Treatment of Oral Premalignant Lesions With 5-ALA PDT

• Sponsor: University of Arkansas (Other)
• Overall Status: Completed
• CT.gov ID: NCT00571974
• Collaborator: (none)
• Enrollment: 29
• Location: 1
• Arms: 2
• Duration (Months): 60
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukoplakia; Erythroplakia	Device: PDL-585, ScleroPLUS laser; Drug: 5-Aminolevulinic Acid (Levulan KerastickTM); Procedure: Fluorescence Diagnosis Imaging	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Combined Phase I/II Single Site Study to Determine the Safety and Efficacy of Photodynamic Therapy (PDT) Utilizing 5-aminolevulinic Acid (5-ALA) and PDT in the Treatment of Premalignant Oral and/or Oropharynx Lesions.
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1 light dose escalation During 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). Procedure: Fluorescence Diagnosis Imaging Interventions: Application of 5-ALA to lesion followed by activation with high power 585 nm pulsed dye laser (PDL-585, ScleroPLUS laser) at 6, 7 and 8 J/cm2.	Device: PDL-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; Drug: 5-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; Other Names: 5-ALA ; Procedure: Fluorescence Diagnosis Imaging; FD Image taken prior to PDL-585 usage
Experimental: Phase 2 - Treatment efficacy of PDT Procedure: Fluorescence Diagnosis Imaging Interventions: Application of 5-ALA to lesion followed by activation with high power 585 nm pulsed dye laser (PDL-585, ScleroPLUS laser) at 8 J/cm2.	Device: PDL-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; Drug: 5-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; Other Names: 5-ALA ; Procedure: Fluorescence Diagnosis Imaging; FD Image taken prior to PDL-585 usage

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205

Sponsors and Collaborators

• University of Arkansas

Investigators

• Principal Investigator: Gal Shafirstein, PhD, University of Arkansas

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Arkansas
• ClinicalTrials.gov Identifier: NCT00571974
• Other Study ID Numbers: 51439
• First Posted: Dec 12, 2007
• Last Update Posted: Mar 24, 2015
• Last Verified: Mar 1, 2015

• Additional relevant MeSH terms: Precancerous Conditions; Leukoplakia; Aminolevulinic Acid

Study Results

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 Detail	Screen failure did meet incl./excl. criteria

Arm/Group Title	Phase I	Phase II
Arm/Group Description	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).	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.
Period Title: Phase I
STARTED	9	0
COMPLETED	9	0
NOT COMPLETED	0	0
Period Title: Phase I
STARTED	0	21
COMPLETED	0	17
NOT COMPLETED	0	4

Baseline Characteristics

Arm/Group Title	Phase I	Phase II	Total
Arm/Group Description	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).	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.	Total of all reporting groups
Overall Participants	11	18	29
Age, Customized (participants) [Number]
<=18 years	0 0%	0 0%	0 0%
Between 18 and 80 years	11 100%	18 100%	29 100%
>=80 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	7 63.6%	7 38.9%	14 48.3%
Male	4 36.4%	11 61.1%	15 51.7%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase I
Arm/Group Description	Participants in the Phase I part of the study.
Measure Participants	9
Number [J/cm2]	8

2. Primary Outcome

Title	The Objective Response Rate is the Number of Participants With Significant Response (SR), Partial Response (PR) or No Response (NR).
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase II
Arm/Group Description	Subjects treated with the MTD.
Measure Participants	17
Participants with Significant Response (SR)	7 63.6%
Participants with Partial Response (PR)	9 81.8%
Participants with no Response (NR)	1 9.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	One-sided exact binomial test to compare the observed response rate to the 20% rate envisioned under the original null hypothesis.
	Method	One-sided exact binomial test
	Comments	Because all but one subject responded to treatment, the Fisher's exact test was addedd.

Adverse Events

Time Frame	1 year
Arm/Group Title	Phase I		Phase II
Arm/Group Description	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).		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.
All Cause Mortality
	Phase I		Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase I		Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Phase I		Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		2/21 (9.5%)
General disorders
Dry mouth	1/9 (11.1%)	1	0/21 (0%)	0
Bad breath	1/9 (11.1%)	1	0/21 (0%)	0
Insomnia	1/9 (11.1%)	1	0/21 (0%)	0
Swollen lip	1/9 (11.1%)	1	0/21 (0%)	0
Redness on chin	1/9 (11.1%)	1	0/21 (0%)	0
Taste altered	1/9 (11.1%)	1	0/21 (0%)	0
Burning sensation	1/9 (11.1%)	1	0/21 (0%)	0
Sensitive to cold	1/9 (11.1%)	1	0/21 (0%)	0
Sensitive	1/9 (11.1%)	1	0/21 (0%)	1
Raw	1/9 (11.1%)	1	0/21 (0%)	1
Soreness	1/9 (11.1%)	1	0/21 (0%)	1
Swelling	1/9 (11.1%)	1	0/21 (0%)	1
Nervous system disorders
Pain	2/9 (22.2%)	2	2/21 (9.5%)	2
Psychiatric disorders
Depression	1/9 (11.1%)	1	0/21 (0%)	0

Limitations/Caveats

Since all but one subject responded to treatment, no correlative analysis of response with change in expression of p53 or Ki-67 was undertaken.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.