The main purpose of this study is to assess the efficacy of melatonin oral gel compared to placebo in the prevention and treatment of oral mucositis in patients with head and neck cancer undergoing concurrent chemoradiation.

Other objectives are to assess the Quality of Life (QoL), to evaluate the safety and tolerability and to assess the pharmacokinetic profile of melatonin oral gel administration, in all cases compared to placebo in patients with head and neck cancer and oral mucositis secondary to concurrent chemoradiation.

The study is designed as a prospective, randomized, double blind and placebo-controlled study.

Eligible patients with head and neck cancer undergoing chemoradiation will be randomized assigned at one-to-one ratio to receive

• Group A: melatonin oral gel 3%
• Group B: placebo

All patients will receive standard symptomatic treatment for oral mucositis along the study according to routine clinical practice of the hospital.

A full PK and safety assessment will be carried out in the first 24 patients included in the study (PK subgroup).

All patients will take melatonin oral gel 3% or placebo oral gel from two to three days before start of systemic treatment until one to four weeks after completion of radiotherapy. In the case of concurrent chemotherapy with cisplatin, patients will remain on study from the first day of chemoradiotherapy during 19 weeks (seven on chemoradiotherapy treatment, a maximum of four weeks after completion of radiotherapy and eight more weeks on observation). In the case of patients receiving cetuximab, since the first infusion of cetuximab will be administered one week before the first day of radiation, the patients will remain on study during 20 weeks (eight weeks on chemoradiotherapy, a maximum of four weeks after completion of radiotherapy and eight more weeks on observation). Investigators should take into account that the minimum duration of the melatonin oral gel 3% treatment would be 8 weeks for patients treated with cisplatin and 9 weeks for patients treated with cetuximab.

Patients with oral mucositis improved to grade 1 (based on RTOG) until one to four weeks after the end of chemoradiation may stop melatonin oral gel 3% or placebo treatments. Patients with grade ≥ 2 oral mucositis at this time-point (four weeks after the end of chemoradiation) will stop treatment per protocol (melatonin or placebo) and will continue with standard treatments and under observation until the last safety visit.

Inclusion Criteria:

1. Male and female patients 18 years or over.

2. Patients who gave written informed consent.

3. Life expectancy ≥ 3 months.

4. Subjects willing to comply with treatment and follow-up.

5. Histologically confirmed diagnosis of non-metastatic TNM-2010 stage III-IV squamous cell carcinoma of the following sites:

   • oral cavity
   • oropharynx
   • or any Head and Neck site with lymph nodes at cervical level II.

   Or histologically confirmed carcinoma of the nasopharynx (differentiated squamous cell carcinoma or NonKeratinizing carcinoma or undifferentiated carcinoma) found eligible for chemoradiation with or without neoadjuvant chemotherapy.

6. Patients who have a treatment plan based on systemic treatment (cisplatin or cetuximab) concurrent with radiation with curative intent. Patients may have received up to 3 cycles of neoadjuvant chemotherapy if local adverse events related to this treatment are fully resolved before study entry. Patients with a plan of postoperative chemoradiation may be included only if the primary tumour is located in the oral cavity.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.

8. Adequate baseline organ function (hematologic, liver, renal, nutritional and metabolic):

   • Haematology:

     • Absolute neutrophil count (ANC) ≥1.5 x 109/L
     • Haemoglobin ≥ 10 g/dL
     • Platelets ≥ 100,000 x 109/L

   • Hepatic:

     • Total bilirubin ≤ 2 X (Upper limit normal) ULN
     • Alanine amino transferase (ALT) and Asparatate aminotransferase (AST) ≤5 x ULN

   • Renal:

     • For patients who will receive cisplatin: Serum creatinine ≤ ULN or, if > ULN calculated creatinine clearance (ClCR) ≥ 60 mL/min.
     • For patients who will receive cetuximab: Serum creatinine <2.0 mg/dl.

   • Nutritional and metabolic:

     • Albumin > 3.0 mg/dl
     • Magnesium > lower limit normal (LLN) for patients who will receive cetuximab

Exclusion Criteria:

1. Patients with blistering disease.
2. Patients who require feeding with either nasogastric tube, gastrostomy or jejunostomy at study entry
3. Patients whose radiotherapy treatment planned dose is lower than 66 Gy
4. Patients being receiving another investigational agent because of participation in another therapeutic trial
5. Patients treated with fluvoxamine, estrogens, cimetidine, 5- and 8 methoxypsoralen and/or carbamazepine
6. Active viral, bacterial or fungal infections of the mouth in the last 14 days (i.e. stomatitis related to herpes virus or candida)
7. Pregnancy or lactation
8. Known allergy to melatonin
9. Prior radiotherapy of the head and neck
10. Patients with a treatment plan consisting of chemoradiation followed by further chemotherapy
11. Patients with a diagnostics of a synchronic neoplasia except for non-melanoma skin cancer curable with local treatment or in situ cervix carcinoma
12. Any investigational agent within 30 days prior to inclusion
13. Male or female of childbearing age who do not agree with taking adequate contraceptive precautions, i.e. use contraception double barrier (e.g. diaphragm plus condoms) or abstinence during the course of the study and for 2 months after the last administration of the study drug for women and 1 month for men
14. Psychological, geographical, familial or sociological conditions that potentially prevent compliance with the study protocol and follow-up schedule according to investigator criteria. These conditions should be discussed with the patient before inclusion in the trial.
15. Any other medical condition that would make the patient inappropiate for study participation according to the Investigator's judgement.