Cutaneous Malignant Melanoma
Conditions
Keywords
Cutaneous malignant melanoma, Vitamin D, Cholecalciferol
Brief summary
To assess whether vitamin D supplementation after surgery of a first cutaneous malignant melanoma protects against relapse of the disease.
Detailed description
To assess whether vitamin D supplementation, in the follow up period after diagnosis and surgery of a first cutaneous malignant melanoma, has a protective effect on relapse of cutaneous malignant melanoma and whether this protective effect correlates with vitamin D levels in serum and vitamin D receptor (VDR) immunoreactivity in the primary tumor.
Interventions
DRUGVitamin D
* prospective interventional randomized double blind placebo controlled trail * clinical setting (tertiary university hospital) * investigator driven, no pharmaceutical sponsor * cutaneous malignant melanoma patients * add- on study (placebo or vitamin D) on top of optimal standard care * 1:1 inclusion ratio (placebo:Vitamin D) * randomisation after informed consent and screening
DRUGPlacebo: Oil
Sponsors
KU Leuven
Universitaire Ziekenhuizen KU Leuven
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Older than 18 years and younger than 80 years of age. 2. Histologically proven malignant melanoma, stage one B (IB) to three (III) Not participating in other clinical trial. 3. The only treatment for melanoma is surgical treatment. 4. Complete resection of melanoma. 5. Single primary invasive cutaneous melanoma 6. Signed ethical committee approved informed consent 7. Serum phosphate, serum calcium at the entry of the study within normal limits of laboratory reference
Exclusion criteria
1. Pregnant/lactating women or planning on becoming pregnant during the study 2. Known hypersensitivity to vitamin D or its components. 3. Pre-existing renal stone disease, chronic renal disease with glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 or renal dialysis. 4. Liver failure or chronic liver disease with liver enzymes \> 2 fold upper limit of normal (ULN). 5. History of parathyroid disease or granulomatous disease (TBC and sarcoidosis) 6. History of malabsorption syndrome or any medical condition that might interfere with vitamin D absorption. 7. History of small intestine resection. 8. History of other malignancy within the last 5 years except for carcinoma in situ of the cervix or basal cell carcinoma or squamous cell carcinoma of the skin or in situ malignant melanoma. 9. Chronic alcohol abuse. 10. Medical or logistic problems likely to preclude completion of the study. 11. Taking medication that predisposes to hypercalcemia (digoxin, lithium, thiazide diuretics) or taking medication that would affect metabolism of vitamin D (anticonvulsants, corticosteroids, H2-receptor antagonists) 12. Intake of vitamin D supplements within 6 months prior to entry of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relapse Free Survival | study duration maximum 9 years and 7 months or until relapse | Disease free survival will be the primary endpoint of this phase III trial. Study duration for one patient is maximum 9 years and 7 months. Patients are supplemented with studymedication (Vitamin D or placebo) for maximum 3.5 years. This is the treatment period. After the treatment period (in which the patients take study medication, placebo or Vitamin D), there is the follow-up period, no more study medication is taken, the study is still double blind, and the patients are followed at the clinical department for relapse and/or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Melanoma Subtype, as Assessed Clinically and Histologically | Time at diagnosis | Vitamin D levels at diagnosis will be correlated with melanoma subtype, as assessed clinically and histologically. |
| Melanoma Site, as Clinically Recorded | Time at diagnosis | Vitamin D levels at diagnosis will be correlated with melanoma site, as clinically recorded. |
| 25(OH)D3 Serum Levels | study duration maximum 3.5 years (Treatment period) or until relapse | 25(OH)D3 serum levels will be recorded at diagnosis and at 6 months intervals up to final study visit. |
