A Phase 2 Study of the AKT Kinase Inhibitor MK-2206 in Patients With Relapsed Refractory Acute Myelogenous Leukemia
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed AML other than acute
promyelocytic leukemia (2008 WHO classification)
- Patients must have persistent or relapsing disease requiring 2nd salvage therapy
(e.g. treatment for second or higher relapse or for primary refractory disease after
failure of two prior treatment regimens); duration of prior complete remission < 12
months if not refractory disease; patients with prior autologous and allogeneic
hematopoietic stem cell transplantation are eligible if patients are off
immunosuppression for >1 month and have no evidence of active graft versus host
disease (GVHD) except grade 1 skin GVHD
- Patients age >= 60 years with less than two prior treatment regimens not candidates
for or have refused standard chemotherapy, excluding subjects with acute
promyelocytic leukemia (APL) or with favorable cytogenetic abnormalities [inv16,
t(8;21)]
- Patient at the time of enrollment should not be a candidate for allogeneic stem cell
transplantation
- ECOG performance status =< 2
- Serum creatinine or calculated creatinine clearance =< 1.5 x upper limit of normal
(ULN) OR >= 60 mL/min for patients with creatinine levels > 1.5 x institutional ULN
- Serum total bilirubin =< 2 x ULN OR direct bilirubin =< ULN for patients with total
bilirubin levels > 2 x ULN, unless elevation is thought to be due to hepatic
infiltration by AML, Gilbert‟s syndrome, or hemolysis
- AST (SGOT) and ALT (SGPT) =< 2.5 x ULN or =< 5 x ULN unless considered to be
secondary to leukemic involvement
- Fasting serum glucose =< 150 mg/dl
- HBA1c =< 9%
- Female patient of childbearing potential must have a negative serum or urine
pregnancy test beta-hCG within 72 hours prior to receiving the first dose of study
medication; the effects of MK-2206 on the developing human fetus at the recommended
therapeutic dose are unknown; for this reason women of childbearing potential and men
must use two forms of contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation; should
a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, the patient should inform the treatment physician
immediately
- Patient, or the patient‟s legal representative, has voluntarily agreed to participate
by giving written informed consent
- Patient is able to swallow tablets and has no surgical or anatomical condition that
will preclude the patient from swallowing and absorbing oral medications on an
ongoing basis
Exclusion Criteria:
- Patients may not be receiving any other investigational agents
- Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without
complete recovery
- Active uncontrolled infection
- Systemic chemotherapy (with the exception of hydroxyurea) within 14 days (or within 5
half-lives for an investigational agent) prior to first dose of study drug, unless
there is evidence of rapidly progressive disease; persistent chronic clinically
significant toxicities from prior chemotherapy must not be > grade 1
- Patients with CNS involvement
- Patient has known hypersensitivity to the components of study drug or its analogs
- Uncontrolled congestive heart failure, unstable angina pectoris
- Uncontrolled cardiac arrhythmia
- History or current evidence of a myocardial infarction during the last 6 months
- QTc prolongation > 450 msec (Bazett's Formula)
- Congenitally long QT syndrome, has received any marketed or experimental compound in
the last 4 weeks or 5 half lives (whichever is shorter) prior to entering the study
with possible or known effects of QT prolongation
- Patient with symptomatic bradycardia, or a history of clinically significant
bradyarrhythmias such as sick sinus syndrome, 2nd degree AV block (Mobitz Type 2)
- Patient with uncontrolled hypertension (i.e., i.e., sustained systolic blood pressure
>= 160 or diastolic >= 90); patients who are controlled on antihypertensive
medication will be allowed to enter the study
- Patient with poorly controlled diabetes defined as HBA1C > 9%
- Patient is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the study
- Patient is known to be Human Immunodeficiency Virus (HIV)-positive with history of
AIDS defining conditions; or CD4 cells prior to leukemia onset =< 400 cells/mm^3; or
patients receiving antiretroviral therapy that affects CYP3A4 such as protease
inhibitors, efavirenz, nevirapine, or zidovudine
- Patient has active Hepatitis B or C or active Hepatitis A