Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Study of Safety and Efficacy of EGFR-TKI EGF816 in Combination With cMET Inhibitor INC280 in Non-small Cell Lung Cancer Patients With EGFR Mutation.

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: NCT02335944
Recruitment Status : Active, not recruiting
First Posted : January 12, 2015
Last Update Posted : August 20, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE October 9, 2014
First Posted Date  ICMJE January 12, 2015
Last Update Posted Date August 20, 2019
Actual Study Start Date  ICMJE January 13, 2015
Estimated Primary Completion Date September 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 19, 2017)
  • Phase Ib: Incidence of dose limiting toxicities (DLTs) and Estimation of the Maximum tolerated dose (MTD) or Recommended Phase II dose (RP2D) [ Time Frame: First 28 days of treatment ]
  • Phase II Groups 1, 2 and 3: Overall Response Rate per RECIST 1.1 [ Time Frame: At least 24 weeks ]
    ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
  • Phase II Group 4 Incidence and severity of AEs/SAEs, dose interruptions, reductions and dose intensity [ Time Frame: At least 24 weeks ]
    Frequency of treatment-emergent adverse events
Original Primary Outcome Measures  ICMJE
 (submitted: January 7, 2015)
  • Phase Ib : Incidence of dose limiting toxicities (DLTs) [ Time Frame: First 28 days of treatment ]
  • Phase II : objective response rate per RECIST v1.1 [ Time Frame: From date of randomization until date of first documented progression or date of death from any cause, whichever comes first, assessed up to 9 months ]
Change History Complete list of historical versions of study NCT02335944 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 19, 2017)
  • Safety of INC280 and EGF816: Incidence and severity of AEs and SAEs, including changes in hematology and chemistry values, vital signs and ECGs (Phase I/II) [ Time Frame: At least 24 weeks ]
    Assessment of the safety of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment
  • Frequency of dose interruption, frequency of reduction and dose intensity (Phase I/II) [ Time Frame: At least 24 weeks ]
    Assessment of the tolerability of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment
  • Overall Response Rate (Phase Ib and Phase II Group 4) [ Time Frame: At least 24 weeks ]
    ORR is defined as proportion of patients with best overall response of (PR+CR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
  • Disease Control Rate (Phase I/II) [ Time Frame: At least 24 weeks ]
    DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
  • Progression Free Survival (Phase I/II) [ Time Frame: At least 24 weeks ]
    Progression-free survival (PFS). PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1
  • Duration of Response (Phase I/II) [ Time Frame: At least 24 weeks ]
    DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1
  • Overall Survival (Phase I/II) [ Time Frame: At least 24 weeks ]
    OS is defined as the time from first dose of the study treatment to the date of death due to any cause.
  • Plasma concentration versus time profiles [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Area under the plasma concentration versus time curve (AUC) of EGF816 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Area under the plasma concentration versus time curve (AUC) of INC280 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Peak plasma concentration (Cmax) of INC280 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Peak plasma concentration (Cmax) of EGF816 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Elimination half life (t1/2) of INC280 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Elimination half life (t1/2) of EGF816 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Time to Response (Phase I/II) [ Time Frame: At least 24 weeks ]
    TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Original Secondary Outcome Measures  ICMJE
 (submitted: January 7, 2015)
  • Number of participants with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: From baseline until 30 days post study treatment ]
  • Safety of INC280 and EGF816 [ Time Frame: continuously during study until 30 days after post study treatment ]
    Safety by looking at hematology and chemistry values, vital signs and electrocardiograms (ECGs). 1 cycle = 28 days
  • Frequency of dose interruption, frequency of reduction and dose intensity [ Time Frame: Day 1 of each cycle, average 9 months ]
    1 cycle = 28 days
  • objective response rate (phase Ib only) [ Time Frame: baseline, every 8 weeks until disease progression, consent withdraw or death up to 9 months ]
  • disease control rate [ Time Frame: baseline, every 8 weeks until disease progression, consent withdraw or death up to 9 months ]
