Patient case: 50-year-old female with Lung cancer. Genetic variant: EGFR (L858R). Other conditions: Lupus.

Clinical trial: Study of Safety and Efficacy of EGF816 in Combination With INC280 in Non-small Cell Lung Cancer Patients With EGFR Mutation.

Summary: The study determines 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.


Eligibility: Inclusion criteria:
  -  Patients with histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (Stage IV) non-small cell lung cancer
  -  Patients 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 first and second 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. Additional management of the patients would be provided by a physician with expertise in management of HBV, if needed.
  -  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 (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.
  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 chemotherapy in the advanced setting are allowed).
  -  Previous treatment with a c-MET inhibitor or HGF-targeting therapy.
  -  Patients with brain metastases. However, patients with controlled brain metastases may participate in the trial. These patients must have completed any radiation therapy and/or surgery > 2 weeks prior to the first dose of study treatment and remain asymptomatic.
  -  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, 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 and 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.

Relevance to patient case: definitely relevant