Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer

Ovarian Serous Adenocarcinoma Clinical Trial

Official title:

A Randomized Phase II/III Study to Assess the Efficacy of Trametinib (GSK 1120212) in Patients With Recurrent or Progressive Low-Grade Serous Ovarian Cancer or Peritoneal Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02101788
• Other study ID #: NCI-2014-00629
• Secondary ID: NCI-2014-00629GO
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: February 27, 2014
• Est. completion date: October 11, 2024

Study information

• Verified date: January 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II/III trial studies how well trametinib works and compares it to standard treatment with either letrozole, tamoxifen, paclitaxel, pegylated liposomal doxorubicin, or topotecan in treating patients with low-grade ovarian cancer or peritoneal cavity cancer that has come back (recurrent), become worse (progressive), or spread to other parts of the body. Trametinib 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 more effective than standard therapy in treating patients with ovarian or peritoneal cavity cancer.

Description:

PRIMARY OBJECTIVE:

I. To estimate the progression-free survival (PFS) hazard ratio of trametinib compared to that of "commercially available therapies" consisting of one of five commercially available agents in women with recurrent low-grade serous carcinoma of the ovary or peritoneum previously treated with platinum-based chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the nature, frequency and maximum degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4 for each treatment arm.

II. To determine the quality of life, as assessed by the Functional Assessment of Cancer Therapy-Ovarian (FACT-O).

IIa. To compare trametinib to the control arm with regard to patients' self-reported acute (up to post-cycle 6) quality of life as measured by the FACT-O-Trial Outcome Index (TOI).

IIb. To compare trametinib to the control arm with regard to patients' self-reported acute (up to post-cycle 6) neurotoxicity as measured by the FACT-Gynecologic Oncology Group (GOG)-Neurotoxicity (NTX).

III. To estimate the objective response rate (RR) of patients in each treatment arm.

IV. To test whether high expression of pERK, as quantified by immunohistochemistry (IHC), is associated with better prognosis (RR or PFS) among patients receiving the randomized treatment.

V. To test whether genetic changes associated with MAPK pathway activation (KRAS, NRAS, HRAS, BRAF, MEK, ERBB2 or NF1) are associated with improved prognosis (RR or PFS) among patients receiving the randomized treatment.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive clinician's choice of either letrozole orally (PO) once daily (QD) on days 1-28, tamoxifen citrate PO twice daily (BID) on days 1-28, paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride (PLD) IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.

ARM B: Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 260
• Est. completion date: October 11, 2024
• Est. primary completion date: April 4, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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 GOG, Federation of Obstetricians and Gynecologists [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)

• At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g. MAJOR: laparotomy, laparoscopy, thoracotomy, VATS [video assisted thorascopic surgery]); there is no restriction on MINOR procedures: (e.g. central venous catheter placement, ureteral stent placement or exchange, tumor core or fine-needle aspirate [FNA] biopsy)

• Patients must have documented low-grade serous carcinoma; confirmation must occur by prospective pathology review prior to study entry; the prospective pathology review can be done on tissue from the recurrent carcinoma or from original diagnostic specimen

• All patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one target 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; all imaging studies must be performed within 28 days prior to registration

• Prior therapy

• Patients must have recurred or progressed following at least one platinum-based chemotherapy regimen

• Patients may have received an unlimited number of prior therapy regimens

• Patients may not have received all of the five choices in the "standard therapy" arm

• 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 radiation therapy, must be discontinued at least 4 weeks prior to registration; any investigational agent must be discontinued at least 28 days prior to registration

• Trametinib, can cause fetal harm when administered to a pregnant woman; women of child-bearing potential (i.e. patients whose reproductive organs remain in place and who have not passed menopause) and men must agree to use a highly effective method of contraception (e.g. hormonal, intrauterine device or; abstinence*) prior to study entry, during the study participation, and for six months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization, cannot be breast-feeding, and must agree to use a highly effective form of contraception throughout the treatment period and for 6 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• Abstinence is only acceptable when this is in line with the preferred and usual lifestyle of the patient

• Patients must have the ability to understand and sign an approved informed consent and authorization permitting release of personal health information

• Patients must have a GOG performance status of 0 or 1

• Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption, such as malabsorption syndrome, bowel obstruction, or major resection of the stomach or bowel

• All prior treatment-related toxicities must be CTCAE v4 grade =< 1 (except alopecia) at the time of randomization

• Patients must have a left ventricular ejection fraction >= lower limit of normal by echocardiogram (ECHO) or multigated acquisition scan (MUGA)

• Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min (within 14 days prior to treatment)

• Bilirubin =< 1.5 times upper limit of normal (within 14 days prior to treatment)

• Alanine aminotransferase (ALT) =< 2.5 times upper limit of normal (within 14 days prior to treatment)

• Aspartate aminotransferase (AST) =< 2.5 times upper limit of normal (within 14 days prior to treatment)

• Albumin >= 2.5 g/dL (within 14 days prior to treatment)

• Prothrombin time (PT) and activated partial thromboplastin time (APTT) =< 1.5 times upper limit of normal (within 14 days prior to treatment)

• Neutrophil count >= 1.5 x 10^9/L (within 14 days prior to treatment)

• Platelet count >= 100 x 10^9/L (within 14 days prior to treatment)

• Hemoglobin >= 9.0 g/dL (within 14 days prior to treatment)

• If letrozole is selected as the control therapy, patients must be postmenopausal, either following bilateral oophorectomy or at least 5 years after spontaneous menopause; patients within 5 years of spontaneous menopause or who have had a hysterectomy without bilateral oophorectomy must have postmenopausal luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels; patients on hormone replacement therapy (HRT) must agree to withdrawal of hormone therapy before letrozole is started

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

• Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib or standard of care agent

• If patients have had a potential index lesion radiated, it must have progressed post radiation therapy to be used as a measurable eligibility lesion

• Patients may not have received prior MEK, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), or v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor therapy

• Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:

• Patients may not be receiving any other anti-cancer or investigational agents

• Because the composition, PK, and metabolism of many herbal supplements are unknown, 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)

• Patients with known leptomeningeal or brain metastases or spinal cord compression 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

• Patients with a bowel obstruction or any other gastrointestinal condition that might affect absorption of the oral drug should be excluded; this would include patients with inability to swallow and retain orally-administered medication, malabsorption syndrome, or those with a major resection of the stomach or bowels

• Patients with a history of interstitial lung disease or pneumonitis

• Patients with a previous or current malignancy at other sites should be excluded, with the exception of:

• Curatively treated local tumors such as carcinoma-in-situ of the cervix, basal or squamous cell carcinoma of the skin

• Tumors for which no relapse has been observed within 5 years

• Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible); patients with human immunodeficiency virus (HIV) are not eligible if on anti-retroviral medications

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients, or to dimethyl sulfoxide (DMSO), or to Cremophor EL (polyoxyethylated castor oil); please note, exclusion for Cremophor is unnecessary unless paclitaxel is the only agent available and the patient randomizes to the conventional therapy option

• Patients with a history or evidence of cardiovascular risk, including any of the following:

• Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN)

• Bazett's corrected QT (QTcB) >= 480 msec

• History or evidence of current clinically significant uncontrolled arrhythmias

• Exception: Subjects with controlled atrial fibrillation for > 30 days prior to randomization are eligible

• History of (within 6 months prior to randomization) acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting

• History or evidence of current >= class II congestive heart failure as defined by New York Heart Association (NYHA)

• Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy

• Patients with intra-cardiac defibrillators or permanent pacemakers

• Known cardiac metastases

• Patients with a history or current evidence/risk of retinal vein occlusion (RVO)

• Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures

• Patients who require use of a concomitant medication that can prolong the QT interval

• Animal reproductive studies have not been conducted with trametinib; therefore, the study drug must not be administered to pregnant women or nursing mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable)

Related Conditions & MeSH terms

• Adenocarcinoma
• Borderline Ovarian Serous Tumor
• Micropapillary Serous Carcinoma
• Ovarian Serous Adenocarcinoma
• Primary Peritoneal Serous Adenocarcinoma
• Recurrence
• Recurrent Primary Peritoneal Serous Adenocarcinoma

Intervention

Drug:
• Letrozole
Given PO
• Paclitaxel
Given IV
• Pegylated Liposomal Doxorubicin Hydrochloride
Given IV

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Drug:
• Tamoxifen Citrate
Given PO
• Topotecan
Given IV
• Trametinib Dimethyl Sulfoxide
Given PO

Locations

Country	Name	City	State
United Kingdom	Belfast City Hospital	Belfast	Northern Ireland
United Kingdom	Bristol Royal Infirmary	Bristol	England
United Kingdom	Addenbrookes Hospital-Medical School	Cambridge	England
United Kingdom	Western General Hospital	Edinburgh	Scotland
United Kingdom	Beatson Oncology Center	Glasgow	Scotland
United Kingdom	Hammersmith Hospital	London	England
United Kingdom	Saint Bartholomew's Hospital	London	England
United Kingdom	The Royal Marsden NHS Foundation Trust-Chelsea	London
United Kingdom	University College London Hospital	London	England
United Kingdom	Christie Hospital	Manchester	England
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Musgrove Park Hospital	Somerset	England
United Kingdom	Saint James's University Hospital	West Yorkshire	England
United States	Providence Regional Cancer System-Aberdeen	Aberdeen	Washington
United States	Jefferson Abington Hospital	Abington	Pennsylvania
United States	New Mexico Cancer Research Alliance	Albuquerque	New Mexico
United States	Southwest Gynecologic Oncology Associates Inc	Albuquerque	New Mexico
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Cancer Care Center at Island Hospital	Anacortes	Washington
United States	Alaska Breast Care and Surgery LLC	Anchorage	Alaska
United States	Alaska Oncology and Hematology LLC	Anchorage	Alaska
United States	Alaska Women's Cancer Care	Anchorage	Alaska
United States	Anchorage Associates in Radiation Medicine	Anchorage	Alaska
United States	Anchorage Oncology Centre	Anchorage	Alaska
United States	Anchorage Radiation Therapy Center	Anchorage	Alaska
United States	Katmai Oncology Group	Anchorage	Alaska
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	Northside Hospital	Atlanta	Georgia
United States	MultiCare Auburn Medical Center	Auburn	Washington
United States	Sutter Auburn Faith Hospital	Auburn	California
United States	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California
United States	Rocky Mountain Cancer Centers-Aurora	Aurora	Colorado
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	The Medical Center of Aurora	Aurora	Colorado
United States	Virginia Mason Bainbridge Island Medical Center	Bainbridge Island	Washington
United States	Saint Alphonsus Cancer Care Center-Baker City	Baker City	Oregon
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Flaget Memorial Hospital	Bardstown	Kentucky
United States	Woman's Hospital	Baton Rouge	Louisiana
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	UHHS-Chagrin Highlands Medical Center	Beachwood	Ohio
United States	Overlake Medical Center	Bellevue	Washington
United States	Swedish Cancer Institute-Eastside Oncology Hematology	Bellevue	Washington
United States	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington
United States	Strecker Cancer Center-Belpre	Belpre	Ohio
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	Saint Charles Health System	Bend	Oregon
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Saint Vincent Healthcare	Billings	Montana
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Central Care Cancer Center - Bolivar	Bolivar	Missouri
United States	Boulder Community Hospital	Boulder	Colorado
United States	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado
United States	Bozeman Health Deaconess Hospital	Bozeman	Montana
United States	Cox Cancer Center Branson	Branson	Missouri
United States	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Trinity Health Medical Center - Brighton	Brighton	Michigan
United States	Saint Joseph Regional Cancer Center	Bryan	Texas
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California
United States	Highline Medical Center-Main Campus	Burien	Washington
United States	Mills-Peninsula Medical Center	Burlingame	California
United States	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin
United States	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Cooper Hospital University Medical Center	Camden	New Jersey
United States	Sutter Cancer Centers Radiation Oncology Services-Cameron Park	Cameron Park	California
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Trinity Health Medical Center - Canton	Canton	Michigan
United States	Caro Cancer Center	Caro	Michigan
United States	Eden Hospital Medical Center	Castro Valley	California
United States	Sandra L Maxwell Cancer Center	Cedar City	Utah
United States	Providence Regional Cancer System-Centralia	Centralia	Washington
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	Oncology Specialists of Charlotte	Charlotte	North Carolina
United States	Southern Oncology Specialists-Charlotte	Charlotte	North Carolina
United States	Memorial Hospital	Chattanooga	Tennessee
United States	Chelsea Hospital	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Cheyenne Regional Medical Center-West	Cheyenne	Wyoming
United States	Northwestern University	Chicago	Illinois
United States	Swedish Covenant Hospital	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Bethesda North Hospital	Cincinnati	Ohio
United States	Good Samaritan Hospital - Cincinnati	Cincinnati	Ohio
United States	TriHealth Cancer Institute-Anderson	Cincinnati	Ohio
United States	TriHealth Cancer Institute-Westside	Cincinnati	Ohio
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
United States	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon
United States	Hematology Oncology Consultants-Clarkston	Clarkston	Michigan
United States	Newland Medical Associates-Clarkston	Clarkston	Michigan