  • progression free survival [ Time Frame: baseline, every 8 weeks until disease progression, consent withdraw or death up to 9 months ]
  • duration of response [ Time Frame: baseline, every 8 weeks until disease progression, consent withdraw or death up to 9 months ]
  • overall survival [ Time Frame: start of treatment until death, average 9 months. ]
  • Plasma concentration versus time profiles [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Area under the plasma concentration versus time curve (AUC) of EGF816 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Area under the plasma concentration versus time curve (AUC) of INC280 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Peak plasma concentration (Cmax) of INC280 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Peak plasma concentration (Cmax) of EGF816 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Elimination half life (t1/2) of INC280 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
  • Elimination half life (t1/2) of EGF816 [ Time Frame: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Safety and Efficacy of EGFR-TKI EGF816 in Combination With cMET Inhibitor INC280 in Non-small Cell Lung Cancer Patients With EGFR Mutation.
Official Title  ICMJE A Phase Ib/II, Multicenter, Open-label Study of EGF816 in Combination With INC280 in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer.
Brief Summary The study is designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of EGF816 in combination with INC280 and to estimate the preliminary anti-tumor activity of EGF816 in combination with INC280 in patients with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Non Small Cell Lung Cancer
Intervention  ICMJE
  • Drug: INC280
    cMET inhibitor
  • Drug: EGF816
    EGFR-TKI
Study Arms  ICMJE Experimental: INC280 plus EGF816
Recruitment in Phase I dose escalation part is completed. Recruitment in Phase II dose expansion is ongoing.
Interventions:
  • Drug: INC280
  • Drug: EGF816
Publications * Jia Y, Juarez J, Li J, Manuia M, Niederst MJ, Tompkins C, Timple N, Vaillancourt MT, Pferdekamper AC, Lockerman EL, Li C, Anderson J, Costa C, Liao D, Murphy E, DiDonato M, Bursulaya B, Lelais G, Barretina J, McNeill M, Epple R, Marsilje TH, Pathan N, Engelman JA, Michellys PY, McNamara P, Harris J, Bender S, Kasibhatla S. EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor. Cancer Res. 2016 Mar 15;76(6):1591-602. doi: 10.1158/0008-5472.CAN-15-2581. Epub 2016 Jan 29.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 30, 2018)
177
Original Estimated Enrollment  ICMJE
 (submitted: January 7, 2015)
80
Estimated Study Completion Date  ICMJE July 31, 2020
Estimated Primary Completion Date September 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • Histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (Stage IV) NSCLC
  • Locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR T790M mutation (or other rare activating mutations that confer sensitivity to 1st and 2nd generation EGFR inhibitors (e.g. L861Q, G719X, S768I)
  • Presence of at least one measurable lesion according to RECIST v.1.1
  • ECOG performance status ≤1
  • Patients must be screened for HBV. Patients who are either HBsAg positive or HBV-DNA positive must be willing and able to take antiviral therapy 1-2 weeks prior to 1st dose of EGF816 treatment and continue on antiviral therapy for at least 4 weeks after the last dose of EGF816.
  • Patients must be screened for HCV. Patients must have negative hepatitis C antibody (HCV Ab) or are HCV Ab positive but with an undetectable level of HCV-RNA. Note: patients with detectable HCV-RNA are not eligible for the study.
  • Phase Ib only: documented progression of disease according to RECIST v1.1 while on continuous treatment with EGFR TKI (e.g.: erlotinib, gefitinib or afatinib).
  • Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant) only: Patients demonstrated a documented clinical benefit (CR (any duration), PR (any duration), or SD for at least 6 months) on prior EGFR TKI (e.g. erlotinib, gefitinib or afatinib, and subsequently demonstrated progression according to RECIST v1.1.
  • Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve) only: Advanced NSCLC patients who have not been previously treated with any therapy known to inhibit EGFR and harbor de novo T790M mutation .
  • Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic) only: patients must harbor an EGFR activating mutation and must be naïve from any line of systemic antineoplastic therapy in the advanced setting.
  • Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1L (treatment-naïve), 2//3L antineoplastic): All patients must harbor an EGFR activating mutation and 2/3L patients must have failed (defined as intolerance to treatment or documented disease progression) a maximum of 2 prior lines of antineoplastic therapy in the advanced setting

