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Phase III, Randomized, Double Blind Trial on Vitamin D Supplementation for Resected Stage II Melanoma Patients

Phase 3
18 Years
75 Years
Open (Enrolling)

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Trial Information

Phase III, Randomized, Double Blind Trial on Vitamin D Supplementation for Resected Stage II Melanoma Patients

Cancer chemoprevention uses natural, synthetic, or biologic chemical agents to reverse,
suppress, or prevent carcinogenic progression (Sporn MB Cancer Res 1976). Genetic changes
exist throughout the field and increase the likelihood that one or more premalignant and
malignant lesions may develop within that field. Multistep carcinogenesis describes a
stepwise accumulation of alterations, both genotypic and phenotypic. Arresting one or
several of the steps may impede or delay the development of cancer. Several epidemiological,
pre-clinical and clinical studies support Vitamin D as preventive and therapeutic cancer
agent, for a wide spectrum of cancer. Calcitriol (1,25-dihydroxyvitamin D [1,25(OH) D]), the
hormonal derivative of vitamin D, has been established since the 1980s as an
antiproliferative and prodifferentiation agent, and as a proapoptotic agent and an inhibitor
of cell migration, which may imply an inhibitory effect in cancer. Vitamin D is more like a
hormone and not strictly a vitamin according to the classical criteria that an essential
nutrient is a substance the body cannot synthesise in sufficient quantities itself. Also,
vitamins are usually involved in biochemical reactions, while 1_,25-dihydroxyvitamin D
exerts its action via VDR. Vitamin D is a group of fat-soluble prohormones, the two major
forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol).
Endogenous synthesis of vitamin D3 takes place in the skin under the influence of ultra
violet B (UVB) radiation. Exogenous vitamin D2 or D3 comes from dietary intake. The overall
vitamin D intake is the sum of cutaneous vitamin D and nutritional vitamin D and D. Vitamin
D on its own has no physiological action. To be physiologically active, vitamin D must first
be hydroxylated in the liver by the enzyme 25-hydroxylase, encoded by CYP27A1 (also called
the 25-hydroxylase) in 25-hydroxyvitamin D or 1,25-hydroxyvitamin D (1,25-hydroxyvitamin D).
The 25-hydroxyvitamin D is inactive, and an additional hydroxylation in the kidney by the
enzyme 1_-hydroxylase, encoded by CYP27B1, (also called 1_-hydroxylase) is necessary for
production of the physiologically active vitamin D metabolite, the 1_,25-dihydroxyvitamin D
(calcitriol). When 1,25(OH) D is sufficiently available, the enzyme mitochondrial protein
encoded by CYP24A1 metabolises the 1_,25-dihydroxyvitamin D in 1_,24,25-dihydroxyvitamin D,
which is further catabolised to calcitroic acid. 25(OH)D and 1,25(OH)2D are transported in
serum by the vitamin D-binding protein (gene name: GC, group-specific component). Ahn
systematically investigated the association of 48 SNPS in four vitamin D metabolizing genes
(CYP27A1, GC, CYP27B1, and CYP24A1) with serum 25(OH)D levels. Four tagSNPS in GC, the major
serum 25(OH)D carrier, were associated with 25(OH)D levels (Ahn et al.Carcinogenesis 2009).
CYP24A1 encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450
proteins are monooxygenases which catalyze many reactions involved in drug metabolism and
synthesis of cholesterol, steroids and other lipids. This mitochondrial protein initiates
the degradation of 1,25-dihydroxyvitamin D by hydroxylation of the side chain. In regulating
the level of vitamin D, this enzyme plays a role in calcium homeostasis and the vitamin D
endocrine system. Of interest, epigenetic silencing of CYP24A1, which is overexpressed in
many cancers, in tumour-derived endothelial cells renders the tumour sensitive to the
anti-angiogenic effects of 1,25(OH) D. Various molecules can inhibit 24-Ohase. These merit
exploration and further development as specific small molecule 24-OHase inhibitors,
especially in combination with 1,25(OH)D or other vitamin D analogues. These may maximize
intracellular 1,25(OH)D content and exert optimal antiproliferative effects (Deeb 2007;
Mantell 2000; Nishimura 1994). Binding of 1,25(OH)D to the vitamin D receptor (VDR)
suppresses proliferation and induces differentiation of cancer cells in tumour tissue,
suggesting that high levels of vitamin D metabolites may be protective against cancer (Deeb
2007; Reichel 1989).

Inclusion Criteria:

1. 18-75 years old with newly diagnosed histologically proven resected melanoma

2. Stage: IIa (T2b, T3a), IIb (T3b T4a) and IIc (T4b), N0, M0

3. Signed informed Consent

4. Willingness to provide blood samples

5. Performance Status of 0-1

6. Hematopoietic functionality at the entry of the study: leukocytes, platelets,
haemoglobin and neutrophiles within the normal limits of laboratory references

7. Hepatic and renal functionality at the entry of the study within the normal range of
each laboratory

8. Serum and urinary calcium within the upper limit of laboratory references.

Exclusion Criteria:

1. Primary not cutaneous melanoma

2. Clinical/radiological evidence or laboratory/pathology report of not completely
resected melanoma

3. History of cancer (other than Carcinoma in situ (CIN) and non melanoma skin cancere

4. Current daily use of at least 600 IU/day of supplemental vitamin D or calcitriol or
high dose of calcium therapy (e.g. calcium citrate with vitamin D) within the prior 6
months greater than 600 mg calcium per day during study

5. History of recurrent renal calculi or hypercalcemia (>10mg/dl), current and chronic
use of oral corticosteroids

6. History of malabsorption syndrome (e.g., pancreatic insufficiency, celiac disease,
Crohn disease or tropical sprue)

7. History of small intestinal resection (e.g., ileal bypass surgery for treatment of
morbid obesity resection > 50 % of slim bowel)

8. Hypersensitivity to cholecalciferol or one of its components

9. Chronic liver disease, chronic renal disease, or renal dialysis

10. History of parathyroid disease and sarcoidosis

11. Pregnancy or breast feeding or planning on becoming pregnant during the 3 years of

12. Chronic alcoholism

13. Any medical condition that in the physician's opinion would potentially interfere
with vitamin D absorption, such as celiac sprue, ulcerative colitis, patients treated
pharmacologically for obesity

14. Any logistic condition that do not allow follow-up of the disease of the patient.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Disease free survival and Overall Survival

Outcome Description:

Disease free survival (DFS) will be the primary end-point of efficacy in this Phase III trial. It will be measured from the date of randomization to the date of progression or death, whatever the cause. Overall Survival will be also evaluated and it is defined as the time from the date of randomization to the date of death from any cause or to the date of last follow-up.

Outcome Time Frame:

3 years of treatment and 2 of follow up

Safety Issue:


Principal Investigator

Alessandro Testori, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

European Institute of Oncology


Italy: The Italian Medicines Agency

Study ID:




Start Date:

May 2010

Completion Date:

January 2019

Related Keywords:

  • Melanoma
  • Melanoma