| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Phase Ib
To determine the RP2D of tepotinib when used in combination with gefitinib (at the approved standard dose of 250 mg) when administered orally once daily over a 21-day cycle in subjects with MET+ advanced NSCLC.
Phase II
To evaluate whether the efficacy in terms of progression free survival (PFS) of
second-line tepotinib in combination with gefitinib is superior to
pemetrexed+cisplatin/carboplatin in subjects with T790M negative, MET+ locally
advanced or metastatic NSCLC harboring an EGFR mutation and having acquired
resistance to first-line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or
afatinib |
|
| E.2.2 | Secondary objectives of the trial |
Phase Ib
To characterize the PK of tepotinib when given in combination with gefitinib
To characterize the PK of gefitinib when given in combination with tepotinib
To assess the safety and tolerability of tepotinib in combination with gefitinib
To evaluate preliminary antitumor activity of tepotinib in combination with gefitinib
Phase II
To evaluate the safety and tolerability of tepotinib in comb with gefitinib
To evaluate the efficacy of tepotinib in combination with gefitinib in T790M negative, MET+ subjects
To evaluate the antitumor activity of tepotinib in combination with gefitinib in T790M positive, MET+ subjects in a separate single-arm cohort (mainland China sites only)
To assess patient-reported outcomes (PROs) with respect to quality of life (QoL), as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and time-to-symptom progression (TTSP), as measured by Lung Cancer Symptom Scale (LCSS) |
|
| 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 |
Pharmacogenomics Substudy:
The Pharmacogenomic Analysis Set will include all subjects who have provided the blood
sample for PGx gene analysis and who have given consent for the PGx analyses.
PGx analyses will be performed on genetic variations of genes such as UGT that may be
involved in the PK, safety and efficacy of tepotinib in combination with gefitinib. In addition,
analyses of other genetic variants that may influence the safety and efficacy of tepotinib in
combination with gefitinib may be explored. The results of these exploratory PGx analyses will
be provided in a separate report. |
|
| E.3 | Principal inclusion criteria |
Phase Ib
a) Histologically or cytologically confirmed advanced NSCLC, regardless of histology subtype, which failed on gefitinib for reasons other than toxicity or compliance;
b) Availability of a fresh or archived pretreatment tumor biopsy (excluding fine needle aspiration and cytology samples). For subjects who have had at least 1 prior anticancer treatment, a biopsy obtained between failure of the most recent anticancer treatment and enrollment is mandatory;
c) MET+ status, as determined by the central laboratory, i.e. c-Met overexpression as determined by immunohistochemistry (IHC) (i.e., IHC 2+ or IHC 3+);
d) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
Phase II
a) Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology);
b) Activating mutation of the EGFR receptor (documented, or as determined by the central laboratory);
c) Acquired resistance on first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib;
d) EGFR T790M status (as determined by the central laboratory, using a validated PCR test);
T790M negative status for the randomized part T790M positive status for the single-arm cohort (mainland China sites only)
e) Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory;
f) MET+ status, as determined by the central laboratory, i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH;
g) ECOG PS of 0 or 1.
|
|
| E.4 | Principal exclusion criteria |
Phase Ib .Subjects are not eligible for Phase Ib if they fulfill any of the following exclusion criteria:
Cancer Related
1.Symptomatic metastasis of brain and/or CNS, uncontrolled with antiepileptics and requiring steroids, unless treated and stable without steroids for at least 10 days within 4 weeks prior to the first dose of trial treatment;
2.Any unresolved toxicity more than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) Grade 2 from previous anticancer therapy;
3.Estimated life expectancy < 3 months;
4.Need for transfusion within 14 days prior to the first dose of trial treatment;
5.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.
Laboratory Values and Organ Function
1.Inadequate hematological function:Hemoglobin < 8.5 g/dLNeutrophils < 1.5 × 109/LPlatelets < 100 × 109/L
2.Inadequate liver function:Total bilirubin > 1.5 × upper limit of normal (ULN)Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 3 × ULN;
For subjects with liver metastases:Total bilirubin > 1.5 × ULNAST/ALT > 5 × ULN
3.Known pre-existing interstitial lung disease
4.Inadequate renal function:
6.Renal impairment as evidenced by serum creatinine 1.5 × ULN, or creatinine clearance (CrCl) < 60 mL/min calculated by the Cockcroft-Gault formula (24 hour CrCl might be requested by the investigator for confirmation, if calculated CrCl is < 60 mL/min. In such case, subjects with 24 hour CrCl < 60 mL/min should be excluded
5.Subjects who have ongoing medical history of acute pancreatitis and/or chronic pancreatitis, with concomitant elevated lipase and/or amylase, clinical symptoms, and/or imaging studies that are indicative of the diagnosis (subjects in mainland China only)
General
1.Impaired cardiac function
Left ventricular ejection fraction (LVEF) < 45% defined by echocardiography (a screening LVEF assessment without history of congestive heart failure [CHF] is not required)
Serious arrhythmia
Unstable angina pectoris
CHF New York Heart Association (NYHA) III and IV (Appendix E)
Myocardial infarction within the last 12 months prior to trial entry
Signs of pericardial effusion
2.Hypertension uncontrolled by standard therapies (not stabilized to <150/90 mmHg)
3.Contraindication to the administration of gefitinib
4.Medical history of liver fibrosis/cirrhosis
5.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;
6.Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the tested product
7.Major surgery within 28 days prior to Day 1 of trial treatment
8.Known human immunodeficiency virus positivity
9.Substance abuse, active infection, or other acute or chronic medical or psychiatric condition or laboratory abnormalities that might increase the risk associated with study participation at the discretion of investigators
10.Female subjects who are pregnant or lactating, or men and women of reproductive potential not willing or not able to employ a highly effective method of birth control/contraception to prevent pregnancy until the end of study. A highly effective method of contraception is defined as those, alone or in combination, that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. This requirement begins 2 weeks before receiving the first trial treatment and ends 3 months after receiving the last treatment
11.Known hypersensitivity to any of the trial treatment ingredients
12.Legal incapacity or limited legal capacity
13.Any other reason that, in the opinion of the principal investigator, precludes the subject from participating in the trial
14.Participation in another interventional clinical trial (except those subjects who were solely involved in other trials where the investigation product was gefitinib, erlotinib, icotinib, or afatinib) within the 30 days prior to randomization/first dose
Phase II
Subjects are not eligible for Phase II if they fulfill any Phase Ib exclusion criteria listed above. Additional exclusion criteria, listed below, apply to Phase II only.
