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A Biomarker-implemented Clinical Study Evaluating Mutations in MET and TP53 in a Population of Treatment-refractory Squamous Cell Carcinoma

Primary Purpose

Squamous Cell Carcinoma

Status
Unknown status
Phase
Phase 2
Locations
Singapore
Study Type
Interventional
Intervention
Afatinib
Sponsored by
National University Hospital, Singapore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Squamous Cell Carcinoma focused on measuring MET, TP53

Eligibility Criteria

21 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • National University Hospital

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Patients genotyped positive for MET-N375S polymorphism

Arm Description

will be treated with orally administered daily dose of afatinib (Gilotrif®) in a fasting state (1 hour before or 2 hours after meals).

Outcomes

Primary Outcome Measures

p-HER2 and p-MET status
using immunohistochemistry.
MET-N375S mRNA copy number
using RNAscope staining.
Identification of MET and TP53 mutations using droplet digital PCR (ddPCR) and Sanger sequencing.
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).
Presence of MET and HER2 amplification using fluorescence in situ hybridization (FISH)
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.
Interaction of cMet and HER2 receptor tyrosine kinases using proximity ligation assay (PLA)
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.

Secondary Outcome Measures

Full Information

First Posted
August 26, 2020
Last Updated
August 26, 2020
Sponsor
National University Hospital, Singapore
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1. Study Identification

Unique Protocol Identification Number
NCT04533321
Brief Title
A Biomarker-implemented Clinical Study Evaluating Mutations in MET and TP53 in a Population of Treatment-refractory Squamous Cell Carcinoma
Official Title
A Biomarker-implemented Clinical Study Evaluating Mutations in MET and TP53 in a Population of Treatment-refractory Squamous Cell Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Unknown status
Study Start Date
September 2020 (Anticipated)
Primary Completion Date
September 2023 (Anticipated)
Study Completion Date
September 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National University Hospital, Singapore

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
Detailed Description
Clinical objectives: To determine the efficacy of afatinib in patients with germline MET-N375S polymorphism. To determine the tolerability of afatinib in chemo-relapsed patients with germline MET-N375S polymorphism. Research objectives: 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. To establish tumour cell lines, spheroids of xenografts for drug screening. Endpoints of study: To determine the response rate of SCC HN/lung with Met-N375S to afatinib. The secondary endpoints include progression-free survival and toxicity. Frequency of MET mutations and TP53 mutations in patients with cancer.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Squamous Cell Carcinoma
Keywords
MET, TP53

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Patients genotyped positive for MET-N375S polymorphism
Arm Type
Other
Arm Description
will be treated with orally administered daily dose of afatinib (Gilotrif®) in a fasting state (1 hour before or 2 hours after meals).
Intervention Type
Drug
Intervention Name(s)
Afatinib
Intervention Description
Afatinib is approved therapy for SCC of the lung after progression with standard of care chemotherapy.
Primary Outcome Measure Information:
Title
p-HER2 and p-MET status
Description
using immunohistochemistry.
Time Frame
3 years
Title
MET-N375S mRNA copy number
Description
using RNAscope staining.
Time Frame
3 years
Title
Identification of MET and TP53 mutations using droplet digital PCR (ddPCR) and Sanger sequencing.
Description
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).
Time Frame
3 years
Title
Presence of MET and HER2 amplification using fluorescence in situ hybridization (FISH)
Description
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.
Time Frame
3 years
Title
Interaction of cMet and HER2 receptor tyrosine kinases using proximity ligation assay (PLA)
Description
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.
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients may be included in the study only if they meet all of the following criteria: Age 18 years or older Histologic or cytologic confirmation of metastatic squamous cell carcinoma of the lung or head and neck region, and has failed standard treatment. No other active malignancy within the past 24 months All subjects must have at least one tumour lesion (primary or metastatic) that is suitable for free-hand or image-guided biopsy at baseline. Clinical study will enroll patients genotyped positive for MET-N375S polymorphism. Eastern Cooperative Oncology Group (ECOG) performance status < 2 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 Capable of swallowing tablets 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. 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Boon Cher Goh
Phone
6779 5555
Email
Boon_Cher_Goh@nuhs.com.sg
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Boon Cher Goh
Organizational Affiliation
National University Hospital, Singapore
Official's Role
Principal Investigator
Facility Information:
Facility Name
National University Hospital
City
Singapore
Country
Singapore
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Boon Cher Goh
Phone
65-6772-4617
Email
Boon_Cher_Goh@nuhs.com.sg

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
22960745
Citation
Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012 Sep 27;489(7417):519-25. doi: 10.1038/nature11404. Epub 2012 Sep 9. Erratum In: Nature. 2012 Nov 8;491(7423):288. Rogers, Kristen [corrected to Rodgers, Kristen].
Results Reference
result
PubMed Identifier
23554766
Citation
Liu Y, Zhang Q, Ren C, Ding Y, Jin G, Hu Z, Xu Y, Shen H. A germline variant N375S in MET and gastric cancer susceptibility in a Chinese population. J Biomed Res. 2012 Sep;26(5):315-8. doi: 10.7555/JBR.26.20110087. Epub 2012 Mar 29.
Results Reference
result

Learn more about this trial

A Biomarker-implemented Clinical Study Evaluating Mutations in MET and TP53 in a Population of Treatment-refractory Squamous Cell Carcinoma

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