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

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

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.

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: INC280; Drug: Gefitinib

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.

• Study Type: Interventional
• Enrollment (Actual): 161
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Auckland, Australia
    • Novartis Investigative Site
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Novartis Investigative Site
  • Victoria
    • East Bentleigh, Victoria, Australia, 3165
      • Novartis Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• China
  • Beijing, China, 100039
    • Novartis Investigative Site
  • Guangzhou, China, 510060
    • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 51000
      • Novartis Investigative Site
  • Shanghai
    • Shanghai, Shanghai, China, 200433
      • Novartis Investigative Site
• France
  • Strasbourg Cedex, France, 67091
    • Novartis Investigative Site
  • Toulouse Cedex 9, France, 31059
    • Novartis Investigative Site
• Germany
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
  • Freiburg, Germany, 79106
    • Novartis Investigative Site
• Israel
  • Ramat Gan, Israel, 52621
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
    • Milano, MI, Italy, 20141
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41124
      • Novartis Investigative Site
• Japan
  • Tokyo
    • Koto ku, Tokyo, Japan, 135 8550
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
  • Korea
    • Gyeonggi do, Korea, Korea, Republic of, 10408
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 05505
      • Novartis Investigative Site
  • Seocho Gu
    • Seoul, Seocho Gu, Korea, Republic of, 06591
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3015 GD
    • Novartis Investigative Site
  • AZ
    • Maastricht, AZ, Netherlands, 5800
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169610
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Taiwan
  • Tainan, Taiwan, 70403
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: INC280 100 mg Cap QD Phase Ib; cap=capsule; QD=once daily	Drug: INC280; During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.; Other Names: Capmatinib; Drug: Gefitinib; Gefitinib 250 mg taken once daily
Experimental: INC280 200 mg Cap QD Phase Ib; cap=capsule; QD=once daily	Drug: INC280; During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.; Other Names: Capmatinib; Drug: Gefitinib; Gefitinib 250 mg taken once daily
Experimental: INC280 400 mg Cap QD Phase Ib; cap=capsule; QD=once daily	Drug: INC280; During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.; Other Names: Capmatinib; Drug: Gefitinib; Gefitinib 250 mg taken once daily
Experimental: INC280 800 mg Cap QD Phase Ib; cap=capsule; QD=once daily	Drug: INC280; During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.; Other Names: Capmatinib; Drug: Gefitinib; Gefitinib 250 mg taken once daily
Experimental: INC280 200 mg Cap BID Phase Ib; cap=capsule; BID=twice daily	Drug: INC280; During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.; Other Names: Capmatinib; Drug: Gefitinib; Gefitinib 250 mg taken once daily
Experimental: INC280 400 mg Cap BID Phase Ib; cap=capsule; BID=twice daily	Drug: INC280; During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.; Other Names: Capmatinib; Drug: Gefitinib; Gefitinib 250 mg taken once daily
Experimental: INC280 600 mg Cap BID Phase Ib; cap=capsule; BID=twice daily	Drug: INC280; During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.; Other Names: Capmatinib; Drug: Gefitinib; Gefitinib 250 mg taken once daily
Experimental: INC280 200 mg Tab BID Phase Ib; tab=tablet; BID=twice daily	Drug: INC280; During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.; Other Names: Capmatinib; Drug: Gefitinib; Gefitinib 250 mg taken once daily
Experimental: INC280 400 mg Tab BID Phase Ib; tab=tablet; BID=twice daily	Drug: INC280; During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.; Other Names: Capmatinib; Drug: Gefitinib; Gefitinib 250 mg taken once daily
Experimental: INC280 400 mg Cap BID Phase II; cap=capsule; BID=twice daily	Drug: INC280; During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.; Other Names: Capmatinib; Drug: Gefitinib; Gefitinib 250 mg taken once daily
Experimental: INC280 400 mg Tab BID Phase II; tab=tablet; BID=twice daily	Drug: INC280; During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.; Other Names: Capmatinib; Drug: Gefitinib; Gefitinib 250 mg taken once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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)
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)
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)
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)
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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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. Erratum In: J Clin Oncol. 2019 Jan 20;37(3):261.

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2012
• Primary Completion (Actual): June 10, 2016
• Study Completion (Actual): May 27, 2020

Study Registration Dates

• First Submitted: April 3, 2012
• First Submitted That Met QC Criteria: June 1, 2012
• First Posted (Estimate): June 4, 2012

Study Record Updates

• Last Update Posted (Actual): April 8, 2021
• Last Update Submitted That Met QC Criteria: March 12, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Lung cancer; EGFR; Erlotinib; Non-small cell lung cancer (NSCLC); lung adenocarcinoma; Gefitinib; c-MET; large-cell lung carcinoma
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Gefitinib
• Other Study ID Numbers: CINC280X2202; 2011-002569-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes