E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
non-small cell lung cancer |
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E.1.1.1 | Medical condition in easily understood language |
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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 evaluate the efficacy of capmatinib plus pembrolizumab in comparison to pembrolizumab alone |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the anti-tumor activity of capmatinib plus pembrolizumab in comparison to pembrolizumab alone
• To characterize the safety profile of capmatinib plus pembrolizumab and pembrolizumab alone
• To characterize the pharmacokinetics of capmatinib and pembrolizumab
• To evaluate the prevalence and incidence of immunogenicity of pembrolizumab
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Histologically confirmed and documented locally advanced stage III (not candidates for surgical resection or definitive chemo-radiation) or stage IV (metastatic) NSCLC (per AJCC/IASLC v.8) for treatment in the first-line setting
- Treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy (other than immunotherapies) is allowed as long as therapy was completed at least 6 months prior to the diagnosis of advanced or metastatic disease.
• Histologically or cytologically confirmed diagnosis of NSCLC that is both EGFR wild type status and ALK- negative rearrangement status:
- Patients with NSCLC of pure squamous cell histology can enter screening without EGFR mutation or ALK rearrangement testing or result; however, patients with pure squamous cell histology who are known to have EGFR mutations in exons 19 or 21 or ALK rearrangements will be excluded.
• Have an archival tumor sample or newly obtained tumor biopsy with high PD-L1 expression (TPS≥ 50%) determined by IHC using FDA approved PD-L1 IHC 22C3 PharmDx assay at a local laboratory or at a Novartis designated central laboratory.
- The archival samples must be most recently available FFPE block or cut tissue sections from the block. Tissue sections must NOT be older than 5 months from the time of sectioning. Archival samples obtained prior to any systemic anti-neoplastic therapy (such as adjuvant therapy) will NOT be acceptable.
- If local laboratory testing of PD-L1 as described above is not available, a newly obtained tumor biopsy or an archival tumor sample is required to confirm the eligibility.
• ECOG performance status ≤ 1
• Have at least 1 measurable lesion by RECIST 1.1; a previously irradiated lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation
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E.4 | Principal exclusion criteria |
1. Prior treatment with a MET inhibitor or HGF-targeting therapy
2. Prior immunotherapy (e.g. anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways).
3. Have known hypersensitivity to any of the excipients of capmatinib (crospovidone, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, magnesium stearate, colloidal silicon dioxide, and various coating premixes).
4. History of severe hypersensitivity reactions to other monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction.
5. Have untreated symptomatic central nervous system (CNS) metastases. Subjects are eligible if CNS metastases have been adequately treated with radiotherapy or surgery and remained stable for >2 weeks after treatment. The subjects must have been off steroids 7 days prior to study treatment
6. Presence or history of a malignant disease, other than NSCLC, that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.
7. 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).
8. Clinically significant, uncontrolled heart diseases.
9. Prior palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment.
10. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 weeks for resection of brain metastases) to starting study treatment or who have not recovered from side effects of such procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy are not counted as major surgery and subjects can be enrolled in the study ≥ 1 week after the procedure.
11. Impairment of GI function or GI disease that may significantly alter the absorption of capmatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
12. Concomitant medication(s) with a “Known Risk of Torsades de Point” per www.qtdrugs.org that cannot be discontinued or replaced by safe alternative medication.
13. Receiving treatment with strong inducers of CYP3A4 that cannot be discontinued at least 1 week prior to the start of treatment with capmatinib and for the duration of the study.
14. Systemic chronic steroid therapy (>10 mg/day prednisone or equivalent) or any immunosuppressive therapy 7 days prior to planned date of first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
15. Participation in a prior investigational study (drug or device) within 30 days prior to first dose of study treatment or within 5-half lives of the investigational product, whichever is longer, or those who are expected to receive any other investigational drug or device during the conduct of the study.
16. Other severe, acute, or chronic medical or psychotic conditions or laboratory abnormalities that in the opinion of the investigator may increase subject's risk associated with study participation, or that may interfere with the interpretation of study results.
17. Have received or will receive a live vaccination within 4 weeks prior to first dose of study treatment. Seasonal flu vaccines that do not contain live vaccine are permitted.
18. Active hepatitis B or C:
• Active hepatitis B is defined by positive HBsAg and detectable HBV DNA level in serum by PCR-based method. Subjects with serologic evidence of chronic HBV infection but have an HBV viral load below the limit of quantification can be enrolled with concurrent viral suppressive therapy.
• Active hepatitis C is defined by quantitative HCV RNA results greater than the lower limits of detection of the assay.
19. Known history of testing positive for Human Immunodeficiency Virus (HIV) infections. For countries where known HIV status is mandatory: test HIV status during screening using a local test.
20. Active, known, or suspected autoimmune disease or documented history of autoimmune disease. Subjects with vitiligo, controlled type I diabetes mellitus on stable insulin, residual autoimmune-related hypothyroidism only requiring hormone replacement, or psoriasis not requiring systemic treatment are permitted.
21. to 24.: see protocol
25. Active infection requiring systemic intravenous therapy.
26. Known history of allogeneic tissue/organ transplantation.
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS) based on local investigator assessment as per RECIST 1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at primary analysis (once 50 subjects have experienced a PFS event) and at final analysis after completion of the study |
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E.5.2 | Secondary end point(s) |
• Objective response rate (ORR), disease control rate (DCR), time-to-response (TTR) and duration of response (DOR) based on local investigator assessment as per RECIST 1.1 and overall survival (OS)
• Incidence and severity of AEs and SAEs, AEs leading to dose interruption, dose reduction and dose discontinuation
• Pharmacokinetic parameters and concentration
• Antidrug antibodies (ADA) prevalence at baseline and ADA incidence on treatment of pembrolizumab
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
at primary analysis (once 50 subjects have experienced a PFS event) and at final analysis after completion 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 | Yes |
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 | 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 | 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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Australia |
Canada |
Hong Kong |
India |
Japan |
Malaysia |
Singapore |
Taiwan |
Thailand |
United States |
Belgium |
France |
Germany |
Greece |
Italy |
Netherlands |
Spain |
United Kingdom |
Czechia |
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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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The end of the study is defined as 30 months after the last subject’s date of randomization or when all enrolled subjects have died, withdrawn consent or been lost to follow up, whichever occurs earlier.
The disease and survival follow-up evaluations might not be completed if Novartis decides to stop enrollment prematurely. In such cases, end of study will be when the treatment period and the safety follow-up have been completed for all subjects. |
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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 | |
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 | 2 |