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Completed

NCT Number: 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

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.

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Key information

Conditions

Non-small Cell Lung Cancer Adenocarcinoma Adenocarcinoma of Lung Bronchial Neoplasms Carcinoma Carcinoma, Bronchogenic Carcinoma, Non-Small-Cell Lung Lung Diseases Lung Neoplasms Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Glandular and Epithelial Respiratory Tract Diseases Respiratory Tract Neoplasms Thoracic Neoplasms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Novartis Investigative Site, Woolloongabba, Queensland, Australia

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

INC280

Drug

During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.

Other names: Capmatinib

Gefitinib

Drug

Gefitinib 250 mg taken once daily

Primary outcomes

  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 outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Registry information

Official study 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

Important dates

Study start
2012
Primary completion
2016
Study completion
2020
First posted
Jun 4, 2012
Registry last updated
Apr 8, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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