Selumetinib in Treating Patients With Recurrent or Persistent Endometrial Cancer

Endometrial Adenocarcinoma Clinical Trial

Official title:

A Phase II Evaluation of AZD6244 (NSC #748727) in the Treatment of Recurrent or Persistent Endometrial Carcinoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01011933
• Other study ID #: NCI-2011-01958
• Secondary ID: NCI-2011-01958GO
• Status: Completed
• Phase: Phase 2
• Start date: September 2009
• Est. completion date: January 2016

Study information

• Verified date: July 2019
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial is studying how well selumetinib works in treating patients with recurrent or persistent endometrial cancer that has come back or is persistent. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Description:

PRIMARY OBJECTIVES:

I. To assess the activity of AZD6244 (selumetinib) for patients with recurrent or persistent endometrial cancer with the frequency of patients who survive progression-free for at least 6 months after initiating therapy or have objective tumor response.

II. To determine the nature and degree of toxicity of AZD6244 as assessed by CTCAE v3.0 in this cohort of patients.

SECONDARY OBJECTIVE:

I. To determine the duration of progression-free survival and overall survival.

EXPLORATORY OBJECTIVES:

I. To explore the associations between select biomarkers and response to AZD6244 (progression-free survival status >6 months and objective tumor response), measures of clinical outcome (progression-free survival and overall survival) or disease status including histologic cell type.

II. Mutations and single nucleotide polymorphisms in BRAF, KRAS2, FGFR2, PI3KCA, AKT1, AKT2, AKT3 and PTEN in DNA from formalin-fixed and paraffin-embedded (FFPE) tumor and/or normal blood cells.

III. Immunohistochemical expression of ERK, pERK, GSK3betta, pGSK3betta, PR-A, PR-B, pPR, ER-alpha, ER-beta, BRAF, KRAS, PTEN, EGFR, pEGFR, EGF, PELP1 and MTA1s in FFPE tumor.

IV. To explore the relationship among the panel of biomarkers evaluated in this cohort including mutations and single nucleotide polymorphisms in BRAF, KRAS2, FGFR2, PI3KCA, AKT1, AKT2, AKT3 and PTEN as well as immunohistochemical expression of ERK, pERK, GSK3betta, pGSK3betta, PR-A, PR-B, pPR, ER-alpha, ER-beta, BRAF, KRAS, PTEN, EGFR, pEGFR, EGF, PELP1 and MTA1s.

OUTLINE: This is a multicenter study.

Patients receive selumetinib orally (PO) twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Blood and archived tumor tissue samples are collected for biomarker studies.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: January 2016
• Est. primary completion date: January 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed* endometrial epithelial carcinoma, including any of the following cell types:

• Endometrioid adenocarcinoma

• Serous adenocarcinoma

• Undifferentiated carcinoma

• Clear cell adenocarcinoma

• Mixed epithelial carcinoma

• Adenocarcinoma not otherwise specified

• Mucinous adenocarcinoma

• Squamous cell carcinoma

• Transitional cell carcinoma

• Mesonephric carcinoma

• Recurrent or persistent disease that is refractory to curative therapy or established treatments

• Measurable disease, defined as = 1 lesion that can be measured in = 1 dimension (longest dimension to be recorded)

• Each lesion must be = 20 mm when measured by conventional techniques (palpation, plain x-ray, CT scan, or MRI) OR = 10 mm when measured by spiral CT scan

• Must have = 1 target lesion to be used to assess response, as defined by RECIST criteria

• Tumors within a previously irradiated field are designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence = 90 days following completion of radiotherapy

• Must have received 1 prior chemotherapeutic regimen for the management of endometrial carcinoma

• Chemotherapy administered as a radiosensitizer in conjunction with primary radiotherapy is considered a systemic chemotherapy regimen

• Not eligible for a higher priority GOG protocol, if one exists (e.g., any active phase III GOG protocol for the same patient population)

• No prior or concurrent CNS disease (treated or untreated) by physical examination, including primary brain tumor or brain metastases

• GOG performance status (PS) 0-2 (for patients who received 1 prior treatment regimen)

• GOG PS 0-1 (for patients who received 2 prior treatment regimens)

• ANC = 1,500/mm^3

• Platelet count = 100,000/mm^3

• Creatinine = 1.5 times upper limit of normal (ULN)

• Bilirubin = 1.5 times ULN

• SGOT = 2.5 times ULN

• Alkaline phosphatase = 2.5 times ULN

• PT/INR = 1.5 OR in-range INR (between 2 and 3) if patient is on a stable dose of therapeutic warfarin

• PTT = 1.5 times ULN

• Oxygen saturation = 88% on room air

• QTc < 450 msec by EKG

• LVEF normal

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for = 6 months after completion of study therapy

• No neuropathy (sensory or motor) > grade 1

• No active infection requiring antibiotics

• Uncomplicated urinary tract infection allowed

• No other invasive malignancy within the past 5 years except for nonmelanoma skin cancer

• No serious, non-healing wound, ulcer, or bone fracture

• No history of abdominal fistula or gastrointestinal perforation

• No intra-abdominal abscess within the past 28 days

• No active bleeding or pathological condition that would carry a high risk of bleeding (e.g., bleeding disorder, coagulopathy, or tumor involving major vessels)

• No seizures not controlled with standard medical therapy

• No clinically significant cardiovascular disease including, but not limited to, any of the following:

• Uncontrolled hypertension, defined as systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg

• Myocardial infarction or unstable angina within the past 6 months

• NYHA class II-IV congestive heart failure

• Serious cardiac arrhythmia requiring medication, including atrial fibrillation requiring rate-controlling medication

• Peripheral vascular disease = grade 2

• Cerebrovascular accident (i.e., CVA, stroke), transient ischemic attack, or subarachnoidal hemorrhage within the past 6 months

• No evidence of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation = 3 beats in a row) by EKG

• Concurrent low molecular weight heparin for treatment of venous thromboembolic disease allowed provided patient is considered clinically stable on this regimen

• Recovered from prior surgery, radiotherapy, or chemotherapy

• At least 1 week since prior hormonal therapy directed at the malignant tumor

• At least 3 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C)

• At least 3 weeks since other prior therapy directed at the malignant tumor, including immunologic agents

• One prior cytotoxic regimen for the management of recurrent or persistent endometrial disease allowed

• No prior non-cytotoxic chemotherapy for the management of endometrial cancer, except hormonal therapy

• No prior anticancer therapy that contraindicates study therapy

• No prior MEK inhibitor AZD6244 or other specific MEK/ERK/MAPK pathway targeted therapy

• No prior chemotherapy for any abdominal or pelvic tumor other than for the treatment for endometrial cancer within the past 5 years

• Prior adjuvant chemotherapy for localized breast cancer allowed provided it was completed > 3 years ago AND the patient remains free of recurrent or metastatic disease

• No prior radiotherapy to any portion of the abdominal cavity or pelvis other than for the treatment of endometrial cancer within the past 5 years

• Prior radiotherapy for localized cancer of the breast, head and neck, or skin is allowed provided it was completed > 3 years ago AND the patient remains free of recurrent or metastatic disease

• No concurrent medication that may prolong the QTc interval

• No other concurrent investigational therapy

• No concurrent combination antiretroviral therapy for HIV-positive patients

Related Conditions & MeSH terms

• Adenocarcinoma
• Carcinoma
• Carcinoma, Adenosquamous
• Endometrial Adenocarcinoma
• Endometrial Adenosquamous Carcinoma
• Endometrial Clear Cell Adenocarcinoma
• Recurrent Uterine Corpus Carcinoma
• Uterine Neoplasms

Intervention

Other:
• Diagnostic Laboratory Biomarker Analysis
Correlative studies

Drug:
• Selumetinib
Given PO

Locations

Country	Name	City	State
United States	Abington Memorial Hospital	Abington	Pennsylvania
United States	Michigan Cancer Research Consortium CCOP	Ann Arbor	Michigan
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Colorado Cancer Center - Anschutz Cancer Pavilion	Aurora	Colorado
United States	MedStar Franklin Square Medical Center/Weinberg Cancer Institute	Baltimore	Maryland
United States	State University of New York Downstate Medical Center	Brooklyn	New York
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	Oakwood Hospital and Medical Center	Dearborn	Michigan
United States	Iowa Lutheran Hospital	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Iowa-Wide Oncology Research Coalition NCORP	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Genesys Regional Medical Center-West Flint Campus	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Hartford Hospital	Hartford	Connecticut
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	Sudarshan K Sharma MD Limted-Gynecologic Oncology	Hinsdale	Illinois
United States	Lyndon Baines Johnson General Hospital	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Saint Vincent Oncology Center	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Allegiance Health	Jackson	Michigan
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Heartland Hematology and Oncology Associates Incorporated	Kansas City	Missouri
United States	North Kansas City Hospital	Kansas City	Missouri
United States	Research Medical Center	Kansas City	Missouri
United States	Saint Joseph Health Center	Kansas City	Missouri
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	Truman Medical Center	Kansas City	Missouri
United States	Sparrow Hospital	Lansing	Michigan
United States	Women's Cancer Center of Nevada	Las Vegas	Nevada
United States	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri
United States	Liberty Hospital	Liberty	Missouri
United States	Saint Mary Mercy Hospital	Livonia	Michigan
United States	Los Angeles County-USC Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	The Hospital of Central Connecticut	New Britain	Connecticut
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Menorah Medical Center	Overland Park	Kansas
United States	Saint Luke's South Hospital	Overland Park	Kansas
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Saint Joseph Mercy Port Huron	Port Huron	Michigan
United States	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas
United States	Women and Infants Hospital	Providence	Rhode Island
United States	Saint Mary's of Michigan	Saginaw	Michigan
United States	Heartland Regional Medical Center	Saint Joseph	Missouri
United States	Saint Joseph Oncology Inc	Saint Joseph	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Cancer Research for the Ozarks NCORP	Springfield	Missouri
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Memorial Medical Center	Springfield	Illinois
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	MedStar Washington Hospital Center	Washington	District of Columbia
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	Methodist West Hospital	West Des Moines	Iowa
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	Main Line Health NCORP	Wynnewood	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants Off Study Therapy for Each Reason Specified.		from study entry until end of study treatment, up to 5 years.
Other	Patient Vital Status	Patients alive or dead after 24 months from time of study entry.	Study entry up to 2 years
Primary	Number of Participants With or Without Progression-free Survival for > 6 Months by Response Evaluation Criteria for Solid Tumors (RECIST)	Number of participants who survived progression-free for more than 6 months.; Progression is defined using Response Evaluation Criteria for Solid Tumors (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions, or unequivocal progression of existing non-target lesions in the opinion of the treating physician, or global deterioration in health status attributable to the disease requiring a change in therapy without objective evidence of progression.	> 6 months from study entry
Primary	Objective Tumor Response Rate Assessed by RECIST	Per Response Evaluation Criteria In Solid Tumors (RECIST) Criteria: Complete Response (CR) is disappearance of all target and non-target lesions and no evidence of new lesions documented by two disease assessments at least 4 weeks apart. Normalization of CA125, if elevated at study entry, is required; Partial Response (PR) is at least a 30% decrease in the sum of longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD; Increasing Disease is at least a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD or the appearance of new lesions within 8 weeks of study entry; Stable Disease is any condition not meeting the above criteria.	From study entry, assessed up to 5 years
Primary	Participants With Severity of Adverse Effects as Assessed by CTCAE v3.0		Each cycle during treatment and 30 days after the last treatment.
Secondary	Duration of Progression-free Survival	Progression is defined according to RECIST v1.0 as at least a 20% increase in the sum of LD target lesions taking as reference the smallest sum LD recorded since study entry, the appearance of one or more new lesions, death due to disease without prior objective documentation of progression, global deterioration in health status attributable to the disease requiring a change in therapy without objective evidence of progression, or unequivocal progression of existing non-target lesions.	Every other cycle for the first 6 months; then every 3 months thereafter for up to 5 years
Secondary	Duration of Overall Survival	Overall survival is defined as the duration of time from study entry to time of death or the date of last contact.	Every cycle during treatment, then every 3 months for the first 2 years, then every six months for the next three years and then annually for the next 5 years.