Clinical Trials List
Protocol NumberCINC280A2201
NCT Number(ClinicalTrials.gov Identfier)NCT02414139
2016-02-22 - 2022-12-22
Phase II
Recruiting5
ICD-10C34
Malignant neoplasm of bronchus and lung
A phase II, multicenter, four-cohort study of oral cMET inhibitor INC280 in adult patients with EGFR wild-type (wt), advanced non-small cell lung cancer (NSCLC) who have received one or two prior lines of systemic therapy for advanced/metastatic disease
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Trial Applicant
NOVARTIS (TAIWAN) CO., LTD.
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Sponsor
Novartis Pharmaceuticals
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
Audit
None
Co-Principal Investigator
- Chih-Hung Chen Division of Hematology & Oncology
- Chih-Hung Chen Division of Hematology & Oncology
- Chien-Ying Liu Division of Hematology & Oncology
- Chih-Liang Wang Division of Hematology & Oncology
- Ming-Mo Hou Division of Hematology & Oncology
- 吳振德 Division of Radiology
- Cheng-Ta Yang Division of Hematology & Oncology
- Shih-Hong Li Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
1 Recruiting
Audit
None
Co-Principal Investigator
- 林育麟 Division of Hematology & Oncology
- CHAO-CHI HO CHAO-CHI HO Division of General Internal Medicine
- Jih-Hsiang Lee Division of Hematology & Oncology
- 廖唯昱 Division of General Internal Medicine
- Chia-Chi Lin Division of Hematology & Oncology
- 陳冠宇 Division of General Internal Medicine
- James Chih-Hsin Yang Division of Hematology & Oncology
- JIN-YUAN SHIH Division of General Internal Medicine
- 許嘉林 Division of General Internal Medicine
The Actual Total Number of Participants Enrolled
0 Recruiting
Audit
None
Condition/Disease
Non-small Cell Lung Cancer
Objectives
A phase II study to evaluate antitumor activity of oral cMET inhibitor INC280 in adult patients with EGFR wild-type, advanced non-small cell lung cancer (NSCLC) as measured by overall response rate (ORR). The study will also evaluate safety and pharmacokinetics of INC280.
Test Drug
INC280
Active Ingredient
INC280
Dosage Form
tablet
Dosage
100mg/tablet, 200mg/tablet
Endpoints
Primary Outcome Measures :
1. Overall Response Rate (ORR) [ Time Frame: at least 18 weeks ]
Proportion of patients with a best overall response defined as complete response (CR) or partial response (PR) by Blinded Independent Review Committee (BIRC) assessment per RECIST 1.1
Secondary Outcome Measures :
1. Duration of Response (DOR) - Key Secondary [ Time Frame: at least 18 weeks ]
Calculated as the time from the date of the first documented CR or PR by Blinded Independent Review Committee (BIRC) per RECIST 1.1 to the first documented progression or death due to any cause for patients with PR or CR.
2. Overall Response Rate (ORR) [ Time Frame: at least 18 weeks ]
ORR (complete response (CR)+ partial response (PR)) per RECIST 1.1 by investigator assessment
3. Duration of Response (DOR) [ Time Frame: at least 18 weeks ]
DOR per RECIST 1.1 by investigator assessment
4. Time to Response (TTR) [ Time Frame: at least 18 weeks ]
TTR per RECIST 1.1 both by BIRC and investigator assessment
5. Disease Control Rate (DCR) [ Time Frame: at least 18 weeks ]
DCR per RECIST 1.1 both by BIRC and investigator assessment
6. Progression-free Survival (PFS) [ Time Frame: at least 18 weeks ]
PFS per RECIST 1.1 both by BIRC and investigator assessment
7. Overall Survival (OS) [ Time Frame: at least 18 weeks ]
OS, defined as time from first dose of INC280 to death due to any cause
8. Number of patients with incidence of adverse events and serious adverse events, change in vital signs, laboratory results (hematology, blood chemistry, and urinalysis) and ECG. [ Time Frame: at least 18 weeks ]
Safety of INC280
9. Cmax, Cmin and plasma concentration-time profiles of INC280 [ Time Frame: 6 weeks ]
Pharmacokinetics of INC280 and metabolite CMN288
1. Overall Response Rate (ORR) [ Time Frame: at least 18 weeks ]
Proportion of patients with a best overall response defined as complete response (CR) or partial response (PR) by Blinded Independent Review Committee (BIRC) assessment per RECIST 1.1
Secondary Outcome Measures :
1. Duration of Response (DOR) - Key Secondary [ Time Frame: at least 18 weeks ]
Calculated as the time from the date of the first documented CR or PR by Blinded Independent Review Committee (BIRC) per RECIST 1.1 to the first documented progression or death due to any cause for patients with PR or CR.
2. Overall Response Rate (ORR) [ Time Frame: at least 18 weeks ]
ORR (complete response (CR)+ partial response (PR)) per RECIST 1.1 by investigator assessment
3. Duration of Response (DOR) [ Time Frame: at least 18 weeks ]
DOR per RECIST 1.1 by investigator assessment
4. Time to Response (TTR) [ Time Frame: at least 18 weeks ]
TTR per RECIST 1.1 both by BIRC and investigator assessment
5. Disease Control Rate (DCR) [ Time Frame: at least 18 weeks ]
DCR per RECIST 1.1 both by BIRC and investigator assessment
6. Progression-free Survival (PFS) [ Time Frame: at least 18 weeks ]
PFS per RECIST 1.1 both by BIRC and investigator assessment
7. Overall Survival (OS) [ Time Frame: at least 18 weeks ]
OS, defined as time from first dose of INC280 to death due to any cause
8. Number of patients with incidence of adverse events and serious adverse events, change in vital signs, laboratory results (hematology, blood chemistry, and urinalysis) and ECG. [ Time Frame: at least 18 weeks ]
Safety of INC280
9. Cmax, Cmin and plasma concentration-time profiles of INC280 [ Time Frame: 6 weeks ]
Pharmacokinetics of INC280 and metabolite CMN288
Inclution Criteria
• Age ≥ 18 years
• Stage IIIB or IV NSCLC (any histology) at the time of study entry
• Histologically or cytologically confirmed diagnosis of NSCLC that is:
• 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. 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,
• AND ALK-negative 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; if local ALK testing is not available, patient status will be determined centrally along with the cMETstatus. 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.
• 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, or
• Cohort 3: Patients with cMET GCN < 4, or
• Cohort 4: 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.
• 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 1st line chemotherapy will be considered as part of the 1st line if given to patients with documented response or stable disease before starting the maintenance therapy. Neo-adjuvant and adjuvant systemic 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.
• 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.
• 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.
• 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 (≤ 9.8 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.
• Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
• Stage IIIB or IV NSCLC (any histology) at the time of study entry
• Histologically or cytologically confirmed diagnosis of NSCLC that is:
• 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. 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,
• AND ALK-negative 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; if local ALK testing is not available, patient status will be determined centrally along with the cMETstatus. 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.
• 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, or
• Cohort 3: Patients with cMET GCN < 4, or
• Cohort 4: 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.
• 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 1st line chemotherapy will be considered as part of the 1st line if given to patients with documented response or stable disease before starting the maintenance therapy. Neo-adjuvant and adjuvant systemic 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.
• 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.
• 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.
• 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 (≤ 9.8 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.
• Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
Exclusion Criteria
• Prior treatment with crizotinib, or any other cMET or HGF inhibitor
• 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)
• Patients with characterized EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 mutations.
• Patients with characterized ALK-positive rearrangement
• 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
• Presence or history of carcinomatous meningitis
• 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
• 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)
• 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
• 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
• 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)
• 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)
• Unable or unwilling to swallow tablets as per dosing schedule
• 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
• 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
• 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
• Other severe, acute, or chronic medical or psychiatric 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
• 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.
• Pregnant or nursing (lactating) women
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during the study and for 7 days after stopping treatment
• 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. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via seminal fluid
• 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)
• Patients with characterized EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 mutations.
• Patients with characterized ALK-positive rearrangement
• 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
• Presence or history of carcinomatous meningitis
• 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
• 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)
• 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
• 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
• 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)
• 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)
• Unable or unwilling to swallow tablets as per dosing schedule
• 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
• 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
• 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
• Other severe, acute, or chronic medical or psychiatric 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
• 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.
• Pregnant or nursing (lactating) women
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during the study and for 7 days after stopping treatment
• 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. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via seminal fluid
The Estimated Number of Participants
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Taiwan
10 participants
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Global
429 participants
