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

This is an interventional treatment trial for Non Small Cell Lung Cancer focused on measuring non small cell lung cancer, NSCLC, EGF816, INC280, tyrosine kinase inhibitor, c-MET Read More

Key Inclusion criteria:

• Participants in Phase Ib and Phase II Groups 1 to 4 with histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (Stage IV) NSCLC Participants in Phase II Group 5 must have stage IIIB/IIIC (not amenable to curative surgery, chemoradiation or radiation) or stage IV NSCLC
• Participants in Phase Ib and Phase II Groups 1 to 4 must have 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), or a characterized de novo EGFRT790M mutation.
• 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

• Phase II Group 5 only: Histologically or cytologically confirmed diagnosis of NSCLC (excluding squamous cell carcinoma) with all the following:

  1. EGFR mutations known to be associated with EGFR TKI sensitivity. This must be assessed as part of the participant standard of care by a validated test for EGFR mutations, as per local regulations. Exon 19 del, L858R, either alone or in combination with other EGFR sensitivity mutation assessed by a Clinical Laboratory Improvement Amendments (CLIA) certified USA laboratory or an accredited local laboratory outside the USA must be documented in the participant source documents before the participant can be consented for pre-screening for MET amplification status.
  2. EGFR T790M negative status for participants who have progressed on first or second generation EGFR TKI, or third generation EGFR TKI other than osimertinib, as per tissue-based result from a CLIA-certified USA laboratory or an accredited local laboratory outside of the USA, by a validated test according to local regulations.
  3. MET gene amplification defined as: Gene copy number (GCN) ≥ 5 per tissue-based result from a CLIA-certified USA laboratory or an accredited local laboratory outside of the USA by a test that is validated according to local regulations with results documented in the participant source documents.
  4. Histological transformation from NSCLC into small cell lung cancer (SCLC) following previous EGFR TKI treatment are excluded.
• Participants must have progressed on one prior line of therapy either to first/second generation EGFR TKIs, osimertinib or other third generation EGFR TKIs for advanced/metastatic disease (stage IIIB/IIIC [not amenable to curative surgery, chemoradiation or radiation or stage IV NSCLC).

Key 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.
• Phase II Group 5: Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
• 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.

For Phase II Group 5: Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.

• Undergone a bone marrow or solid organ transplant.
• Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory).

For Group 5: Participants with known history of testing positive for human immunodeficiency virus (HIV) infection, and with a history of Acquired ImmunoDeficiency Syndrome (AIDS) defining opportunistic infections in the last 12 months prior to the first dose of study treatment must be excluded

• 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)

• Participants in Phase Ib and Phase II Groups 1 to 4: 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)

Participants in Phase II Group 5 have out of range laboratory values defined as:

1. Absolute Neutrophil Count (ANC) <1.5 x 109/L (1.5 x 103/μL) without growth factor support
2. Hemoglobin (Hgb) <9 g/dL (90 g/L)
3. Platelets (PLT) <100 x 109/L (100 x 103/μL)
4. Total bilirubin >1.5 x upper limit of normal (ULN)
5. AST and/or ALT > 2.5 x ULN except for participants with liver metastasis, who may not be included if AST and/or ALT > 5 x ULN
6. Alkaline phosphatase (ALP) >5 xULN
7. Calculated creatinine clearance (using Cockcroft-Gault formula) < 50 mL/min
8. Asymptomatic serum amylase increase grade 1 and 2 are allowed if at the beginning of the study is confirmed to have no signs and/or symptoms suggesting pancreatitis or pancreatic injury
9. Serum lipase > ULN - 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.