| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced (stage IIIB/IV) non-small cell lung cancer with MET exon 14 (METex14) skipping alterations |
| Carcinoma polmonare non a piccole cellule avanzato (stadio IIIB / IV) con alterazioni saltate di MET exon 14 (METex14) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung cancer |
| Tumore ai polmoni |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001165 |
| E.1.2 | Term | Adenocarcinoma lung stage IV |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001160 |
| E.1.2 | Term | Adenocarcinoma lung |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001164 |
| E.1.2 | Term | Adenocarcinoma lung stage III |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
COHORT A (METex14 skipping alterations):
To assess the efficacy of tepotinib in subj. with advanced NSCLC
harboring the METex14 skipping alterations, as per objective response
acc. to RECIST ver. 1.1, based on independent review in
• - Subjects tested positive for METex14 skipping alterations, regardless
of MET amplification status
• -Subjects tested positive for METex14 skipping alterations based on
liquid biopsy (LBx), regardless of MET amplification status
• -Subjects tested positive for METex14 skipping alterations based on
tumor biopsy (TBx), regardless of MET amplification status.
COHORT B (MET amplification):
• To assess the efficacy of tepotinib in subjects with advanced (Stage
IIIB/IV) NSCLC, as per objective 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 alterations. |
COHORT A (alterazioni di salto METex14):
Per valutare l'efficacia di tepotinib in subj. con NSCLC avanzato
ospitare le alterazioni di salto METex14, come da risposta obiettiva
acc. per RECIST ver. 1.1, sulla base di una revisione indipendente in
• - Soggetti testati positivi per alterazioni saltate di METex14, indipendentemente
dello stato di amplificazione MET
• -Soggetti testati positivi per alterazioni di salto di METex14 basate su
biopsia liquida (LBx), indipendentemente dallo stato di amplificazione del MET
• -Soggetti testati positivi per alterazioni di salto di METex14 basate su
biopsia tumorale (TBx), indipendentemente dallo stato di amplificazione del MET.
COHORT B (amplificazione MET):
• Valutare l'efficacia di tepotinib in soggetti con avanzato (stadio
IIIB / IV) NSCLC, come da accordo di risposta obiettiva. per RECIST Ver. 1.1,
basato su una revisione indipendente in:
• - Subj.test positivo per l'amplificazione MET in LBx e negativo per
Alterazioni di salto METex14. |
|
| E.2.2 | Secondary objectives of the trial |
E.2.2 Obiettivi secondari:
COHORT A and B:
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.2.2 Obiettivi secondari:
COH0RT A e B:
Per valutare ulteriormente l'efficacia di tepotinib
- Valutare la tollerabilità e la sicurezza di tepotinib
- Valutare la PK di tepotinib e il suo / i suo / i metabolita / i
- Valutare la qualità della vita correlata alla salute (HRQoL)
Obiettivi esplorativi
-Per esplorare un possibile collegamento tra biomarcatori del percorso c-Met
attivazione, altre vie oncogeniche rilevanti nel plasma, nel siero e
tessuto tumorale e l'attività di tepotinib
- Per esplorare la relazione di concentrazione dell'intervallo QT / QTc in base a
Ciclo 1, giorno 1 e ciclo 2, giorno 1 dati
- Indagare la relazione esposizione-risposta |
|
| 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
Version: V5.0
Date: 10/05/2018
Title: Pharmacogenetics
Objectives: 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.
|
Farmacogenetica
Versione: V5.0
Data: 10/05/2018
Titolo: Farmacogenetica
Obiettivi: il DNA estratto per l'analisi delle varianti genetiche può essere esplorato per potenziali geni coinvolti nel PK, farmacodinamica, efficacia e sicurezza di tepotinib. Biomarcatori di c-Met e altre attivazioni di pathway, come ma non limitato a phospho-c-Met, Livelli di HGF, mutazioni genetiche c-Met e loro potenziale correlazione con saranno valutate la prognosi e l'attività di tepotinib. Questo consiste di analizzare il tipo e il livello di alterazione dei biomarcatori nel siero o nel tessuto tumorale e valutarne l'associazione con gli endpoint clinici. Saranno valutati campioni di sangue per PGx per valutare le variazioni genetiche dei geni. I test di farmacogenetica potrebbero includere la valutazione dei polimorfismi genetici responsabili del metabolismo dei farmaci e dei geni di trasporto e possono anche essere utilizzati per valutare i polimorfismi associati alla discendenza caucasica o asiatica. Possono essere inclusi altri biomarcatori e tecnologie, la cui rilevanza scientifica emerge al momento dell'analisi pianificata per le materie incluse nello studio.
