Non-small Cell Lung Cancer
Conditions
Keywords
EGFR, c-MET, Lung cancer, Gefitinib, Erlotinib, Non-small cell lung cancer (NSCLC), lung adenocarcinoma, large-cell lung carcinoma
Brief summary
This study assessed the safety and efficacy of escalating doses INC280 when added to gefitinib in patients with lung cancer that were known to have dysregulation of the c-MET pathway and who had failed after benefiting on a prior treatment with either gefitinib or erlotinib.
Detailed description
The Phase Ib dose escalation part was aimed at the determination of the MTD/RP2D of capmatinib in combination with 250 mg gefitinib in patients with NSCLC patients with epidermal growth factor receptor (EGFR) mutation and cMET dysregulation and showing disease progression following EGFR tyrosine-kinase inhibitor (EGFR TKI) therapy. Dose escalation started with a dose of 100 mg/day to a maximum of 1200 mg/day, as capsule or tablet formulation. Successive cohorts of patients were to receive increasing doses of capmatinib in combination with a 250 mg once daily (qd) dose of gefitinib until the MTD/RP2D of capmatinib had been determined. The Phase II dose expansion part consisted of 400 mg capmatinib twice daily (bid), as either capsules or tablets, in combination with 250 mg gefitinib.
Interventions
DRUGINC280
During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
DRUGGefitinib
Gefitinib 250 mg taken once daily
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented EGFR mutation * Documented c-MET dysregulation * Prior clinical benefit on EGFR inhibitors and then subsequent progression -≥ 18 year old * Life expectancy of ≥ 3 months * ECOG performance status ≤ 2
Exclusion criteria
* Unable to swallow tables once or twice daily * Previous treatment with c-MET inhibitor * Any unresolved toxicity from previous anticancer therapy greater than grade 1 * History of cystic fibrosis * History of acute or chronic pancreatitis * Unable to undergo MRI or CT scans * Known history of HIV * Undergone a bone marrow or solid organ transplant * Clinically significant wound or lung tumor lesions with increased likelihood of bleeding * Pregnant or nursing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II : Overall Response Rate (ORR) | Until disease progression, up to 60.8 weeks | Overall response rate is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), as per RECIST 1.1 (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Up to 215 weeks | A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | Up to 421 weeks | Serious adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 |
| Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Up to 417 weeks | Number of patients with dose reductions of INC280 by dose level as a measure of tolerability. |
| Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Up to 417 weeks | Number of patients with dose interruptions of gefitinib by dose level as a measure of tolerability |
| Phase II: Overall Survival (OS) | From date of treatment until death due to any cause, up to 70.2 months | Overall survival is defined as the time from the start of treatment date to the date of death, due to any cause |
| Phase II: Progression Free Survival (PFS) | Up to 60.8 months | Progression-free survivalis the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. |
| Phase I: PK Parameters AUCtau of INC280 and Gefitinib | Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days) | PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Area under the plasma concentration-time curve (AUC) from time zero to the end of dosing interval at steady state (tau), where tau=24 hours for once daily dosing and tau=12 hours for twice daily dosing |
| Phase I: PK Parameters Cmax of INC280 and Gefitinib | Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days) | PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Cmax is the maximum observed plasma concentration of INC280 and gefitinib |
| Phase I: PK Parameters Tmax of INC280 and Gefitinib | Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days) | PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Tmax is the time to reach maximum plasma concentration of INC280 and gefitinib |
| Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days) | PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Apparent systemic plasma clearance rate of INC280 and gefitinib |
| Phase I: PK Parameters Half-life of INC280 and Gefitinib | Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose)(Cycle=28 days) | PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. The elimination half-life of INC280 and gefitinib associated with the terminal slope (Lamda\_z) of a semi-logarithmic plasma concentration-time curve |
