A Safety and Efficacy Study of INC280 and Gefitinib in Patients With EGFR Mutated, c-MET-amplified NSCLC Who Have Progressed After EGFRi Treatment

Non-small Cell Lung Cancer Clinical Trial

Official title:

A Phase IB/II, Open Label, Multicenter Study of INC280 Administered Orally in Combination With Gefitinib in Adult Patients With EGFR Mutated, c-MET-amplified Non-small Cell Lung Cancer Who Have Progressed After EGFR Inhibitor Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01610336
• Other study ID #: CINC280X2202
• Secondary ID: 2011-002569-39
• Status: Completed
• Phase: Phase 2
• Start date: April 5, 2012
• Est. completion date: May 27, 2020

Study information

• Verified date: March 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 161
• Est. completion date: May 27, 2020
• Est. primary completion date: June 10, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer

Intervention

Drug:
• INC280
During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
• Gefitinib
Gefitinib 250 mg taken once daily

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Auckland
Australia	Novartis Investigative Site	East Bentleigh	Victoria
Australia	Novartis Investigative Site	Woolloongabba	Queensland
Belgium	Novartis Investigative Site	Leuven
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Guangzhou
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Shanghai	Shanghai
France	Novartis Investigative Site	Strasbourg Cedex
France	Novartis Investigative Site	Toulouse Cedex 9
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Freiburg
Israel	Novartis Investigative Site	Ramat Gan
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Japan	Novartis Investigative Site	Koto ku	Tokyo
Korea, Republic of	Novartis Investigative Site	Gyeonggi do	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Maastricht	AZ
Netherlands	Novartis Investigative Site	Rotterdam
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Taiwan	Novartis Investigative Site	Tainan
Taiwan	Novartis Investigative Site	Taipei
Thailand	Novartis Investigative Site	Bangkok

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Australia,  Belgium,  China,  France,  Germany,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Singapore,  Spain,  Taiwan,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	Baseline, Day 15 of cycle 1 (Cycle=28days)
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.	Up to 215 weeks
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.	Until disease progression, up to 60.8 weeks
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	Up to 421 weeks
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	Up to 421 weeks
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.	Up to 417 weeks
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	Up to 417 weeks
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	From date of treatment until death due to any cause, up to 70.2 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.	Up to 60.8 months
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.	Up to 23.2 months
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	Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
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	Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
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	Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
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	Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
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	Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose)(Cycle=28 days)