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

NCT01935973 | Completed Phase 1

• 5 other identifiers: NCI-2013-01659GOG-0229OP50CA098258U10CA180868U10CA027469
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 22

Brief Summary

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.

Conditions

Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Cancer

Outcome Measures

Primary Outcomes (4)

• PFS by regimen administered using RECIST version 1.1 (Phase II)

  The null hypothesis will be tested against the alternative with a stratified log-rank test.

  The duration of time from study entry to time of progression or death, whichever occurs first, assessed up to 5 years

• Frequency of adverse events defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related

  Reported using the descriptions found in the National Cancer Institute (NCI) CTCAE version 4.0.

  Up to 30 days after last study treatment

• Severity of adverse events, graded using the NCI CTCAE version 4.0 (Safety assessment and phase II)

  Up to 30 days after last study treatment

• Incidence of dose-limiting toxicity (DLT), graded according to the current version of NCI CTCAE (Safety assessment)

  If 3 or fewer patients out of 12 experience DLTs in course 1 (including treatment delays for course 2 of greater than 2 weeks due to toxicities), then the regimen will be deemed safe for administration in the phase II study. If 4 or more patients out of 12 experience DLTs, then the regimen will be declared unsafe.

  28 days

Secondary Outcomes (6)

• KRAS status (mutant or wild type)

  Baseline

• Tumor response by regimen, assessed using RECIST

  Up to 5 years

• PFS by regimen

  The duration of time from study entry to time of progression or death, whichever occurs first, assessed up to 5 years

• OS by regimen

  The duration of time from study entry to time of death or the date of last contact, assessed up to 5 years

• Response duration by KRAS mutation and regimen

  From the first date of response until disease progression or death, assessed up to 5 years

Other Outcomes (1)

• Baseline genomic biomarkers

  Baseline

Study Arms (2)

Arm I (trametinib)

ACTIVE COMPARATOR

Patients receive trametinib PO 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.

Other: Laboratory Biomarker Analysis; Drug: Trametinib

Arm II (trametinib and Akt inhibitor GSK2141795)

EXPERIMENTAL

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.

Other: Laboratory Biomarker Analysis; Drug: Trametinib; Drug: Uprosertib

Interventions

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm I (trametinib); Arm II (trametinib and Akt inhibitor GSK2141795)

Trametinib DRUG

Given PO

Also known as: GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist

Arm I (trametinib); Arm II (trametinib and Akt inhibitor GSK2141795)

Uprosertib DRUG

Given PO

Also known as: GSK2141795, Oral Akt Inhibitor GSK2141795

Arm II (trametinib and Akt inhibitor GSK2141795)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:

Sponsors & Collaborators

• National Cancer Institute (NCI): lead
• NRG Oncology: collaborator

Study Sites (22)

Hartford Hospital

Hartford, Connecticut, 06102, United States

Location

The Hospital of Central Connecticut

New Britain, Connecticut, 06050, United States

Location

Augusta University Medical Center

Augusta, Georgia, 30912, United States

Location

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, 60637, United States

Location

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

University of New Mexico Cancer Center

Albuquerque, New Mexico, 87102, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Carolinas Medical Center/Levine Cancer Institute

Charlotte, North Carolina, 28203, United States

Location

Case Western Reserve University

Cleveland, Ohio, 44106, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Hillcrest Hospital Cancer Center

Mayfield Heights, Ohio, 44124, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Women and Infants Hospital

Providence, Rhode Island, 02905, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Virginia Cancer Center

Charlottesville, Virginia, 22908, United States

Location

Virginia Commonwealth University/Massey Cancer Center

Richmond, Virginia, 23298, United States

Location

MeSH Terms

Interventions

trametinib; GSK2141795

Study Officials

• Shannon N Westin

  NRG Oncology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2013
• First Posted: September 5, 2013
• Study Start: September 30, 2013
• Primary Completion: September 8, 2015
• Study Completion: September 8, 2015
• Last Updated: October 14, 2020

Record last verified: 2020-10

Locations

US (22)