|
|
| E.3 | Principal inclusion criteria |
1. Histologically confirmed advanced adenocarcinoma of the lung, having failed at least one but not more than 2 lines of systemic therapy, including a platinum-doublet-containing regimen, but having failed a maximum of 2 lines of active therapy;
2. METex14 skipping alterations, as determined by the central laboratory. Both, archival and
fresh biopsies are acceptable; In case METex14 skipping alteration has been observed in a subject in a pre-trial setting, it should be ensured that sufficient tissue is available for re-testing before trial entry. Only subjects with METex14 skipping mutation based on trial central testing will be
enrolled into the trial.
3. Signed, written informed consent by subject or legal representative prior to any trial-specific screening procedure;
4. 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);
5. Measurable disease in accordance with RECIST version 1.1;
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1."
7. 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.
8. 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 |
"1. Histologically confirmed advanced adenocarcinoma of the lung, having failed at least one but not more than 2 lines of systemic therapy, including a platinum-doublet-containing regimen, but having failed a maximum of 2 lines of active therapy;
2. METex14 skipping alterations, as determined by the central laboratory. Both, archival and
fresh biopsies are acceptable; In case METex14 skipping alteration has been observed in a subject in a pre-trial setting, it should be ensured that sufficient tissue is available for re-testing before trial entry. Only subjects with METex14 skipping mutation based on trial central testing will be
enrolled into the trial.
3. Signed, written informed consent by subject or legal representative prior to any trial-specific screening procedure;
4. 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);
5. Measurable disease in accordance with RECIST version 1.1;
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1."
7. 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.
8. 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 (documented results; local testing acceptable) that predict sensitivity to EGFR-therapy, including, but not limited to exon 19 deletions and exon 21 alterations;
2. Subjects with characterized ALK rearrangements (documented results; local testing acceptable);
3. Active brain metastases (defined as neurologically stable for < 4 weeks and/or symptomatic and/or requiring treatment with steroids and/or leptomeningeal disease). Subjects must have completed any prior treatment for brain metastases = 4 weeks prior to start of therapy (= 2 weeks for stereotactic radiosurgery/gamma knife). Subjects who are neurologically stable on symptomatic therapy with anticonvulsants with low drug interaction risk or whose steroids
are being tapered are eligible. Asymptomatic untreated brain metastases = 1cm are eligible;
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, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of trial treatment;
7. Inadequate hematological, liver, renal, cardiac function; 8. Prior treatment with other agents targeting the HGF/c-Met pathway; 9. 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).
|
1. Subjects with characterized EGFR (documented results; local testing acceptable) that predict sensitivity to EGFR-therapy, including, but not limited to exon 19 deletions and exon 21 alterations;
2. Subjects with characterized ALK rearrangements (documented results; local testing acceptable);
3. Active brain metastases (defined as neurologically stable for < 4 weeks and/or symptomatic and/or requiring treatment with steroids and/or leptomeningeal disease). Subjects must have completed any prior treatment for brain metastases = 4 weeks prior to start of therapy (= 2 weeks for stereotactic radiosurgery/gamma knife). Subjects who are neurologically stable on symptomatic therapy with anticonvulsants with low drug interaction risk or whose steroids
are being tapered are eligible. Asymptomatic untreated brain metastases = 1cm are eligible;
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, 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 rate (confirmed Cr or PR) determinated according to RECIST Version 1.1, based on indipendent review. |
| 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 |
| Baseline up to 20 months |
| Baseline up to 20 months |
|
| 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). |
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, 15: 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 |
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, 15: 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 | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 13 |
| 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 | Information not present in EudraCT |
| 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 |
| China |
| Israel |
| Japan |
| Korea, Democratic People's Republic of |
| Korea, Republic of |
| Taiwan |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Switzerland |
|
| 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
|
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. |
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 | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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