Exclusion Criteria:

  • Phase Ib:

    • More than one previous treatment line with erlotinib, gefitinib or afatinib
    • Previous treatment with any investigational agent known to inhibit EGFR (mutant or wild-type)
    • Patients who have received more than three prior lines of antineoplastic therapies (including EGFR TKI) in advanced setting.
  • Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant):

    • More than 3 prior lines of systemic antineoplastic therapies (including EGFR TKI) in the advanced setting
    • More than 1 previous treatment line with 1st or 2nd generation EGFR TKI (e.g. erlotinib, gefitinib, afatinib) in the advanced setting
    • Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
    • Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
  • Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve):

    • More than two previous treatment lines of systemic antineoplastic therapies in the advanced setting
    • Previous treatment with an investigational or marketed agent that inhibits EGFR. EGFR inhibitors include (but not limited to) all generations of EGFR TKI (e.g.erlotinib, gefitinib, afatinib, AZD9291, CO-1686, ASP8273, EGF816) or other anti-EGFR or EGFR monoclonal antibody therapy or dual TKI inhibitors.
  • Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic):

    • De novo EGFR T790M mutation identified by central assessment
    • Previous treatment with any systemic antineoplastic therapy in the advanced setting (NSCLC stage IIIB or IV. Patients who received only one cycle of antineoplastic therapy in the advanced setting are allowed).
  • Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1/3L antineoplastic):

    • More than 2 prior lines of systemic antineoplastic therapies in the advanced setting
    • Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
    • Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
  • Previous treatment with a c-MET inhibitor or HGF-targeting therapy.
  • Patients with symptomatic brain metastases.
  • Presence or History of another malignancy. Exception: Patients who have been disease-free for 3 years, or patients with a history of adequately treated in-situ carcinoma of the uterine cervix, completely resected basal or squamous cell carcinoma, non-melanomatous cancer of skin, history of stage IA melanoma that has been cured, are eligible.
  • Undergone a bone marrow or solid organ transplant.
  • Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory)
  • Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use at the time of study entry except for control of brain metastases, topical applications, inhaled sprays, eye drops or local injections
  • Patients with clinically significant, uncontrolled cardiovascular disease
  • Presence or history of interstitial lung disease or interstitial pneumonitis
  • Patients have not recovered from all toxicities related to prior anticancer therapies to grade ≤1 (CTCAE v 4.03)
  • Patients have out of range laboratory values defined as

    1. Absolute Neutrophil Count (ANC) <1.5 x 109/L (1.5x103/µL)
    2. Hemoglobin (Hb) <9 g/dL (90g/L)
    3. Platelets (PLT) <75 x 109/L (75x103/µL)
    4. Total bilirubin >1.5 x upper limit of normal (ULN).
    5. AST and/or ALT >3 x ULN
    6. Patients with liver metastasis may not be included if AST and/or ALT >5 xULN
    7. Alkaline phosphatase (ALP) >5 xULN
    8. Calculated creatinine clearance < 45mL/min (0.75 mL/sec)using Cockroft-Gault formula
    9. Asymptomatic serum amylase or lipase > Grade 2
    10. Serum amylase or serum lipase CTCAE grade ≥ 1 with signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g. elevated P-amylase, abnormal imaging findings of pancreas, etc)
  • Patients have the following laboratory values outside of the laboratory normal limits or cannot be corrected to within normal limits with supplements during screening: Potassium, Magnesium, Phosphorus, Total calcium (corrected for serum albumin)

Other protocol-defined inclusion/exclusion criteria may apply.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   France,   Germany,   Italy,   Korea, Republic of,   Norway,   Singapore,   Spain,   Taiwan,   United States
Removed Location Countries Hong Kong
 
Administrative Information
NCT Number  ICMJE NCT02335944
Other Study ID Numbers  ICMJE CINC280X2105C
2014-000726-37 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
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

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP