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Melatonin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response in Locally Advanced Oral Squamous Cell Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04137627
Recruitment Status : Completed
First Posted : October 24, 2019
Results First Posted : December 9, 2019
Last Update Posted : December 9, 2019
Sponsor:
Information provided by (Responsible Party):
dr. Diani Kartini,SpB(K)Onk, Indonesia University

Brief Summary:

Backgrounds

Squamous cell carcinoma of the oral cancer (OSCC) is the sixth most common malignancy. Surgery is the mainstay of treatment for oral cancers. In locally advanced and unresectable oral cancer, surgery presents challenges primarily because the head and neck region have many critical structures that can be damaged by tumor or treatment. Damage to the critical structures can result in significant structural, cosmetic and functional deficits that negatively impact quality of life.

Use of NC was found to achieve resectability in 39% of locally advanced unresectable oral cancers. Patil et al. reported response rate with the three drugs regimen (TPF) for NC was 32% and 27,37% for two drugs regimen (TP). The overall response rate in the TPF group was significantly higher than that in the PF group, both in the induction-chemotherapy phase and after locoregional therapy (33,3% vs 19,9%, p = 0,004). Chemoresistancy has become the challenge in OSCC treatment affecting tumor response to chemotherapy.

Hypoxic microenvironment found in OSCC is marked by the high expression of HIF-1α. CD44 and CD133 as a cancer stem cells marker in head and neck (HNSCC) and miR-210 known as hypoxamiR has been reported to contribute chemoresistancy. As hypoxia inarguably one of the main causes of chemoresistancy, it is agreeable to use melatonin as an antioxidant to reduce the hypoxic condition in tumor microenvironment. Melatonin, a potent endogenous antioxidant agent is proven to have an oncostatic effect, was given in expect to reduce the tumor hypoxic condition so that it would increase the tumor response on NC. Majority of the clinical study use oral melatonin given once daily in 20 mg dose as the minimal dose to yield anti-tumor effects.

The purpose of this study is to prove the effectiveness of melatonin to increase clinical response in locally advanced OSCC patients when treated with NC. The effect of melatonin in reducing tumor hypoxia will be seen through its effect in decreasing the gene expressions of HIF-1α, miR-210, CD44, and CD133.

Methods

Study Design

This study is a double blind, randomized clinical trial using placebo as comparison running from June 2017 to July 2018 . Locally advanced OSSC (stage IVA and IVB) patients that will receive NC were included in the study. Fifty patients treated at two centres (RSCM and RSKD) were randomly allocated into two arms. Twenty-five patients received melatonin combined with three regiment NC (Taxane, Cisplatin, and 5-FU) and the other received placebo with NC. However only 25 out of 50 patients had completed the study protocol (13 patients in melatonin arm and 12 in placebo arm)

Evaluation of Clinical Response

The clinical response were assessed by evaluating pre-treatment and post treatment MRI with the aid of RECIST 1.1. First, it is necessary to estimate the overall tumor burden at baseline (target and non-target lesion) and use this as a comparator for subsequent measurement. The tumor response then being determined according to the definition criteria according to RECIST 1.1, as follows: Complete response (CR) is the disappearance of all target lesions. Partial response (PR) means there is at least 30% decrement in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) means there is at least a 20% increment in the sum of diameters of target lesions or an absolute increment of at least 5 mm. Stable disease (SD) is when there is neither a sufficient shrinkage nor sufficient increment of target lesion. Patients who categorized as PR and CR undergone surgery while those with SD and PD undergone core biopsy.

Genes expression examination

The primer for HIF-1α miR210, CD44, and CD133 genes amplification was design using a Primer Quest Tool IDT software. The total sequence of each gene attained from GenBank data source: National Centre for Biotechnology Information (NCBI). The steps of gene expression examination are RNA isolation, cDNA synthesis, and absolute quantification qPCR. qPCR result was analyzed based on the gene expression concentration compare to the pre-determined standard curve (positive control) of each genes.

Statistical analysis

The data was analysed with statistics software SPSS 20. Saphiro Wilk was used to test data normal distribution. Data with normal distribution and with p > 0,05 presented in mean +- standard deviation (SD). Data with abnormal data distribution presented in median (minimal and maximal value). The statistical difference of gene concentration level (numerical data) between melatonin and placebo was analysed using normality test of Saphiro Wilk. Data with normal distribution was tested using unpaired-T test, while data with abnormal distribution was tested using Mann Whitney. Statistically significant different stated as p < 0,05.


