| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Locally advanced or metastatic NSCLC histology (confirmed by either histology or cytology) with documented activating mutation of the EGFR receptor including T790M status
Resistance on previous first line osimertinib |
|
| 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 |
| To assess the efficacy of tepotinib combined with osimertinib in participants with advanced or metastatic EGFRm+ NSCLC and MET amplification, determined centrally by FISH. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the efficacy of tepotinib combined with osimertinib in participants with advanced or metastatic EGFRm+ NSCLC and MET amplification determined centrally by blood-based next generation sequencing.
To assess the efficacy of tepotinib monotherapy in participants with advanced or metastatic EGFRm+ NSCLC and MET amplification determined centrally by FISH.
To assess tolerability and safety in participants with advanced or metastatic EGFRm+ NSCLC and MET amplification treated with the combination of tepotinib plus osimertinib.
To assess tolerability and safety in participants with advanced or metastatic EGFRm+ NSCLC and MET amplification treated with tepotinib monotherapy.
To further assess efficacy of tepotinib combined with osimertinib in participants with advanced or metastatic EGFRm+ NSCLC and MET
amplification, determined centrally by FISH
please refer to protocol for more information |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Are ≥ 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 [ie, ≥ 20 years of age in Japan]), at the time of signing the informed consent.
2. Are participants with the following:
a) Locally advanced or metastatic NSCLC histology (confirmed by either histology or cytology) with documented activating EGFR mutation of the EGFR receptor including T790M status
b) Presence of at least 1 independently verified measurable lesion in accordance with RECIST 1.1, that can be accurately assessed at baseline with ≥ 10 mm in the longest diameter (except lymph nodes which must Have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI), which is suitable for accurate repeated measurements and that preferably was not previously irradiated or biopsied
c) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a minimum life expectancy of 12 weeks
d) Acquired resistance on previous first-line-osimertinib. Participants must meet both of the following 2 criteria:
-Radiological documentation of disease progression on first-line-osimertinib.
- Objective clinical benefit documented during previous osimertinib therapy, defined by either partial or complete radiological response, or
durable stable disease (SD) (SD should last > 6 months) after initiation of osimertinib
e) Have received only first line osimertinib as a prior line of therapy in the noncurative advanced or metastatic NSCLC setting
f) MET amplification as determined by either FISH testing (central or local) on tumor tissue (TBx) or central blood-based next generation
sequencing (LBx). Tumor and blood samples must be collected following progression on prior first-line osimertinib at Prescreening.
-Submission of tumor tissue and blood sample obtained after progression on first line osimertinib, is mandatory for all patients for
MET amplification testing.
-Submission of tumor tissue during Prescreening or Screening is mandatory for patients with tumor tissue tested by local FISH, to
confirm MET amplification status. Central confirmation is not mandated prior to the start of study treatment
3.Woman no WOBCP, or, use a highly effective contraception. Man: Contraception or no intercourse with a WOBCP1. |
|
| E.4 | Principal exclusion criteria |
1. Spinal cord compression or brain metastasis unless asymptomatic, stable or not requiring steroids for at least 2 weeks prior to start of study intervention. Prior radiotherapy or surgery for brain metastases such as stereotactic radiosurgery/gammaknife must have been completed ≥ 2 weeks, all others ≥ 4 weeks prior to start of therapy. Participants with leptomeningeal disease are ineligible.
2. Any unresolved toxicity Grade 2 or more according to NCI-CTCAE version 5, from previous anticancer therapy with the exception of alopecia.
3. Need for transfusion within 14 days prior to the first dose of study intervention.
4. Participants who have brain metastasis as the only measurable lesion
5. Inadequate hematological function:
Hemoglobin < 8.5 g/dL
Neutrophils < 1.5 × 109/L
Platelets < 100 × 109/L.
6. Inadequate liver function:
Total bilirubin > 1.5 × ULN
AST/ALT/ALP > 3 × ULN
For participants with liver metastases:
i. Total bilirubin > 1.5 × ULN
ii. AST/ALT/ALP > 5 × ULN
iii. For participants with bone metastases: ALP > 5 × ULN.
7. Inadequate renal function:
Renal impairment as evidenced by serum creatinine 1.5 × ULN, or creatinine clearance (CrCl) < 30 mL/min calculated by the Cockcroft-Gault formula (24-hour CrCl might be requested by the Investigator for confirmation, if calculated CrCl is < 50 mL/min. In such case, participants with 24-hour CrCl < 30 mL/min should be excluded).
