Study of oral cMET inhibitor INC280 in patients with EGFR wild-type (wt), advanced non-small cell lung cancer (NSCLC)
- Conditions
- Advanced non-small cell ling cancerMedDRA version: 21.1Level: 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-IT
- Lead Sponsor
- OVARTIS FARMA S.P.A.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 456
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 wt. 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 wild-type 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 prescreening for cMET amplification and cMET mutation status (except for patients who are treatment-naïve potentially eligible for Sub-Cohorts 5a, 5b
and Cohort 7 or if molecular pre-screening will be performed by NGS and local status is not available). 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 ALK rearrangement negative. 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,
except for patients who are treatment-naïve potentially eligible for Sub- Cohorts 5a, 5b and Cohort 7; if local ALK testing is not available, patient
status will be determined centrally along with the cMET status. Patients with NSCLC of pure squamous cell histology can enter pre-screening without ALK
testing or result, however patients with pure squamous cell histology that are known to have ALK rearrangement will be excluded.
c. AND (as determined by central assessment at a Novartis designated laboratory) either:
Cohort 1: Pre-treated patients with cMET GCN = 6, including:
- Sub-cohort 1a: Patients with cMET GCN = 10, or
- Sub-cohort 1b: Patients with cMET GCN = 6 and < 10, or
Cohort 2: Pre-treated patients with cMET GCN = 4 and < 6, or Cohort 3: Pre-treated patients with cMET GCN < 4, or Cohort 4: Pre-treated patients with cMET mutations regardless of cMET GCN, or Cohort 5: Treatment-naïve patients with cMET dysregulation, including:
- Sub-cohort 5a: Patients with cMET GCN = 10, or
- Sub-cohort 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
Cohort 7: Treatment-naïve patients with cMET mutations regardless of cMET GCN
cMET (and ALK, if applicable) 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.
For other inclusion criteria see the protocol
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 255
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 201
1. Prior treatment with crizotinib, or any other cMET or HGF inhibitor
2. Patients with known hypersensitivity to any of the excipients of INC280 (crospovidone, mannitol, microcrystalline cellulose, povidone, sodium lauryl
sulfate, magnesium stearate, colloidal silicon dioxide, and various coating premixes)
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 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
8 Clinically significant, uncontrolled heart diseases such as:
- 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 ms (male patients), = 460 ms (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. 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
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:
- Strong inducers of CYP3A4
12. 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)
13. Unable or unwilling to swallow tablets as per dosing schedule
For other exclusion criteria see the protocol
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To demonstrate the antitumor activity of INC280, as measured by overall response rate (ORR) by Blinded Independent Review Committee (BIRC)<br>assessment, by cohort/sub-cohort;Secondary Objective: -To evaluate ORR and DOR by investigator assessment, by cohort/subcohort<br>- To evaluate time to response (TTR), disease control rate (DCR) and progression-free survival (PFS) by investigator and by BIRC assessment, by<br>cohort/sub-cohort<br>- To evaluate overall survival (OS), by cohort/sub-cohort<br>- To evaluate INC280 safety profile as monotherapy in NSCLC patients with advanced/metastatic disease<br>- To characterize the pharmacokinetics of INC280;Primary end point(s): Overall response rate (ORR) determined by blinded independent review committee 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 Secondary end point(s): 1. Duration of Response (DOR) assessed by BIRC per RECIST 1.1<br>2. ORR and DOR by investigator assessment<br>3. Time to Response (TTR) , Disease Control Rate (DCR) and Progression Free Survival (PFS) assessed both by BIRC and investigator:<br>4. Overall Survival (OS)<br>5. INC280 safety profile<br>6. INC280 pharmacokinetic evaluation;Timepoint(s) of evaluation of this end point: as defined per protocol