Trametinib With or Without GSK2141795 in Treating Patients With Recurrent or Persistent Endometrial Cancer



Status:Active, not recruiting
Conditions:Cervical Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:18 - Any
Updated:2/8/2019
Start Date:September 30, 2013

Use our guide to learn which trials are right for you!

A Randomized Phase I Study With a Safety Lead-In to Assess the Antitumor Efficacy of the MEK Inhibitor Trametinib Alone or in Combination With GSK2141795, an AKT Inhibitor, in Patients With Recurrent or Persistent Endometrial Cancer NCT #01935973

This randomized phase I trial studies how well trametinib with or without GSK 2141795
(protein kinase B [Akt] inhibitor GSK2141795) works in treating patients with endometrial
cancer that has come back (recurrent) or does not go to remission despite treatment
(persistent). Trametinib and Akt inhibitor GSK2141795 may stop the growth of tumor cells by
blocking some of the enzymes needed for cell growth. It is not yet known whether trametinib
is a more effective treatment for endometrial cancer when given with or without ATK inhibitor
GSK2141795.

PRIMARY OBJECTIVES:

I. To assess the relative activity of trametinib (mitogen-activated protein kinase [MEK]
inhibitor) alone or in combination with GSK2141795 (AKT inhibitor) for patients with
recurrent or persistent endometrial cancer by progression-free survival. (Phase II) II. To
determine the frequency and severity of adverse events as assessed by Common Terminology
Criteria for Adverse Events (CTCAE). (Phase II) III. To determine the tolerability of the
combination regimen of trametinib and GSK2141795 through determination of dose-limiting
toxicity in a two-stage safety lead in study. (Safety assessment lead-in)

SECONDARY OBJECTIVES:

I. To estimate the association between baseline Kirsten rat sarcoma viral oncogene homolog
(KRAS) status and clinical activity (e.g. response and progression-free survival [PFS]) for
patients with recurrent or persistent endometrial cancer who are treated with trametinib
alone or in combination with GSK2141795.

II. To estimate overall survival (OS) of patients with recurrent or persistent endometrial
cancer treated with trametinib therapy alone (excluding patients who cross-over) and
trametinib/GSK2141795 combination therapy in the two subgroups of patients defined above.

III. Prognostic factors will be examined for associations with patients who do not crossover.

IV. To estimate objective response and response duration associated with trametinib therapy
and trametinib/GSK2141795 combination therapy in the two subgroups of patients defined above.

V. To estimate the relative proportion of patients responding or have 6-month PFS on the
therapies administered on this study with those studies that may serve as a historical
control.

TERTIARY OBJECTIVES:

I. To estimate the association between baseline genomic biomarkers in the
phosphatidylinositol 3 kinase (PI3K)/AKT pathway and clinical activity (e.g. response and
PFS) in two subgroups of patients defined above with recurrent or persistent endometrial
cancer who are treated with trametinib alone or in combination with GSK2141795.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity. Patients
achieving disease progression may cross over to Arm II.

ARM II: 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.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Patients must have recurrent or persistent endometrial carcinoma, which is refractory
to curative therapy or established treatments; histologic confirmation of the original
primary tumor is required

- Patients with the following histologic epithelial cell types are eligible:
endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma,
mixed epithelial carcinoma, uterine clear cell carcinoma, and adenocarcinoma not
otherwise specified (N.O.S.)

- Formalin-fixed, paraffin-embedded tumor tissue must be submitted to Baylor College of
Medicine (BCM) - Cancer Genetics Laboratory for Clinical Laboratory Improvement
Amendments (CLIA)-certified KRAS mutation testing; results must be reported on the
eligibility checklist during registration in order to receive treatment assignment

- Note: if CLIA-certified KRAS mutation tumor testing is available from local or
other source (e.g., Foundation Medicine) this report can be submitted to
Statistical and Data Center (SDC) to meet this requirement

- All patients must have measurable disease; measurable disease is defined by Response
Evaluation Criteria in Solid Tumors (RECIST) (version 1.1); measurable disease is
defined as at least one lesion that can be accurately measured in at least one
dimension (longest diameter to be recorded); each lesion must be >= 10 mm when
measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper
measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes
must be >= 15 mm in short axis when measured by CT or MRI

- Patients must have at least one "target lesion" to be used to assess response on this
protocol as defined by RECIST version 1.1; tumors within a previously irradiated field
will be designated as "non-target" lesions unless progression is documented or a
biopsy is obtained to confirm persistence at least 90 days following completion of
radiation therapy

- Gynecologic Oncology Group (GOG) performance status of 0 or 1

- Recovery from effects of recent surgery, radiotherapy, or chemotherapy

- Patients should be free of active infection requiring antibiotics (with the exception
of uncomplicated urinary tract infection [UTI])

- Any hormonal therapy directed at the malignant tumor must be discontinued at least one
week prior to registration

- Any other prior therapy directed at the malignant tumor, including chemotherapy and
immunotherapy, must be discontinued at least three weeks prior to registration; any
investigational agent must be discontinued at least 30 days prior to registration

- Any prior radiation therapy must be discontinued at least four weeks prior to
registration

- At least 4 weeks must have elapsed since the patient underwent any major surgery
(e.g., major: laparotomy, laparoscopy); there is no delay in treatment for minor
procedures (e.g., tumor core biopsy)

- Patients must have had one prior chemotherapeutic regimen for management of
endometrial carcinoma; initial treatment may include chemotherapy, chemotherapy and
radiation therapy, or consolidation/maintenance therapy; chemotherapy administered in
conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic
chemotherapy regimen

- Patients are allowed to receive, but are not required to receive, one additional
cytotoxic regimen for management of recurrent or persistent disease

- Patients MAY HAVE received non-cytotoxic (biologic or targeted) agent(s) as part of
initial treatment and/or for management of recurrent or persistent disease, with the
below stated exceptions (see NOTE below); prior hormonal therapy is allowed, but must
be discontinued at least one week prior to registration

- NOTE: Prior therapy with PI3K inhibitors, AKT inhibitors and/or mammalian target
of rapamycin (mTor) inhibitors (e.g., everolimus, temsirolimus) is NOT allowed;
prior therapy with MEK inhibitors (e.g., AZD6244 or selumetinib) is NOT allowed

- Absolute neutrophil count (ANC) >= 1,500/mcl

- Platelets >= 100,000/mcl

- Hemoglobin >= 9 g/dl

- Creatinine =< 1.5 x institutional/laboratory upper limit of normal (ULN) OR calculated
creatinine clearance (Cockcroft-Gault formula) >= 50 ml/min OR 24-hour urine
creatinine clearance >= 50 ml/min

- Bilirubin =< 1.5 x ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN

- Alkaline phosphatase =< 2.5 x ULN

- Albumin >= 2.5 g/dL

- Fasting glucose < 160 mg/dL

- Hemoglobin A1C (HbA1C) =< 8 if patient has diabetes

- Thyroid-stimulating hormone (TSH) within institutional/laboratory normal limits

- Left ventricular ejection fraction (LVEF) greater than or equal to
institutional/laboratory lower limit of normal (LLN) by echocardiogram (ECHO) or multi
gated acquisition scan (MUGA)

- International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x
ULN

- For patients on Coumadin, INR/prothrombin time (PT)/PTT must be > 1.5 ULN

- Hemodynamic parameters:

- Systolic blood pressure < 140 mmHg

- Diastolic blood pressure < 90 mmHg

- All prior treatment-related toxicities must be CTCAE v4 grade =< 1 (except alopecia)
at the time of randomization

- Patients with abnormal fasting glucose values at screening will be excluded (fasting
glucose >= 160); 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 hemoglobin A1C (HbA1C) =< 8% at screening

- Patients must be able to swallow and retain orally-administered medication and must
not have any clinically significant gastrointestinal abnormalities that may alter
absorption such as malabsorption syndrome or major resection of the stomach or bowels

- Women of child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation AND for 4 months following discontinuation; women of
child-bearing potential must have a negative serum pregnancy test within 14 days prior
to randomization; should a woman become pregnant or suspect she is pregnant while she
is participating in this study, she should inform her treating physician immediately

- Patients must meet pre-entry requirements as specified

- Patients must have signed an approved informed consent and authorization permitting
release of personal health information

Exclusion Criteria:

- Patients who have had prior therapy with GSK2141795 or any other PI3K/AKT/MTOR pathway
inhibitor

- Patients who have prior therapy with trametinib or any other MEK inhibitor

- Patients who have mucinous, squamous, sarcomas, or carcinosarcomas

- Patient with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer are excluded if there is any evidence of other malignancy
being present within the last three years; patients are also excluded if their
previous cancer treatment contraindicates this protocol eligibility

