Borderline Ovarian Serous Tumor, Low Grade Ovarian Serous Adenocarcinoma, Micropapillary Serous Carcinoma, Primary Peritoneal Carcinoma, Primary Peritoneal Low Grade Serous Adenocarcinoma, Recurrent Borderline Ovarian Surface Epithelial-Stromal Tumor
Conditions
Brief summary
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.
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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
DRUGSelumetinib
Given PO
Given PO
Sponsors
NRG Oncology
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
19 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response | Every other cycle | Complete and Partial Tumor Response by (Response Evaluation Criteria in Solid Tumors) RECIST 1.0 |
| 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
| Measure | Time frame |
|---|---|
| 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 |
| Progression-free Survival | Every other cycle |
Countries
United States
Participant flow
Recruitment details
The study was activated on 9/22/2008 and closed to accrual on 1/31/2011 (suspended from 1/4/2010 to 8/9/2010).
Participants by arm
| Arm | Count |
|---|---|
| AZD6244 AZD6244 (NSC #748727) 100 mg orally BID until disease progression or adverse effects prohibit further therapy (1 cycle =28 days) | 52 |
| Total | 52 |
Baseline characteristics
| Characteristic | AZD6244 |
|---|---|
| Age, Customized 20-29 years | 3 participants |
| Age, Customized 30-39 years | 11 participants |
| Age, Customized 40-49 years | 8 participants |
| Age, Customized 50-59 years | 17 participants |
| Age, Customized 60-69 years | 9 participants |
| Age, Customized 70-79 years | 4 participants |
| Age, Customized 80-89 years | 0 participants |
| Sex: Female, Male Female | 52 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 52 / 52 |
| serious Total, serious adverse events | 33 / 52 |
Outcome results
Primary
Adverse Events (Grade 3 or Higher) During First Cycle of Treatment
Time frame: Cycle 1
Population: Eligible and treated patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Leukopenia | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Thrombocytopenia | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Neutropenia | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Anemia | 2 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Allergy/Immunology | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Auditory/Ear | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Cardiac | 2 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Coagulation | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Constitutional | 4 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Dermatologic | 12 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Gastrointestinal | 13 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Genitourinary/Renal | 2 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Hemorrhage | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Infection | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Lymphatics | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Metabolic | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Musculoskeletal | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Neurosensory | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Other Neurological | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Ocular/Visual | 0 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Pain | 4 percentage of patients |
| AZD6244 | Adverse Events (Grade 3 or Higher) During First Cycle of Treatment | Pulmonary | 4 percentage of patients |
Primary
Area Under the Curve (AUC) for AZD6244, 100 mg Administered Orally Twice Daily.
Time frame: Pre-dose, and 1, 3, and 6 hours after administration of drug on Day 7 after the start of AZD6244 treatment
Population: Eligible and Treated Patients with all pharmacokinetic time points available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD6244 | Area Under the Curve (AUC) for AZD6244, 100 mg Administered Orally Twice Daily. | 2419 ng x hr/mL |
Primary
Maximum Concentration (Cmax) for AZD6244, 100 mg Administered Orally Twice Daily.
Time frame: Pre-dose, and 1, 3, and 6 hours after administration of drug on Day 7 after the start of AZD6244 treatment
Population: Eligible and Treated Patients with at least one post-dose pharmacokinetic time point available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD6244 | Maximum Concentration (Cmax) for AZD6244, 100 mg Administered Orally Twice Daily. | 585 ng/mL |
Primary
Tumor Response
Complete and Partial Tumor Response by (Response Evaluation Criteria in Solid Tumors) RECIST 1.0
Time frame: Every other cycle
Population: Eligible and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD6244 | Tumor Response | 15.4 percentage of patients |
Secondary
Number of Courses Received
Time frame: Every cycle
Population: Eligible and Treated Patients. Two patients still on study and have received 68 and 79 cycles of treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD6244 | Number of Courses Received | 5 courses |
Secondary
Overall Survival
Time frame: 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
Population: Eligible and Treated Patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD6244 | Overall Survival | 32.4 Months |
Secondary
Progression-free Survival
Time frame: Every other cycle
Population: Eligible and Treated Patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD6244 | Progression-free Survival | 11.3 months |