Tepotinib Phase II study in advanced lung cancer harboring MET exon 14 (METex14) skipping alterations and MET amplification

• Register: EUCTR
• Last refreshed on: 21 July 2021
• Main ID: EUCTR2015-005696-24-BE
• Date of registration: 26/04/2016
• Prospective Registration: Yes
• Primary sponsor: Merck KGaA
• Public title: Tepotinib Phase II study in advanced lung cancer harboring MET exon 14 (METex14) skipping alterations and MET amplification
• Scientific title: A Phase II, single-arm trial to investigate tepotinib in advanced (locally advanced or metastatic) non-small cell lung cancer with MET exon 14 (METex14) skipping alterations or MET amplification (VISION)
• Date of first enrolment: 04/07/2016
• Target sample size: 200
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-005696-24
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, France, Germany, Israel, Italy, Japan, Netherlands, Poland, Spain, Switzerland, United States

Contacts

• Name: Communication Center
• Affiliation: Merck KGaA

• Name: Communication Center
• Affiliation: Merck KGaA

Key inclusion & exclusion criteria

Inclusion criteria:
1. Histologically or cytologically confirmed advanced (Stage IIIB/IV) NSCLC (all histologies including squamous and sarcomatoid); 2. Treatment naive patients in first-line or pre-treated patients with no more than 2 lines of prior therapy
3. Subjects with MET alterations, namely METex14 skipping alterations in plasma and/or tissue, as determined by the central laboratory or by an assay with appropriate regulatory status will, be enrolled into the trial. For these subjects, sufficient tumor tissue and/or plasma is requested to allow additional testing MET amplification only in plasma defined by a positive LBx test, as determined by the central laboratory or by an assay with appropriate regulatory status Based on the outcome of the interim analysis in 12 LBx selected subjects: MET amplification only in tissue defined by a positive TBx with a gain of at least 4 copies of the MET gene, as determined by the central laboratory or by an assay with appropriate regulatory status.
4. Signed, written informed consent by subject or legal representative prior to any trial-specific screening procedure;
5. Male or female, = 18 years of age (or having reached the age of majority according to local laws and regulations, if the age of majority is > 18 years of age); [i.e., = 20 years of age in Japan]);
6. Measurable disease in accordance with RECIST version 1.1;
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 8. A female subjects is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential as defined in Appendix VIII OR
b. A woman of childbearing potential who agrees to use a highly effective contraception (i.e., methods with a failure rate of less than 1 % per year) as detailed in in Appendix VII of this protocol 2 weeks before start of first dose of study treatment, during the treatment period and for at least 4 weeks after the last dose of study treatment. Women of childbearing potential must have a negative pregnancy test (ß-HCG test in serum) prior to enrollment.
9. A male subject must agree to use and to have their female partners of childbearing potential to use a highly effective contraception (i.e., methods with a failure rate of less than 1 % per year) as detailed in Appendix VII of this protocol from the first dose of study treatment, during the treatment period and for at least 3 months after the last dose of study treatment and refrain from donating sperm during this period. Male subjects should always use a barrier method such as condom concomitantly.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 90
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 110

Exclusion criteria:
1. Subjects with characterized EGFR activating mutations that predict sensitivity to anti-EGFR-therapy, including, but not limited to exon 19 deletions and exon 21 alterations;
2. Subjects with characterized ALK rearrangements; that predict sensitivity to anti-ALK therapy
3. Subjects with symptomatic brain metastases who are neurologically unstable, and/or have required an increase in steriod dose within 2 weeks and/or have received prior stereotactic radiosurgery/gamma knife within 2 weeks and/or prior treatment for brain metastases within 4 weeks prior to the start of therapy. Subjects with leptomeningeal disease are ineligible;
4. Any unresolved toxicity Grade 2 or more according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) from previous anticancer therapy;
5. Need for transfusion within 14 days prior to the first dose of trial treatment;
6. Prior chemotherapy, biological therapy, radiation therapy, hormonal therapy for anti-cancer purposes, targeted therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of trial treatment
7. Subjects who have brain metastasis as the only measureable lesion
8. Inadequate hematological, liver, renal, cardiac function
9. Prior treatment with other agents targeting the HGF/c-Met pathway;
10. Past or current history of neoplasm other than NSCLC, except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least 5 years (for a full list of exlustion criteria please see the study protocol)