| Phase II: Duration of Response (DoR) | Up to 23.2 months | Duration of overall response (DOR) is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression or death due to underlying cancer. |
| Phase Ib and II: Number of Participants With Adverse Events (AEs) | Up to 421 weeks | Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Percentage of Change From Baseline in C-MET H Score at Cycle 1 Day 15 | Baseline, Day 15 of cycle 1 (Cycle=28days) | Inhibition of c-MET signaling by pre- and post- treatment immunohistochemistry of p-c-MET |
Countries
Australia, Belgium, China, France, Germany, Israel, Italy, Japan, Netherlands, Singapore, South Korea, Spain, Taiwan, Thailand
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| INC280 100 mg Cap QD Phase Ib cap=capsule; QD=once daily | 5 |
| INC280 200 mg Cap QD Phase Ib cap=capsule; QD=once daily | 7 |
| INC280 400 mg Cap QD Phase Ib cap=capsule; QD=once daily | 6 |
| INC280 800 mg Cap QD Phase Ib cap=capsule; QD=once daily | 7 |
| INC280 200 mg Cap BID Phase Ib cap=capsule; BID=twice daily | 4 |
| INC280 400 mg Cap BID Phase Ib cap=capsule; BID=twice daily | 12 |
| INC280 600 mg Cap BID Phase Ib cap=capsule; BID=twice daily | 5 |
| INC280 200 mg Tab BID Phase Ib tab=tablet; BID=twice daily | 7 |
| INC280 400 mg Tab BID Phase Ib tab=tablet; BID=twice daily | 8 |
| INC280 400 mg Cap BID Phase II cap=capsule; BID=twice daily | 53 |
| INC280 400 mg Tab BID Phase II tab=tablet; BID=twice daily | 47 |
| Total | 161 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 2 | 8 | 6 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 | 1 | 2 |
| Overall Study | Non-Compliance with study treatment | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 4 | 6 | 6 | 5 | 3 | 10 | 1 | 6 | 6 | 40 | 36 |
| Overall Study | Protocol Deviation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Subject/Guardian decision | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 2 | 2 |
| Overall Study | Transfer to another trial | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | INC280 100 mg Cap QD Phase Ib | INC280 200 mg Cap QD Phase Ib | INC280 400 mg Cap QD Phase Ib | INC280 800 mg Cap QD Phase Ib | INC280 200 mg Cap BID Phase Ib | INC280 400 mg Cap BID Phase Ib | INC280 600 mg Cap BID Phase Ib | INC280 200 mg Tab BID Phase Ib | INC280 400 mg Tab BID Phase Ib | INC280 400 mg Cap BID Phase II | INC280 400 mg Tab BID Phase II | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 57.8 years STANDARD_DEVIATION 11.05 | 60.4 years STANDARD_DEVIATION 15.27 | 59.5 years STANDARD_DEVIATION 6.89 | 51.3 years STANDARD_DEVIATION 8.88 | 64.5 years STANDARD_DEVIATION 8.89 | 55.9 years STANDARD_DEVIATION 10.81 | 61.0 years STANDARD_DEVIATION 8.46 | 60.9 years STANDARD_DEVIATION 12.86 | 58.4 years STANDARD_DEVIATION 5.01 | 58.6 years STANDARD_DEVIATION 10.5 | 62.8 years STANDARD_DEVIATION 9.32 | 59.7 years STANDARD_DEVIATION 10.2 |
| Race/Ethnicity, Customized East Asian | 4 Participants | 6 Participants | 6 Participants | 7 Participants | 3 Participants | 9 Participants | 4 Participants | 3 Participants | 7 Participants | 53 Participants | 16 Participants | 118 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 5 Participants | 7 Participants |
| Race/Ethnicity, Customized Mixed Ethnicity | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 11 Participants | 17 Participants |
| Race/Ethnicity, Customized Russian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Southeast Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 8 Participants | 12 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 4 Participants | 5 Participants | 4 Participants | 4 Participants | 2 Participants | 5 Participants | 5 Participants | 33 Participants | 19 Participants | 88 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 8 Participants | 3 Participants | 2 Participants | 3 Participants | 20 Participants | 28 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 5 | 0 / 7 | 0 / 6 | 1 / 7 | 0 / 4 | 1 / 12 | 3 / 5 | 0 / 7 | 1 / 8 | 6 / 53 | 2 / 47 |
| other Total, other adverse events | 5 / 5 | 7 / 7 | 6 / 6 | 7 / 7 | 4 / 4 | 12 / 12 | 4 / 5 | 6 / 7 | 7 / 8 | 49 / 53 | 47 / 47 |
| serious Total, serious adverse events | 1 / 5 | 2 / 7 | 2 / 6 | 3 / 7 | 0 / 4 | 4 / 12 | 3 / 5 | 5 / 7 | 3 / 8 | 12 / 53 | 19 / 47 |
Outcome results
Primary
Phase Ib: Frequency of Dose Limiting Toxicities (DLTs)
A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.
