Clinical trial NCT01011933: Selumetinib in Treating Patients With Recurrent or Persistent Endometrial Cancer
Official title: A Phase II Evaluation of AZD6244 (NSC #748727) in the Treatment of Recurrent or Persistent Endometrial Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Endometrial Adenocarcinoma
Endometrial Adenosquamous Carcinoma
Endometrial Clear Cell Adenocarcinoma
Recurrent Uterine Corpus Carcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: NRG Oncology
First posted: 2009-11-11
Enrollment: 54
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With or Without Progression-free Survival for > 6 Months by Response Evaluation Criteria for Solid Tumors (RECIST)
timeFrame: > 6 months from study entry
measure: Objective Tumor Response Rate Assessed by RECIST
timeFrame: From study entry, assessed up to 5 years
measure: Participants With Severity of Adverse Effects as Assessed by CTCAE v3.0
timeFrame: Each cycle during treatment and 30 days after the last treatment.
Secondary outcomes:
measure: Duration of Progression-free Survival
timeFrame: Every other cycle for the first 6 months; then every 3 months thereafter for up to 5 years
measure: Duration of Overall Survival
timeFrame: 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.
Other outcomes:
measure: Number of Participants Off Study Therapy for Each Reason Specified.
timeFrame: from study entry until end of study treatment, up to 5 years.
measure: Patient Vital Status
timeFrame: Study entry up to 2 years
Locations:
city: Los Angeles
country: United States
facility: Los Angeles County-USC Medical Center
state: California
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center - Anschutz Cancer Pavilion
state: Colorado
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Hartford
country: United States
facility: Smilow Cancer Hospital Care Center at Saint Francis
state: Connecticut
city: New Britain
country: United States
facility: The Hospital of Central Connecticut
state: Connecticut
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Hinsdale
country: United States
facility: Sudarshan K Sharma MD Limted-Gynecologic Oncology
state: Illinois
city: Springfield
country: United States
facility: Memorial Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University/Melvin and Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Saint Vincent Oncology Center
state: Indiana
city: Clive
country: United States
facility: Medical Oncology and Hematology Associates-West Des Moines
state: Iowa
city: Clive
country: United States
facility: Mercy Cancer Center-West Lakes
state: Iowa
city: Des Moines
country: United States
facility: Iowa Methodist Medical Center
state: Iowa
city: Des Moines
country: United States
facility: Iowa-Wide Oncology Research Coalition NCORP
state: Iowa
city: Des Moines
country: United States
facility: Medical Oncology and Hematology Associates-Des Moines
state: Iowa
city: Des Moines
country: United States
facility: Medical Oncology and Hematology Associates-Laurel
state: Iowa
city: Des Moines
country: United States
facility: Mercy Medical Center - Des Moines
state: Iowa
city: Des Moines
country: United States
facility: Iowa Lutheran Hospital
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: West Des Moines
country: United States
facility: Methodist West Hospital
state: Iowa
city: West Des Moines
country: United States
facility: Mercy Medical Center-West Lakes
state: Iowa
city: Overland Park
country: United States
facility: Menorah Medical Center
state: Kansas
city: Overland Park
country: United States
facility: Saint Luke's South Hospital
state: Kansas
city: Prairie Village
country: United States
facility: Kansas City NCI Community Oncology Research Program
state: Kansas
city: Baltimore
country: United States
facility: MedStar Franklin Square Medical Center/Weinberg Cancer Institute
state: Maryland
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Hospital
state: Michigan
city: Ann Arbor
country: United States
facility: Michigan Cancer Research Consortium CCOP
state: Michigan
city: Dearborn
country: United States
facility: Oakwood Hospital and Medical Center
state: Michigan
city: Detroit
country: United States
facility: Saint John Hospital and Medical Center
state: Michigan
city: Flint
country: United States
facility: Hurley Medical Center
state: Michigan
city: Flint
country: United States
facility: Genesys Regional Medical Center-West Flint Campus
state: Michigan
city: Jackson
country: United States
facility: Allegiance Health
state: Michigan
city: Kalamazoo
country: United States
facility: Borgess Medical Center
state: Michigan
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Lansing
country: United States
facility: Sparrow Hospital
state: Michigan
city: Livonia
country: United States
facility: Saint Mary Mercy Hospital
state: Michigan
city: Pontiac
country: United States
facility: Saint Joseph Mercy Oakland
state: Michigan
city: Port Huron
country: United States
facility: Saint Joseph Mercy Port Huron
state: Michigan
city: Saginaw
country: United States
facility: Saint Mary's of Michigan
state: Michigan
city: Warren
country: United States
facility: Saint John Macomb-Oakland Hospital
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Truman Medical Center
state: Missouri
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Kansas City
country: United States
facility: Saint Joseph Health Center
state: Missouri
city: Kansas City
country: United States
facility: North Kansas City Hospital
state: Missouri
city: Kansas City
country: United States
facility: Heartland Hematology and Oncology Associates Incorporated
state: Missouri
city: Kansas City
country: United States
facility: Research Medical Center
state: Missouri
city: Lee's Summit
country: United States
facility: Saint Luke's East - Lee's Summit
state: Missouri
city: Liberty
country: United States
facility: Liberty Hospital
state: Missouri
city: Saint Joseph
country: United States
facility: Heartland Regional Medical Center
state: Missouri
city: Saint Joseph
country: United States
facility: Saint Joseph Oncology Inc
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Springfield
country: United States
facility: Cancer Research for the Ozarks NCORP
state: Missouri
city: Springfield
country: United States
facility: CoxHealth South Hospital
state: Missouri
city: Las Vegas
country: United States
facility: Women's Cancer Center of Nevada
state: Nevada
city: Brooklyn
country: United States
facility: State University of New York Downstate Medical Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute-Tulsa
state: Oklahoma
city: Abington
country: United States
facility: Abington Memorial Hospital
state: Pennsylvania
city: Bryn Mawr
country: United States
facility: Bryn Mawr Hospital
state: Pennsylvania
city: Paoli
country: United States
facility: Paoli Memorial Hospital
state: Pennsylvania
city: Wynnewood
country: United States
facility: Lankenau Medical Center
state: Pennsylvania
city: Wynnewood
country: United States
facility: Main Line Health NCORP
state: Pennsylvania
city: Providence
country: United States
facility: Women and Infants Hospital
state: Rhode Island
city: Houston
country: United States
facility: Lyndon Baines Johnson General Hospital
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
Study officials:
affiliation: NRG Oncology
name: Robert Coleman
role: PRINCIPAL_INVESTIGATOR
References:
citation: Coleman RL, Sill MW, Thaker PH, Bender DP, Street D, McGuire WP, Johnston CM, Rotmensch J. A phase II evaluation of selumetinib (AZD6244, ARRY-142886), a selective MEK-1/2 inhibitor in the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2015 Jul;138(1):30-5. doi: 10.1016/j.ygyno.2015.04.005. Epub 2015 Apr 14.