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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.

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ClinicalTrials.gov Identifier: NCT02335944
Recruitment Status : Recruiting
First Posted : January 12, 2015
Last Update Posted : October 9, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Non Small Cell Lung Cancer Drug: INC280 Drug: EGF816 Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 177 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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.
Actual Study Start Date : January 13, 2015
Estimated Primary Completion Date : February 28, 2019
Estimated Study Completion Date : December 23, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: INC280 plus EGF816
Recruitment in Phase I dose escalation part is completed. Recruitment in Phase II dose expansion is ongoing.
Drug: INC280
cMET inhibitor

Drug: EGF816
EGFR-TKI




Primary Outcome Measures :
  1. 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 ]
  2. 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)

  3. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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)

  4. 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)

  5. 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

  6. 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

  7. 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.

  8. 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 ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. 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 ]
  13. 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 ]
  14. 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 ]
  15. 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)



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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:

  • 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.


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): NCT02335944


Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com

Locations
United States, California
City of Hope National Medical Center SC Completed
Duarte, California, United States, 91010
United States, Florida
H. Lee Moffitt Cancer Center & Research Institute H Lee Moffitt Completed
Tampa, Florida, United States, 33612
United States, Massachusetts
Massachusetts General Hospital Mass General Recruiting
Boston, Massachusetts, United States, 02114
Contact: Lecia Sequist    617-724-4000      
Contact: Beth Kennedy    +1 617 724 1223    EAKENNEDY@mgh.harvard.edu   
Principal Investigator: Lecia Sequist         
Australia, Victoria
Novartis Investigative Site Active, not recruiting
Melbourne, Victoria, Australia, 3000
Canada, Alberta
Novartis Investigative Site Active, not recruiting
Edmonton, Alberta, Canada, T6G 1Z2
France
Novartis Investigative Site Active, not recruiting
Marseille cedex 05, France, 13385
Novartis Investigative Site Completed
Villejuif Cedex, France, 94805
Germany
Novartis Investigative Site Active, not recruiting
Heidelberg, Baden-Württemberg, Germany, 69126
Novartis Investigative Site Active, not recruiting
Koeln, Nordrhein-Westfalen, Germany, 50937
Italy
Novartis Investigative Site Active, not recruiting
Bologna, BO, Italy, 40138
Novartis Investigative Site Completed
Modena, MO, Italy, 41124
Novartis Investigative Site Active, not recruiting
Perugia, PG, Italy, 06129
Korea, Republic of
Novartis Investigative Site Active, not recruiting
Seoul, Korea, Korea, Republic of, 05505
Norway
Novartis Investigative Site Active, not recruiting
Oslo, Norway, NO-0424
Singapore
Novartis Investigative Site Active, not recruiting
Singapore, Singapore, 119228
Novartis Investigative Site Active, not recruiting
Singapore, Singapore, 169610
Spain
Novartis Investigative Site Active, not recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Active, not recruiting
La Coruna, Galicia, Spain, 15006
Novartis Investigative Site Active, not recruiting
Las Palmas De Gran Canarias, Las Palmas De Gran Canaria, Spain, 35016
Novartis Investigative Site Active, not recruiting
Madrid, Spain, 28007
Novartis Investigative Site Active, not recruiting
Madrid, Spain, 28041
Taiwan
Novartis Investigative Site Active, not recruiting
Taipei, Taiwan ROC, Taiwan, 10041
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02335944     History of Changes
Other Study ID Numbers: CINC280X2105C
2014-000726-37 ( EudraCT Number )
First Posted: January 12, 2015    Key Record Dates
Last Update Posted: October 9, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
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


Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
non small cell lung cancer,
NSCLC,
EGF816,
INC280,
tyrosine kinase inhibitor,
c-MET

Additional relevant MeSH terms:
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