A Phase I Dose Defining Study For MK-2206 Combined With Gefitinib In NSCLC Population Enriched With EGFR Mutation
1. Patients must have histologically or cytologically-confirmed locally advanced or
metastatic NSCLC who have received EGFR inhibitors (such as gefitinib, erlotinib) for
at least 3 months and progressed and also received at least one line of
platinum-based chemotherapy. In the MTD expansion cohort, patients must have
documented progression on gefitinib, erlotinib, afatinib(BIBW2992) or PF299804 within
4 weeks of starting gefitinib and MK2206 treatment. There should be no anticancer
treatment between above mentioned treatment and protocol treatment.
2. Patient is male or female and ≥ 20 years of age on the day of signing informed
3. Patient must have performance status ≤ 2 on the ECOG Performance Scale.
4. Patient must have adequate organ function
5. Female patient of childbearing potential has a negative serum or urine pregnancy test
β-hCG within 72 hours prior to receiving the first dose of study medication.
6. Patient have completed any targeted therapy (excluding gefitinib, erlotinib or any
small molecule EGFR tyrosine kinase inhibitors ), any chemotherapy regimens and
therapeutic radiation for a minimum of 30 days prior to starting of treatment, and
palliative radiotherapy covering less than 30% bone marrow for a minimum 14 days
prior to starting of treatment.
7. Prior usage of BIBW2992 are allowed if patient failed on BIBW2992 over 3-month
8. Patient, or the patient's legal representative, has voluntarily agreed to participate
by giving written informed consent.
9. Patient is able to swallow capsules and has no surgical or anatomical condition that
will preclude the patient from swallowing and absorbing oral medications on an
1. Patient who has had chemotherapy, radiotherapy, biological therapy, or BIBW2992
(except gefitinib, erlotinib) within 30 days (6 weeks for nitrosoureas, mitomycin C
or bevacizumab), or 5x half-life, whichever is longer, prior to starting of
treatment, or who has not recovered from the adverse events due to previous agents
administered more than 30 days prior to Study Day 1. If the patient has residual
toxicity from prior treatment, toxicity must be ≤ Grade 1.
2. Patients who has had major surgery within 4 weeks prior to starting of treatment or
expect major surgery in the study duration.
3. Patient is currently participating or has participated in a study with an
investigational compound or device within 30 days, or 5x half-life from prior agents,
whichever is longer, of Day 1 of this study.
4. Patient has known active CNS metastases and/or carcinomatous meningitis. However,
patients with CNS metastases who have completed a course of therapy would be eligible
for the study provided they are clinically stable for 1 month prior to entry as
defined as: (1) no evidence of new or enlarging CNS metastasis (2) off steroids or on
a stable dose of steroids.
5. Patient with a primary central nervous system tumor.
6. Patient has known hypersensitivity to the components of study drug or its analogs.
7. Patient has a history or current evidence of heart disease.
8. Patient with evidence of clinically significant bradycardia (HR < 50), or a history
of clinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degree AV
block (Mobitz Type 2), or patients taking non-dihydropyridine calcium channel
blockers, or digoxin.
9. Patient with uncontrolled hypertension (i.e. ≥160/90 mHg). Patients who are
controlled on antihypertensive medication will be allowed to enter the study.
10. Patient at significant risk for hypokalemia (eg. patients on high dose diuretics, or
with recurrent diarrhea)
11. Patient is a known diabetic patient
12. Patient has a history or current evidence of any condition, therapy, or lab
abnormality that might confound the results of the study, interfere with the
patient's participation for the full duration of the study, or is not in the best
interest of the patient to participate, in the opinion of the treating investigator.
13. Patient has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
14. Patient is, at the time of signing informed consent, a regular user (including
"recreational use") of any illicit drugs or had a recent history (within the last
year) of drug or alcohol abuse.
15. Patient is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the study.
16. Patient is known to be Human Immunodeficiency Virus (HIV)-positive
17. Patient currently has active Hepatitis.
18. Patient has symptomatic ascites or pleural effusion. A patient who is clinically
stable following treatment for these conditions is eligible.
19. Patient is receiving treatment with oral corticosteroids (note: inhaled
corticosteroids or premedication for chemotherapy are permitted).
20. Patient is using a potent CYP3A4 inhibitor or inducer (See Appendix 6.2) for a list
of potent CYP3A4 inhibitors or inducers). Patients who have discontinued any of
these medications must have a wash-out period of at least 5 days or at least 5
half-lives of the drug (whichever is longer) prior to the first dose MK-2206.
21. Patient who has received gefitinib and discontinued due to gefitinib-related