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Sampson Radiation Oncology	Clinton	North Carolina
United States	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Mission Cancer and Blood - West Des Moines	Clive	Iowa
United States	Community Cancer Institute	Clovis	California
United States	University Oncology Associates	Clovis	California
United States	Big Horn Basin Cancer Center	Cody	Wyoming
United States	Billings Clinic-Cody	Cody	Wyoming
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Rocky Mountain Cancer Centers-Penrose	Colorado Springs	Colorado
United States	Columbus NCI Community Oncology Research Program	Columbus	Ohio
United States	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	John B Amos Cancer Center	Columbus	Georgia
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	The Mark H Zangmeister Center	Columbus	Ohio
United States	MD Anderson in The Woodlands	Conroe	Texas
United States	Bay Area Hospital	Coos Bay	Oregon
United States	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida
United States	Commonwealth Cancer Center-Corbin	Corbin	Kentucky
United States	Alegent Health Mercy Hospital	Council Bluffs	Iowa
United States	Greater Regional Medical Center	Creston	Iowa
United States	Michiana Hematology Oncology PC-Crown Point	Crown Point	Indiana
United States	Northside Hospital-Forsyth	Cumming	Georgia
United States	Parkland Memorial Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Carle at The Riverfront	Danville	Illinois
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Sutter Davis Hospital	Davis	California
United States	Grandview Hospital	Dayton	Ohio
United States	Beaumont Hospital - Dearborn	Dearborn	Michigan
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Delaware Health Center-Grady Cancer Center	Delaware	Ohio
United States	Delaware Radiation Oncology	Delaware	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	Denver Health Medical Center	Denver	Colorado
United States	National Jewish Health-Main Campus	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado
United States	Rocky Mountain Cancer Centers-Midtown	Denver	Colorado
United States	Rocky Mountain Cancer Centers-Rose	Denver	Colorado
United States	Rose Medical Center	Denver	Colorado
United States	SCL Health Saint Joseph Hospital	Denver	Colorado
United States	The Women's Imaging Center	Denver	Colorado
United States	Western States Cancer Research NCORP	Denver	Colorado
United States	Broadlawns Medical Center	Des Moines	Iowa
United States	Iowa Lutheran Hospital	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Laurel	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Mercy Medical Center	Durango	Colorado
United States	Southwest Oncology PC	Durango	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	Great Lakes Cancer Management Specialists-Doctors Park	East China Township	Michigan
United States	Easton Hospital	Easton	Pennsylvania
United States	Swedish Cancer Institute-Edmonds	Edmonds	Washington
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Elkhart Clinic	Elkhart	Indiana
United States	Elkhart General Hospital	Elkhart	Indiana
United States	Michiana Hematology Oncology PC-Elkhart	Elkhart	Indiana
United States	Walter Knox Memorial Hospital	Emmett	Idaho
United States	Mountain Blue Cancer Care Center - Swedish	Englewood	Colorado
United States	Swedish Medical Center	Englewood	Colorado
United States	Saint Elizabeth Hospital	Enumclaw	Washington
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Saint Francis Hospital	Evanston	Illinois
United States	Deaconess Clinic Downtown	Evansville	Indiana
United States	Providence Regional Cancer Partnership	Everett	Washington
United States	Fairbanks Memorial Hospital	Fairbanks	Alaska
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Clinic North-Fargo	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Saint Francis Hospital	Federal Way	Washington
United States	Virginia Mason Federal Way Medical Center	Federal Way	Washington
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Aurora Health Center-Fond du Lac	Fond Du Lac	Wisconsin
United States	Palo Alto Medical Foundation-Fremont	Fremont	California
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	Gibbs Cancer Center-Gaffney	Gaffney	South Carolina
United States	Northeast Georgia Medical Center-Gainesville	Gainesville	Georgia
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Aurora Health Care Germantown Health Center	Germantown	Wisconsin
United States	MultiCare Gig Harbor Medical Park	Gig Harbor	Washington
United States	Tacoma/Valley Radiation Oncology Centers-Gig Harbor	Gig Harbor	Washington
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	Mountain Blue Cancer Care Center	Golden	Colorado
United States	National Jewish Health-Western Hematology Oncology	Golden	Colorado
United States	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina
United States	Wayne Memorial Hospital	Goldsboro	North Carolina
United States	Wayne Radiation Oncology	Goldsboro	North Carolina
United States	Aurora Cancer Care-Grafton	Grafton	Wisconsin
United States	Nebraska Cancer Specialists/Oncology Hematology West PC	Grand Island	Nebraska
United States	Corewell Health Grand Rapids Hospitals - Butterworth Hospital	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	Great Falls Clinic	Great Falls	Montana
United States	Banner North Colorado Medical Center	Greeley	Colorado