Time frame: Up to 215 weeks
Population: Safety Set: All patients in phase Ib who received at least one full or partial dose of INC280 or gefitinib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Cough | 0 Participants |
| INC280 100 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dyspnoea | 0 Participants |
| INC280 100 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dizziness | 0 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dyspnoea | 0 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dizziness | 0 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Cough | 0 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dizziness | 0 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Cough | 0 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dyspnoea | 0 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dyspnoea | 0 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Cough | 0 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dizziness | 1 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dizziness | 0 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Cough | 0 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dyspnoea | 0 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dizziness | 0 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Cough | 0 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dyspnoea | 0 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dyspnoea | 1 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Cough | 1 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dizziness | 0 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dizziness | 0 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dyspnoea | 0 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Cough | 0 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dizziness | 0 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Dyspnoea | 0 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | Cough | 0 Participants |
Primary
Phase II : Overall Response Rate (ORR)
Overall response rate is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), as per RECIST 1.1 (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Until disease progression, up to 60.8 weeks
Population: Full analysis set: all patients in phase II who receive at least one full or partial dose of INC280 or gefitinib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase II : Overall Response Rate (ORR) | 12 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase II : Overall Response Rate (ORR) | 17 Participants |
Secondary
Phase Ib and II: Number of Participants With Adverse Events (AEs)
Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time frame: Up to 421 weeks
Population: Safety Set: All patients in phase Ib and II who received at least one full or partial dose of INC280 or gefitinib and and had at least one valid postbaseline safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | AEs | 5 Participants |
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | Grade 3/4 AEs | 3 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | AEs | 7 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | Grade 3/4 AEs | 4 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | AEs | 6 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | Grade 3/4 AEs | 2 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | AEs | 7 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | Grade 3/4 AEs | 4 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | AEs | 4 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | Grade 3/4 AEs | 2 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | Grade 3/4 AEs | 6 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | AEs | 12 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | Grade 3/4 AEs | 4 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | AEs | 5 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | AEs | 7 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | Grade 3/4 AEs | 6 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | AEs | 8 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Participants With Adverse Events (AEs) | Grade 3/4 AEs | 4 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Participants With Adverse Events (AEs) | AEs | 51 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Participants With Adverse Events (AEs) | Grade 3/4 AEs | 24 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Participants With Adverse Events (AEs) | AEs | 47 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Participants With Adverse Events (AEs) | Grade 3/4 AEs | 35 Participants |
Secondary
Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs)
Serious adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time frame: Up to 421 weeks
Population: Safety Set: All patients in phase Ib and II who received at least one full or partial dose of INC280 or gefitinib and and had at least one valid postbaseline safety assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | 1 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | 2 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | 2 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | 3 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | 0 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | 4 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | 3 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | 5 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | 3 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | 12 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | 19 Participants |
Secondary
Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level
Number of patients with dose interruptions of gefitinib by dose level as a measure of tolerability
Time frame: Up to 417 weeks
Population: Safety set: All patients in phase Ib and II who received at least one full or partial dose of INC280 or gefitinib.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | >3 dose interruptions | 0 Participants |
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | With only one dose interruption | 0 Participants |
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Without dose interruptions | 5 Participants |
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 2 dose interruptions | 0 Participants |
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 3 dose interruptions | 0 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Without dose interruptions | 5 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 3 dose interruptions | 0 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | With only one dose interruption | 2 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 2 dose interruptions | 0 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | >3 dose interruptions | 0 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 2 dose interruptions | 0 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | >3 dose interruptions | 0 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | With only one dose interruption | 0 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Without dose interruptions | 6 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 3 dose interruptions | 0 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 3 dose interruptions | 1 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 2 dose interruptions | 0 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | >3 dose interruptions | 0 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Without dose interruptions | 4 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | With only one dose interruption | 2 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | >3 dose interruptions | 0 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 2 dose interruptions | 0 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 3 dose interruptions | 0 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | With only one dose interruption | 0 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Without dose interruptions | 4 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 2 dose interruptions | 1 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Without dose interruptions | 6 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | With only one dose interruption | 3 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 3 dose interruptions | 2 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | >3 dose interruptions | 0 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 2 dose interruptions | 0 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | >3 dose interruptions | 1 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | With only one dose interruption | 0 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Without dose interruptions | 4 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 3 dose interruptions | 0 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 2 dose interruptions | 1 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Without dose interruptions | 4 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | >3 dose interruptions | 2 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 3 dose interruptions | 0 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | With only one dose interruption | 0 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 2 dose interruptions | 0 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | With only one dose interruption | 2 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 3 dose interruptions | 1 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Without dose interruptions | 4 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | >3 dose interruptions | 1 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Without dose interruptions | 42 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 3 dose interruptions | 0 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | >3 dose interruptions | 1 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | With only one dose interruption | 9 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 2 dose interruptions | 1 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 3 dose interruptions | 2 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | 2 dose interruptions | 4 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | With only one dose interruption | 16 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Without dose interruptions | 25 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | >3 dose interruptions | 0 Participants |
Secondary
Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level
Number of patients with dose reductions of INC280 by dose level as a measure of tolerability.
