Phase II Trial of MK-2206 (an AKT Inhibitor) in Combination With Endocrine Therapy in Patients With Hormone Receptor Positive Breast Cancer
1. Patient must have clinical stage IV invasive mammary carcinoma, previously documented
by histological analysis, which is ER-positive and/or PR-positive by
immunohistochemistry (IHC), which had previous endocrine therapy in the metastatic
setting or had metastatic recurrence within 6 months of adjuvant endocrine therapy.
Patients may have either measurable or non-measurable disease, both are allowed. Any
number of prior hormone or chemotherapy agents are acceptable.
2. Patient is female and greater than or equal to 18 years of age on the day of signing
3. Patient must have performance status of 0 or 1 on the ECOG Performance Scale.
4. Patient must have adequate organ function as indicated by the following laboratory
Absolute neutrophil count (ANC) greater than or equal to 1,500 /μL Platelets greater
than or equal to 100,000 /μL Hemoglobin greater than or equal to 9 g/dL
Serum creatinine or calculated creatinine clearance† - less than or equal to 1.5 x
upper limit of normal (ULN) OR greater than or equal to 60 mL/min for patients with
creatinine levels greater than 1.5 x institutional ULN
Serum total bilirubin less than or equal to 1.5 x ULN OR direct bilirubin less than
or equal to ULN for patients with total bilirubin levels greater than 1.5 x ULN AST
(SGOT) and ALT (SGPT) less than or equal to 2.5 x ULN or less than or equal to 5 x
ULN in patients with known liver metastasis
Prothrombin time (PT)/INR less than or equal to 1.2 x ULN Partial thromboplastin time
(PTT) less than or equal to 1.2 x ULN
Metabolic -HBA1C less than or equal to 8%
† Creatinine clearance should be calculated per institutional standard.
‡ Fasting is defined as at least 8 hours without oral intake.
5. Female patient of childbearing potential must have a negative serum or urine
pregnancy test β-hCG within 72 hours prior to receiving the first dose of study
6. Post-menopausal female subjects should be defined prior to protocol enrollment by any
of the following:
- Subjects at least 55 years of age
- Subjects under 55 years of age and amenorrheic for at least 12 months or
follicle-stimulating hormone (FSH) values greater than or equal to 40 IU/L and
estradiol levels less or equal to 20IU/L
- Prior bilateral oophorectomy or prior radiation castration with amenorrhea for
at least 6 months
7. Patient, or the patient's legal representative, has voluntarily agreed to participate
by giving written informed consent.
8. 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
9. Patients may receive concurrent radiation therapy to painful bone metastases or areas
of impending bone fracture as long as radiation therapy is initiated prior to study
entry. Patients who have received prior radiotherapy must have recovered from any
toxicity induced by this treatment (toxicity grade less than or equal to 1).
10. Patients must be disease-free of prior invasive cancers for greater than 5 years with
the exception of basal or squamous cancer of the skin or cervical carcinoma in situ.
1. Patient who has had chemotherapy, radiotherapy, or biological therapy within 3 weeks
(6 weeks for nitrosoureas, mitomycin C or bevacizumab), or who has not recovered from
the adverse events due to previous agents administered more than 4 weeks prior to
Study Day 1. If the patient has residual toxicity from prior treatment,toxicity must
be less than or equal to Grade 1.
2. Patients must be at least 4 weeks post major surgical procedure, and all surgical
wounds must be fully healed.
3. Patient is currently participating or has participated in a study with an
investigational compound or device within 30 days of Study Day 1.
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 at least 1 month prior to entry
as defined as: (1) no evidence of new or enlarging CNS metastasis (2)off steroids
that are used to minimize surrounding brain edema.
5. Patient has 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 clinically significant heart disease
- Clinically significant congestive heart failure, unstable angina pectoris,
- Clinically significant cardiac arrhythmia, history or current evidence of a
myocardial infarction during the last 6 months,and/or a current ECG tracing that
is abnormal in the opinion of the treating Investigator.
- Baseline QTc prolongation greater than 450 msec (Bazett's Formula). Medications
included in Arizona CERT Lists 1 and 2 (Appendix D) must be excluded. The
concomitant use of drugs that are associated with increased risk for QT
prolongation should be avoided in patients with congenital long QT syndrome
(Appendix D, Arizona CERT List 3). Similarly, the concomitant use of drugs that
are weakly associated with QT prolongation should be generally avoided (Appendix
D, Arizona CERT List 4). Arizona CERT List 3 and 4 drugs should be used at the
discretion of the Investigator and restricted where applicable. Any therapy
given with these drugs should be used with caution, and patients receiving these
medications should be carefully monitored.
8. Patient with evidence of clinically significant bradycardia (heart rate less than 50
), or a history of clinically significant bradyarrhythmias such as sick sinus
syndrome, 2nd degree AV block (Mobitz Type 2), or patients taking beta blockers,
non-dihydropyridine calcium channel blockers, or digoxin.
9. Patient with uncontrolled hypertension (i.e., 160/90 mHg SiBP). Patients who are
controlled on antihypertensive medication will be allowed to enter the study.
10. Patient at significant risk for hypokalemia (e.g., patients on high dose diuretics,
or with recurrent diarrhea).
11. Patient with poorly controlled diabetes defined as HbA1C greater than 8%.
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 has known history of Hepatitis B or C or active Hepatitis A.
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 are permitted).