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A Phase 2 Study of the AKT Kinase Inhibitor MK-2206 in Patients With Relapsed Refractory Acute Myelogenous Leukemia


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Recurrent Adult Acute Myeloid Leukemia

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Trial Information

A Phase 2 Study of the AKT Kinase Inhibitor MK-2206 in Patients With Relapsed Refractory Acute Myelogenous Leukemia


PRIMARY OBJECTIVES:

I. Determine the proportion of patients achieving CR, CRp or PR as best response within 3
cycles of therapy with MK-2206.

SECONDARY OBJECTIVES:

I. Describe the disease-free survival of patients that achieve CR/CRp. II. Determine the
toxicity profile of single-agent MK-2206 in this patient population.

III. To determine the biologic effects of MK-2206 on leukemia cells.

OUTLINE:

Patients receive AKT inhibitor MK-2206 orally (PO) once weekly. Treatment repeats every 28
days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.


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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Response rate defined as CR, CRp, or PR

Outcome Description:

Response rates will be estimated with 95% confidence intervals, for all subjects and for patient subgroups defined by disease characteristics at registration. The association between response and patient characteristics will be examined by Wilcoxon rank sum test or Fisher Exact test. Disease free survival will be estimated using Kaplan Meier method.

Outcome Time Frame:

12 weeks of treatment

Safety Issue:

No

Principal Investigator

Marina Konopleva

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2010-02186

NCT ID:

NCT01253447

Start Date:

October 2010

Completion Date:

Related Keywords:

  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Recurrent Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109
M D Anderson Cancer CenterHouston, Texas  77030