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

NCT04137627 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: MLTOSCC
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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.

Conditions

Oral Squamous Cell Carcinoma; Neoadjuvant Chemotherapy

Keywords

Melatonin; Locally Advanced Oral Squamous Cell Carcinoma; Neoadjuvant Chemotherapy

Outcome Measures

Primary Outcomes (1)

• Clinical Response as Measured by RECIST 1.1. Criteria

  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.

  1 Year

Secondary Outcomes (4)

• Change in Expression of HIF-1⍺ as Measured by qRT-PCR Absolute Quantification

  1 Year

• Change in Expression of miR-210 as Measured by qRT-PCR Absolute Quantification

  1 Year

• Change in Expression of CD44 as Measured by qRT-PCR Absolute Quantification

  1 Year

• Change in Expression of CD133 as Measured by qRT-PCR Absolute Quantification

  1 Year

Study Arms (2)

Melatonin

EXPERIMENTAL

The group received standard treatment with the oral administration of Melatonin

Drug: Melatonin 20 MG Oral Capsule

Placebo

PLACEBO COMPARATOR

The group received standard treatment with the oral administration of Placebo

Drug: Placebo oral capsule

Interventions

Melatonin 20 MG Oral Capsule DRUG

The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.

Melatonin

Placebo oral capsule DRUG

The administration of placebo capsule in addition to neoadjuvant chemotherapy

Placebo

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with locally advanced oral squamous cell carcinoma
• Patients with locally advanced oral squamous cell carcinoma who are planned with neoadjuvant chemotherapy
• 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
• Patients who are willing to sign the informed consent form to be our subject participants
• Karnofky \>50

You may not qualify if:

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

Sponsors & Collaborators

• Indonesia University: lead

Study Sites (1)

Faculty of Medicine, Universitas Indonesia

Jakarta Pusat, DKI Jakarta, 10430, Indonesia

Location

Related Publications (1)

• Kartini D, Taher A, Panigoro SS, Setiabudy R, Jusman SW, Haryana SM, Abdullah M, Rustamadji P, Purwanto DJ, Sutandyo N, Suroyo I, Siregar BH, Maruli H, Sungkar S. Effect of melatonin supplementation in combination with neoadjuvant chemotherapy to miR-210 and CD44 expression and clinical response improvement in locally advanced oral squamous cell carcinoma: a randomized controlled trial. J Egypt Natl Canc Inst. 2020 Feb 28;32(1):12. doi: 10.1186/s43046-020-0021-0.

  PMID: 32372215 DERIVED

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck

Interventions

Melatonin

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Tryptamines; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Limitations and 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.

Results Point of Contact

• Title: Dr. dr. Diani Kartini, Sp.B-K(Onk)
• Organization: Universitas Indonesia

d.kartini@gmail.com

+628122684919

Study Officials

• Diani Kartini, MD

  Indonesia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: double-blind masking
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Lecturer, Staff of Oncology Division of Department of Surgery, Principal Investigator

Model Details: one group receive standard treatment with melatonin, while the other group receive standard treatment with placebo

Study Record Dates

• First Submitted: October 22, 2019
• First Posted: October 24, 2019
• Study Start: July 4, 2017
• Primary Completion: July 30, 2018
• Study Completion: December 18, 2018
• Last Updated: December 9, 2019
• Results First Posted: December 9, 2019

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will not share

Locations

ID (1)