Time frame: Up to 417 weeks
Population: Safety Set: All patients in phase Ib and II who received at least one full or partial dose of INC280 or gefitinib.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | >3 dose reductions | 0 Participants |
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Only 1 dose reduction | 0 Participants |
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Without dose reductions | 5 Participants |
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 2 dose reductions | 0 Participants |
| INC280 100 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 3 dose reductions | 0 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Without dose reductions | 6 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 3 dose reductions | 0 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Only 1 dose reduction | 1 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 2 dose reductions | 0 Participants |
| INC280 200 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | >3 dose reductions | 0 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 2 dose reductions | 1 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | >3 dose reductions | 0 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Only 1 dose reduction | 0 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Without dose reductions | 5 Participants |
| INC280 400 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 3 dose reductions | 0 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 3 dose reductions | 0 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 2 dose reductions | 0 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | >3 dose reductions | 0 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Without dose reductions | 6 Participants |
| INC280 800 mg Cap QD Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Only 1 dose reduction | 1 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | >3 dose reductions | 0 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 2 dose reductions | 0 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 3 dose reductions | 1 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Only 1 dose reduction | 2 Participants |
| INC280 200 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Without dose reductions | 1 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 2 dose reductions | 1 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Without dose reductions | 8 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Only 1 dose reduction | 2 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 3 dose reductions | 0 Participants |
| INC280 400 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | >3 dose reductions | 1 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 2 dose reductions | 1 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | >3 dose reductions | 0 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Only 1 dose reduction | 2 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Without dose reductions | 1 Participants |
| INC280 600 mg Cap BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 3 dose reductions | 1 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 2 dose reductions | 1 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Without dose reductions | 5 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | >3 dose reductions | 1 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 3 dose reductions | 0 Participants |
| INC280 200 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Only 1 dose reduction | 0 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 2 dose reductions | 1 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Only 1 dose reduction | 1 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 3 dose reductions | 0 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Without dose reductions | 5 Participants |
| INC280 400 mg Tab BID Phase Ib | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | >3 dose reductions | 1 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Without dose reductions | 30 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 3 dose reductions | 1 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | >3 dose reductions | 3 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Only 1 dose reduction | 13 Participants |
| INC280 400 mg Cap BID Phase II | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 2 dose reductions | 6 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 3 dose reductions | 1 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | 2 dose reductions | 5 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Only 1 dose reduction | 17 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Without dose reductions | 23 Participants |
| INC280 400 mg Tab BID Phase II | Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | >3 dose reductions | 1 Participants |
Secondary
Phase II: Duration of Response (DoR)
Duration of overall response (DOR) is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression or death due to underlying cancer.
Time frame: Up to 23.2 months
Population: Full analysis set subjects in phase II with confirmed complete response (CR) or partial response (PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase II: Duration of Response (DoR) | 5.6 Months |
| INC280 200 mg Cap QD Phase Ib | Phase II: Duration of Response (DoR) | 5.6 Months |
Secondary
Phase II: Overall Survival (OS)
Overall survival is defined as the time from the start of treatment date to the date of death, due to any cause
Time frame: From date of treatment until death due to any cause, up to 70.2 months
Population: Full analysis set: all patients in phase II who receive at least one full or partial dose of INC280 or gefitinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase II: Overall Survival (OS) | 12.3 Months |
| INC280 200 mg Cap QD Phase Ib | Phase II: Overall Survival (OS) | 15.2 Months |
Secondary
Phase II: Progression Free Survival (PFS)
Progression-free survivalis the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.
Time frame: Up to 60.8 months
Population: Full analysis set: all patients in phase II who receive at least one full or partial dose of INC280 or gefitinib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase II: Progression Free Survival (PFS) | 5.1 Months |
| INC280 200 mg Cap QD Phase Ib | Phase II: Progression Free Survival (PFS) | 5.5 Months |
Secondary
Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib
PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Apparent systemic plasma clearance rate of INC280 and gefitinib
Time frame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
Population: Pharmacokinetic analysis set: all patients having at least one evaluable PK profile of INC280 and/or gefitinib. Patients were included on the estimation of this PK parameter if a sufficient number of blood samples was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | INC 280 | 26.9 L/hr | Standard Deviation 15 |
| INC280 100 mg Cap QD Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | Gefitinib | 33.3 L/hr | Standard Deviation 6.78 |
| INC280 200 mg Cap QD Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | INC 280 | 29.4 L/hr | Standard Deviation 15.7 |
| INC280 200 mg Cap QD Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | Gefitinib | 32.9 L/hr | Standard Deviation 9.65 |
| INC280 400 mg Cap QD Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | Gefitinib | 36.5 L/hr | Standard Deviation 8.41 |
| INC280 400 mg Cap QD Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | INC 280 | 16.3 L/hr | Standard Deviation 7.61 |
| INC280 800 mg Cap QD Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | Gefitinib | 19.5 L/hr | — |
| INC280 800 mg Cap QD Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | INC 280 | 47.7 L/hr | Standard Deviation 49.1 |
| INC280 200 mg Cap BID Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | Gefitinib | 30.8 L/hr | Standard Deviation 8.61 |
| INC280 200 mg Cap BID Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | INC 280 | 27.0 L/hr | Standard Deviation 14.7 |
| INC280 400 mg Cap BID Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | INC 280 | 24.2 L/hr | Standard Deviation 18.3 |
| INC280 400 mg Cap BID Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | Gefitinib | 41.0 L/hr | Standard Deviation 24.1 |
| INC280 600 mg Cap BID Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | INC 280 | 18.4 L/hr | Standard Deviation 9.31 |
| INC280 200 mg Tab BID Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | INC 280 | 15.4 L/hr | Standard Deviation 3.89 |
| INC280 200 mg Tab BID Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | Gefitinib | 36.9 L/hr | Standard Deviation 8.81 |
| INC280 400 mg Tab BID Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | Gefitinib | 32.5 L/hr | Standard Deviation 4.99 |
| INC280 400 mg Tab BID Phase Ib | Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | INC 280 | 14.4 L/hr | Standard Deviation 3.1 |
Secondary
Phase I: PK Parameters AUCtau of INC280 and Gefitinib
PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Area under the plasma concentration-time curve (AUC) from time zero to the end of dosing interval at steady state (tau), where tau=24 hours for once daily dosing and tau=12 hours for twice daily dosing
Time frame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
Population: Pharmacokinetic analysis set: all patients having at least one evaluable PK profile of INC280 and/or gefitinib. Patients were included on the estimation of this PK parameter if a sufficient number of blood samples was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | INC280 | 4510 hr∙ng/mL | Standard Deviation 1960 |
| INC280 100 mg Cap QD Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | Gefitinib | 7690 hr∙ng/mL | Standard Deviation 1400 |
| INC280 200 mg Cap QD Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | INC280 | 9140 hr∙ng/mL | Standard Deviation 5550 |
| INC280 200 mg Cap QD Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | Gefitinib | 8070 hr∙ng/mL | Standard Deviation 2080 |
| INC280 400 mg Cap QD Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | Gefitinib | 7140 hr∙ng/mL | Standard Deviation 1830 |
| INC280 400 mg Cap QD Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | INC280 | 29200 hr∙ng/mL | Standard Deviation 12700 |
| INC280 800 mg Cap QD Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | Gefitinib | 12800 hr∙ng/mL | — |
| INC280 800 mg Cap QD Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | INC280 | 30300 hr∙ng/mL | Standard Deviation 19800 |
| INC280 200 mg Cap BID Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | Gefitinib | 8440 hr∙ng/mL | Standard Deviation 2360 |
| INC280 200 mg Cap BID Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | INC280 | 9660 hr∙ng/mL | Standard Deviation 5780 |
| INC280 400 mg Cap BID Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | INC280 | 21400 hr∙ng/mL | Standard Deviation 8420 |
| INC280 400 mg Cap BID Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | Gefitinib | 8500 hr∙ng/mL | Standard Deviation 5330 |
| INC280 600 mg Cap BID Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | INC280 | 37300 hr∙ng/mL | Standard Deviation 18800 |
| INC280 200 mg Tab BID Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | INC280 | 13900 hr∙ng/mL | Standard Deviation 4470 |
| INC280 200 mg Tab BID Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | Gefitinib | 7160 hr∙ng/mL | Standard Deviation 2040 |
| INC280 400 mg Tab BID Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | Gefitinib | 7820 hr∙ng/mL | Standard Deviation 1130 |
| INC280 400 mg Tab BID Phase Ib | Phase I: PK Parameters AUCtau of INC280 and Gefitinib | INC280 | 28700 hr∙ng/mL | Standard Deviation 5460 |
Secondary
Phase I: PK Parameters Cmax of INC280 and Gefitinib
PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Cmax is the maximum observed plasma concentration of INC280 and gefitinib
Time frame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
Population: Pharmacokinetic analysis set: all patients having at least one evaluable PK profile of INC280 and/or gefitinib. Patients were included on the estimation of this PK parameter if a sufficient number of blood samples was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | INC280 | 826 ng/mL | Standard Deviation 521 |
| INC280 100 mg Cap QD Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | Gefitinib | 417 ng/mL | Standard Deviation 42.9 |
| INC280 200 mg Cap QD Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | INC280 | 1490 ng/mL | Standard Deviation 1430 |
| INC280 200 mg Cap QD Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | Gefitinib | 378 ng/mL | Standard Deviation 85.2 |
| INC280 400 mg Cap QD Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | INC280 | 4620 ng/mL | Standard Deviation 3060 |
| INC280 400 mg Cap QD Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | Gefitinib | 405 ng/mL | Standard Deviation 144 |
| INC280 800 mg Cap QD Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | INC280 | 6570 ng/mL | Standard Deviation 4360 |
| INC280 800 mg Cap QD Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | Gefitinib | 357 ng/mL | Standard Deviation 225 |
| INC280 200 mg Cap BID Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | INC280 | 1950 ng/mL | Standard Deviation 985 |
| INC280 200 mg Cap BID Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | Gefitinib | 480 ng/mL | Standard Deviation 191 |
| INC280 400 mg Cap BID Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | Gefitinib | 464 ng/mL | Standard Deviation 209 |
| INC280 400 mg Cap BID Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | INC280 | 4220 ng/mL | Standard Deviation 2100 |
| INC280 600 mg Cap BID Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | Gefitinib | 255 ng/mL | Standard Deviation 158 |
| INC280 600 mg Cap BID Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | INC280 | 4840 ng/mL | Standard Deviation 1990 |
| INC280 200 mg Tab BID Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | INC280 | 2550 ng/mL | Standard Deviation 676 |
| INC280 200 mg Tab BID Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | Gefitinib | 479 ng/mL | Standard Deviation 167 |
| INC280 400 mg Tab BID Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | INC280 | 6760 ng/mL | Standard Deviation 1740 |
| INC280 400 mg Tab BID Phase Ib | Phase I: PK Parameters Cmax of INC280 and Gefitinib | Gefitinib | 355 ng/mL | Standard Deviation 74.1 |
Secondary
Phase I: PK Parameters Half-life of INC280 and Gefitinib
PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. The elimination half-life of INC280 and gefitinib associated with the terminal slope (Lamda\_z) of a semi-logarithmic plasma concentration-time curve
Time frame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose)(Cycle=28 days)
Population: Pharmacokinetic analysis set: all patients having at least one evaluable PK profile of INC280 and/or gefitinib. Patients were included on the estimation of this PK parameter if a sufficient number of blood samples was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | INC280 | 3.86 hours | Standard Deviation 0.564 |
| INC280 100 mg Cap QD Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | Gefitinib | 18.8 hours | — |
| INC280 200 mg Cap QD Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | INC280 | 5.10 hours | Standard Deviation 2.01 |
| INC280 200 mg Cap QD Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | Gefitinib | 26.9 hours | Standard Deviation 4.63 |
| INC280 400 mg Cap QD Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | INC280 | 3.16 hours | Standard Deviation 0.361 |
| INC280 400 mg Cap QD Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | Gefitinib | 36.3 hours | Standard Deviation 8.2 |
| INC280 800 mg Cap QD Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | INC280 | 3.67 hours | Standard Deviation 0.796 |
| INC280 800 mg Cap QD Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | Gefitinib | 37.8 hours | — |
| INC280 200 mg Cap BID Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | INC280 | 3.19 hours | Standard Deviation 0.942 |
| INC280 200 mg Cap BID Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | Gefitinib | 16.3 hours | Standard Deviation 2.16 |
| INC280 400 mg Cap BID Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | INC280 | 3.01 hours | Standard Deviation 1.38 |
| INC280 400 mg Cap BID Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | Gefitinib | 18.7 hours | Standard Deviation 7.75 |
| INC280 200 mg Tab BID Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | Gefitinib | 17.8 hours | Standard Deviation 5.08 |
| INC280 200 mg Tab BID Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | INC280 | 3.75 hours | Standard Deviation 1.94 |
| INC280 400 mg Tab BID Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | INC280 | 3.17 hours | Standard Deviation 0.783 |
| INC280 400 mg Tab BID Phase Ib | Phase I: PK Parameters Half-life of INC280 and Gefitinib | Gefitinib | 23.9 hours | — |
Secondary
Phase I: PK Parameters Tmax of INC280 and Gefitinib
PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Tmax is the time to reach maximum plasma concentration of INC280 and gefitinib
Time frame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
Population: Pharmacokinetic analysis set: all patients having at least one evaluable PK profile of INC280 and/or gefitinib. Patients were included on the estimation of this PK parameter if a sufficient number of blood samples was available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | Gefitinib | 3.92 Hours |
| INC280 100 mg Cap QD Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | INC280 | 1.96 Hours |
| INC280 200 mg Cap QD Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | Gefitinib | 6.00 Hours |
| INC280 200 mg Cap QD Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | INC280 | 2.00 Hours |
| INC280 400 mg Cap QD Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | INC280 | 2.00 Hours |
| INC280 400 mg Cap QD Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | Gefitinib | 6.02 Hours |
| INC280 800 mg Cap QD Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | INC280 | 2.05 Hours |
| INC280 800 mg Cap QD Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | Gefitinib | 5.94 Hours |
| INC280 200 mg Cap BID Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | INC280 | 1.50 Hours |
| INC280 200 mg Cap BID Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | Gefitinib | 5.00 Hours |
| INC280 400 mg Cap BID Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | Gefitinib | 6.00 Hours |
| INC280 400 mg Cap BID Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | INC280 | 2.00 Hours |
| INC280 600 mg Cap BID Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | Gefitinib | 11.3 Hours |
| INC280 600 mg Cap BID Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | INC280 | 5.00 Hours |
| INC280 200 mg Tab BID Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | INC280 | 2.00 Hours |
| INC280 200 mg Tab BID Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | Gefitinib | 6.00 Hours |
| INC280 400 mg Tab BID Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | Gefitinib | 6.00 Hours |
| INC280 400 mg Tab BID Phase Ib | Phase I: PK Parameters Tmax of INC280 and Gefitinib | INC280 | 1.08 Hours |
Other Pre-specified
Phase I: Percentage of Change From Baseline in C-MET H Score at Cycle 1 Day 15
Inhibition of c-MET signaling by pre- and post- treatment immunohistochemistry of p-c-MET
Time frame: Baseline, Day 15 of cycle 1 (Cycle=28days)
Population: Full analysis set patients in phase Ib with p cMET H score measured. Few tumor samples were available since tumor biopsy was optional for this study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| INC280 100 mg Cap QD Phase Ib | Phase I: Percentage of Change From Baseline in C-MET H Score at Cycle 1 Day 15 | -100 Percentage |
| INC280 400 mg Cap BID Phase Ib | Phase I: Percentage of Change From Baseline in C-MET H Score at Cycle 1 Day 15 | -100 Percentage |
| INC280 400 mg Cap BID Phase II | Phase I: Percentage of Change From Baseline in C-MET H Score at Cycle 1 Day 15 | -31 Percentage |