Clinical Trial Results:
Tolerabililty of laser-assisted cisplatin+5-fluorouracil― an exploratory proof of concept study of topical combination chemotherapy for basal cell carcinoma
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Summary
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EudraCT number |
2018-000141-39 |
Trial protocol |
DK |
Global end of trial date |
07 Feb 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Oct 2021
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First version publication date |
24 Oct 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
110118
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03541252 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Department of Dermatology, Bispebjerg Hospital
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Sponsor organisation address |
Nielsine Nielsens Vej 9, Copenhagen NV, Denmark, 2400
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Public contact |
Emily Wenande, Bispebjerg Hospital, Department of Dermatology, +45 40505590, emilycathrinew@hotmail.com
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Scientific contact |
Emily Wenande, Bispebjerg Hospital, Department of Dermatology, +45 40505590, emilycathrinew@hotmail.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 Feb 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 Feb 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Feb 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To investigate tolerability and efficacy of ablative fractional laser-assisted cisplatin+5-FU therapy for basal cell carcinoma
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Protection of trial subjects |
Physician monitoring and care should any potential side effects arise
Topical anesthetic during laser therapies
A manually customized well (Duoderm, Denmark) demarcated the treatment area to avoid drug-induced LSRs of surrounding healthy skin.
Patients were advised to take paracetamol if they experienced pain after the procedure.
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Background therapy |
N/A | ||
Evidence for comparator |
N/A | ||
Actual start date of recruitment |
01 Mar 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Denmark: 20
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Worldwide total number of subjects |
20
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EEA total number of subjects |
20
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
3
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From 65 to 84 years |
14
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85 years and over |
3
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Recruitment
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Recruitment details |
Study recruitment initiation: 17/09/2018 Recruitment completion: 11/06/2019 Single recruitment site: Department of Dermatology, Bispebjerg Hospital, Nielsine Nielsens Vej 9, 2400 Copenhagen NV, Denmark | ||||||||||||||||||
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Pre-assignment
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Screening details |
Screening was performed based on inclusion criteria. Included subjects had a histologically-verified, untreated superficial or nodular BCCs on the scalp, face, extremities or trunk, >18 years of age at baseline, legally competent, Fitzpatrick skin phototype I-III, non-pregnant. 54 patients were screened for participation, 20 were included | ||||||||||||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
Blinding implementation details |
N/A
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Arms
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Arm title
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AFL+cisplatin+5-FU | ||||||||||||||||||
Arm description |
The study was an open-label uncontrolled trial. All patients received the intervention: ablative fractional laser followed by topical cisplatin and 5-fluorouracil cream | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Cisplatin 0,1%
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Cutaneous use
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Dosage and administration details |
60 minute topical application (0.25 ml/cm2) of 0.1% cisplatin solution
A second treatment was performed at day 30 if residual BCC persisted clinically, as evaluated by OCT or RCM.
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Investigational medicinal product name |
5-Fluorouracil 5%
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Investigational medicinal product code |
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Other name |
5-FU
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Pharmaceutical forms |
Cream
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Routes of administration |
Cutaneous use
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Dosage and administration details |
5% 5‐FU cream (Efudix) applied (0.125 ml/cm2) and left under occlusion. Two reapplications of 5‐FU are again performed by investigators on day 1 and 3–5, resulting in a total exposure period of 7 days.
A second treatment was performed at day 30 if residual BCC persisted clinically, as evaluated by OCT or RCM.
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: 1 of the 20 patients withdrew from the study before Day 30 (thus 19 patients completed the Day 30 and Month 3 milestones) Only patients who achieved tumor clearance at month 3 (18/19) were seen at month 6-9. Similarly only patients who achieved tumor clearance at month 6-9 (17/18) were seen at month 12. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: 1 of the 20 patients withdrew from the study before Day 30. 19 patients completed the Day 30 and Month 3 milestones. |
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Patient population to complete the study
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Overall tumor clearance and histological subtype specific responses
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End points reporting groups
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Reporting group title |
AFL+cisplatin+5-FU
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Reporting group description |
The study was an open-label uncontrolled trial. All patients received the intervention: ablative fractional laser followed by topical cisplatin and 5-fluorouracil cream | ||
Subject analysis set title |
Patient population to complete the study
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Overall tumor clearance and histological subtype specific responses
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End point title |
Local Skin Reactions (LSRs) Baseline - Month 3 | ||||||||||||
End point description |
Grading according to six parameters: redness, edema, flaking, crusting, pustules, and erosion. Each parameter was graded on a standardized 5‐point severity scale (0–4) representing none, mild, moderate, prominent, and severe. A total composite score reflecting overall LSR severity was then calculated based on the sum of all parameters (max score: 24).
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End point type |
Primary
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End point timeframe |
Days 1, 3–5, 14, 30, and month 3
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Statistical analysis title |
Fisher's exact tests | ||||||||||||
Statistical analysis description |
Fisher's exact tests assessed differences in LSR score intensity depending on single and double treatment. P values were two‐sided, exact, and considered statistically significant when <0.05.
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Comparison groups |
AFL+cisplatin+5-FU v Patient population to complete the study
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Number of subjects included in analysis |
40
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Analysis specification |
Post-hoc
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Analysis type |
other [1] | ||||||||||||
P-value |
≥ 0.506 [2] | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||
Point estimate |
0.01
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0 | ||||||||||||
upper limit |
1 | ||||||||||||
| Notes [1] - 1 day post‐treatment, LSRs primarily consisted of erythema and edema, with a median composite score of 7/24 (IQR 6–9). Erythema peaked at days 3–5, accompanied by treatment area flaking and tumor‐ associated erosion. As a result, composite LSR scores reached their maximum at 9 (IQR 6–11). By day 14, a thick crust had formed over eroded areas. On days 30 and month 3, a gradual decline in residual erythema was seens reflected by lower composite scores of 4 (IQR 2–6) and 2 (IQR 1–3). [2] - No significant difference in erythema or other LSRs was detected between groups receiving single or double treatment (P ≥ 0.506). |
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End point title |
Histological Tumor Clearance Month 3 | |||||||||||||||
End point description |
BCC tumor clearance based histological evaluation (biopsy) 3 months post-treatment.
No statistical analyses have been specified for this primary end point. The study was designed as an exploratory study with no formal statistical sample size calculation. Nineteen BCCs of superficial or nodular subtype were considered sufficient to investigate benefit and risk of the treatment.
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End point type |
Secondary
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End point timeframe |
Evaluated by biopsy at month 3
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| Notes [3] - Of 20 enrolled patients, one patient withdrew before this milestone and one refused biopsy [4] - 1/19 patients refused biopsy and did this not contribute to the analysis |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Clinical Tumor Clearance Month 6 | |||||||||||||||
End point description |
To monitor BCC tumor clearance based on clinical assessments and dermoscopy, supported by non-invasive imaging
No statistical analyses have been specified for this end point. The study was designed as an exploratory study with no formal statistical sample size calculation.
Taking into account all patients seen at 3 months follow-up (n=19), overall tumor remission after 6 months was 89 % (17/19) with a clearance rate of 100% (6/6) for sBCC and 85% (11/13) for nBCC (p= 1,000).
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End point type |
Secondary
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End point timeframe |
Month 6-9
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| Notes [5] - Patient 20 withdrew before this milestone |
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Statistical analysis title |
Mann Whitney U | |||||||||||||||
Statistical analysis description |
Nonparametric Mann-Whitney U test assessed differences in tumor response depending on BCC subtype
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Comparison groups |
AFL+cisplatin+5-FU v Patient population to complete the study
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Number of subjects included in analysis |
38
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Analysis specification |
Post-hoc
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Analysis type |
other | |||||||||||||||
P-value |
= 1 [6] | |||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | |||||||||||||||
Parameter type |
Median difference (final values) | |||||||||||||||
Point estimate |
1
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0 | |||||||||||||||
upper limit |
1 | |||||||||||||||
| Notes [6] - No difference |
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End point title |
Clinical Tumor Clearance Month 12 | |||||||||||||||
End point description |
To monitor BCC tumor clearance based on clinical assessments and dermoscopy, supported by non-invasive imaging
No statistical analyses have been specified for this end point. The study was designed as an exploratory study with no formal statistical sample size calculation.
Depending on subtype, clearance rates at 12 months were 100 % (6/6) for sBCC and 69 % (9/13) for nBCC (p= 0,145)
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End point type |
Secondary
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End point timeframe |
Month 12
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| Notes [7] - Patient 20 withdrew before this milestone |
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Statistical analysis title |
Mann Whitney U | |||||||||||||||
Comparison groups |
AFL+cisplatin+5-FU v Patient population to complete the study
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Number of subjects included in analysis |
38
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Analysis specification |
Post-hoc
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Analysis type |
other | |||||||||||||||
P-value |
= 0.145 | |||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | |||||||||||||||
Parameter type |
Median difference (final values) | |||||||||||||||
Point estimate |
0.01
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0 | |||||||||||||||
upper limit |
1 | |||||||||||||||
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End point title |
Cosmesis | ||||||||||||||||||
End point description |
Cosmesis was rated by patients and physicians on 4‐point scale (0–3) representing “poor - 0,” “fair - 1,” “good - 2,” or “excellent - 3.”
