Clinical trial NCT01610336: A Safety and Efficacy Study of INC280 and Gefitinib in Patients With EGFR Mutated, c-MET-amplified NSCLC Who Have Progressed After EGFRi Treatment
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Keywords: EGFR
c-MET
Lung cancer
Gefitinib
Erlotinib
Non-small cell lung cancer (NSCLC)
lung adenocarcinoma
large-cell lung carcinoma
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-06-04
Enrollment: 161
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase Ib: Frequency of Dose Limiting Toxicities (DLTs)
timeFrame: Up to 215 weeks
measure: Phase II : Overall Response Rate (ORR)
timeFrame: Until disease progression, up to 60.8 weeks
Secondary outcomes:
measure: Phase Ib and II: Number of Participants With Adverse Events (AEs)
timeFrame: Up to 421 weeks
measure: Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: Up to 421 weeks
measure: Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level
timeFrame: Up to 417 weeks
measure: Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level
timeFrame: Up to 417 weeks
measure: Phase II: Overall Survival (OS)
timeFrame: From date of treatment until death due to any cause, up to 70.2 months
measure: Phase II: Progression Free Survival (PFS)
timeFrame: Up to 60.8 months
measure: Phase II: Duration of Response (DoR)
timeFrame: Up to 23.2 months
measure: Phase I: PK Parameters AUCtau of INC280 and Gefitinib
timeFrame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
measure: Phase I: PK Parameters Cmax of INC280 and Gefitinib
timeFrame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
measure: Phase I: PK Parameters Tmax of INC280 and Gefitinib
timeFrame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
measure: Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib
timeFrame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
measure: Phase I: PK Parameters Half-life of INC280 and Gefitinib
timeFrame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose)(Cycle=28 days)
Other outcomes:
measure: Phase I: Percentage of Change From Baseline in C-MET H Score at Cycle 1 Day 15
timeFrame: Baseline, Day 15 of cycle 1 (Cycle=28days)
Locations:
city: Woolloongabba
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: East Bentleigh
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Auckland
country: Australia
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Shanghai
country: China
facility: Novartis Investigative Site
state: Shanghai
city: Beijing
country: China
facility: Novartis Investigative Site
city: Guangzhou
country: China
facility: Novartis Investigative Site
city: Strasbourg Cedex
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 9
country: France
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Koto ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Gyeonggi do
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Maastricht
country: Netherlands
facility: Novartis Investigative Site
state: AZ
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Wu YL, Zhang L, Kim DW, Liu X, Lee DH, Yang JC, Ahn MJ, Vansteenkiste JF, Su WC, Felip E, Chia V, Glaser S, Pultar P, Zhao S, Peng B, Akimov M, Tan DSW. Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With EGFR-Mutated, MET Factor-Dysregulated Non-Small-Cell Lung Cancer. J Clin Oncol. 2018 Nov 1;36(31):3101-3109. doi: 10.1200/JCO.2018.77.7326. Epub 2018 Aug 29.