General
Any contraindication to the administration of either pemetrexed+cisplatin or pemetrexed+carboplatin
Cancer Related
1.Prior systemic anticancer treatment with eg. chemotherapy or any other agents excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo]adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed)
2.Prior treatment with other agents targeting the HGF/c-Met pathway |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1- Phase 1b: Number of subjects experiencing at least one dose limiting toxicity (DLT)
2- Phase 1b: Percentage of subjects with adverse events (AEs)
3- Phase 2 (randomized): Progression free survival (PFS) time: Investigator assessments or site radiologist assessment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1- Up to Day 21 of Cycle 1
2- Baseline up to Day 30 after the last dose of study treatment
3- Up to 8 months |
|
| E.5.2 | Secondary end point(s) |
1. Phase 2 (randomized): Progression free survival (PFS) time: Independent review assessments
2. Phase 2 (single arm cohort): Progression free survival (PFS) time: Investigator and Independent review assessment
3. Overall Survival (OS) Time
4. Percentage of subjects with objective response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) criteria
5. Percentage of subjects with disease control according to RECIST version 1.1 criteria
6. Phase 1b: Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Time AUC (0-t)
7. Percentage of subject with treatment emergent adverse events (TEAEs), treatment related TEAEs, SAEs, treatment related SAEs, TEAEs with toxicity >= 3, treatment related TEAEs >= 3, and TEAEs leading to permanent treatment discontinuation
8. Phase 1b: Area Under the Plasma Concentration Versus Time Curve within 1 dosing interval (AUC 0-tau)
9. Phase 1b: Maximum Observed Plasma Concentration (Cmax)
10. Phase 1b: Average Plasma Concentration (Cavg)
11. Phase 1b: Minimum Concentration (Cmin)
12. Phase 1b:Time to Maximum Concentration (Tmax)
13. Phase 1b: Area Under the Curve From Time Zero to Infinity (AUC 0-inf)
14. Phase 1b: Apparent Body Clearance of the drug from Plasma (CL/F)
15. Phase 1b: Apparent Volume of Distribution (Vz/F)
16. Phase 1b: Volume of Distribution at Steady State (Vss/F)
17. Phase 1b: Apparent Terminal Rate Constant (λ z)
18. Phase 1b: Apparent Terminal Half-Life (t1/2)
19. Percentage of subjects with death with reasons within 30 (±3) days after the last dose of study drug
20. Percentage of subjects with abnormalities in safety laboratory tests as graded by NCI-CTCAE (Version 4.0)
21. Percentage of subjects with abnormalities incl. vital signs, 12-lead ECG changes, physical examination, body weight, and Eastern Cooperative Oncology Group (ECOG) PS.
22. Health related quality of life (HRQoL)
23. Time-to-Symptom Progression (TTSP) measured by Lung Cancer Symptom Scale (LCSS). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1- Time from randomiz. to death or up to 8 mo whichever occur first
2- Time from 1st drug adm. to death or up to 8 mo whichever occur 1st
3- Time from random. to death or up to 10 mo whichever occur 1st
4- endpoint number 7 and 8: Every 6 wks until Wk 72 and every 12 weeks after Wk 72 til radiol. documented PD, death, end of trial, or starting a new treatment, whichever occurs first
5- Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 h post dose on D 1 and 15 of Cycle 1
6- 0 up to D 30 after the last dose 7 to 18- Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 h post dose on D 1 and 15 of Cycle 1
19- 30 days after the last dose
20, and 21- 0 up to Day30 after the last dose
22 and 23- D 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 15, 17 and every 4 cycles thereafter until PD, and end of treatment |
|
| 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 | No |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| to determine the recomended Phase II dose |
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| pemetrexed + cisplatin/carboplatin |
|
| 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 | 2 |
| 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 |
| Austria |
| Bosnia and Herzegovina |
| Bulgaria |
| Canada |
| China |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Democratic People's Republic of |
| Malaysia |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Singapore |
| Slovakia |
| Slovenia |
| Spain |
| Taiwan |
| United Kingdom |
| 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 in Phase II when death has been reported for two thirds of the subjects |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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