E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 the MET gene |
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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 |
To compare the efficacy of capmatinib versus docetaxel |
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E.2.2 | Secondary objectives of the trial |
Key secondary objective:
To compare the Overall Response Rate (ORR) of capmatinib and docetaxel
Other secondary objectives:
To assess the antitumor activity of capmatinib versus docetaxel
To evaluate Overall Survival (OS) in participants treated with capmatinib versus docetaxel
To evaluate the safety profile of capmatinib versus docetaxel
To characterize the pharmacokinetics of capmatinib in this study population
To assess the effect of capmatinib versus docetaxel on patient-reported disease-related symptoms, functioning, and health-related quality of life (HRQoL)
To assess intracranial anti-tumor activity of capmatinib and docetaxel in participants with Central Nervous System (CNS) lesions at baseline by BIRC
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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 surgery, radiation or multi modality therapy) or IV NSCLC at the time of study entry.
4. Histologically or cytologically confirmed diagnosis of NSCLC that is: • EGFR wt. This should have been assessed as part of the participant’s standard of care by a validated test for EGFR mutations as per local guidelines. • AND ALK rearrangement negative. This should have been assessed as part of the participant’s standard of care by a validated test. •AND has METΔex14 mutation as determined by Novartis-designated central laboratory or by locally performed, tissue-based test, validated according to local regulation, from a Clinical Laboratory Improvement Amendments (CLIA)-certified US laboratory or an accredited local laboratory outside of the US. The positive METΔex14 mutation result as determined per local test must be documented in the participant's source documents and in the CRF prior to entering main screening. 5. Mandatory provision of a formalin-fixed, paraffin embedded tumor tissue sample (archival tumor block or slides, or a newly obtained tumor sample)with quality and quantity sufficient to allow the confirmation of MET Δex14 mutation status (as defined in the study [laboratory manual]). This pertains to all participants, including those who have a MET Δex14 mutation result from a local test. Tumor samples must contain at least 10% tumor content.
6. Participants must have progressed on one or two prior lines of systemic therapy for advanced/metastatic disease (stage IIIB/IIIC [not candidates for surgery, radiation or multi modality therapy] or IV NSCLC), and must be docetaxel naive and candidates for single agent chemotherapy (docetaxel). Treatment failure is defined as documented disease progression or intolerance to treatment, however participants must have progressed on or after the last therapy before study entry.
7. ECOG performance status (PS) of 0 - 1.
8. Participants must have a life expectancy of at least 3 months.
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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. If participants are on corticosteroids for endocrine deficiencies or tumor-associated symptoms other than CNS related, dose must have been stabilized (or decreasing) for at least 5 days before Cycle 1 Day 1.
3. Participants with known druggable molecular alterations (such as ROS1 translocation or BRAF mutation, etc.) which might be a candidate for alternative targeted therapies as applicable per local regulations and treatment guidelines.
4. Participants with known druggable molecular alterations (such as ROS1 and RET rearrangement, BRAF mutation, KRAS mutation, NTRK fusion, etc.) which might be a candidate for alternative targeted therapies.
5. Substance abuse, active infection or other severe, acute, or chronic medical or psychotic conditions or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation, or that may interfere with the interpretation of study results. Active infections include but are not limited to Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). Screening for known chronic conditions is not required. Participants with known serologic evidence of chronic HBV or HCV infection, whose disease is controlled under antiviral therapy, according to local regulations are eligible. Participants with known history of testing positive for human immunodeficiency virus (HIV) infection, and with a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last 12 months prior to the first dose of study treatment must be excluded. HIV participants at high risk or with history of uncontrolled opportunistic infection must also be excluded. To ensure that effective anti-retroviral treatment (ART) is tolerated and that toxicities are not confused with investigational drug toxicities, trial participants should be on established ART for at least four weeks prior to enrollment, they should have the disease under control and suppressed viral loads defined as per local guideline. HIV participants co-infected with hepatitis virus must also be excluded.
6. For female participants treated with docetaxel, a highly effective contraception must be used during the study. Local prescribing information relating the time limits for such precautions and any additional restrictions will be followed. Highly effective contraception methods include: - Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. - Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), or total hysterectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment. - Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant. - Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.
7. Participants who received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, TY21a typhoid vaccines and COVID-19 vaccines) within 30 days prior to the first dose of study treatment.
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E.5 End points |
E.5.1 | Primary end point(s) |
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 primary analysis and safety analyses will be performed after observing approximately 62 PFS events as assessed by BIRC. A final analysis will be performed at the end of the study. |
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E.5.2 | Secondary end point(s) |
All calculated per RECIST 1.1, both by BIRC and investigator: • Overall response rate (ORR) • Duration of response (DOR) • Time to response (TTR) • Disease control rate (DCR)
All calculated per RECIST 1.1, by investigator: • PFS
Overall Survival
Incidence of adverse events and serious adverse events, change in vital signs, laboratory results and ECG
Plasma concentrations
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) questionnaires
Time to symptom deterioration for chest pain, cough and dyspnea in the European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13 as well as global health status/QoLper QLQ-C30 questionnaire
Overall intracranial response rate (OIRR), duration of intracranial response (DOIR), time to intracranial response (TTIR), intracranial disease control rate (IDCR) by BIRC as per RANO-BM criteria
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analysis and safety analyses will be performed after observing approximately 62 PFS events as assessed by BIRC. 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 | No |
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 | 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) | 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 | No |
E.8.1.6 | Cross over | Yes |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 47 |
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 |
Brazil |
India |
Korea, Republic of |
Malaysia |
Russian Federation |
South Africa |
Thailand |
Viet Nam |
Belgium |
France |
Germany |
Hungary |
Italy |
Lithuania |
Portugal |
Netherlands |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 17 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |