Clinical Trials /

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.

NCT02335944

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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: 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.

Clinical Trial IDs

  • ORG STUDY ID: CINC280X2105C
  • SECONDARY ID: 2014-000726-37
  • NCT ID: NCT02335944

Conditions

  • Non Small Cell Lung Cancer

Interventions

DrugSynonymsArms
INC280INC280 plus EGF816
EGF816INC280 plus EGF816

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
INC280 plus EGF816ExperimentalRecruitment in Phase I dose escalation part is completed. Recruitment in Phase II dose expansion is ongoing.
  • INC280
  • EGF816

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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)

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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
Measure:Frequency of dose interruption, frequency of reduction and dose intensity (Phase I/II)
Time Frame:At least 24 weeks
Safety Issue:
Description: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
Measure:Overall Response Rate (Phase Ib and Phase II Group 4)
Time Frame:At least 24 weeks
Safety Issue:
Description: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)
Measure:Disease Control Rate (Phase I/II)
Time Frame:At least 24 weeks
Safety Issue:
Description: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)
Measure:Progression Free Survival (Phase I/II)
Time Frame:At least 24 weeks
Safety Issue:
Description: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
Measure:Duration of Response (Phase I/II)
Time Frame:At least 24 weeks
Safety Issue:
Description: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
Measure:Overall Survival (Phase I/II)
Time Frame:At least 24 weeks
Safety Issue:
Description:OS is defined as the time from first dose of the study treatment to the date of death due to any cause.
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Time to Response (Phase I/II)
Time Frame:At least 24 weeks
Safety Issue:
Description: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)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • non small cell lung cancer
  • NSCLC
  • EGF816
  • INC280
  • tyrosine kinase inhibitor
  • c-MET

Last Updated

July 9, 2021