| Stage of Melanoma Patient | Time at diagnosis | Stage of melanoma patient at diagnosis according to the 8th American Joint Committee of Cancer (AJCC) Melanoma staging and classification. The eighth edition of the AJCC staging system is currently the most widely accepted and standardized approach to melanoma staging and classification at initial diagnosis. Melanoma staging is based on the American Joint Committee on Cancer (AJCC) staging system that uses three key pieces of information for assigning Tumor-Node-Metastasis (TNM) classifications. AJCC staging ifacilitates accurate risk stratification and is essential to guide patient treatment. The higher the stage, the more severe the melanoma. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety Endpoints:Incidence and Severity of Adverse Events | study duration maximum 3.5 years (Treatment period) or until relapse | Incidence and severity of adverse events will be recorded every 3 months up to final study visit (from the treatment period). |
Countries
Belgium, Hungary
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vitamin D Every month 100 000 units of Vitamin D in syringe oral dispenser is taken . Study duration is maximum 3,5 years or until relapse occurs
Vitamin D: - prospective interventional randomized double blind placebo controlled trail
* clinical setting (tertiary university hospital)
* investigator driven, no pharmaceutical sponsor
* cutaneous malignant melanoma patients
* add- on study (placebo or vitamin D) on top of optimal standard care
* 1:1 inclusion ratio (placebo:Vitamin D)
* randomisation after informed consent and screening | 218 |
| Placebo: Oil Every month 100 000 units of vitamin D in syringe Oral dispenser is taken. Study duration is maximum of 3.5 years or until relapse occurs
oil | 218 |
| Total | 436 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period | Adverse Event | 1 | 0 |
| Treatment Period | Consent withdrawn by subject | 1 | 0 |
| Treatment Period | Personal | 0 | 1 |
Baseline characteristics
| Characteristic | Vitamin D | Placebo: Oil | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 61 Participants | 54 Participants | 115 Participants |
| Age, Categorical Between 18 and 65 years | 157 Participants | 164 Participants | 321 Participants |
| Current smoking Never Smoked | 85 Participants | 105 Participants | 190 Participants |
| Current smoking No | 99 Participants | 76 Participants | 175 Participants |
| Current smoking Unknown | 1 Participants | 0 Participants | 1 Participants |
| Current smoking Yes | 33 Participants | 37 Participants | 70 Participants |
| Education (highest level) Other | 1 Participants | 1 Participants | 2 Participants |
| Education (highest level) Primary | 9 Participants | 8 Participants | 17 Participants |
| Education (highest level) Secondary school | 75 Participants | 68 Participants | 143 Participants |
| Education (highest level) University graduated | 27 Participants | 42 Participants | 69 Participants |
| Education (highest level) Unknown | 1 Participants | 0 Participants | 1 Participants |
| Education (highest level) Vocational training | 43 Participants | 40 Participants | 83 Participants |
| Education (highest level) Vocational university | 62 Participants | 59 Participants | 121 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 112 Participants | 125 Participants | 237 Participants |
| Sex: Female, Male Male | 106 Participants | 93 Participants | 199 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 13 / 218 | 13 / 218 |
| other Total, other adverse events | 180 / 218 | 178 / 218 |
| serious Total, serious adverse events | 28 / 218 | 33 / 218 |
Outcome results
Primary
Relapse Free Survival
Disease free survival will be the primary endpoint of this phase III trial. Study duration for one patient is maximum 9 years and 7 months. Patients are supplemented with studymedication (Vitamin D or placebo) for maximum 3.5 years. This is the treatment period. After the treatment period (in which the patients take study medication, placebo or Vitamin D), there is the follow-up period, no more study medication is taken, the study is still double blind, and the patients are followed at the clinical department for relapse and/or death.
Time frame: study duration maximum 9 years and 7 months or until relapse
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin D | Relapse Free Survival | 41 Participants |
| Placebo: Oil | Relapse Free Survival | 32 Participants |
p-value: =0.32495% CI: [0.79, 2.03]Fisher Exact
Secondary
25(OH)D3 Serum Levels
25(OH)D3 serum levels will be recorded at diagnosis and at 6 months intervals up to final study visit.
Time frame: study duration maximum 3.5 years (Treatment period) or until relapse
Population: The number of patients differs from baseline with the other time points for different reasons: patient was already End of study, no sample taken because of various reasons,...
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D | 25(OH)D3 Serum Levels | End of study (end of study medication) | 43 ng/ml | Standard Deviation 12 |
| Vitamin D | 25(OH)D3 Serum Levels | At Month 6 | 43 ng/ml | Standard Deviation 11 |
| Vitamin D | 25(OH)D3 Serum Levels | At Month 12 | 44 ng/ml | Standard Deviation 11 |
| Vitamin D | 25(OH)D3 Serum Levels | At Month 18 | 44 ng/ml | Standard Deviation 11 |
| Vitamin D | 25(OH)D3 Serum Levels | At Month 24 | 42 ng/ml | Standard Deviation 11 |
| Vitamin D | 25(OH)D3 Serum Levels | At Month 30 | 44 ng/ml | Standard Deviation 12 |
| Vitamin D | 25(OH)D3 Serum Levels | At Month 36 | 40 ng/ml | Standard Deviation 12 |
| Vitamin D | 25(OH)D3 Serum Levels | Baseline | 24 ng/ml | Standard Deviation 9 |
| Placebo: Oil | 25(OH)D3 Serum Levels | At Month 36 | 25 ng/ml | Standard Deviation 7 |
| Placebo: Oil | 25(OH)D3 Serum Levels | Baseline | 23 ng/ml | Standard Deviation 9 |
| Placebo: Oil | 25(OH)D3 Serum Levels | At Month 24 | 24 ng/ml | Standard Deviation 9 |
| Placebo: Oil | 25(OH)D3 Serum Levels | At Month 6 | 23 ng/ml | Standard Deviation 9 |
| Placebo: Oil | 25(OH)D3 Serum Levels | End of study (end of study medication) | 27 ng/ml | Standard Deviation 9 |
| Placebo: Oil | 25(OH)D3 Serum Levels | At Month 12 | 24 ng/ml | Standard Deviation 9 |
| Placebo: Oil | 25(OH)D3 Serum Levels | At Month 30 | 27 ng/ml | Standard Deviation 8 |
| Placebo: Oil | 25(OH)D3 Serum Levels | At Month 18 | 24 ng/ml | Standard Deviation 11 |
Secondary
Melanoma Site, as Clinically Recorded
Vitamin D levels at diagnosis will be correlated with melanoma site, as clinically recorded.
Time frame: Time at diagnosis
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vitamin D | Melanoma Site, as Clinically Recorded | Foot | 12 Participants |
| Vitamin D | Melanoma Site, as Clinically Recorded | Head-neck | 31 Participants |
| Vitamin D | Melanoma Site, as Clinically Recorded | Arm - hand | 45 Participants |
| Vitamin D | Melanoma Site, as Clinically Recorded | Leg | 55 Participants |
| Vitamin D | Melanoma Site, as Clinically Recorded | Genitals | 1 Participants |
| Vitamin D | Melanoma Site, as Clinically Recorded | Back | 55 Participants |
| Vitamin D | Melanoma Site, as Clinically Recorded | Abdomen- chest | 18 Participants |
| Placebo: Oil | Melanoma Site, as Clinically Recorded | Back | 53 Participants |
| Placebo: Oil | Melanoma Site, as Clinically Recorded | Abdomen- chest | 26 Participants |
| Placebo: Oil | Melanoma Site, as Clinically Recorded | Arm - hand | 37 Participants |
| Placebo: Oil | Melanoma Site, as Clinically Recorded | Foot | 12 Participants |
| Placebo: Oil | Melanoma Site, as Clinically Recorded | Genitals | 2 Participants |
| Placebo: Oil | Melanoma Site, as Clinically Recorded | Head-neck | 27 Participants |
| Placebo: Oil | Melanoma Site, as Clinically Recorded | Leg | 61 Participants |
Secondary
Melanoma Subtype, as Assessed Clinically and Histologically
Vitamin D levels at diagnosis will be correlated with melanoma subtype, as assessed clinically and histologically.
Time frame: Time at diagnosis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vitamin D | Melanoma Subtype, as Assessed Clinically and Histologically | Nodular melanoma | 38 Participants |
| Vitamin D | Melanoma Subtype, as Assessed Clinically and Histologically | Superficial spreading melanoma | 115 Participants |
| Vitamin D | Melanoma Subtype, as Assessed Clinically and Histologically | Acrolentigineus melanoma | 8 Participants |
| Vitamin D | Melanoma Subtype, as Assessed Clinically and Histologically | Lentigo maligna melanoma | 7 Participants |
| Vitamin D | Melanoma Subtype, as Assessed Clinically and Histologically | Unknown | 22 Participants |
| Vitamin D | Melanoma Subtype, as Assessed Clinically and Histologically | Other | 27 Participants |
| Placebo: Oil | Melanoma Subtype, as Assessed Clinically and Histologically | Unknown | 21 Participants |
| Placebo: Oil | Melanoma Subtype, as Assessed Clinically and Histologically | Nodular melanoma | 29 Participants |
| Placebo: Oil | Melanoma Subtype, as Assessed Clinically and Histologically | Lentigo maligna melanoma | 5 Participants |
| Placebo: Oil | Melanoma Subtype, as Assessed Clinically and Histologically | Superficial spreading melanoma | 142 Participants |
| Placebo: Oil | Melanoma Subtype, as Assessed Clinically and Histologically | Other | 15 Participants |
| Placebo: Oil | Melanoma Subtype, as Assessed Clinically and Histologically | Acrolentigineus melanoma | 6 Participants |
Secondary
Stage of Melanoma Patient
Stage of melanoma patient at diagnosis according to the 8th American Joint Committee of Cancer (AJCC) Melanoma staging and classification. The eighth edition of the AJCC staging system is currently the most widely accepted and standardized approach to melanoma staging and classification at initial diagnosis. Melanoma staging is based on the American Joint Committee on Cancer (AJCC) staging system that uses three key pieces of information for assigning Tumor-Node-Metastasis (TNM) classifications. AJCC staging ifacilitates accurate risk stratification and is essential to guide patient treatment. The higher the stage, the more severe the melanoma.
Time frame: Time at diagnosis
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vitamin D | Stage of Melanoma Patient | IA | 24 Participants |
| Vitamin D | Stage of Melanoma Patient | IB | 101 Participants |
| Vitamin D | Stage of Melanoma Patient | IIA | 29 Participants |
| Vitamin D | Stage of Melanoma Patient | IIB | 18 Participants |
| Vitamin D | Stage of Melanoma Patient | IIC | 10 Participants |
| Vitamin D | Stage of Melanoma Patient | IIIA | 14 Participants |
| Vitamin D | Stage of Melanoma Patient | IIIB | 9 Participants |
| Vitamin D | Stage of Melanoma Patient | IIIC | 10 Participants |
| Vitamin D | Stage of Melanoma Patient | IIID | 0 Participants |
| Vitamin D | Stage of Melanoma Patient | Unkown | 3 Participants |
| Placebo: Oil | Stage of Melanoma Patient | IIIC | 14 Participants |
| Placebo: Oil | Stage of Melanoma Patient | IA | 26 Participants |
| Placebo: Oil | Stage of Melanoma Patient | IIIA | 10 Participants |
| Placebo: Oil | Stage of Melanoma Patient | IB | 108 Participants |
| Placebo: Oil | Stage of Melanoma Patient | Unkown | 1 Participants |
| Placebo: Oil | Stage of Melanoma Patient | IIA | 30 Participants |
| Placebo: Oil | Stage of Melanoma Patient | IIIB | 8 Participants |
| Placebo: Oil | Stage of Melanoma Patient | IIB | 14 Participants |
| Placebo: Oil | Stage of Melanoma Patient | IIID | 1 Participants |
| Placebo: Oil | Stage of Melanoma Patient | IIC | 6 Participants |
Other Pre-specified
Safety Endpoints:Incidence and Severity of Adverse Events
Incidence and severity of adverse events will be recorded every 3 months up to final study visit (from the treatment period).
Time frame: study duration maximum 3.5 years (Treatment period) or until relapse
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamin D | Safety Endpoints:Incidence and Severity of Adverse Events | 44 Events |
| Placebo: Oil | Safety Endpoints:Incidence and Severity of Adverse Events | 36 Events |