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Advanced (stage IIIB/IV) non-small cell lung cancer with MET exon 14 (METex14) skipping alterations

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: tepotinib
Product Code: MSC2156119J
Pharmaceutical Form: Tablet
INN or Proposed INN: tepotinib
Current Sponsor code: MSC2156119J
Other descriptive name: MSC2156119J
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Product Name: tepotinib
Product Code: MSC2156119J
Pharmaceutical Form: Tablet
INN or Proposed INN: tepotinib
Current Sponsor code: MSC2156119J
Other descriptive name: MSC2156119J
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Product Name: tepotinib
Product Code: MSC2156119J
Pharmaceutical Form: Tablet
INN or Proposed INN: TEPOTINIB
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 250-

Primary Outcome(s)

Secondary Objective: ALL COHORTS:
To further assess the efficacy of tepotinib
- To assess tolerability and safety of tepotinib
- To assess PK of tepotinib and its metabolite(s)
- To assess Health-Related Quality of Life (HRQoL)
Exploratory Objectives
-To explore a possible link between biomarkers of c-Met pathway activation, other relevant oncogenic pathways in plasma, serum and tumor tissue, and the activity of tepotinib
- To explore the QT/QTc interval concentration relationship based on Cycle 1, Day 1 and Cycle 2, Day 1 data
- To investigate the exposure-response relationship

Main Objective: PART 1:
COHORT A (METex14 skipping alterations):
To assess the efficacy of tepotinib in subj. with locally advanced or metast. NSCLC harboring the METex14 skipping alterations or MET amplif., as per objective response acc. to RECIST v. 1.1, based on independent review in
- Subj. positive for METex14 skipping alterations, regardless of MET amplif. status
-Subj. positive for METex14 skipping alterations based on liquid biopsy (LBx), regardless of MET amplification status
-Subj. tested positive for METex14 skipping alterations based on tumor biopsy (TBx), regardless of MET ampl. status.

PART 1:
COHORT B (MET amplification):
• To assess the efficacy of tepotinib in subjects with locally advanced or metastatic NSCLC, as per obj. response accord. to RECIST Ver. 1.1, based on independent review in:
- Subj.tested positive for MET amplification in LBx, and negative for METex14 skipping alter.

PART 2:
Cohort C (confirm. part for METex14 skipping alterations), ref to protocol

Primary end point(s): Objective response rate (confirmed CR or PR) determined according to
RECIST Version 1.1, based on independent review.

Timepoint(s) of evaluation of this end point: Baseline up to 20 months

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 2, 3, 6, 7: Baseline until PD/ death within 84 days of last tumor assessment; assessed up to 20 months
8: Baseline until death , assessed up to 20 months
1, 4, 5, 10, 11: Baseline up to 20 months
9: From the first dose of study drug administration until 33 days after the last dose of study drug administration, assessed up to 20 months
12 to 14: pre-dose, at 1.5 hours post-dose and at 4 hours post-dose on Cycle 1, Day 1 and on Cycle 2, Day 1

Secondary end point(s): 1. Objective response rate assessed as per Investigator
2. Duration of response as assessed by independent review committee
3. Duration of response as assessed by investigator
4. Objective disease control Rate as assessed by independent review committee
5. Objective disease control Rate as assessed by investigator
6. Progression free survival as assessed by independent review committee
7. Progression free survival as assessed by investigator
8. Overall survival
9. Number of subjects with TEAEs and deaths
10. Number of subjects with markedly abnormal vital signs, ECG, physical examination and ECOG PS.
11. Health Related Quality of Life Parameters
12. Maximum plasma concentration (Cmax) of Drug
13. Volume of distribution (Vz/F) of drug
14. Total Clearance (Cl) of drug 15. Number of subjects with markedly abnormal clinical laboratory tests (hematology and coagulation,
biochemistry and urinalysis).

Secondary ID(s)

VISION

MS200095-0022

Source(s) of Monetary Support

Merck KGaA

Ethics review

Status: Approved
Approval date: 04/07/2016
Contact: