| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-small cell lung cancer with MET exon 14 skipping mutations |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025048 |
| E.1.2 | Term | Lung cancer non-small cell recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025054 |
| E.1.2 | Term | Lung cancer non-small cell stage IIIB |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025055 |
| E.1.2 | Term | Lung cancer non-small cell stage IV |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 evaluate the anti-tumor activity of capmatinib in combination with spartalizumab
Randomized part: To compare the efficacy of capmatinib in combination with spartalizumab versus capmatinib plus placebo
|
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Objective:
Randomized part: To compare overall survival of capmatinib plus
spartalizumab versus capmatinib plus placebo
Other Secondary Objectives:
Run-in part:
• To assess safety and tolerability of capmatinib plus spartalizumab
• To further evaluate the anti-tumor activity of capmatinib plus
spartalizumab
Randomized part
• To assess safety and tolerability of capmatinib plus spartalizumab
versus capmatinib plus placebo
• To further evaluate the anti-tumor activity of capmatinib plus
spartalizumab versus capmatinib plus placebo
• To evaluate patient reported outcomes of capmatinib plus
spartalizumab versus capmatinib plus placebo
• To evaluate the prevalence and incidence of immunogenicity of
spartalizumab plus capmatinib
Both parts:
• To evaluate the PK of capmatinib and spartalizumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to understand and voluntarily sign the Informed Consent Form (ICF) and ability to comply with the study visit schedule and the other protocol requirements. Written informed consent must be obtained prior to any study specific procedures that are not part of standard of care. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness.
2. Male or female patients must be ≥ 18 years of age.
3. Histologically or cytologically confirmed and documented stage IIIB, IIIC or IV (per American Joint Committee on Cancer (AJCC) staging system version 8), unresectable, squamous or non-squamous NSCLC which is in addition:
a. harboring METΔex14 mutations, as determined by central pre-screening assessment performed at a Novartis designated laboratory, if not previously determined locally (only local assays agreed by Novartis will be accepted).
b. Negative for any mutations that are known to sensitize to EGFR inhibitors, such as exon 19 deletions or L858R substitution
c. Negative for ALK rearrangements
Note: Patients with NSCLC of pure squamous cell histology can enter the study 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.
4. Have an archival tumor sample or newly obtained tumor biopsy.
a. The archival samples must be most recently available FFPE block or cut tissue sections from the block.
b. Patients must be suitable and willing to undergo study-required biopsies if there is no archival sample available.
5. Patients must not have received any systemic therapy for advanced/metastatic disease (stage IIIB, IIIC or IV NSCLC). Neo-adjuvant and adjuvant systemic therapies are permitted if relapse occurred > 12 months from the end of therapy.
6. At least one measurable lesion as defined by RECIST 1.1 as per investigator assessment.
7. Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (Common Terminology Criteria for Adverse Events [CTCAE] v 5.0). Patients with any grade of alopecia are allowed to enter the study.
8. Patients must have adequate organ function including the following laboratory values at the screening visit:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support
• Platelets ≥75 x 109/L
• Hemoglobin (Hgb) > 9 g/dL
• Calculated creatinine clearance (using Cockcroft-Gault formula, see Appendix 4) ≥ 45 mL/min
• Total bilirubin < 1.5 x Upper Limit of Normal (ULN)
• Aspartate transaminase (AST) < 3 x ULN, except for patients with liver metastasis, who can be included if AST < 5 x ULN
• Alanine transaminase (ALT) < 3 x ULN, except for patients with liver metastasis, who can be included if ALT < 5 x ULN
• Alkaline phosphatase (ALP) < 5 x ULN
• Asymptomatic serum amylase increased < grade 2. Patients with grade 1 or grade 2 serum amylase increased at the beginning of the study must be confirmed to have no signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
• Serum lipase < 1.5 x ULN
9. Eastern Cooperative Oncology Group (ECOG Performance Status (PS) of 0 or 1.
10. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
11. For subjects of Part 2 only: Patients must have known PD-L1 tumor expression status as determined by IHC using the Dako PD-L1 IHC 22C3 pharmDx assay at a local laboratory or at a Novartis designated central laboratory.
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|
| E.4 | Principal exclusion criteria |
1. Prior treatment with a PD-1/PD-L1 inhibitor, MET inhibitor or HGF inhibitor.
2. Patients with 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).
3. 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.
4. Presence of symptomatic CNS metastases, or CNS metastases that require local CNS directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids 2 weeks prior to study entry. Patients with treated symptomatic brain metastases should be neurologically stable (for ≥ 4 weeks post-treatment and prior to study entry) and at a dose of ≤ 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
5. Presence or history of carcinomatous meningitis.
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 criterion include the following: completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.
