Clinical study of oral cMET inhibitor INC280 in adult patients with advanced non-small cell lung cancer who have received one or two prior lines of therapy

Conditions: Advanced non-small cell ling cancer
MedDRA version: 18.0Level: PTClassification code 10061873Term: Non-small cell lung cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2014-003850-15-ES

Lead Sponsor: ovartis Farmacéutica, S.A.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 207

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. 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 (as determined by central assessment at a Novartis designated laboratory) either:
? Cohort 1: Patients with cMET GCN ? 6, or
? Cohort 2: Patients with cMET GCN ? 4 and < 6
? Cohort 3: Patients with cMET GCN < 4
cMET testing may be performed while patient is still receiving anti-cancer therapy. However, the patient can only be screened for the main study once the patient has discontinued the last prior systemic treatment due to either disease progression or intolerance.
4. Patients must have received one or two prior lines of systemic therapy for advanced/metastatic disease (stage IIIB or IV NSCLC). 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.
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, except for patients with Gilbert?s syndrome, who may only be included if total bilirubin ? 3.0 x ULN or direct bilirubin ? 1.5 x ULN
? Aspartate transaminase (AST) ? 3 x ULN, except for patients with liver metastasis, who are included if AST ? 5 x ULN
? Alanine transaminase (ALT) ? 3 x ULN, except for patients with liver metastasis, who are only included if ALT ? 5 x ULN
? Alkaline phosphatase (ALP) ? 5.0 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-a

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 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
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 include the following: completely resected basal cell and squamous cell skin cancers, indolent malignancies that currently do not require treatment, and completely resected carcinoma in situ of any type
7. 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 > 480 msec
8. 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
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 INC280 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 be enrolled in the study ? 1 week after the procedure
10. 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:
? Strong and moderate inhibitors of CYP3A4
? Strong inducers of CYP3A4
? Proton pump inhibitors (PPI)
11. Impairment of GI function or GI disease that may significantly alter the absorption of INC280 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome)
12. Unable or unwilling to swallow tablets as per dosing schedule
13. Patients receiving unstable or increasing doses of corticosteroids. If patients 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 first dose of INC280
14. Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be discontinued at least

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the antitumor activity of INC280, as measured by overall response rate (ORR) by Blinded Independent Review Committee (BIRC) assessment, by cohort;Secondary Objective: To evaluate duration of response (DOR) as assessed by BIRC, by cohort<br>To evaluate ORR and DOR by investigator assessment, by cohort<br>To evaluate time to response (TTR), disease control rate (DCR) and progression-free survival (PFS) by investigator and by BIRC assessment, by cohort<br>To evaluate overall survival (OS), by cohort<br>To evaluate INC280 safety profile as monotherapy in NSCLC patients who have received one or two prior lines of systemic therapy for advanced/metastatic disease<br>To characterize the pharmacokinetics of INC280;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;Timepoint(s) of evaluation of this end point: as defined per protocol

Secondary Outcome Measures

Name	Time	Method

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