- Patients with symptomatic or untreated leptomeningeal or brain metastasis or spinal
cord compression

- Patients with a history of interstitial lung disease or pneumonitis

- Patients with known immediate or delayed hypersensitivity reaction or idiosyncrasy to
drugs chemically related to the trametinib, GSK2141795 or dimethyl sulfoxide (DMSO)

- Current use of a prohibited medication; the following medications or non-drug
therapies are prohibited:

- Other anti-cancer therapy while on study treatment

- 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)

- Drugs that potently inhibit cytochrome P450 family 3, subfamily A, polypeptide 4
(CYP3A4) should be prohibited or used with caution; drugs which are strong inducers of
CYP3A and may result in lower exposures of GSK2141795 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

- Caution should be exercised when dosing trametinib concurrently with medications
with narrow therapeutic windows that are substrates of CYP2C8; drugs that
potently inhibit or induce CYP3A4 should be administered with caution

- Because the lists of these agents are constantly changing, it is important to
regularly consult a frequently-updated list such as
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; 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

- The following medications (including but not limited to) are prohibited during
the study:

- PROHIBITED-highly sensitive and/or low therapeutic index

- Cisapride

- Pimozide

- Astemizole

- Rosuvastatin, sulfasalazine

- PROHIBITED-strong inducers/inhibitors of CYP3A4

- Clarithromycin, telithromycin, rifamycin class agents (e.g., rifampin,
rifabutin, rifapentine), troleandomycin

- Itraconazole, ketoconazole

- Nefazodone

- Atazanavir, delavirdine, indinavir, lopinavir, nelfinavir, ritonavir,
saquinavir, nevirapine

- Carbamazepine, phenobarbital, phenytoin

- The following medications (including but not limited to) that may alter the
concentrations of trametinib or GSK2141795 or have their elimination altered by
trametinib or GSK2141795 should be administered WITH CAUTION:

- USE WITH CAUTION-Drugs potentially affecting trametinib or GSK2141795
concentrations

- Quinidine, diltiazem, verapamil

- Fluvoxamine, fluoxetine, paroxetine, nefazodone

- Aprepitant, cimetidine

- Fluconazole, terbinafine, voriconazole

- Ciprofloxacin, erythromycin, isoniazid

- Mibefradil, diltiazem, verapamil

- Aprepitant, oxandrolone, tizanidine, gemfibrozil

- USE WITH CAUTION-Drugs that may inhibit permeability (P)-glycoprotein (gp)
and breast cancer resistance protein (BCRP)

- Valspodar

- Atorvastatin

- Carvedilol

- Methadone

- Meperidine

- Omeprazole

- USE WITH CAUTION-Drugs that may have their concentrations altered by
trametinib or GSK2141795

- Repaglinide, rosiglitazone, pioglitazone

- Alfentanil, fentanyl

- Quinidine

- Cilostazol

- Astemizole

- Diergotamine, ergotamine, eletriptan

- Pimozide

- Buspirone

- Felodipine

- Sildenafil, tadalafil, vardenafil

- Cerivastatin, lovastatin, simvastatin, atorvastatin

- Alprazolam, diazepam, midazolam, triazolam

- Cyclosporine, sirolimus, tacrolimus

- Cisapride

- Cyclosporine, torsemide, chloroquine, zopiclone

- Eplerenone

- Chloroquine, zopiclone

- Use of repaglinide, rosiglitazone and/or pioglitazone is permitted only
after consultation with the Cancer Therapy Evaluation Program (CTEP) Medical
Monitor

- Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (unless cleared)
will be excluded

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- History or current evidence/risk of retinal vein occlusion (RVO)

- History or evidence of cardiovascular risk including any of the following:

- LVEF < LLN

- 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
registration are eligible)

- History of acute coronary syndromes (including myocardial infarction and unstable
angina), coronary angioplasty, or stenting within 6 months prior to registration

- 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 or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive
therapy

- Patients with intra-cardiac defibrillators or permanent pacemakers

- Known cardiac metastases

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Patients who are pregnant or nursing; women of childbearing potential should be
advised to avoid pregnancy and use effective methods of contraception; if a patient
becomes pregnant while the patient receives trametinib and/or GSK2141795, the
potential hazard to the fetus should be explained to the patient
We found this trial at
22
sites
1201 Camino de Salud Northeast
Albuquerque, New Mexico 87131
(505) 272-4946
University of New Mexico Cancer Center It’s been 40 years since the New Mexico State...
?
mi
from
Albuquerque, NM
Click here to add this to my saved trials
1300 Jefferson Park Avenue
Charlottesville, Virginia 22908
434-243-6784
University of Virginia Cancer Center We are fortunate in having state of the art clinical...
?
mi
from
Charlottesville, VA
Click here to add this to my saved trials
401 College Street
Richmond, Virginia 23298
(804) 828-0450
Virginia Commonwealth University Massey Cancer Center Founded in 1974, VCU Massey Cancer Center is a...
?
mi
from
Richmond, VA
Click here to add this to my saved trials
Augusta, Georgia 30912
?
mi
from
Augusta, GA
Click here to add this to my saved trials
401 North Broadway
Baltimore, Maryland 21287
410-955-5000
Johns Hopkins University-Sidney Kimmel Cancer Center The name Johns Hopkins has become synonymous with excellence...
?
mi
from
Baltimore, MD
Click here to add this to my saved trials
171 Ashley Avenue
Charleston, South Carolina 29425
843-792-1414
Medical University of South Carolina The Medical University of South Carolina (MUSC) has grown from...
?
mi
from
Charleston, SC
Click here to add this to my saved trials
Charlotte, North Carolina 28204
?
mi
from
Charlotte, NC
Click here to add this to my saved trials
5841 S Maryland Ave
Chicago, Illinois 60637
1-773-702-6180
University of Chicago Comprehensive Cancer Center The University of Chicago Comprehensive Cancer Center (UCCCC) is...
?
mi
from
Chicago, IL
Click here to add this to my saved trials
10900 Euclid Ave
Cleveland, Ohio 44106
216-368-2000
Case Western Reserve Univ Continually ranked among America's best colleges, Case Western Reserve University has...
?
mi
from
Cleveland, OH
Click here to add this to my saved trials
2049 E 100th St
Cleveland, Ohio 44106
(216) 444-2200
Cleveland Clinic Foundation The Cleveland Clinic (formally known as The Cleveland Clinic Foundation) is a...
?
mi
from
Cleveland, OH
Click here to add this to my saved trials
?
mi
from
Columbus, OH
Click here to add this to my saved trials
80 Seymour St
Hartford, Connecticut 6102
(860) 545-5000
The Hartford Hospital Hartford Hospital is the major teaching hospital affiliated with the University of...
?
mi
from
Hartford, CT
Click here to add this to my saved trials
Houston, Texas 77030
?
mi
from
Houston, TX
Click here to add this to my saved trials
?
mi
from
Lexington, KY
Click here to add this to my saved trials
Mayfield Heights, Ohio 44124
?
mi
from
Mayfield Heights, OH
Click here to add this to my saved trials
100 Grand St
New Britain, Connecticut 06050
(860) 224-5011
The Hospital of Central Connecticut The Hospital of Central Connecticut is dedicated to fostering, sustaining...
?
mi
from
New Britain, CT
Click here to add this to my saved trials
1275 York Ave
New York, New York 10021
(212) 639-2000
Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering Cancer Center — the world's oldest and...
?
mi
from
New York, NY
Click here to add this to my saved trials
940 NE 13th St
Oklahoma City, Oklahoma 73190
(405) 271-6458
University of Oklahoma Health Sciences Center The OU Health Sciences Center is composed of seven...
?
mi
from
Oklahoma City, OK
Click here to add this to my saved trials
Philadelphia, Pennsylvania 19111
?
mi
from
Philadelphia, PA
Click here to add this to my saved trials
111 S 11th St
Philadelphia, Pennsylvania 19107
(215) 955-6000
Thomas Jefferson University Hospital Our hospitals in Center City Philadelphia share a 13-acre campus with...
?
mi
from
Philadelphia, PA
Click here to add this to my saved trials
Providence, Rhode Island 02905
?
mi
from
Providence, RI
Click here to add this to my saved trials
660 S Euclid Ave
Saint Louis, Missouri 63110
(314) 362-5000
Washington University School of Medicine Washington University Physicians is the clinical practice of the School...
?
mi
from
Saint Louis, MO
Click here to add this to my saved trials