| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced (locally advanced or metastatic) non-small cell lung cancer with MET exon 14 (METex14) skipping alterations |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 |
|
| E.2.2 | Secondary objectives of the trial |
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
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenetics study: the DNA extracted for genetic variant analysis may be explored for potential genes involved in the PK, pharmacodynamics, efficacy and safety of tepotinib. Biomarkers of c-Met and other pathway activations, such as but not limited to phospho-c-Met, HGF levels, c-Met genetic mutations, and their potential correlation with prognosis and activity of tepotinib will be assessed. This consists of analyzing the type and the level of biomarkers alteration in serum or tumor tissue and evaluating their association with clinical endpoints. Blood samples for PGx will be evaluated to assess genetic variations of genes. Pharmacogenetics testing might include assessment of genetic polymorphisms responsible for drug metabolism and transport genes and may also be used for assessing polymorphisms linked to Caucasian or Asian descent. Other biomarkers and technologies may be included, the scientific relevance of which emerges at the time of the planned analysis for subjects included in the trial.
|
|
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed advanced (locally advanced or metastatic) NSCLC (all types 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 (β-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. |
|
| E.4 | Principal 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 steroid dose within 2 weeks and/or have received prior stereotactic radiosurgery/gamma knife within 2 weeks and/or other 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) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Objective response (confirmed CR or PR) determined according to
RECIST Version 1.1, based on independent review. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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). |
|
| E.5.2.1 | 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 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| China |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Spain |
| Switzerland |
| Taiwan |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the trial is defined as the time point at which all subjects have discontinued trial drug (due to either disease progression, undue toxicity or withdrawal, and, therefore, are not likely to benefit from tepotinib any longer) and two thirds of the subjects have died. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
Print
