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A Phase I Dose Defining Study For MK-2206 Combined With Gefitinib In NSCLC Population Enriched With EGFR Mutation

Phase 1
20 Years
Open (Enrolling)
Non Small Cell Lung Cancer

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Trial Information

A Phase I Dose Defining Study For MK-2206 Combined With Gefitinib In NSCLC Population Enriched With EGFR Mutation

Preclinical data from communication with Merck clinical and pre-clinical group support the
application of MK2206 and an EGFR-TKI, and the synergistic effect of this combination. This
proposed study is a phase I dose defining study to define the MTD (Maximum Tolerated Dose)
of MK-2206 when combined with gefitinib.

MK-2206 is a potent, orally active, allosteric inhibitor of human AKT1, AKT2, and AKT3 with
preclinical anti-tumor activity.

This is a Phase I, single-center, open-label, non-randomized, dose-escalation study in
patients with locally advanced or metastatic NSCLC. Patients who previously failed and
progressed through EGFR inhibitor such as erlotinib or gefitinib and up to one line of
chemotherapy will be enrolled into the study. Patients will be administered with oral
MK-2206 and a standard dose of EGFR inhibitor gefitinib.

This study will be conducted in three cohorts to identify a recommended Phase II dose (RP2D)
of MK-2206 in combination with standard dose of gefitinib (250 mg QD). Cohorts of 3
patients will be enrolled sequentially on escalating doses of MK-2206 administered in
combination with a standard dose of gefitinib. Patients will advance doses of MK2206 if 0/3
patients or 0-1/6 develop DLT (Dose-Limiting Toxicity). If 1/3 patient develops DLT, the
cohort will be expanded to 6. If 2/6 patients developed DLT, the dose will be de-escalate
to 90 mg Qwk. The highest dose cohort with 0-1/6 with DLT will be deemed as MTD and used as
cohort expansion for a total of 15 patients.

Inclusion Criteria:

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
ongoing basis.

Exclusion Criteria:

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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

to provide safety assessment and define dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of MK-2206 in combination with gefitinib in NSCLC

Outcome Time Frame:

21 days

Safety Issue:


Principal Investigator

Chih-Hsin Yang, MD, Ph.D

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Taiwan University Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

September 2010

Completion Date:

December 2013

Related Keywords:

  • Non Small Cell Lung Cancer
  • dose defining
  • MK-2206
  • NSCLC With EGFR Mutation
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms