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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01610336
Recruitment Status : Completed
First Posted : June 4, 2012
Results First Posted : April 8, 2021
Last Update Posted : April 8, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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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.

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Drug: INC280 Drug: Gefitinib Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 161 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: 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
Actual Study Start Date : April 5, 2012
Actual Primary Completion Date : June 10, 2016
Actual Study Completion Date : May 27, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arms and Interventions
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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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: Capmatinib

Drug: Gefitinib
Gefitinib 250 mg taken once daily


Outcome Measures
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Primary Outcome Measures :
  1. Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) [ Time Frame: 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.

  2. Phase II : Overall Response Rate (ORR) [ Time Frame: 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.



Secondary Outcome Measures :
  1. Phase Ib and II: Number of Participants With Adverse Events (AEs) [ Time Frame: Up to 421 weeks ]
    Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

  2. Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) [ Time Frame: Up to 421 weeks ]
    Serious adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

  3. Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level [ Time Frame: Up to 417 weeks ]
    Number of patients with dose reductions of INC280 by dose level as a measure of tolerability.

  4. Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level [ Time Frame: Up to 417 weeks ]
    Number of patients with dose interruptions of gefitinib by dose level as a measure of tolerability

  5. Phase II: Overall Survival (OS) [ Time Frame: 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

  6. Phase II: Progression Free Survival (PFS) [ Time Frame: 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.

  7. Phase II: Duration of Response (DoR) [ Time Frame: 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.

  8. Phase I: PK Parameters AUCtau 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) ]

    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


  9. Phase I: PK Parameters Cmax 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) ]

    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


  10. Phase I: PK Parameters Tmax 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) ]

    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


  11. Phase I: PK Parameters 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) ]

    PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis.

    Apparent systemic plasma clearance rate of INC280 and gefitinib


  12. Phase I: PK Parameters Half-life 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) ]

    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



Other Outcome Measures:
  1. Phase I: Percentage of Change From Baseline in C-MET H Score at Cycle 1 Day 15 [ Time Frame: Baseline, Day 15 of cycle 1 (Cycle=28days) ]
    Inhibition of c-MET signaling by pre- and post- treatment immunohistochemistry of p-c-MET


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01610336


Locations
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Australia, Queensland
Novartis Investigative Site
Woolloongabba, Queensland, Australia, 4102
Australia, Victoria
Novartis Investigative Site
East Bentleigh, Victoria, Australia, 3165
Australia
Novartis Investigative Site
Auckland, Australia
Belgium
Novartis Investigative Site
Leuven, Belgium, 3000
China, Guangdong
Novartis Investigative Site
Guangzhou, Guangdong, China, 51000
China, Shanghai
Novartis Investigative Site
Shanghai, Shanghai, China, 200433
China
Novartis Investigative Site
Beijing, China, 100039
Novartis Investigative Site
Guangzhou, China, 510060
France
Novartis Investigative Site
Strasbourg Cedex, France, 67091
Novartis Investigative Site
Toulouse Cedex 9, France, 31059
Germany
Novartis Investigative Site
Frankfurt, Germany, 60590
Novartis Investigative Site
Freiburg, Germany, 79106
Israel
Novartis Investigative Site
Ramat Gan, Israel, 52621
Italy
Novartis Investigative Site
Milano, MI, Italy, 20133
Novartis Investigative Site
Milano, MI, Italy, 20141
Novartis Investigative Site
Modena, MO, Italy, 41124
Japan
Novartis Investigative Site
Koto ku, Tokyo, Japan, 135 8550
Korea, Republic of
Novartis Investigative Site
Gyeonggi do, Korea, Korea, Republic of, 10408
Novartis Investigative Site
Seoul, Korea, Korea, Republic of, 05505
Novartis Investigative Site
Seoul, Seocho Gu, Korea, Republic of, 06591
Novartis Investigative Site
Seoul, Korea, Republic of, 03080
Novartis Investigative Site
Seoul, Korea, Republic of, 06351
Netherlands
Novartis Investigative Site
Maastricht, AZ, Netherlands, 5800
Novartis Investigative Site
Amsterdam, Netherlands, 1066 CX
Novartis Investigative Site
Rotterdam, Netherlands, 3015 GD
Singapore
Novartis Investigative Site
Singapore, Singapore, 169610
Spain
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site
Madrid, Spain, 28034
Taiwan
Novartis Investigative Site
Tainan, Taiwan, 70403
Novartis Investigative Site
Taipei, Taiwan, 10002
Thailand
Novartis Investigative Site
Bangkok, Thailand, 10400
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01610336    
Other Study ID Numbers: CINC280X2202
2011-002569-39 ( EudraCT Number )
First Posted: June 4, 2012    Key Record Dates
Results First Posted: April 8, 2021
Last Update Posted: April 8, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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

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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
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
EGFR
c-MET
Lung cancer
Gefitinib
 Erlotinib
Non-small cell lung cancer (NSCLC)
lung adenocarcinoma
large-cell lung carcinoma
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
 Carcinoma, Bronchogenic
Bronchial Neoplasms
Gefitinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action