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A Biomarker-implemented Clinical Study Evaluating Mutations in MET and TP53 in a Population of Treatment-refractory 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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04533321
Recruitment Status : Not yet recruiting
First Posted : August 31, 2020
Last Update Posted : August 31, 2020
Information provided by (Responsible Party):
National University Hospital, Singapore

Brief Summary:
Afatinib is approved therapy for SCC of the lung after progression with standard of care chemotherapy. There is also evidence of improvement of progression free survival of patients with metastatic/recurrent SCC of the head and neck after failure of chemotherapy in patients treated with afatinib. Therefore, treatment of patients with these 2 conditions with afatinib is not experimental, and will follow conventional clinical management.

Condition or disease Intervention/treatment Phase
Squamous Cell Carcinoma Drug: Afatinib Phase 2

Detailed Description:

Clinical objectives:

  1. To determine the efficacy of afatinib in patients with germline MET-N375S polymorphism.
  2. To determine the tolerability of afatinib in chemo-relapsed patients with germline MET-N375S polymorphism.

Research objectives:

  1. To determine the prevalence of MET and TP53 mutations, as well as HER2 and MET amplification, in various cancers, particularly head and neck cancers and lung cancers.
  2. To establish tumour cell lines, spheroids of xenografts for drug screening.

Endpoints of study:

  1. To determine the response rate of SCC HN/lung with Met-N375S to afatinib.
  2. The secondary endpoints include progression-free survival and toxicity.
  3. Frequency of MET mutations and TP53 mutations in patients with cancer.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Biomarker-implemented Clinical Study Evaluating Mutations in MET and TP53 in a Population of Treatment-refractory Squamous Cell Carcinoma
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Patients genotyped positive for MET-N375S polymorphism
will be treated with orally administered daily dose of afatinib (Gilotrif®) in a fasting state (1 hour before or 2 hours after meals).
Drug: Afatinib
Afatinib is approved therapy for SCC of the lung after progression with standard of care chemotherapy.

Primary Outcome Measures :
  1. p-HER2 and p-MET status [ Time Frame: 3 years ]
    using immunohistochemistry.

  2. MET-N375S mRNA copy number [ Time Frame: 3 years ]
    using RNAscope staining.

  3. Identification of MET and TP53 mutations using droplet digital PCR (ddPCR) and Sanger sequencing. [ Time Frame: 3 years ]

    DNA from the tumour specimens will be harvested for sequencing to identify cases with somatic mutations of TP53 gene. Changes in codon sequences will be reported.

    Germline DNA from the patients will be harvested from whole blood, and the polymorphic MET variant will be determined using ddPCR. Customised probes detecting wildtype MET allele or MET-N375S allele are designed to for genotyping (homozygous/heterozygous).

  4. Presence of MET and HER2 amplification using fluorescence in situ hybridization (FISH) [ Time Frame: 3 years ]
    FFPE samples retrieved from patients genotyped with MET-N375S polymorphism will be subjected to MET and HER2 testing Abbott PathVysion DNA test kits. Data will be analysed with fluorescence microscopy. HER2 amplification will be defined as gene copies versus chromosome 17 polysomy. MET amplification will be defined as gene copies per nucleus.

  5. Interaction of cMet and HER2 receptor tyrosine kinases using proximity ligation assay (PLA) [ Time Frame: 3 years ]
    PLA will be performed using DUOLINK in situ hybridization. Validation MET and HER2 antibodies will be used for the assay, and signal will be detected with fluorescence microscopy. Detection and quantification of positive signals will determine the presence of MET-HER2 interaction in clinical specimens.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   21 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients may be included in the study only if they meet all of the following criteria:

    1. Age 18 years or older
    2. Histologic or cytologic confirmation of metastatic squamous cell carcinoma of the lung or head and neck region, and has failed standard treatment.
    3. No other active malignancy within the past 24 months
    4. All subjects must have at least one tumour lesion (primary or metastatic) that is suitable for free-hand or image-guided biopsy at baseline.
    5. Clinical study will enroll patients genotyped positive for MET-N375S polymorphism.
    6. Eastern Cooperative Oncology Group (ECOG) performance status < 2
    7. Adequate organ function as defined by:

      a. Bone marrow function i. Haemoglobin ≥ 9g/dl ii. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L iii. Platelet count ≥ 75 x 109/L. b. Liver function i. Bilirubin < 2.5x upper limit of normal (ULN) ii. Alanine transaminase (ALT) and aspartate transaminase (AST) < 2.5x ULN or < 5x ULN if liver metastases are present iii. Prothrombin time (PT) within the normal range for the institution. c. Renal function i. Plasma creatinine <1.5x institutional ULN

    8. Capable of swallowing tablets
    9. Recovery from any previous drug- or procedure-related toxicity to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 Grade 0 or 1 (except alopecia), or to baseline preceding the prior treatment.
    10. Signed informed consent obtained before any study specific procedure. Subjects must be able to understand and be willing to sign the written informed consent.

Exclusion Criteria:

  • 1. Chemotherapy, radiotherapy, surgery, immunotherapy or other therapy within 3 weeks of starting investigational medicinal product (IMP).

    2. Pregnancy or breastfeeding. 3. Women of childbearing potential not employing adequate contraception. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of study medication, and a negative result must be documented before start of study medication. Women of childbearing potential and men, must agree to use adequate contraception (barrier method of birth control) upon signing the informed consent form until at least 3 months after the last study drug administration 4. Known or suspected allergy to the investigational agent or any agent given in association with this study.

    5. Concurrent cancer which is distinct in primary site or histology from the cancer being evaluated in this study 6. Patients with CTCAE Grade 2 or higher peripheral neuropathy. 7. History of significant cardiac disease: congestive cardiac failure > NYHA class II, ongoing unstable angina, new-onset angina or myocardial infarction within the past 3 months

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 identifier (NCT number): NCT04533321

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Contact: Boon Cher Goh 6779 5555

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National University Hospital
Singapore, Singapore
Contact: Boon Cher Goh    65-6772-4617   
Sponsors and Collaborators
National University Hospital, Singapore
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Principal Investigator: Boon Cher Goh National University Hospital, Singapore
Publications of Results:
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Responsible Party: National University Hospital, Singapore Identifier: NCT04533321    
Other Study ID Numbers: MC01/02/20
First Posted: August 31, 2020    Key Record Dates
Last Update Posted: August 31, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National University Hospital, Singapore:
Additional relevant MeSH terms:
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Carcinoma, Squamous Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action