Selumetinib Sulfate in Treating Woman With Recurrent Low-Grade Ovarian Cancer or Peritoneum Cancer

A Phase II Trial of AZD6244 (NSC# 748727) in Women With Recurrent Low-Grade Serous Carcinoma of the Ovary or Peritoneum

This phase II trial studies the side effects and how well selumetinib sulfate works in treating patients with low-grade ovarian cancer that has come back (recurrent). Selumetinib sulfate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Study Overview

• Status: Completed
• Conditions: Primary Peritoneal Carcinoma; Low Grade Ovarian Serous Adenocarcinoma; Borderline Ovarian Serous Tumor; Micropapillary Serous Carcinoma; Primary Peritoneal Low Grade Serous Adenocarcinoma; Recurrent Borderline Ovarian Surface Epithelial-Stromal Tumor
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Selumetinib Sulfate; Drug: Selumetinib

Detailed Description

PRIMARY OBJECTIVES:

I. To examine the tumor response rate of patients on AZD6244 (selumetinib sulfate) (NSC #748727).

II. To examine the acute toxicity of AZD6244 (NSC #748727) during the first course of treatment using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

III. To define the pharmacokinetic profile for AZD6244, 100 mg administered orally twice daily.

SECONDARY OBJECTIVES:

I. To examine the toxicity of AZD6244 (NSC #748727) using the 21 major categories of the CTCAE version 3.0.

II. To examine the dose and number of courses of AZD6244 (NSC #748727) given. III. To estimate the progression free survival, and overall survival of women receiving AZD6244 (NSC #748727).

TRANSLATIONAL RESEARCH OBJECTIVES:

I. To examine deoxyribonucleic acid (DNA) isolation with sequencing of braf, and ras mutation analysis and to explore their relationship with tumor response with AZD6244 (NSC #748727).

II. To examine protein levels of phosphorylated (p)-ERK/ERKERK) and explore their relationship with tumor response in patients treated with AZD6244 (NSC #748727).

OUTLINE:

Patients receive selumetinib sulfate orally (PO) twice a day (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection periodically for correlative and pharmacokinetic studies and to analyze selumetinib sulfate peak concentrations and the corresponding peak time values. Previously collected archived tumor tissue samples are obtained to determine protein levels of p-ERK/ERKERK, DNA isolation and sequencing of BRAF and ras mutation analysis by immunohistochemistry (IHC).

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then once a year for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Institute Palo Alto
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
    • New Britain, Connecticut, United States, 06050
      • The Hospital of Central Connecticut
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Beebe Medical Center
    • Newark, Delaware, United States, 19718
      • Christiana Care Health System-Christiana Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Hinsdale, Illinois, United States, 60521
      • Hinsdale Hematology Oncology Associates Incorporated
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Saint Vincent Hospital and Health Care Center
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center-Bramhall Campus
  • Maryland
    • Elkton, Maryland, United States, 21921
      • Christiana Care - Union Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • Michigan
    • Battle Creek, Michigan, United States, 49017
      • Bronson Battle Creek
    • Big Rapids, Michigan, United States, 49307
      • Spectrum Health Big Rapids Hospital
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health at Butterworth Campus
    • Grand Rapids, Michigan, United States, 49503
      • Mercy Health Saint Mary's
    • Grand Rapids, Michigan, United States, 49503
      • Cancer Research Consortium of West Michigan NCORP
    • Holland, Michigan, United States, 49423
      • Holland Community Hospital
    • Muskegon, Michigan, United States, 49444
      • Mercy Health Mercy Campus
    • Muskegon, Michigan, United States, 49442
      • Mercy Health Partners-Hackley Campus
    • Traverse City, Michigan, United States, 49684
      • Munson Medical Center
    • Wyoming, Michigan, United States, 49519
      • Metro Health Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Springfield, Missouri, United States, 65804
      • Cancer Research for the Ozarks NCORP
    • Springfield, Missouri, United States, 65807
      • CoxHealth South Hospital
    • Springfield, Missouri, United States, 65804
      • Mercy Hospital Springfield
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper Hospital University Medical Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center/Levine Cancer Institute
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Presbyterian Medical Center
    • Greenville, North Carolina, United States, 27834
      • Gynecologic Oncology Network
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44111
      • Cleveland Clinic Cancer Center/Fairview Hospital
    • Columbus, Ohio, United States, 43214
      • Riverside Methodist Hospital
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
    • Columbus, Ohio, United States, 43222
      • Mount Carmel Health Center West
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
    • Mayfield Heights, Ohio, United States, 44124
      • Hillcrest Hospital Cancer Center
    • Mentor, Ohio, United States, 44060
      • UH Seidman Cancer Center at Lake Health Mentor Campus
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
    • Tulsa, Oklahoma, United States, 74146
      • Oklahoma Cancer Specialists and Research Institute-Tulsa
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Memorial Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Patients age greater than 18 with the following tumors are included in the study:

  • Patients initially diagnosed with low-grade serous ovarian or peritoneal carcinoma that recur as low grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas as defined by Gynecologic Oncology Group [GOG], International Federation of Gynecology and Obstetrics [FIGO] World Health Organization [WHO] or Silverberg)
  • Patients initially diagnosed with serous borderline ovarian or peritoneal carcinoma that recur as low grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas as defined by GOG, FIGO WHO or Silverberg)

• Patients must have measurable disease:

  • Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded); each "target" lesion must be >= 20 mm when measured by conventional techniques, including palpation, plain x-ray, computed tomography (CT), and magnetic resonance imaging (MRI), or >= 10 mm when measured by spiral CT

• Patient must have documented low grade serous carcinoma (invasive micropapillary serous); confirmation must occur before patient is considered eligible for the trial

  • Patients whose primary tumor was low-grade serous ovarian or peritoneal carcinoma must have a pretreatment sample of their tumor from their primary or recurrent tumor that documents low grade serous carcinoma (invasive micropapillary serous)
  • Patients whose primary tumor was serous borderline ovarian or peritoneal carcinoma must have a pretreatment sample of their tumor from their recurrent tumor that documents low grade serous carcinoma (invasive micropapillary serous)
• Creatinine CTCAE grade 0-1 (< 1.5 x upper limit of normal [ULN])
• Bilirubin CTCAE grade 0-1 (< 1.5 x ULN)
• Transaminases CTCAE grade 0-1 (< 2.5 x ULN)
• Neutrophil CTCAE grade 0-1 (>= 1500/mcl)
• Platelets CTCAE grade 0-1 (>= 100,000/mcl)
• Neuropathy =< CTCAE grade 1
• No restrictions on prior therapy; patients cannot have previously received AZD6244
• Patients of childbearing potential must have a negative pregnancy test and must agree to practice an effective means of birth control prior to study entry, for the duration of study participation, and for four weeks after dosing with AZD6244 ceases
• Patients who have met the pre-entry requirements
• Patients must have signed an approved informed consent and authorization permitting release of personal health information
• Patients must have a GOG performance status of 0 or 1

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Patients may not be receiving any other investigational agents
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 or its excipient Captisol
• Previous mitogen-activated protein kinase (MEK) inhibitor use
• Patients with corrected QT (QTc) interval > 450 msecs or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) including heart failure that meets New York Heart Association (NYHA) class III and IV definitions are excluded
• Required use of a concomitant medication that can prolong the QT interval
• Patients should not receive any drugs known to affect or with the potential to affect selected CYP450 isoenzymes
• Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because the effects of AZD6244 on the developing human fetus at the recommended therapeutic dose are unknown; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated with AZD6244
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD6244; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment (selumetinib sulfate); Patients receive selumetinib sulfate PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Selumetinib Sulfate; Given PO; Other Names: AZD-6244 Hydrogen Sulfate; AZD6244 Hydrogen Sulfate; AZD6244 Hydrogen Sulphate; Koselugo; Selumetinib Sulphate; Drug: Selumetinib; Given PO; Other Names: AZD6244; ARRY-142886; MEK Inhibitor AZD6244

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor Response	Complete and Partial Tumor Response by (Response Evaluation Criteria in Solid Tumors) RECIST 1.0	Every other cycle
Adverse Events (Grade 3 or Higher) During First Cycle of Treatment		Cycle 1
Area Under the Curve (AUC) for AZD6244, 100 mg Administered Orally Twice Daily.		Pre-dose, and 1, 3, and 6 hours after administration of drug on Day 7 after the start of AZD6244 treatment
Maximum Concentration (Cmax) for AZD6244, 100 mg Administered Orally Twice Daily.		Pre-dose, and 1, 3, and 6 hours after administration of drug on Day 7 after the start of AZD6244 treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-free Survival	Every other cycle
Number of Courses Received	Every cycle
Overall Survival	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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: NRG Oncology
• Investigators: Principal Investigator: John H Farley, NRG Oncology

Publications and helpful links

General Publications

• Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, Mannel R, Yamada SD, Mutch D, Rodgers WH, Birrer M, Gershenson DM. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 2013 Feb;14(2):134-40. doi: 10.1016/S1470-2045(12)70572-7. Epub 2012 Dec 21.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 17, 2007
• Primary Completion (ACTUAL): July 23, 2013
• Study Completion (ACTUAL): November 13, 2020

Study Registration Dates

• First Submitted: October 22, 2007
• First Submitted That Met QC Criteria: October 25, 2007
• First Posted (ESTIMATE): October 30, 2007

Study Record Updates

• Last Update Posted (ACTUAL): December 3, 2020
• Last Update Submitted That Met QC Criteria: December 2, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Disease Attributes; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Neoplasms, Connective Tissue; Cystadenocarcinoma; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Neoplasms, Fibrous Tissue; Neoplasms, Fibroepithelial; Carcinoma; Recurrence; Adenocarcinoma; Cystadenocarcinoma, Serous; Brenner Tumor
• Other Study ID Numbers: NCI-2009-00604 (REGISTRY: CTRP (Clinical Trial Reporting Program)); U10CA180868 (U.S. NIH Grant/Contract); U10CA027469 (U.S. NIH Grant/Contract); CDR0000563965; GOG-0239 (OTHER: CTEP)