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End point type |
Secondary
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End point timeframe |
Month 3, Month 6-9 and Month 12
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| Notes [8] - Cosmesis was not rated on the patient with residual at month 3 |
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Statistical analysis title |
Wilcoxon tests | ||||||||||||||||||
Statistical analysis description |
Wilcoxon tests were used to assess differences in physician and patient‐reported cosmesis
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Comparison groups |
AFL+cisplatin+5-FU v Patient population to complete the study
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Number of subjects included in analysis |
36
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Analysis specification |
Post-hoc
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Analysis type |
other [9] | ||||||||||||||||||
P-value |
= 0.082 | ||||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||||||||
Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
- | ||||||||||||||||||
upper limit |
- | ||||||||||||||||||
Variability estimate |
Standard error of the mean
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| Notes [9] - Physician‐ and patient‐reported cosmesis was rated “good - 2” or “excellent -3” in 79% and 94% cases respectively at 3‐months (P = 0.082). Cosmesis was not impacted by the number of treatments patients received (P ≥ 0.212). Most patients (83%) showed persisting erythema at month 3, which in 17% was graded as “prominent.” Cosmetic outcomes were similarly rated by patients and evaluators as “good” or “excellent” in 94 % (17/18) and 100 % (17/17) of cases at 6 and 12 months (p= 0,289 and p= 0,250). |
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End point title |
Safety | |||||||||
End point description |
Safety assessment was based on the number of patients who experienced local pain/discomfort, infection, side effects to treatment. At 3‐month follow‐up, any scarring or dyspigmentation was
graded based on a 4‐point scale (0–3) (none, mild, moderate, and severe).
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End point type |
Secondary
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End point timeframe |
Month 3, Month 6-9, Month 12
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Statistical analysis title |
Wilcoxon tests | |||||||||
Statistical analysis description |
Month 3: among 18 cleared tumors, 50% presented with some degree of scarring (9/18); the severity of which was most commonly mild (67%; 6/9). Hyperpigmentation was observed in 56% (10/18), with moderate severity noted in one patient. No correlation was shown between dyspigmentation and tumor location. Mild hypopigmentation was recorded in 17% (3/18). Scarring or dyspigmentation was
not impacted by number of treatments (P ≥ 0.172) or tumor subtype (P ≥ 0.186).
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Comparison groups |
AFL+cisplatin+5-FU v Patient population to complete the study
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Number of subjects included in analysis |
38
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Analysis specification |
Post-hoc
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Analysis type |
other [10] | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Wilcoxon (Mann-Whitney) | |||||||||
Parameter type |
Median difference (final values) | |||||||||
Point estimate |
0.01
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0 | |||||||||
upper limit |
1 | |||||||||
| Notes [10] - Mild dyspigmentation was commonly observed at 6 and 12 months. Appearance of scarring resolved in the majority of patients at 6 months (scar 8/18) and at 12 months (scar 4/17). In contrast to 3-month findings, hypopigmentation was more prominent at 6- (61%; 11/18) and at 12 months (65%; 11/17). Hyperpigmentation decreased from 56% (10/18) at 3 months to 22% (4/18) at 6 months (p= 0,267) and persisted in two patients at end of study (12% (2/17) (p= 0,065) |
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Adverse events information
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Timeframe for reporting adverse events |
From date of inclusion to final visit at month 12
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Adverse event reporting additional description |
Local skin reactions (defined per protocolas erythema, edema, crusting, flaking, pustlation, erosion) were not considered adverse events.
No systemic adverse events were deemed related to treatment timewise/based on product summaries
AEs related to treatment were limited to pruritus (32%) and oozing (100%). Local pain or infection did not occur.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||
Dictionary version |
6
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Reporting groups
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Reporting group title |
AFL+cisplatin+5-FU
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Reporting group description |
The study was an open-label uncontrolled trial. All patients received the intervention: ablative fractional laser followed by topical cisplatin and 5-fluorouracil cream | ||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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04 Sep 2019 |
The protocol was amended to include two additional followup visits at month 6-9 and months 12 in order to examine long-term clearance rates of treated tumors as well as clinical side effects such as scarring, dyspigmentation, erythema and cosmesis.
Thus, patients who had not presented with tumor residual at month 3 were evaluated clinically and by OCT imaging at months 6-9 as well as month 12 (provided that they remained clear at month 6-9. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Low sample size No control group No randomization or blinding | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/32960987 |
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