MELABLOCK: A Clinical Trial on the Efficacy and Safety of Propranolol 80 mg in Melanoma Patients

The effectiveness of propranolol in infantile hemangiomas, the apparent better response to propranolol in breast cancer and the use of propranolol in a proportion of patients who did not develop melanoma recurrence suggested to use this unselective β---blocker to test the study hypothesis. The investigators propose a randomized double---blind placebo---controlled clinical trial (RTC) to evaluate whether the treatment with propranolol 80 mgR/die reduce the risk of CMM recurrence and mortality. Patients with resected stage II/IIIA CMM will be recruited in various Centers in Italy. Participants will be randomly assigned to propranolol treatment or placebo (1:1 ratio), treated for at least 1 year and followed for 2 years. Recruitment will proceed simultaneously at the different Centers, and will be completed in 2 years. The primary outcome of the entire trial will be, however, estimated by assessing a reduction in overall mortality at five years. The investigators will also evaluate general CMM recurrence and CMM specific mortality.

Sex

All

Minimum age

18 Years

Maximum age

75 Years

Inclusion Criteria:

1. Stage: Ib (T1b, T2a), IIa (T2b, T3a), IIb (T3b T4a) and IIc (T4b), N0, M0; IIIA (N1a, N1b)
2. Signed Informed Consent;
3. Performance Status of 0---1 (ECOG);
4. Hematopoietic functionality at the entry of the study: leukocytes, platelets, hemoglobin and neutrophils within the normal limits of laboratory references;
5. Hepatic and renal functionality at the entry of the study: LDH, bilirubin, AST, ALT, alkalinephosphatase, BUN and serum creatinine within the normal range of each laboratory;

Exclusion Criteria:

1. Primary not cutaneous melanoma;
2. Clinical/radiological evidence or laboratory/pathology report of not completely resectedmelanoma;
3. History of cancer
4. Current use or past use in the last two years of any b---blockers for any other medical condition
5. Current use of verapamil, diltiazem or similar calcium channel blocker
6. Current use of centrally acting antihypertensive drugs as α---methyldopa, clonidine
7. Hypersensitivity to propranolol or to any of the excipients;
8. Acute heart failure or during episodes of heart failure decompensation requiring i.v.

   inotropic therapy;
9. Cardiogenic shock;
10. Sinoatrial block ;
11. Second or third degree atrio---ventricular block;
12. Marked bradycardia (less than 60 beats/min) ;
13. Extreme hypotension (systolic blood pressure \<100mmHg) ;
14. Severe asthma or severe chronic obstructive pulmonary disease ;
15. Sick sinus syndrome;
16. Severe forms of peripheral arterial occlusive disease and Raynaud's syndrome;
17. Metabolic acidosis
18. Asthma
19. Diabetes
20. Heart failure
21. History of psoriasis
22. Pregnancy or breast feeding or planning on becoming pregnant during the 3 years of treatment (for major details see the Section "Pregnancy in the Study", below);
23. Any medical condition that in the physician's opinion would potentially interfere with the patient ability to adhere to protocol and treatment;
24. Any logistic condition that do not allow follow---up of the disease of the patient.
25. Hypersensitivity to propranolol, child bearing or breastfeeding.
26. Pheocromocytoma 27. Prinzmetal's Angina 28. Fasting -

• BACKGROUNDAronow WS. Current role of beta-blockers in the treatment of hypertension. Expert Opin Pharmacother. 2010 Nov;11(16):2599-607. doi: 10.1517/14656566.2010.482561. Epub 2010 Apr 28. PMID 20426702
• BACKGROUNDBarron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a population- based study. J Clin Oncol. 2011 Jul 1;29(19):2635-44. doi: 10.1200/JCO.2010.33.5422. Epub 2011 May 31. PMID 21632503
• BACKGROUNDBielecka-Dabrowa A, Aronow WS, Rysz J, Banach M. Current place of beta-blockers in the treatment of hypertension. Curr Vasc Pharmacol. 2010 Nov;8(6):733-41. doi: 10.2174/157016110793563861. PMID 20626337
• BACKGROUNDChen JM, Heran BS, Perez MI, Wright JM. Blood pressure lowering efficacy of beta-blockers as second-line therapy for primary hypertension. Cochrane Database Syst Rev. 2010 Jan 20;2010(1):CD007185. doi: 10.1002/14651858.CD007185.pub2. PMID 20091622
• BACKGROUNDCruickshank JM. Are we misunderstanding beta-blockers. Int J Cardiol. 2007 Aug 9;120(1):10-27. doi: 10.1016/j.ijcard.2007.01.069. Epub 2007 Apr 12. PMID 17433471
• BACKGROUNDDe Giorgi V, Gandini S, Grazzini M, Benemei S, Marchionni N, Geppetti P. Effect of beta-blockers and other antihypertensive drugs on the risk of melanoma recurrence and death. Mayo Clin Proc. 2013 Nov;88(11):1196-203. doi: 10.1016/j.mayocp.2013.09.001. PMID 24182700
• BACKGROUNDDe Giorgi V, Grazzini M, Gandini S, Benemei S, Lotti T, Marchionni N, Geppetti P. Treatment with beta-blockers and reduced disease progression in patients with thick melanoma. Arch Intern Med. 2011 Apr 25;171(8):779-81. doi: 10.1001/archinternmed.2011.131. PMID 21518948
• Lamy S, Lachambre MP, Lord-Dufour S, Beliveau R. Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vascul Pharmacol. 2010 Nov-Dec;53(5-6):200-8. doi: 10.1016/j.vph.2010.08.002. Epub 2010 Aug 20.