ALA in 1.5 ml solution); soaked onto white gauze and applied to lesion, covered with sterile Xeroform gauze
PROCEDUREFluorescence Diagnosis Imaging
FD Image taken prior to PDL-585 usage
Sponsors
University of Arkansas
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* At least one grossly visible premalignant lesion (i.e. leukoplakia or erythroplakia) in the oral cavity or oropharynx, with a confirmed diagnosis of leukoplakia with or without dysplasia,measuring ≥ 10 mm in diameter. * Informed of alternative treatment methods including watchful waiting, laser ablation, or surgical resection. * Eligible for long-term follow-up for at least one year and be able to tolerate biopsies. * Subject has signed an informed consent. * Subject is between the ages of 18 - 80 years of age. * Male or Female * Zubrod performance status of 0 or 1 at screening. See Appendix A
Exclusion criteria
* Known sensitivity to porphyrins or photoactive medications - See Appendix B * Invasive carcinoma of the lesion as demonstrated by biopsy. * Subjects with inherited or acquired blood clotting defects * Women who are breast feeding, have a positive (+) urine pregnancy test, or refuse to use 2 effective means of contraception during drug exposure and up to 48 hours after. * Subjects with porphyria * Life expectancy less than 12 months * Inability or unwillingness of subject to give written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose | Day 2 | The traditional 3+3 dose escalation design was employed. Three cohorts were enrolled at 3 subjects per cohort, and treated with escalating radiant exposures of 6, 7, or 8 J/cm2. In each cohort, the number of dose-limiting toxicities (DLTs) were observed. Dose escalation rules were the same as those provided by Storer 1989. |
| The Objective Response Rate is the Number of Participants With Significant Response (SR), Partial Response (PR) or No Response (NR). | Day 90 | The response rate was quantified by examination by an experienced head and neck surgeon and classified as follows: significant response (SR) was one where the lesion had greater than 75% resolution, partial response (PR) was one in which the lesion was reduced in size by at least 25%, and no response (NR) was one where the lesion was reduced by less than 25% in size. |
Countries
United States
Participant flow
Recruitment details
Subjects were identified in the head and neck oncology clinic and enrolled into the study within the time period of January 1, 2007 to November 18, 2009.
Pre-assignment details
Screen failure did meet incl./excl. criteria
Participants by arm
| Arm | Count |
|---|---|
| Phase I To determine the maximum tolerated energy density of the Pulse Dye Laser operated at 585 nm with a pulse time of 1.5 ms (PDL-585), when used in combination with 5-aminolevulinic acid (5-ALA) applied topically to the premalignant lesion.
The maximum tolerated energy density will be called the Maximum Tolerated Dose (MTD). | 11 |
| Phase II During Phase II, to assess the treatment efficacy of PDL-585 when used at the MTD in combination with 5-ALA applied topically to the premalignant lesion. Treatment efficacy will be assessed by means of the 90-day Objective Response rate observed among study subjects treated at the MTD. | 18 |
| Total | 29 |
Baseline characteristics
| Characteristic | Phase I | Phase II | Total |
|---|---|---|---|
| Age, Customized <=18 years | 0 participants | 0 participants | 0 participants |
| Age, Customized >=80 years | 0 participants | 0 participants | 0 participants |
| Age, Customized Between 18 and 80 years | 11 participants | 18 participants | 29 participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 4 Participants | 11 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 9 | 2 / 21 |
| serious Total, serious adverse events | 0 / 9 | 0 / 21 |
Outcome results
Primary
Maximum Tolerated Dose
The traditional 3+3 dose escalation design was employed. Three cohorts were enrolled at 3 subjects per cohort, and treated with escalating radiant exposures of 6, 7, or 8 J/cm2. In each cohort, the number of dose-limiting toxicities (DLTs) were observed. Dose escalation rules were the same as those provided by Storer 1989.
Time frame: Day 2
Population: Three cohorts were enrolled at 3 subjects per cohort, and treated with escalating radiant exposures (laser doses) of 6, 7, or 8 J/cm2. In each cohort, the number of dose-limiting toxicities (DLTs) were observed. The highest radiant light dose attained that did not produce more than 2 DLTs was declared to be the maximum tolerated dose (MTD).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Maximum Tolerated Dose | 8 J/cm2 |
Primary
The Objective Response Rate is the Number of Participants With Significant Response (SR), Partial Response (PR) or No Response (NR).
The response rate was quantified by examination by an experienced head and neck surgeon and classified as follows: significant response (SR) was one where the lesion had greater than 75% resolution, partial response (PR) was one in which the lesion was reduced in size by at least 25%, and no response (NR) was one where the lesion was reduced by less than 25% in size.
Time frame: Day 90
Population: The Simon two-stage minimax design with 9 subjects in the first stage and 8 subjects in the second stage, yielding 17 subjects overall.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | The Objective Response Rate is the Number of Participants With Significant Response (SR), Partial Response (PR) or No Response (NR). | Participants with Significant Response (SR) | 7 participants |
| Phase I | The Objective Response Rate is the Number of Participants With Significant Response (SR), Partial Response (PR) or No Response (NR). | Participants with Partial Response (PR) | 9 participants |
| Phase I | The Objective Response Rate is the Number of Participants With Significant Response (SR), Partial Response (PR) or No Response (NR). | Participants with no Response (NR) | 1 participants |
Comparison: The Simon two-stage minimax design with 9 subjects in the first stage and 8 subjects in the second stage, yielding 17 subjects overall. This design's early termination rule was ≤3/9 responses in the first stage, and its success criterion was ≥7/17 responses overall. This design had 80% power at 5% alpha to distinguish an efficacious 50% response rate from a null-hypothesis 20% response rate.p-value: 0.0001One-sided exact binomial test