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

• Sponsor: Indonesia University (Other)
• Overall Status: Completed
• CT.gov ID: NCT04137627
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arms: 2
• Actual Duration (Months): 17.5
• Patients Per Site Per Month: 2.9

Study Details

Study Description

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

Study Design

• Study Type: Interventional
• 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 placeboone 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: Jul 4, 2017
• Actual Primary Completion Date: Jul 30, 2018
• Actual Study Completion Date: Dec 18, 2018

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Clinical Response as Measured by RECIST 1.1. Criteria [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 [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 [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 [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 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Faculty of Medicine, Universitas Indonesia	Jakarta Pusat	DKI Jakarta	Indonesia	10430

Sponsors and Collaborators

• Indonesia University

Investigators

• Principal Investigator: Diani Kartini, MD, Indonesia University

Study Documents (Full-Text)

• Study Protocol - Oct 28, 2019
• Statistical Analysis Plan - Oct 28, 2019

More Information

Publications

None provided.

• 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: Oct 24, 2019
• Last Update Posted: Dec 9, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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, Lecturer, Staff of Oncology Division of Department of Surgery, Principal Investigator, Indonesia University: Melatonin; Locally Advanced Oral Squamous Cell Carcinoma; Neoadjuvant Chemotherapy
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Melatonin

Study Results

Participant Flow

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	The group received standard treatment with the oral administration of Melatonin Melatonin 20 MG Oral Capsule: The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.	The group received standard treatment with the oral administration of Placebo Placebo oral capsule: The administration of placebo capsule in addition to neoadjuvant chemotherapy
Period Title: Overall Study
STARTED	25	25
COMPLETED	13	12
NOT COMPLETED	12	13

Baseline Characteristics

Arm/Group Title	Melatonin Group	Placebo Group	Total
Arm/Group Description	Participants who received Melatonin (treatment arm) who finished study protocol	Participants who received Placebo (control arm) who finished study protocol	Total of all reporting groups
Overall Participants	13	12	25
Age, Customized (Count of Participants)
Less than or equal to 50 years	5 38.5%	7 58.3%	12 48%
Greater than 50 years	8 61.5%	5 41.7%	13 52%
Sex: Female, Male (Count of Participants)
Female	5 38.5%	5 41.7%	10 40%
Male	8 61.5%	7 58.3%	15 60%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
Indonesia	13 100%	12 100%	25 100%
Tumor Location (Count of Participants)
Tongue	10 76.9%	9 75%	19 76%
Buccal	1 7.7%	1 8.3%	2 8%
Palate	0 0%	1 8.3%	1 4%
Mandible	1 7.7%	1 8.3%	2 8%
Gingiva (Gum)	1 7.7%	0 0%	1 4%
Stage (Count of Participants)
Stage IV A	12 92.3%	10 83.3%	22 88%
Stage IV B	1 7.7%	2 16.7%	3 12%
Keratinized/non-keratinized (Count of Participants)
Keratinized	12 92.3%	6 50%	18 72%
Non-keratinized	1 7.7%	6 50%	7 28%
Differentiation (Count of Participants)
Well Differentiated	5 38.5%	4 33.3%	9 36%
Moderately Differentiated	5 38.5%	3 25%	8 32%
Poorly Differentiated	3 23.1%	5 41.7%	8 32%
Grade (Count of Participants)
High Grade	6 46.2%	11 91.7%	17 68%
Low Grade	7 53.8%	1 8.3%	8 32%
Medication adherence (Count of Participants)
Strict adherence	10 76.9%	9 75%	19 76%
Poor adherence	3 23.1%	3 25%	6 24%

Outcome Measures

1. Primary Outcome

Title	Clinical Response as Measured by RECIST 1.1. Criteria
Description	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.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	The group received standard treatment with the oral administration of Melatonin Melatonin 20 MG Oral Capsule: The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.	The group received standard treatment with the oral administration of Placebo Placebo oral capsule: The administration of placebo capsule in addition to neoadjuvant chemotherapy
Measure Participants	13	12
Positive Response	5 38.5%	5 41.7%
Negative Response	8 61.5%	7 58.3%

2. Secondary Outcome

Title	Change in Expression of HIF-1⍺ as Measured by qRT-PCR Absolute Quantification
Description	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.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	The group received standard treatment with the oral administration of Melatonin Melatonin 20 MG Oral Capsule: The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.	The group received standard treatment with the oral administration of Placebo Placebo oral capsule: The administration of placebo capsule in addition to neoadjuvant chemotherapy
Measure Participants	13	12
Pre-Treatment	0.018	0.0048
Post-Treatment	0.012	0.0087
Change (Posttreatment - Pretreatment)	-0.008	0.0027

3. Secondary Outcome

Title	Change in Expression of miR-210 as Measured by qRT-PCR Absolute Quantification
Description	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.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	The group received standard treatment with the oral administration of Melatonin Melatonin 20 MG Oral Capsule: The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.	The group received standard treatment with the oral administration of Placebo Placebo oral capsule: The administration of placebo capsule in addition to neoadjuvant chemotherapy
Measure Participants	13	12
Pre-Treatment	162.8 (54.92)	175.2 (34.3)
Post-Treatment	53.8 (16.65)	53.5 (14.28)
Change (Posttreatment - Pretreatment)	-109.09 (51.62)	-103.71 (36.24)

4. Secondary Outcome

Title	Change in Expression of CD44 as Measured by qRT-PCR Absolute Quantification
Description	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.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	The group received standard treatment with the oral administration of Melatonin Melatonin 20 MG Oral Capsule: The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.	The group received standard treatment with the oral administration of Placebo Placebo oral capsule: The administration of placebo capsule in addition to neoadjuvant chemotherapy
Measure Participants	13	12
Pre-Treatment	0.0349	0.0095
Post-Treatment	0.0115	0.0187
Change (Posttreatment - Pretreatment)	-0.0114	0.0082

5. Secondary Outcome

Title	Change in Expression of CD133 as Measured by qRT-PCR Absolute Quantification
Description	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.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	The group received standard treatment with the oral administration of Melatonin Melatonin 20 MG Oral Capsule: The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.	The group received standard treatment with the oral administration of Placebo Placebo oral capsule: The administration of placebo capsule in addition to neoadjuvant chemotherapy
Measure Participants	13	12
Pre-Treatment	1.13	1.07
Post-Treatment	1.42	1.88
Change (Posttreatment - Pretreatment)	0.43	0.55

Adverse Events

Time Frame	56 Weeks
Arm/Group Title	Melatonin		Placebo
Arm/Group Description	The group received standard treatment with the oral administration of Melatonin Melatonin 20 MG Oral Capsule: The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.		The group received standard treatment with the oral administration of Placebo Placebo oral capsule: The administration of placebo capsule in addition to neoadjuvant chemotherapy
All Cause Mortality
	Melatonin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/12 (0%)
Serious Adverse Events
	Melatonin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Melatonin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		12/12 (100%)
General disorders
Fatigue	2/13 (15.4%)		3/12 (25%)
Nervous system disorders
Sleep Pattern Disturbance	2/13 (15.4%)		2/12 (16.7%)
Headache	3/13 (23.1%)		1/12 (8.3%)
Decreased Alertness	2/13 (15.4%)		0/12 (0%)
Sleepiness	4/13 (30.8%)		3/12 (25%)
Hallucination	1/13 (7.7%)		0/12 (0%)
Psychiatric disorders
Emotional Changes	2/13 (15.4%)		3/12 (25%)

Limitations/Caveats

There is a significant number of participants that are enrolled at the initial period of study but did not complete the whole study protocol due to various reasons, therefore statistical power of this study becomes lowered.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.