AKT Inhibitor MK-2206 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT01253447
Collaborator
(none)
19
2
1
42
9.5
0.2

Study Details

Study Description

Brief Summary

This phase II trial is studying how well AKT inhibitor MK-2206 works in treating patients with relapsed or refractory acute myeloid leukemia (AML). AKT inhibitor MK-2206 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

PRIMARY OBJECTIVES:
  1. Determine the proportion of patients achieving Morphologic Complete Response (CR), Morphologic CR with incomplete count recovery (CRp) or Partial Response (PR) as best response within 3 cycles of therapy with MK-2206.
SECONDARY OBJECTIVES:
  1. Describe the disease-free survival of patients that achieve CR/CRp.

  2. Determine the toxicity profile of single-agent MK-2206 in this patient population.

  3. 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
19 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2 Study of the AKT Kinase Inhibitor MK-2206 in Patients With Relapsed Refractory Acute Myelogenous Leukemia
Study Start Date :
Oct 1, 2010
Actual Primary Completion Date :
Oct 1, 2013
Actual Study Completion Date :
Apr 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (Akt inhibitor MK2206)

Akt inhibitor MK2206 200 mg orally once a week for each 28 day treatment cycle

Drug: Akt inhibitor MK2206
200 mg orally (PO) once weekly. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Other Names:
  • MK2206
  • Other: laboratory biomarker analysis
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With a Response of CR, CRp, or PR [12 weeks of treatment]

      Responses defined by International Working Group (IWG) 2003 Response Criteria: Morphologic Complete Response (CR): Peripheral blood counts: No circulating blasts, Neutrophil count >/= 1.0 x10^9/L, Platelet count >/= 100 x10^9/L; Bone marrow aspirate and biopsy: </= 5% blasts, No detectable Auer rods, No extramedullary leukemia. Partial Response (PR): No circulating blasts, Neutrophil count >/=1.0 x10^9/L, Platelet count >/= 100 x10^9/L, >/= 50 % reduction in bone marrow blast to 6% to 25%, or blasts </= 5% if Auer rods are present. Morphologic CR with incomplete count recovery (CRp): All criteria for CR except for residual neutropenia (<1x10^9/L) or thrombocytopenia (<100 x10^9/L).

    2. Number of Participants With Treatment-related Non-hematological Toxicity [Up to 30 days post-treatment]

      Toxicity assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 4.0 (CTCAEv4.0)

    Secondary Outcome Measures

    1. Maximum Percentage Change in Apoptosis [Baseline to 12 courses]

      Peripheral blood Acute Myeloid Leukemia (AML) cells (total 2 x 10^6) used to determine induction of apoptosis in AML stem cells by 4-color flow cytometry assay (CD34/CD38/CD123/annexin). Two-sample t-test conducted to compare changes between the responders and non-responders. Responders are participants who obtain a CR, CRp, or PR, with or without cytogenetic response.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients must have histologically or cytologically confirmed AML other than acute promyelocytic leukemia (2008 World Health Organization (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

    • The Eastern Cooperative Oncology Group (ECOG) performance status =< 2

    • Serum creatinine or calculated creatinine clearance =< 1.5 * upper limit of normal (ULN) OR >= 60 mL/min for patients with creatinine levels > 1.5 * institutional ULN

    • Serum total bilirubin =< 2 * ULN OR direct bilirubin =< ULN for patients with total bilirubin levels > 2 * ULN, unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis

    • asparate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT /SGPT) =< 2.5 * ULN or =< 5 * 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- Human chorionic gonadotropin (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 central nervous system (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

    • corrected Q-T interval (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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UT MD Anderson Cancer Center Houston Texas United States 77030
    2 Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Seattle Washington United States 98109

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Marina Konopleva, MD, PHD, UT MD Anderson Cancer Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01253447
    Other Study ID Numbers:
    • NCI-2010-02186
    • NCI-2010-02186
    • 2010-0243
    • 8731
    • N01CM00039
    • NCT01654978
    First Posted:
    Dec 3, 2010
    Last Update Posted:
    Aug 27, 2018
    Last Verified:
    Jul 1, 2018

    Study Results

    Participant Flow

    Recruitment Details Recruitment Period: October 27, 2010 to October 30, 2012. All recruitment done in medical clinics, either UT MD Anderson Cancer Center or Fred Hutchinson Cancer Research Center.
    Pre-assignment Detail
    Arm/Group Title Treatment (Akt Inhibitor MK2206)
    Arm/Group Description Akt inhibitor MK2206 200 mg orally once a week for each 28 day treatment cycle
    Period Title: Overall Study
    STARTED 19
    COMPLETED 17
    NOT COMPLETED 2

    Baseline Characteristics

    Arm/Group Title Treatment (Akt Inhibitor MK2206)
    Arm/Group Description Akt inhibitor MK2206 200 mg orally once a week for each 28 day treatment cycle
    Overall Participants 19
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    72
    Sex: Female, Male (Count of Participants)
    Female
    7
    36.8%
    Male
    12
    63.2%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    1
    5.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    1
    5.3%
    White
    16
    84.2%
    More than one race
    0
    0%
    Unknown or Not Reported
    1
    5.3%
    Region of Enrollment (participants) [Number]
    United States
    19
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With a Response of CR, CRp, or PR
    Description Responses defined by International Working Group (IWG) 2003 Response Criteria: Morphologic Complete Response (CR): Peripheral blood counts: No circulating blasts, Neutrophil count >/= 1.0 x10^9/L, Platelet count >/= 100 x10^9/L; Bone marrow aspirate and biopsy: </= 5% blasts, No detectable Auer rods, No extramedullary leukemia. Partial Response (PR): No circulating blasts, Neutrophil count >/=1.0 x10^9/L, Platelet count >/= 100 x10^9/L, >/= 50 % reduction in bone marrow blast to 6% to 25%, or blasts </= 5% if Auer rods are present. Morphologic CR with incomplete count recovery (CRp): All criteria for CR except for residual neutropenia (<1x10^9/L) or thrombocytopenia (<100 x10^9/L).
    Time Frame 12 weeks of treatment

    Outcome Measure Data

    Analysis Population Description
    No participant was not evaluable for response.
    Arm/Group Title Treatment (Akt Inhibitor MK2206)
    Arm/Group Description Akt inhibitor MK2206 200 mg orally once a week for each 28 day treatment cycle
    Measure Participants 18
    CR
    0
    0%
    CRp
    1
    5.3%
    PR
    0
    0%
    2. Primary Outcome
    Title Number of Participants With Treatment-related Non-hematological Toxicity
    Description Toxicity assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 4.0 (CTCAEv4.0)
    Time Frame Up to 30 days post-treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Akt Inhibitor MK2206)
    Arm/Group Description Akt inhibitor MK2206 200 mg orally once a week for each 28 day treatment cycle Akt inhibitor MK2206: 200 mg orally (PO) once weekly. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. laboratory biomarker analysis: Correlative studies
    Measure Participants 18
    Neutropenic Fever
    2
    10.5%
    Documented infection
    6
    31.6%
    Pneumonia
    2
    10.5%
    Fever of Unknown Origin
    2
    10.5%
    QTc Prolongation
    4
    21.1%
    Maculopapular Rash
    10
    52.6%
    Hyperglycemia
    12
    63.2%
    Posterior reversible encephalopathy (PRES Syndrome
    1
    5.3%
    3. Secondary Outcome
    Title Maximum Percentage Change in Apoptosis
    Description Peripheral blood Acute Myeloid Leukemia (AML) cells (total 2 x 10^6) used to determine induction of apoptosis in AML stem cells by 4-color flow cytometry assay (CD34/CD38/CD123/annexin). Two-sample t-test conducted to compare changes between the responders and non-responders. Responders are participants who obtain a CR, CRp, or PR, with or without cytogenetic response.
    Time Frame Baseline to 12 courses

    Outcome Measure Data

    Analysis Population Description
    The Assay did not work so no comparison can be made.
    Arm/Group Title Treatment (Akt Inhibitor MK2206)
    Arm/Group Description Akt inhibitor MK2206 200 mg orally once a week for each 28 day treatment cycle
    Measure Participants 0

    Adverse Events

    Time Frame Participants followed for up to a total of 12 cycles (up to 36 weeks), with serious adverse events captured from consent until 30 days after last dose of drug. Overall adverse events were collected from January 26, 2011 to October 22, 2012.
    Adverse Event Reporting Description
    Arm/Group Title Treatment (Akt Inhibitor MK2206)
    Arm/Group Description Akt inhibitor MK2206 200 mg orally once a week for each 28 day treatment cycle
    All Cause Mortality
    Treatment (Akt Inhibitor MK2206)
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Treatment (Akt Inhibitor MK2206)
    Affected / at Risk (%) # Events
    Total 12/19 (63.2%)
    Blood and lymphatic system disorders
    Leukocytosis 1/19 (5.3%) 1
    Neutrophil count decreased 1/19 (5.3%) 1
    Platelet count decreased 1/19 (5.3%) 1
    Cardiac disorders
    Myocardial infarction 1/19 (5.3%) 1
    General disorders
    Fatigue 3/19 (15.8%) 3
    Infections and infestations
    Anorectal infection 1/19 (5.3%) 1
    Febrile neutropenia 5/19 (26.3%) 6
    Infections 2/19 (10.5%) 2
    Sepsis 3/19 (15.8%) 3
    Soft Tissue Infection (cellulitis) 1/19 (5.3%) 1
    Investigations
    Pain in extremity 1/19 (5.3%) 1
    Metabolism and nutrition disorders
    Hyperglycemia 5/19 (26.3%) 6
    Hyperkalemia 1/19 (5.3%) 1
    Hypertension 1/19 (5.3%) 1
    Musculoskeletal and connective tissue disorders
    Back pain 1/19 (5.3%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms 1/19 (5.3%) 1
    Nervous system disorders
    Reversible posterior leukoencephalopathy syndrome 1/19 (5.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Hypoxia 1/19 (5.3%) 1
    Lung infection 1/19 (5.3%) 1
    Bilateral carck in lungs 1/19 (5.3%) 1
    Skin and subcutaneous tissue disorders
    Pruritus 1/19 (5.3%) 1
    Rash acneiform 1/19 (5.3%) 1
    Rash maculo-papular 4/19 (21.1%) 4
    Mucor fungal infection 1/19 (5.3%) 1
    Other (Not Including Serious) Adverse Events
    Treatment (Akt Inhibitor MK2206)
    Affected / at Risk (%) # Events
    Total 19/19 (100%)
    Blood and lymphatic system disorders
    Edema limbs 3/19 (15.8%) 3
    Cardiac disorders
    Electrocardiogram QT corrected interval prolonged 1/19 (5.3%) 1
    Sinus tachycardia 1/19 (5.3%) 1
    Ear and labyrinth disorders
    Hearing impaired 1/19 (5.3%) 1
    Endocrine disorders
    Hidradenitis 1/19 (5.3%) 1
    Eye disorders
    Periorbital edema 1/19 (5.3%) 1
    Gastrointestinal disorders
    Anorexia 2/19 (10.5%) 2
    Diarrhea 10/19 (52.6%) 11
    Poor Appetitue, Gastrointestinal 1/19 (5.3%) 1
    Hemorrhoids 1/19 (5.3%) 1
    Mucositis oral 2/19 (10.5%) 2
    Nausea 2/19 (10.5%) 2
    Oral hemorrhage 1/19 (5.3%) 1
    Sore throat 1/19 (5.3%) 1
    Vomiting 2/19 (10.5%) 2
    General disorders
    Epistaxis 3/19 (15.8%) 3
    Fatigue 8/19 (42.1%) 8
    Infections and infestations
    Throat Yeast infection 1/19 (5.3%) 1
    Injury, poisoning and procedural complications
    Fall 1/19 (5.3%) 1
    Investigations
    Chills 1/19 (5.3%) 1
    Fever 3/19 (15.8%) 3
    Pancytopenia 1/19 (5.3%) 1
    Metabolism and nutrition disorders
    Creatinine increased 1/19 (5.3%) 1
    Hyperglycemia 13/19 (68.4%) 26
    Hypokalemia 1/19 (5.3%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/19 (5.3%) 1
    Back Pain 1/19 (5.3%) 1
    Bone Pain 1/19 (5.3%) 1
    Gait disturbance 1/19 (5.3%) 1
    Generalized muscle weakness 1/19 (5.3%) 1
    Pain 2/19 (10.5%) 5
    Nervous system disorders
    Dizziness 1/19 (5.3%) 1
    Headache 3/19 (15.8%) 3
    Intracranial hemorrhage 1/19 (5.3%) 1
    Tremor 1/19 (5.3%) 1
    Psychiatric disorders
    Anxiety 1/19 (5.3%) 1
    Depression 1/19 (5.3%) 1
    Insomnia 2/19 (10.5%) 2
    Irritability 1/19 (5.3%) 1
    Renal and urinary disorders
    Hematuria 1/19 (5.3%) 1
    acute renal insufficiency, elevated creatinine 1/19 (5.3%) 1
    Urinary frequency 1/19 (5.3%) 1
    Urinary tract pain 1/19 (5.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Cough 4/19 (21.1%) 4
    Dyspnea 10/19 (52.6%) 11
    Laryngitis 1/19 (5.3%) 1
    Skin and subcutaneous tissue disorders
    Bruising 2/19 (10.5%) 2
    Dry skin 1/19 (5.3%) 1
    Flushing 1/19 (5.3%) 1
    Hyperhidrosis 1/19 (5.3%) 1
    Pruritus 4/19 (21.1%) 4
    Rash maculo-papular 5/19 (26.3%) 6
    Night Sweats 1/19 (5.3%) 1
    Petechiae 1/19 (5.3%) 1
    Skin ulceration 3/19 (15.8%) 3
    Leukemia Cutis 1/19 (5.3%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Marina Konopleva, MD, PHD / Professor
    Organization The University of Texas (UT) MD Anderson Cancer Center
    Phone
    Email CR_Study_Registration@mdanderson.org
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01253447
    Other Study ID Numbers:
    • NCI-2010-02186
    • NCI-2010-02186
    • 2010-0243
    • 8731
    • N01CM00039
    • NCT01654978
    First Posted:
    Dec 3, 2010
    Last Update Posted:
    Aug 27, 2018
    Last Verified:
    Jul 1, 2018