non-small cell lung cancer with MET exon 14 skipping mutations MedDRA version: 20.1 Level: LLT Classification code 10025048 Term: Lung cancer non-small cell recurrent System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10025054 Term: Lung cancer non-small cell stage IIIB System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10025055 Term: Lung cancer non-small cell stage IV System Organ Class: 100000004864
Conditions
Interventions
Product Name: capmatinib
Product Code: INC280
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Capmatinib
Current Sponsor code: INC280
Concentration unit: mg milligram(s)
Concentration typ
Sponsors
Novartis Pharma AG
Eligibility
Sex/Gender
All
Inclusion criteria
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 MET?ex14 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
Exclusion criteria
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,
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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 ;Secondary Objective: 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 • To assess the overall survival • To evaluate patient reported outcomes 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 Both parts: • To evaluate the PK of capmatinib and spartalizumab • To evaluate the prevalence and incidence of immunogenicity of spartalizumab plus capmatinib;Primary end point(s): Run-in part: Overall Response Rate (ORR) by Blinded Independent Review Committee (BIRC) as per RECIST 1.1 Randomized part: Progression Free Survival (PFS) by BIRC as per RECIST 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key Secondary Objective: 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 • ORR by investigator as per RECIST 1.1 • Disease Control Rate (DCR), Duration of Response (DOR), PFS, and Time to Response (TTR) by BIRC and investigator assessment as per RECIST 1.1 • OS • 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 QLQ-C30 as secondary PRO variables of interest. 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 QLQ-C30 as secondary PRO variables of interest. Both parts: • Concentrations and derived PK parameters of capmatinib and spartalizumab • Antidrug antibody (ADA) prevalence at baseline and ADA incidence on treatment with spartalizumab;Timepoint(s) of evaluation of this end point: throughout the study | — |
Countries
Argentina, Austria, Belgium, Brazil, Canada, China, France, Germany, India, Italy, Japan, Korea, Republic of, Portugal, Romania, Russian Federation, Spain, United States
Contacts
Public ContactInformation&Communication Médicales
Novartis Pharma S.A.S
Outcome results
None listed