Condition or disease Intervention/treatment Phase
Oral Squamous Cell Carcinoma Neoadjuvant Chemotherapy Drug: Melatonin 20 MG Oral Capsule Drug: Placebo oral capsule Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: one group receive standard treatment with melatonin, while the other group receive standard treatment with placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: double-blind masking
Primary Purpose: Supportive Care
Official Title: Effect of Melatonin in Combination With Neoadjuvant Chemotherapy to HIF-1⍺, CD44, CD133, and miR-210 Expression and Clinical Response in Locally Advanced Oral Squamous Cell Carcinoma (OSCC)
Actual Study Start Date : July 4, 2017
Actual Primary Completion Date : July 30, 2018
Actual Study Completion Date : December 18, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Melatonin

Arm Intervention/treatment
Experimental: Melatonin
The group received standard treatment with the oral administration of Melatonin
Drug: Melatonin 20 MG Oral Capsule
The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.

Placebo Comparator: Placebo
The group received standard treatment with the oral administration of Placebo
Drug: Placebo oral capsule
The administration of placebo capsule in addition to neoadjuvant chemotherapy




Primary Outcome Measures :
  1. Clinical Response as Measured by RECIST 1.1. Criteria [ Time Frame: 1 Year ]
    Clinical Response is measured using RECIST 1.1. criteria. CR (Complete response) is defined as disappearance of all target lesion, and pathological lymph node showing reduction of its shortest axis to less than 10 mm. PR (Partial response) is defined as reduction of total target lesion diameter at least by 30%. PD (Progressive disease) is defined as total target lesion diameter increased in size atleast by 20% or 5 mm OR occurence of one new lesion. SD (Stable disease) is defined as absence of reduction or increasing of target lesion. Patients with PR and CR are considered as positive response. Patients with SD and PD are considered as negative response.


Secondary Outcome Measures :
  1. Change in Expression of HIF-1⍺ as Measured by qRT-PCR Absolute Quantification [ Time Frame: 1 Year ]
    Expression of HIF-1⍺ is measured at the initial period of the study (baseline) and after 3 neoadjuvant chemotherapy cycles are completed using qRT-PCR Absolute Quantification. Change was calculated from two time points as the value at the later time point minus the value at the earlier time point.

  2. Change in Expression of miR-210 as Measured by qRT-PCR Absolute Quantification [ Time Frame: 1 Year ]
    Expression of miR-210 is measured at the initial period of the study (baseline) and after 3 neoadjuvant chemotherapy cycles are completed using qRT-PCR Absolute Quantification. Change was calculated from two time points as the value at the later time point minus the value at the earlier time point.

  3. Change in Expression of CD44 as Measured by qRT-PCR Absolute Quantification [ Time Frame: 1 Year ]
    Expression of CD44 is measured at the initial period of the study (baseline) and after 3 neoadjuvant chemotherapy cycles are completed using qRT-PCR Absolute Quantification. Change was calculated from two time points as the value at the later time point minus the value at the earlier time point.

  4. Change in Expression of CD133 as Measured by qRT-PCR Absolute Quantification [ Time Frame: 1 Year ]
    Expression of CD133 is measured at the initial period of the study (baseline) and after 3 neoadjuvant chemotherapy cycles are completed using qRT-PCR Absolute Quantification. Change was calculated from two time points as the value at the later time point minus the value at the earlier time point.



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with locally advanced oral squamous cell carcinoma
  2. Patients with locally advanced oral squamous cell carcinoma who are planned with neoadjuvant chemotherapy
  3. Patients with locally advanced oral squamous cell carcinoma who are planned with neoadjuvant chemotherapy who have not received any definitive treatment modalities, including surgical resection and chemoradiation therapy before the study conducted
  4. Patients who are willing to sign the informed consent form to be our subject participants
  5. Karnofky >50

Exclusion Criteria:

  1. Patients who are already treated with definitive therapy for locally advanced oral squamous cell carcinoma
  2. Patients who are not eligible to be treated with chemotherapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04137627


Locations
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Indonesia
Faculty of Medicine, Universitas Indonesia
Jakarta Pusat, DKI Jakarta, Indonesia, 10430
Sponsors and Collaborators
Indonesia University
Investigators
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Principal Investigator: Diani Kartini, MD Indonesia University
  Study Documents (Full-Text)

Documents provided by dr. Diani Kartini,SpB(K)Onk, Indonesia University:
Study Protocol  [PDF] October 28, 2019
Statistical Analysis Plan  [PDF] October 28, 2019


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Responsible Party: dr. Diani Kartini,SpB(K)Onk, Lecturer, Staff of Oncology Division of Department of Surgery, Principal Investigator, Indonesia University
ClinicalTrials.gov Identifier: NCT04137627    
Other Study ID Numbers: MLTOSCC
First Posted: October 24, 2019    Key Record Dates
Results First Posted: December 9, 2019
Last Update Posted: December 9, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by dr. Diani Kartini,SpB(K)Onk, Indonesia University:
Melatonin
Locally Advanced Oral Squamous Cell Carcinoma
Neoadjuvant Chemotherapy
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Melatonin
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Central Nervous System Depressants