Clinical study of oral cMET inhibitor INC280 in adult patients with advanced non-small cell lung cancer
- 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-SE
- Lead Sponsor
- ovartis Pharma Services AG
- 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 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 (Lindeman et al 2013),
b.AND ALK-negative rearrangement. This should have been assessed as part of the patient standard of care by a validated test,
c.AND (as determined by central assessment at a Novartis designated laboratory) either:
Cohort 1: Patients with cMET GCN = 6, including: 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, or
Cohort 3: Patients with cMET GCN < 4, or
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 Subcohorts (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 or cohort 7 treatment naïve patients with cMET mutations regardless of cMET GCN.
4.To be eligible 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). To be eligible in cohort 6 patients must have failed one prior line of systemic therapy for advanced/metastatic disease
(stage IIIB or IV NSCLC). To be eligible in cohort 5 and cohort 7: patients must not have received any systemic therapy for advanced/metastatic disease.
5.At least one measurable lesion as defined by RECIST 1.1.
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). ECOG performance status (PS) of 0 or 1.
Please refer to protocol for further details and additional exclusion criteria.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.
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 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.
• 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.
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:
• Strong inducers of CYP3A4
12. Impairment of GI function or GI disease that may significantly alter 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 tumor associated 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 non enzyme-inducing anticonvulsants are eligible
16. For cohort 1 to 4 and cohort 6 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 seve
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 /sub-cohort;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 Objective: To evaluate duration of response (DOR) as assessed by BIRC, by<br>cohort/sub-cohort<br>To evaluate ORR and DOR by investigator assessment, by cohort/subcohort<br>To evaluate time to response (TTR), disease control rate (DCR) and<br>progression-free survival (PFS) by investigator and by BIRC assessment, by cohort/sub-cohort<br>To evaluate overall survival (OS), by cohort/sub-cohort<br>To evaluate INC280 safety profile as monotherapy in NSCLC patients <br>To characterize the pharmacokinetics of INC280 and metabolite CMN288
- Secondary Outcome Measures
Name Time Method