Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Acute Myeloid Leukemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01907815
First received: July 22, 2013
Last updated: September 16, 2014
Last verified: August 2014
  Purpose

This phase II trial studies how well trametinib and Akt inhibitor GSK2141795 work in treating patients with acute myeloid leukemia. Trametinib and Akt inhibitor GSK2141795 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.


Condition Intervention Phase
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
Untreated Adult Acute Myeloid Leukemia
Drug: Akt inhibitor GSK2141795
Drug: trametinib
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Study of MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Acute Myeloid Leukemia (AML) With RAS Mutations

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Complete response rate (CRR, defined as CR+CRp) assessed by the Response Evaluation Criteria in Solid Tumors [ Time Frame: Up to 16 weeks ] [ Designated as safety issue: No ]
    The chi-square test or the Fisher's exact test will be applied to assess the association between categorical variables. 95% confidence interval will be estimated for the combination regimen.


Secondary Outcome Measures:
  • Time to progression [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
    Estimated using the Kaplan-Meier method. Log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be used to include multiple covariates in the time-to-event analysis.

  • Progression free survival [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
    Estimated using the Kaplan-Meier method. Log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be used to include multiple covariates in the time-to-event analysis.

  • Overall survival [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
    Estimated using the Kaplan-Meier method. Log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be used to include multiple covariates in the time-to-event analysis.

  • Incidence of adverse events (AE) assessed by the National Cancer Institute CTCAE version 4.0 [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: Yes ]
    Toxicity data will be summarized using frequency tables by AE severity and by relationship to study drug. Toxicity rate with 95% credible interval will be estimated for the combination regimen.


Other Outcome Measures:
  • Maximum percentage change in total and phospho-proteins [ Time Frame: Baseline to 12 weeks post therapy ] [ Designated as safety issue: No ]
    Change in total and phospho-proteins assessed by densitometric quantitative data by western blot analysis, or mean fluorescent intensities by flow cytometry and will be assessed for each patient for all time points and graphically plotted for each dose level.

  • Percentage change in cellular proteins [ Time Frame: Baseline to day 28 post treatment ] [ Designated as safety issue: No ]
    The 95% confidence interval will be assessed.


Estimated Enrollment: 45
Study Start Date: October 2013
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (trametinib, Akt inhibitor GSK2141795)
Patients receive trametinib PO QD and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Akt inhibitor GSK2141795
Given PO
Other Name: GSK2141795
Drug: trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • Mekinist
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the proportion of patients achieving complete remission (CR) or CR with incomplete recovery of platelets (CRp) as best response within 4 cycles of therapy of trametinib in combination with GSK2141795 (Akt inhibitor GSK2141795) in acute myeloid leukemia (AML) patients with rat sarcoma (RAS) mutations.

SECONDARY OBJECTIVES:

I. To determine the disease-free survival of patients achieving CR/CRp. II. To determine the duration of response of patients achieving CR/CRp. III. To determine the toxicity profile of trametinib in combination with GSK2141795 in this patient population.

IV. To determine the biologic effects of trametinib in combination with GSK2141795 on leukemia cells.

OUTLINE:

Patients receive trametinib orally (PO) once daily (QD) and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 weeks.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed AML, other than acute promyelocytic leukemia, as defined by the 2008 World Health Organization (WHO) criteria that have relapsed or refractory to standard chemotherapy; unsuitable for standard chemotherapy or unwilling to undergo standard chemotherapy; subjects >= 60 years of age with newly diagnosed AML who are not candidates for or have refused standard chemotherapy are eligible
  • 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
  • Positive for RAS mutation (neuroblastoma RAS viral [v-ras] oncogene homolog [NRAS] codon 12, 13, 61 mutation or Kirsten rat sarcoma viral oncogene homolog [KRAS] codon 12, 13, 61 mutation) at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory prior to study entry; mutational testing will be performed on bone marrow sample and/or peripheral blood; patients with previously known RAS mutations prior to study entry may be considered positive for RAS mutation for eligibility prior to a CLIA-certified laboratory confirmation of such a mutation at the discretion of the investigator; (appropriate blood and/or bone marrow samples must be taken for RAS determination and submitted to a CLIA-certified laboratory prior to study entry); however, if such a mutation is not confirmed by the M D Anderson Cancer Center (MDACC)/other center's CLIA-certified laboratory, the patient may be permitted to stay on the study if they wish and consent to do so but such patients' data will be analyzed separately
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 4 weeks
  • Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
  • All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) prior to the first dose of the study drug
  • Serum total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (isolated total bilirubin > 1.5 institutional ULN is acceptable if bilirubin is fractionated and direct bilirubin is < 35%)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN
  • Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault formula) >= 60 mL/min
  • Fasting serum glucose =< 150 mg/dl (fasting is defined as at least 8 hours without oral intake)
  • Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) AND at least 50%; LVEF can be assessed by either echocardiogram (ECHO) or multi gated acquisition scan (MUGA)
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study, during the study participation, and for four months after the last dose of drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • History of another malignancy; exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above
  • History of interstitial lung disease or pneumonitis
  • Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization; daily or weekly chemotherapy (with the exception of hydroxyurea) without the potential for delayed toxicity within 14 days prior to randomization unless there is evidence of rapidly progressive disease
  • Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib/GSK2141795 and during the study
  • Symptomatic or untreated leptomeningeal disease or brain metastases or spinal cord compression
  • Patients with abnormal fasting glucose values (> 150 mg/dl) at screening will be excluded; in addition, patients with type 1 diabetes will also be excluded; however, patients with type 2 diabetes will be allowed if diagnosed >= 6 months prior to enrollment, and if presenting with regular hemoglobin A1C (HbA1C) =< 8% at screening
  • Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO) or GSK2141795
  • Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:

    • Other anti-cancer therapy while on study treatment; (Note: megestrol [Megace] if used as an appetite stimulant is allowed)
    • Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
    • The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], gingko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)

      • Note: for proliferative disease, hydroxyurea will be allowed during weeks 1 and 2 of cycle 1 of study; hydroxyurea may be started or the dose changed during that 2-week period if it is clinically indicated; if a subject not previously on a stable dose of hydroxyurea needs to begin hydroxyurea or a subject on a stable dose needs to have their dose increased during the first 2 weeks, the investigator will notify the clinical team that this has been initiated
  • Drugs that potently inhibit cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) should either be prohibited or used with caution; drugs which are strong inducers of cytochrome P450 family 3, subfamily A (CYP3A) should also be prohibited; drugs that are substrates of CYP3A4 or cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8) with a narrow therapeutic index may be prohibited; drugs that are sensitive substrates of CYP3A4 or CYP2C8 should be used with caution; it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • History or current evidence/risk of retinal vein occlusion (RVO)
  • History or evidence of cardiovascular risk including any of the following:

    • LVEF < institutional LLN or < 50%
    • A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec
    • History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)
    • History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to study dose are eligible)
    • Patient with symptomatic bradycardia, or a history of clinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degree atrioventricular (AV) block (Mobitz type 2)
    • History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to study dose
    • History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
    • Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy
    • Patients with intra-cardiac defibrillators
    • Known cardiac metastases
  • Known active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection, are eligible); patients with human immunodeficiency virus (HIV) are not eligible if on anti-retroviral medications
  • Any serious/and or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures
  • The study drug must not be administered to pregnant women or nursing mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib/GSK2141795, the potential hazard to the fetus should be explained to the patient and partner (as applicable)
  • HIV-positive patients on combination antiretroviral therapy are ineligible
  • Hypoxia (oxygen saturation < 90% on room air) or in the opinion of the investigator any pulmonary compromise leading to hypoxia, at the time of study entry
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01907815

Locations
United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: Olatoyosi M. Odenike    773-702-3354    todenike@medicine.bsd.uchicago.edu   
Principal Investigator: Olatoyosi M. Odenike         
United States, Maryland
University of Maryland/Greenebaum Cancer Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Maria R. Baer    410-328-8708    mbaer@umm.edu   
Principal Investigator: Maria R. Baer         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Nitin Jain    713-745-6080    njain@mdanderson.org   
Principal Investigator: Nitin Jain         
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Roland B. Walter    206-667-3599    rwalter@fhrcc.org   
Principal Investigator: Roland B. Walter         
Sponsors and Collaborators
Investigators
Principal Investigator: Nitin Jain M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01907815     History of Changes
Other Study ID Numbers: NCI-2013-01354, NCI-2013-01354, 2013-0001, 9443, N01CM00039, P30CA016672
Study First Received: July 22, 2013
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Monocytic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Erythroblastic, Acute
Neoplasms by Histologic Type
Neoplasms
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases
Myeloproliferative Disorders
Trametinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 18, 2014