7. Impaired cardiac function or clinically significant cardiac disease (for details see protocol)
8. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting study treatment or patients who have not recovered from radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to starting study treatment or patients who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment is allowed.
9. 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 will not be counted as major surgery and patients can start study treatment ≥ 1 week after the procedure.
10. Patients receiving:
• strong inducers of CYP3A4 that cannot be discontinued at least 1 week prior to the start of study treatment and for the duration of the study,
• medications with a “Known Risk of Torsades de Pointes” per www.qtdrugs.org that cannot be discontinued or replaced by safe alternative medication,
• hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), thrombopoietin mimetics or erythroid stimulating agents in the last 2 weeks prior to start of study treatment. If thrombopoietin mimetics or erythroid stimulating agents were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained.
• live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
• systemic chronic steroid therapy (>10mg/day prednisone or equivalent) or any other immunosuppressive therapy within 7 days prior to planned date of first dose of study treatment. Note: Topical, inhaled, nasal and ophthalmic steroids are allowed.
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. Unable or unwilling to swallow tablets as per dosing schedule.
13. Active, known or suspected autoimmune disease or a documented history of autoimmune disease. Note: Patients with vitiligo, controlled type I diabetes mellitus on stable insulin dose, residual autoimmune-related hypothyroidism only requiring hormone replacement or psoriasis not requiring systemic treatment are permitted
14. History of allogenic bone marrow or solid organ transplant.
15. Presence or history of interstitial lung disease, non-infectious pneumonitis or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
16. Human Immunodeficiency Virus (HIV) infection. Note: Positive HIV test at screening where locally required.
17. Active HBV or HCV infection. Patients whose disease is controlled under antiviral therapy are eligible.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Run-in part: Overall Response Rate (ORR) by investigator assessment as
per RECIST 1.1
Randomized part: Progression Free Survival (PFS) by BIRC as per
RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
ORR: when all subjects have been treated for at least 16 weeks or have discontinued earlier, and at final analysis
PFS: interim analysis when approximately 145 PFS events (75% information fraction) have been observed and all subjects have been randomized to the study; primary analysis when 193 PFS events have been observed
|
|
| E.5.2 | Secondary end point(s) |
Key Secondary Objective:
Randomized part:
Overall survival (OS)
Other Secondary Objectives:
Run-in part:
• Safety: incidence and severity of AEs and SAEs, changes in laboratory
values, vital signs and ECGs. Any clinically significant lab, vital signs,
ECG abnormalities will be captured as an AE
• Tolerability: dose interruptions, reductions, and dose intensity
• Disease Control Rate (DCR) and PFS by investigator assessment as per
RECIST 1.1
Randomized part:
• Safety: incidence and severity of AEs and SAEs, changes in laboratory
values, vital signs and ECGs. Any clinically significant lab, vital signs, ECG abnormalities will be captured as an AE
• Tolerability: dose interruptions, reductions, and dose intensity
• PFS by investigator assessment as per RECIST 1.1
• DCR, DOR, ORR and TTR by BIRC and investigator assessment as per
RECIST 1.1
• Change from baseline in EORTC QLQ-C30, QLQ-LC13 and EQ-5D-5L
• Time to definitive 10 points deterioration symptom scores for pain in
chest, coughing and dyspnea per QLQ-LC13 questionnaire as three
primary PRO variables of interest and time to definitive deterioration in
global health status/QoL, shortness of breath and pain per EORTC QLQC30
as secondary PRO variables of interest.
• Antidrug antibody (ADA) prevalence at baseline and ADA incidence on
treatment with spartalizumab
Both parts:
• Concentrations and derived PK parameters of capmatinib and
spartalizumab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| throughout the study / at protocol defined time points |
|
| 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 | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| Brazil |
| Canada |
| China |
| India |
| Japan |
| Korea, Republic of |
| United States |
| Austria |
| France |
| Romania |
| Spain |
| Germany |
| Italy |
| Belgium |
| Portugal |
| Russian Federation |
|
| 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
|
LVLS, unless another clinical study or an alternative treatment option
becomes available to continue the provision of capmatinib, and all
subjects ongoing are transferred to that clinical study or alternative
treatment option. For subjects who had received at least one dose of
spartalizumab, all required safety assessments up to 150 days from the
last dose of spartalizumab treatment must be completed and at least 2
post-baseline tumor assessments are obtained. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 11 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 8 |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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