Melatonin Oral Gel for Oral Mucositis in Patients With Head and Neck Cancer Undergoing Chemoradiation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase IB-II Clinical Trial of Melatonin Oral Gel for the Prevention and Treatment of Oral Mucositis in Patients With Head and Neck Cancer Undergoing Chemoradiation.

Conditions
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Oral Mucositis

Intervention / Treatment
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* Drug: Melatonin oral gel 3%
* Drug: Placebo oral gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients 18 years or over. Patients who gave written informed consent. Life expectancy ≥ 3 months. Subjects willing to comply with treatment and follow-up. 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. 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. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1. 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: Patients with blistering disease. Patients who require feeding with either nasogastric tube, gastrostomy or jejunostomy at study entry Patients whose radiotherapy treatment planned dose is lower than 66 Gy Patients being receiving another investigational agent because of participation in another therapeutic trial Patients treated with fluvoxamine, estrogens, cimetidine, 5- and 8 methoxypsoralen and/or carbamazepine Active viral, bacterial or fungal infections of the mouth in the last 14 days (i.e. stomatitis related to herpes virus or candida) Pregnancy or lactation Known allergy to melatonin Prior radiotherapy of the head and neck Patients with a treatment plan consisting of chemoradiation followed by further chemotherapy Patients with a diagnostics of a synchronic neoplasia except for non-melanoma skin cancer curable with local treatment or in situ cervix carcinoma Any investigational agent within 30 days prior to inclusion 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 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. Any other medical condition that would make the patient inappropiate for study participation according to the Investigator's judgement.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Melatonin<br>Melatonin oral gel 3% | Drug: Melatonin oral gel 3%<br> <br> |
| Placebo Comparator: Placebo<br>Placebo oral gel | Drug: Placebo oral gel<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number (percentage) of patients who develop severe oral mucositis (grade 3-4 according to the RTOG scale) |  | up to 19-20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number (percentage) of patients who develop severe oral mucositis (grade 3-4 according to NCI-CTCAE) |  | up to 19-20 weeks | 
| Number of days with mucositis of any grade according to the RTOG scale |  | up to 19-20 weeks | 
| Number of days with grade 3-4 mucositis according to the RTOG scale |  | up to 19-20 weeks | 
| Time to onset of grade 3-4 mucositis according to the RTOG scale from starting systemic antineoplastic treatment |  | up to 19-20 weeks | 
| Change from baseline in EORTC QLQ-C30 and EORTC QLQ-H&N35 scores at 4w after RT start |  | up to 4-5 weeks | 
| Change from baseline in EORTC QLQ-C30 and EORTC QLQ-H&N35 scores at one week after completion of RT |  | up to 8-9 weeks | 
| Change from baseline in EORTC QLQ-C30 and EORTC QLQ-H&N35 scores at 3 months after completion of RT or before surgery - if it is required post-chemoradiation due persistent or recurrent disease |  | up to 19-20 weeks | 
| Change from baseline in ECOG-Performance status score at different time points along the study |  | up to 19-20 weeks | 
| Number (percentage) of patients with grade 1-4 NCI-CTCAE adverse events related to IMP (melatonin oral gel 3%) |  | up to 19-20 weeks | 
| Number (percentage) of patients who develop cisplatin or cetuximab-associated grade 1-4 adverse events according to the NCI-CTCAE scale |  | up to 19-20 weeks | 
| Number (percentage) of patients who develop radiation-associated adverse events different from oral mucositis according to the RTOG scale |  | up to 19-20 weeks | 
| Pharmacokinetics evaluation [Cmax] |  | up to 11-12 weeks | 
| Pharmacokinetics evaluation [Tmax] |  | up to 11-12 weeks | 
| Pharmacokinetics evaluation [AUC] |  | up to 11-12 weeks | 
| Pharmacokinetics evaluation [T1/2] |  | up to 11-12 weeks | 
| Pharmacokinetics evaluation [Vd] |  | up to 11-12 weeks | 
| Pharmacokinetics evaluation [Clearance] |  | up to 11-12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mucositis, Head and Neck cancer, Chemoradiation