CrCl (mL/min) = [(140 – age(year)) × weight(kg)] 72 × serum creatinine (mg/dL) {× 0.85 for females}
8. History of ILD or interstitial pneumonitis including radiation pneumonitis that required steroid treatment.
9. Impaired cardiac function:
Left ventricular ejection fraction < 45% defined by echocardiography
Grade 4 arrhythmia (NCI-CTCAE v5.0)
Unstable angina pectoris
Congestive Heart Failure New York Heart Association III and IV
Myocardial infarction, stroke, or transient ischemic attack within the last 6 months prior to study entry.
10. Corrected QT interval by Fredericia (QTcF) > 470 ms for women and > 450 ms for men at screening.
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives, or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes.
11. Hypertension uncontrolled by standard therapies (not stabilized to < 150/90 mmHg).
12. Contraindication to the administration of osimertinib.
13. Medical history of liver fibrosis/cirrhosis.
14. Past or current history of neoplasm other than NSCLC, except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix, benign prostate neoplasm/hypertropia or other cancer curatively treated and with no evidence of disease for at least 5 years.
15. Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the tested product.
16. Major surgery within 28 days prior to Day 1 of study intervention.
17. Known human immunodeficiency virus positivity.
18. Known hypersensitivity to any of the study intervention ingredients.
19. Has not received an EGFR-TKI containing treatment directly prior to enrollment into the study, ie, chemotherapy or checkpoint inhibitor treatment with/without vascular endothelial growth factor inhibitors either in monotherapy or in combination are allowed, if these treatments do not represent the most recent treatment lines prior to enrollment
20. Prior treatment with other agents targeting the HGF/MET pathway such as crizotinib, capmatinib, savolitinib, foretinib, glesatinib, cabozantinib, merestinib, onartuzumab, rilotumumab, emibetuzumab, and ficlatuzumab.
21. Participants currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of study intervention) medications or herbal supplements known to be potent inducers of CYP3A4.
22. Participation in another interventional clinical study (except those participants who were solely involved in other studies where the
investigational product was osimertinib in the first-line of therapy) within the 30 days prior to randomization/first dose. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Objective response (confirmed complete response [CR] or partial response [PR]) determined according to Response Evaluation Criteria in Solid Tumors
(RECIST) Version 1.1 as per Independent Review Committee (IRC). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Cycles of 21 days until disease progression (according to RECIST Version 1.1), death, adverse event leading to discontinuation, study withdrawal or consent withdrawal. |
|
| E.5.2 | Secondary end point(s) |
Objective response (CR or PR) determined according to RECIST Version 1.1 as per IRC.
Occurrence of Adverse Events (AEs) and treatment related AEs.
Occurrence of abnormalities (Grade = 3) in laboratory test values (hematology and coagulation, biochemistry) and urinalysis.
Occurrence of markedly abnormal vital sign measurements, change in body weight, and Eastern Cooperative Oncology Group (ECOG)
performance status.
Occurrence of clinically significantly abnormal electrocardiograms (ECGs).
Objective response according to RECIST Version 1.1 assessed by Investigator.
Confirmed CR assessed by IRC and by Investigator.
Duration of response assessed from CR or PR until progressive disease (PD), death, or last tumor assessment assessed by IRC and by
Investigator.
Disease control (confirmed CR + PR or stable disease [SD] lasting at least 12 weeks) as assessed by IRC and by Investigator.
Progression free survival according to RECIST Version 1.1 by IRC and by Investigator.
Overall survival
Patient-reported outcomes/health-related quality of life as reported using the following:
EuroQol Five Dimension Five Level Scale
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30
Non–small Cell Lung Cancer Symptom
Assessment Questionnaire.
Single- and multiple-dose PK profile of osimertinib, tepotinib, and their metabolites including but not limited to AUC0-t, Cmax, and tmax after first dose (Day
1) and after multiple study intervention dose administrations (Day 15) (safety run-in).
Population PK profile of osimertinib, tepotinib, and their metabolites, including, but not limited to, CL/f and VZ/f based on sparse PK sampling on Day 1,
Cycle 1 and 2.
Mutation status in EGFR and other pathways |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| Malaysia |
| Philippines |
| Singapore |
| Hong Kong |
| Taiwan |
| China |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Thailand |
| Turkey |
| United States |
| Viet Nam |
| Belgium |
| France |
| Germany |
| Netherlands |
| Spain |
|
| 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 study is defined as the date of study intervention discontinuation by all participants (due to either disease progression, undue toxicity, or withdrawal, and, therefore, are not likely to benefit from the study intervention any longer) and two thirds of the participants have died or were followed up for at least 3 years, whatever occurs first. After the end of the study a final analysis, including an analysis of efficacy and safety, will be conducted in all participants.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 19 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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