E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
EGFR mutated, T790M negative NSCLC |
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E.1.1.1 | Medical condition in easily understood language |
Type of lung cancer, called non-small cell lung cancer (NSCLC) with certain genetic alterations (called mutations) of a gene called epidermal growth factor receptor (EGFR) |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Run-in part: to confirm the recommended dose of capmatinib in combination with osimertinib for the randomized part
Randomized part: to compare the progression-free survival (PFS) of capmatinib in combination with osimertinib versus platinum-based doublet chemotherapy |
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E.2.2 | Secondary objectives of the trial |
Key secondary objective:
To compare the Overall Response Rate (ORR) of capmatinib in combination with osimertinib
To compare the overall intracranial response rate (OIRR) of capmatinib in combination with osimertinib
Other secondary objectives:
To characterize the safety and tolerability of capmatinib in combination with osimertinib
To characterize the pharmacokinetics of capmatinib, osimertinib, and osimertinib's active metabolites (AZ5104 and AZ7550)
To assess the tumor response of capmatinib in combination with osimertinib
To assess PFS2 (PFS after next-line of treatment)
To evaluate the association between MET amplification status as measured in ctDNA at baseline with PFS and ORR
To evaluate overall survival (OS) in participants treated with capmatinib in combination with osimertinib
To evaluate the safety profile of capmatinib in combination with osimertinib
To assess intracranial anti-tumor activity of capmatinib in combination with osimertinib |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent must be obtained prior to participation in the study.
2. Adult ≥ 18 years old at the time of informed consent.
3.Stage IIIB/IIIC (not amenable to curative surgery, chemoradiation or radiation) or stage IV NSCLC at the time of study entry.
4.Histologically or cytologically confirmed diagnosis of NSCLC with EGFR mutations known to be associated with EGFR TKI sensitivity, EGFR T790M negative, and MET gene amplification defined as Gene Copy Number (GCN) ≥ 5 per central Novartis designated laboratory.
5. Mandatory provision of a formalin-fixed, paraffin embedded tumor tissue sample (a newly obtained tumor sample, or archival tumor block/slides taken after progression on prior line of EGFR TKI.
6.Participants must have progressed on one prior line of therapy (either to 1st/2nd generation EGFR TKIs, osimertinib, or other 3rd generation EGFR TKIs used per local standard of care) for advanced/metastatic disease and must be eligible candidates for platinum (cisplatin or carboplatin) - pemetrexed doublet based chemotherapy.
7. At least one measurable lesion as defined by RECIST 1.1.
8. ECOG performance status (PS) of 0 or 1.
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E.4 | Principal exclusion criteria |
1. Prior treatment with any MET inhibitor or HGF-targeting therapy.
2. Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms
3. Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention)
4. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome
5. Treatment with a prior 1st or 2nd generation EGFR TKIs (e.g. erlotinib, gefitinib, afatinib, dacomitinib) osimertinib or another third generation EGFR TKIs such as almonertinib and furmonertinib within 14 days or approximately 5x half-life, whichever is shorter, of the first dose of study treatment.
6. Unable or unwilling to swallow tablets as per dosing schedule
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E.5 End points |
E.5.1 | Primary end point(s) |
Run-in: Incidence of Dose Limiting Toxicities (DLT) during cycle 1 Randomized part: Progression-free survival (PFS) by BIRC as per RECIST 1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The interim analysis (IA) for futility is planned for PFS in this study when approximately 65 events have occurred (40% of total PFS events) at approximately 18.5 months from the date of first participant randomized in the randomized part of the study. A final analysis will be performed at the end of the study. |
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E.5.2 | Secondary end point(s) |
Run-in Part: • Safety: Incidence, type, and severity of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 5.00 including changes in laboratory values, vital signs, liver assessments and cardiac assessments; Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all drug components • Plasma PK concentrations and derived PK parameters • All calculated per RECIST 1.1 by investigator: Overall response rate (ORR), Duration of response (DOR), Time to response (TTR), Disease control rate (DCR), Progression free survival (PFS)
Randomized part: All calculated per RECIST 1.1, both by BIRC and investigator: • Overall response rate (ORR) • Overall intracranial response rate (OIRR) • Duration of response (DOR) • Time to response (TTR) • Disease control rate (DCR)
All calculated by investigator: • PFS2 (PFS after next-line of treatment)
The association between MET amplification status as measured in ctDNA at baseline with PFS and ORR by BIRC using RECIST 1.1 criteria
Characterize the pharmacokinetics of capmatinib, osimertinib, and osimertinib's active metabolites (AZ5104 and AZ7550) by assessing plasma PK concentrations
Overall Survival
Safety profile of capmatinib in combination with osimertinib
Change from baseline in European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13, QLQ-C30, EuroQoL-5 Dimension-5 Level/EQ-5D-5L, and NCCN Fact Brain Symptoms Index questionnaires
Intracranial anti-tumor activity in participants with Central Nervous System (CNS) lesions at baseline (e.g. Duration of intracranial response (DOIR), time to intracranial response (TTIR) and intracranial disease control rate (IDCR), all by BIRC as per RANO-BM criteria).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The interim analysis (IA) for futility is planned for PFS in this study when approximately 65 events have occurred (40% of total PFS events) at approximately 18.5 months from the date of first participant randomized in the randomized part of the study. A final analysis will be performed at the end of the study. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
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 |
Argentina |
Chile |
China |
Colombia |
Hong Kong |
India |
Israel |
Japan |
Korea, Republic of |
Malaysia |
Singapore |
Taiwan |
Thailand |
United States |
Viet Nam |
Austria |
France |
Lithuania |
Poland |
Bulgaria |
Romania |
Spain |
Germany |
Italy |
Croatia |
Hungary |
Portugal |
Russian Federation |
Slovenia |
United Kingdom |
Serbia |
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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
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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 | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |