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

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.

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.

Study Overview

• Status: Completed
• Conditions: Oral Mucositis
• Intervention / Treatment: Drug: Melatonin oral gel 3%; Drug: Placebo oral gel

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari de la Vall d'Hebron
  • Barcelona, Spain, 08026
    • Hospital de la Santa Creu i Sant Pau
  • Girona, Spain, 17007
    • Institut Catala D'Oncologia Girona
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28040
    • Hospital San Carlos, Madrid
  • Málaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria
  • Santander, Spain, 39008
    • Hospital Universitario Marques de Valdecilla
  • Zaragoza, Spain, 50009
    • Hospital Miguel Servet
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Institut Català d'Oncologia ICO Badalona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Institut Català d'Oncologia L'Hospitalet
  • La Coruña
    • Santiago de Compostela, La Coruña, Spain, 15706
      • Hospital Clínico Universitario de Santiago

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Melatonin; Melatonin oral gel 3%	Drug: Melatonin oral gel 3%
Placebo Comparator: Placebo; Placebo oral gel	Drug: Placebo oral gel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Other Outcome Measures

Outcome Measure	Time Frame
Change from baseline in oral pain intensity measured by VAS at different time points along the study.	two times a week up to 19-20 weeks
Number (percentage) of patients who need minor or major opioids	up to 19-20 weeks
Number (percentage) of patients who need special procedures on nutritional status (feeding tube, jejunostomy, gastrostomy)	up to 19-20 weeks
Radiotherapy treatment breaks (cause)	up to 8-10 weeks
Radiotherapy treatment breaks (number of days)	up to 8-10 weeks
Total dose and intensity of radiotherapy: Total Gy;	up to 8-10 weeks
Total dose and intensity of radiotherapy: Gy/week;	up to 8-10 weeks
Total dose and intensity of radiotherapy: Gy/day	up to 8-10 weeks
Milligrams of systemic antineoplastic treatment administered (dose intensity: mg/m2/week)	up to 8-10 weeks
Number (percentage) of patients with complete response using the RECIST 1.1 criteria	2 months after completion of radiotherapy
Number (percentage) of patients with partial response using the RECIST 1.1 criteria	2 months after completion of radiotherapy
Number (percentage) of patients with stable disease using the RECIST 1.1 criteria	2 months after completion of radiotherapy
Number (percentage) of patients with progression disease using the RECIST 1.1 criteria	2 months after completion of radiotherapy

Collaborators and Investigators

• Sponsor: Spherium Biomed
• Collaborators: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau; Hospital San Carlos, Madrid; Hospital Universitario La Paz; Hospital Miguel Servet; Hospital Universitario Marqués de Valdecilla; Hospital Universitario Virgen de la Victoria; Hospital Clinico Universitario de Santiago; Institut Català d'Oncologia L'Hospitalet; Hospital Universitari de la Vall de Hebron; Institut Català d'Oncologia ICO Girona; Institut Català d'Oncologia ICO Badalona
• Investigators: Principal Investigator: Alicia Lozano, MD, Institut Català d'Oncologia L'Hospitalet

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 22, 2017

Study Registration Dates

• First Submitted: December 3, 2015
• First Submitted That Met QC Criteria: December 10, 2015
• First Posted (Estimate): December 15, 2015

Study Record Updates

• Last Update Posted (Actual): March 1, 2018
• Last Update Submitted That Met QC Criteria: February 28, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Chemoradiation; Mucositis; Head and Neck cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Diseases; Gastroenteritis; Stomatognathic Diseases; Mouth Diseases; Head and Neck Neoplasms; Mucositis; Stomatitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: JAN13004-30

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided