| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced non-small cell ling cancer |
|
| 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 | 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) |
|
| 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 antitumor activity of INC280, as measured by overall
response rate (ORR) by Blinded Independent Review Committee (BIRC)
assessment, by cohort/sub-cohort |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate duration of response (DOR) as assessed by BIRC, by cohort/sub-cohort
To evaluate ORR and DOR by investigator assessment, by cohort/subcohort
To evaluate time to response (TTR), disease control rate (DCR) and progression-free survival (PFS) by investigator and by BIRC assessment, by cohort/sub-cohort
To evaluate overall survival (OS), by cohort/sub-cohort
To evaluate INC280 safety profile as monotherapy in NSCLC patients
To characterize the pharmacokinetics of INC280 and metabolite CMN288 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years
2. Stage IIIB or IV NSCLC (any histology) at the time of study entry,
3. Histologically or cytologically confirmed diagnosis of NSCLC that is:
a.EGFR wild-type. This should have been assessed as part of the patient standard of care by a validated test for EGFR mutations, as per the Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors from College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology (Lindeman et al 2013). The EGFR wt status (for exon 19 deletions and exon 21 L858R substitution mutations)
must be documented in the patient source documents before the patient can be consented for pre-screening for cMET amplification and cMET mutation status. Patients with NSCLC of pure squamous cell histology can enter pre-screening without EGFR mutation testing or result, however patients with pure squamous cell histology and are known to have EGFR mutations in exons 19 or 21 will be excluded,
b. AND ALKnegative rearrangement. This should have been assessed as part of the patient standard of care by a validated test. The ALK rearrangement negative status must be documented in the patient source documents before the patient can be consented for pre-screening for cMET amplification and cMET mutation status; if local ALK testing is not available patient status will be determined centrally along with the cMET status.
c. AND (as determined by central assessment at a Novartis designated
laboratory) either:
•Cohort 1: Patients with cMET GCN ≥ 6, or
•Sub-cohort 1a: Patients with cMET GCN of ≥10, or
•Sub-cohort 1b: Patients with cMET GCN of ≥ 6 and < 10, or
•Cohort 2: Patients with cMET GCN ≥ 4 and < 6
•Cohort 3: Patients with cMET GCN < 4
•Cohort 4: Patients with cMET mutation regardless of cMET GCN or
•Cohort 5 : Patients treatment-naïve with cMET dysregulation for advanced/metastatic disease in 2 Sub-cohorts (5a - patients with cMET GCN of ≥10 or 5b - patients with cMET mutations regardless of cMET GCN) or cohort 6 Pre-treated patients with either cMET GCN ≥ 10 without cMET mutations or cMET mutations regardless of cMET GCN.
4.To be ligible in cohort 1 to 4 : Patients must have failed one or two prior lines of systemic therapy for advanced/metastatic disease (stage IIIB or IV NSCLC). Treatment failure is defined as documented disease progression or intolerance to treatment. Maintenance therapy given after first line chemotherapy will be considered as part of the first line if given to patients with documented response or stable disease before starting the maintenance therapy. Neoadjuvant and adjuvant systematic therapies will count as one prior line of treatment if relapse occurred within 12 months from the end of the neo-adjuvant or adjuvant systemic therapy. To be eligible in cohort 5 : patients must not have received any systemic therapy for advanced/metastatic disease.Neoadjuvant and
adjuvant systematic therapies will count as one prior line of treatment if relapse occurred > 12 months from the end of the neo-adjuvant or adjuvant systemic therapy.
5. At least one measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation.
6. Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03). Patients with any grade of alopecia are allowed to enter the study.
7. 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) ≥ 45 mL/min
• Total bilirubin ≤ 1.5 x ULN,
• Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver metastasis, who may only be included if AST ≤ 5 x ULN
• Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver metastasis, who may only be included if ALT ≤ 5 x ULN
• Alkaline phosphatase (ALP) ≤ 5 x ULN
• Asymptomatic serum amylase ≤ grade 2. Patients with grade 1 or grade 2 serum amylase 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 ≤ ULN
• Fasting plasma glucose ≤ 175 mg/dL (≤ 9.7 mmol/L)
• Patients must have the following laboratory values within the laboratory normal limits or corrected to within normal limits with supplements during screening: • Potassium, Magnesium, Phosphorus, Total calcium (corrected for serum albumin)
8. ECOG performance status (PS) of 0 or 1. 9. Willing and able to comply with scheduled visits, treatment plan and laboratory tests
Please refer to protocol for further details |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with crizotinib, or any other cMET or HGF inhibitor
2. Patients with known hypersensitivity to any of the excipients of INC280
3. Patients with characterized EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 mutations.
4. Patients with characterized ALK-positive rearrangement
5. Patients 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
6. Presence or history of carcinomatous meningitis
7. Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy ithin 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
8. Clinically significant, uncontrolled heart diseases.
• Unstable angina within 6 months prior to screening
• Myocardial infarction within 6 months prior to screening
• History of documented congestive heart failure (New York Heart Association functional classification III-IV)
• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening
• Ventricular arrhythmias
• Supraventricular and nodal arrhythmias not controlled with medication
• Other cardiac arrhythmia not controlled with medication
• QTcF ≥ 450 msec (male patients), ≥ 460 msec (female patients) on the screening ECG (as mean of triplicate ECG)
9. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting INC280 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 INC280 or patients who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting INC280 is allowed
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 INC280 or who have not recovered from side effects of such procedure.
11. Patients receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to the start of treatment with INC280 and for the duration of the study: the absorption of INC280 13. Unable or unwilling to swallow tablets as per dosing schedule 14. Patients receiving unstable or increasing doses of corticosteroids. If patients are on corticosteroids for endocrine deficiencies or tumorassociated symptoms other than CNS related, dose must have been stabilized (or decreasing) for at least 5 days before first dose of INC280 15. Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be discontinued at least 1 week before first dose of INC280, and for the duration of the study. Patients on nonenzyme-inducing anticonvulsants are eligible 16. For cohort 1 to 4 and cohort 6 Previous anti-cancer previous anti-cancer and investigational agents within 4 weeks or ≤ 5 x half-life of the agent (whichever is longer) before first dose of INC280. If previous treatment is a monoclonal antibody, then the treatment must be discontinued at least 4 weeks before first dose of INC280. If previous treatment is an oral targeted agent, then the treatment must be discontinued at least 5 x half-life of the agent before the first dose of INC280. 17. 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 18. Any other condition that would, in the Investigator's judgment, contraindicate patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection (including active hepatitis B and C), inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc 19. Pregnant or nursing (lactating) women 20. Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing and for 7 days after stopping treatment 21 Sexually active males unless they use a condom during intercourse while taking drug and for 7 days after stopping treatment and should not father a child in this period 22 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) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR, proportion of patients with a best overall response defined as complete response or partial response (CR+PR) by BIRC assessment per RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. DOR, calculated as the time from the date of the first documented CR or PR by BIRC per RECIST 1.1 to the first documented progression or death due to any cause for patients with PR or CR
2. ORR (CR+PR) and DOR per RECIST 1.1 by investigator assessment
3. All calculated per RECIST 1.1, both by BIRC and investigator:
• TTR, calculated as the time from first dose of INC280 to first documented response (CR+PR) for patients with PR or CR
• DCR, calculated as the proportion of patients with best overall response of CR, PR, or SD
• PFS, defined as time from first dose of INC280 to progression or death due to any cause
4. OS, defined as time from first dose of INC280 to death due to any cause
5. Incidence of adverse events and serious adverse events, change in vital signs, laboratory results (hematology, blood chemistry, and urinalysis) and ECG
6. Plasma concentration-time profiles and pharmacokinetic parameters estimated by non-compartmental analysis or population PK modeling |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 |
| Israel |
| Japan |
| Lebanon |
| Mexico |
| Singapore |
| United States |
| Russian Federation |
| Turkey |
| Austria |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Sweden |
| Korea, Republic of |
| Taiwan |
|
| 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
|
The end of study is defined as the earliest occurrence of one of the following:
- All patients have died or discontinued from the study
- Another clinical study becomes available that can continue to provide INC280 in this patient population and all patients ongoing are eligible to be transferred to that clinical study
- INC280 is commercially available and ongoing patients are able to obtain reimbursement of commercial supply |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
Print