United States	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Saint Francis Hospital	Greenville	South Carolina
United States	Rocky Mountain Cancer Centers-Greenwood Village	Greenwood Village	Colorado
United States	Gibbs Cancer Center-Pelham	Greer	South Carolina
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	Academic Hematology Oncology Specialists	Grosse Pointe Woods	Michigan
United States	Great Lakes Cancer Management Specialists-Van Elslander Cancer Center	Grosse Pointe Woods	Michigan
United States	Michigan Breast Specialists-Grosse Pointe Woods	Grosse Pointe Woods	Michigan
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Hartford Hospital	Hartford	Connecticut
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania
United States	Saint Peter's Community Hospital	Helena	Montana
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois
United States	Sudarshan K Sharma MD Limited-Gynecologic Oncology	Hinsdale	Illinois
United States	Pulmonary Medicine Center of Chattanooga-Hixson	Hixson	Tennessee
United States	CHI Saint Vincent Cancer Center Hot Springs	Hot Springs	Arkansas
United States	Houston Methodist Hospital	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	MD Anderson West Houston	Houston	Texas
United States	Memorial Hermann Texas Medical Center	Houston	Texas
United States	Novant Health Cancer Institute - Huntersville	Huntersville	North Carolina
United States	Southern Oncology Specialists-Huntersville	Huntersville	North Carolina
United States	Tennessee Valley Gynecologic Oncology	Huntsville	Alabama
United States	Ascension Saint Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Swedish Cancer Institute-Issaquah	Issaquah	Washington
United States	Allegiance Health	Jackson	Michigan
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Onslow Memorial Hospital	Jacksonville	North Carolina
United States	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina
United States	Mercyhealth Hospital and Cancer Center - Janesville	Janesville	Wisconsin
United States	Freeman Health System	Joplin	Missouri
United States	Mercy Hospital Joplin	Joplin	Missouri
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	CHI Health Good Samaritan	Kearney	Nebraska
United States	Heartland Hematology and Oncology	Kearney	Nebraska
United States	Kadlec Clinic Hematology and Oncology	Kennewick	Washington
United States	Northwest Cancer Clinic	Kennewick	Washington
United States	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin
United States	Armstrong Center for Medicine and Health	Kittanning	Pennsylvania
United States	Community Howard Regional Health	Kokomo	Indiana
United States	IU Health La Porte Hospital	La Porte	Indiana
United States	Providence Regional Cancer System-Lacey	Lacey	Washington
United States	Rocky Mountain Cancer Centers-Lakewood	Lakewood	Colorado
United States	Saint Anthony Hospital	Lakewood	Colorado
United States	Saint Clare Hospital	Lakewood	Washington
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Lancaster Radiation Oncology	Lancaster	Ohio
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	Women's Cancer Center of Nevada	Las Vegas	Nevada
United States	MD Anderson League City	League City	Texas
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Lewistown Hospital	Lewistown	Pennsylvania
United States	Saint Joseph Hospital East	Lexington	Kentucky
United States	Saint Joseph Radiation Oncology Resource Center	Lexington	Kentucky
United States	Saint Elizabeth Regional Medical Center	Lincoln	Nebraska
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Rocky Mountain Cancer Centers-Littleton	Littleton	Colorado
United States	Hope Cancer Clinic	Livonia	Michigan
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Logan Regional Hospital	Logan	Utah
United States	Saint Joseph London	London	Kentucky
United States	Rocky Mountain Cancer Centers-Sky Ridge	Lone Tree	Colorado
United States	Sky Ridge Medical Center	Lone Tree	Colorado
United States	Longmont United Hospital	Longmont	Colorado
United States	Rocky Mountain Cancer Centers-Longmont	Longmont	Colorado
United States	PeaceHealth Saint John Medical Center	Longview	Washington
United States	Jewish Hospital	Louisville	Kentucky
United States	Saints Mary and Elizabeth Hospital	Louisville	Kentucky
United States	The James Graham Brown Cancer Center at University of Louisville	Louisville	Kentucky
United States	UofL Health Medical Center Northeast	Louisville	Kentucky
United States	Banner McKee Medical Center	Loveland	Colorado
United States	Virginia Mason Lynnwood Medical Center	Lynnwood	Washington
United States	Great Lakes Cancer Management Specialists-Macomb Medical Campus	Macomb	Michigan
United States	Michigan Breast Specialists-Macomb Township	Macomb	Michigan
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	Aurora Bay Area Medical Group-Marinette	Marinette	Wisconsin
United States	Saint Mary's Oncology/Hematology Associates of Marlette	Marlette	Michigan
United States	Matthews Radiation Oncology Center	Matthews	North Carolina
United States	Novant Health Cancer Institute - Matthews	Matthews	North Carolina
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio
United States	UH Seidman Cancer Center at Landerbrook Health Center	Mayfield Heights	Ohio
United States	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio
United States	Idaho Urologic Institute-Meridian	Meridian	Idaho
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	Jackson Memorial Hospital-Holtz Children's Hospital	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana
United States	Woodland Cancer Care Center	Michigan City	Indiana
United States	Aurora Cancer Care-Milwaukee	Milwaukee	Wisconsin
United States	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin
United States	Aurora Sinai Medical Center	Milwaukee	Wisconsin
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Memorial Regional Cancer Center Day Road	Mishawaka	Indiana
United States	Michiana Hematology Oncology PC-Mishawaka	Mishawaka	Indiana
United States	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana
United States	Community Medical Center	Missoula	Montana
United States	Saint Patrick Hospital - Community Hospital	Missoula	Montana
United States	Memorial Medical Center	Modesto	California
United States	Monroe Cancer Center	Monroe	Michigan
United States	Novant Health Cancer Institute - Mooresville	Mooresville	North Carolina
United States	Good Samaritan Regional Health Center	Mount Vernon	Illinois
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	Palo Alto Medical Foundation-Camino Division	Mountain View	California
United States	Palo Alto Medical Foundation-Gynecologic Oncology	Mountain View	California
United States	Intermountain Medical Center	Murray	Utah
United States	Trinity Health Muskegon Hospital	Muskegon	Michigan
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	The Hospital of Central Connecticut	New Britain	Connecticut
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Licking Memorial Hospital	Newark	Ohio
United States	Newark Radiation Oncology	Newark	Ohio
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Chancellor Center for Oncology	Newburgh	Indiana
United States	Corewell Health Lakeland Hospitals - Niles Hospital	Niles	Michigan
United States	Sutter Cancer Research Consortium	Novato	California
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	Mercy Hospital Oklahoma City	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Alegent Health Lakeside Hospital	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Hematology and Oncology Consultants PC	Omaha	Nebraska
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Saint Alphonsus Cancer Care Center-Ontario	Ontario	Oregon
United States	Memorial GYN Plus	Ooltewah	Tennessee
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin
United States	Palo Alto Medical Foundation Health Care	Palo Alto	California
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	Midlands Community Hospital	Papillion	Nebraska
United States	Parker Adventist Hospital	Parker	Colorado
United States	Rocky Mountain Cancer Centers-Parker	Parker	Colorado
United States	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania
United States	West Penn Hospital	Pittsburgh	Pennsylvania
United States	UM Sylvester Comprehensive Cancer Center at Plantation	Plantation	Florida
United States	Michiana Hematology Oncology PC-Plymouth	Plymouth	Indiana
United States	Hope Cancer Center	Pontiac	Michigan
United States	Michigan Healthcare Professionals Pontiac	Pontiac	Michigan
United States	Newland Medical Associates-Pontiac	Pontiac	Michigan
United States	Trinity Health Saint Joseph Mercy Oakland Hospital	Pontiac	Michigan
United States	Lake Huron Medical Center	Port Huron	Michigan
United States	Jefferson Healthcare	Port Townsend	Washington
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	Harrison HealthPartners Hematology and Oncology-Poulsbo	Poulsbo	Washington
United States	Peninsula Cancer Center	Poulsbo	Washington
United States	Women and Infants Hospital	Providence	Rhode Island
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Rocky Mountain Cancer Centers - Pueblo	Pueblo	Colorado
United States	Saint Mary Corwin Medical Center	Pueblo	Colorado
United States	MultiCare Good Samaritan Hospital	Puyallup	Washington
United States	Tacoma/Valley Radiation Oncology Centers-Puyallup	Puyallup	Washington
United States	Aurora Cancer Care-Racine	Racine	Wisconsin
United States	Duke Raleigh Hospital	Raleigh	North Carolina
United States	Duke Women's Cancer Care Raleigh	Raleigh	North Carolina
United States	Corewell Health Reed City Hospital	Reed City	Michigan
United States	Center of Hope at Renown Medical Center	Reno	Nevada
United States	Renown Regional Medical Center	Reno	Nevada
United States	University of Rochester	Rochester	New York
United States	Great Lakes Cancer Management Specialists-Rochester Hills	Rochester Hills	Michigan
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri
United States	Sutter Cancer Centers Radiation Oncology Services-Roseville	Roseville	California
United States	Sutter Roseville Medical Center	Roseville	California
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan
United States	Saint George Regional Medical Center	Saint George	Utah
United States	Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Corewell Health Lakeland Hospitals - Saint Joseph Hospital	Saint Joseph	Michigan
United States	Heartland Regional Medical Center	Saint Joseph	Missouri
United States	Barnes-Jewish Hospital	Saint Louis	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	LDS Hospital	Salt Lake City	Utah
United States	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah
United States	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Stanford Cancer Center South Bay	San Jose	California
United States	Kootenai Clinic Cancer Services - Sandpoint	Sandpoint	Idaho
United States	Palo Alto Medical Foundation-Santa Cruz	Santa Cruz	California
United States	Sutter Pacific Medical Foundation	Santa Rosa	California
United States	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	FHCC South Lake Union	Seattle	Washington
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	Kaiser Permanente Washington	Seattle	Washington
United States	Minor and James Medical PLLC	Seattle	Washington
United States	Pacific Gynecology Specialists	Seattle	Washington
United States	Swedish Medical Center-Ballard Campus	Seattle	Washington
United States	Swedish Medical Center-Cherry Hill	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	University of Washington Medical Center - Montlake	Seattle	Washington
United States	University of Washington Medical Center - Northwest	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Women's Cancer Center of Seattle	Seattle	Washington
United States	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin
United States	Providence Regional Cancer System-Shelton	Shelton	Washington
United States	Jewish Hospital Medical Center South	Shepherdsville	Kentucky
United States	Welch Cancer Center	Sheridan	Wyoming
United States	Saint Michael Cancer Center	Silverdale	Washington
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	North Shore Medical Center	Skokie	Illinois
United States	Memorial Hospital of South Bend	South Bend	Indiana
United States	Michiana Hematology Oncology PC-South Bend	South Bend	Indiana
United States	Northern Indiana Cancer Research Consortium	South Bend	Indiana
United States	South Bend Clinic	South Bend	Indiana
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	MultiCare Deaconess Cancer and Blood Specialty Center - Downtown	Spokane	Washington
United States	MultiCare Deaconess Cancer and Blood Specialty Center - North	Spokane	Washington
United States	MultiCare Deaconess Cancer and Blood Specialty Center - Valley	Spokane Valley	Washington
United States	Baystate Medical Center	Springfield	Massachusetts
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Geisinger Medical Group	State College	Pennsylvania
United States	Bhadresh Nayak MD PC-Sterling Heights	Sterling Heights	Michigan
United States	Houston Methodist Sugar Land Hospital	Sugar Land	Texas
United States	MD Anderson in Sugar Land	Sugar Land	Texas
United States	Aurora Medical Center in Summit	Summit	Wisconsin
United States	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	Franciscan Research Center-Northwest Medical Plaza	Tacoma	Washington
United States	MultiCare Tacoma General Hospital	Tacoma	Washington
United States	Northwest Medical Specialties PLLC	Tacoma	Washington
United States	Northwest NCI Community Oncology Research Program	Tacoma	Washington
United States	Tacoma/Valley Radiation Oncology Centers-Jackson Hall	Tacoma	Washington
United States	Tacoma/Valley Radiation Oncology Centers-Saint Joe's	Tacoma	Washington
United States	Ascension Saint Joseph Hospital	Tawas City	Michigan
United States	National Jewish Health-Northern Hematology Oncology	Thornton	Colorado
United States	Rocky Mountain Cancer Centers-Thornton	Thornton	Colorado
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	Munson Medical Center	Traverse City	Michigan
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	Vince Lombardi Cancer Clinic-Two Rivers	Two Rivers	Wisconsin
United States	MGC Hematology Oncology-Union	Union	South Carolina
United States	Carle Cancer Center	Urbana	Illinois
United States	The Carle Foundation Hospital	Urbana	Illinois
United States	Sutter Cancer Centers Radiation Oncology Services-Vacaville	Vacaville	California
United States	Sutter Solano Medical Center/Cancer Center	Vallejo	California
United States	Legacy Salmon Creek Hospital	Vancouver	Washington
United States	PeaceHealth Southwest Medical Center	Vancouver	Washington
United States	University Hospitals Sharon Health Center	Wadsworth	Ohio
United States	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington
United States	Advanced Breast Care Center PLLC	Warren	Michigan
United States	Great Lakes Cancer Management Specialists-Macomb Professional Building	Warren	Michigan
United States	Macomb Hematology Oncology PC	Warren	Michigan
United States	Michigan Breast Specialists-Warren	Warren	Michigan
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Sibley Memorial Hospital	Washington	District of Columbia
United States	Aurora Cancer Care-Waukesha	Waukesha	Wisconsin
United States	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin
United States	Aurora West Allis Medical Center	West Allis	Wisconsin
United States	Saint Mary's Oncology/Hematology Associates of West Branch	West Branch	Michigan
United States	Chester County Hospital	West Chester	Pennsylvania
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	Methodist West Hospital	West Des Moines	Iowa
United States	Saint Ann's Hospital	Westerville	Ohio
United States	UHHS-Westlake Medical Center	Westlake	Ohio
United States	Michiana Hematology Oncology PC-Westville	Westville	Indiana
United States	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado
United States	Dickstein Cancer Treatment Center	White Plains	New York
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	University of Michigan Health - West	Wyoming	Michigan
United States	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington
United States	Providence Regional Cancer System-Yelm	Yelm	Washington
United States	Rush-Copley Healthcare Center	Yorkville	Illinois
United States	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology

Countries where clinical trial is conducted

United States,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS)	Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan.Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the PFS endpoint definition.	Time from study entry to time of progression or death, an average of 7 months for arm A and 13 months for arm B
Secondary	Incidence of Adverse Events (AEs)	Number of treated patients with Adverse Events (grade 3 or higher) observed while receiving randomized therapy. Excludes AEs observed among control patients treated with trametinib after crossover.Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the AE endpoint definition.	During treatment period and up to 100 days after stopping the study treatment
Secondary	Overall Survival	Overall survival (OS) was defined as the number of months between study enrollment and death from any cause. Patients still alive at the last follow-up were censored on the date of last contact. Patients with disease progression on the Control arm were allowed to cross over to the trametinib arm. Per the protocol, the intent-to-treat OS analysis was not adjusted for crossover.	Time from study entry to time of death or date of last contact, an average of 29 months for arm A and 37 months for arm B
Secondary	Objective Tumor Response Rate (Complete Response and Partial Response)	The Response Rates were estimated as the binomial proportion of patients with Best Overall Response of Complete or Partial response according to RECIST 1.1 criteria.	Time from study entry to time of progression or death, an average of 7 months for arm A and 13 months for arm B
Secondary	Patients Reported Acute Quality of Life	Patient reported quality of life was measured with the Treatment Outcome Index (TOI) of the Functional Assessment of Cancer Therapy for ovarian cancer (FACT-O TOI). The FACT-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). . The FACT-O TOI score is calculated as the sum of the subscale scores if more than 80% of the FACT-O TOI items provide valid answers and all of the component subscales have valid scores. The FACT-O TOI score ranges 0-100 with a large score suggesting better QOL. Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the quality of life endpoint definition	1. baseline (prior to cycle 1), 12 weeks (prior to cycle 4), 24 weeks (4 weeks post cycle 6), 36 weeks post cycle 1, 52 weeks post cycle 1.
Secondary	Patient Reported Acute Peripheral Neuropathy Symptoms	Patient reported peripheral neuropathy symptoms was measured with the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - neurotoxicity subscale (short version) (FACT/GOG-Ntx subscale). The FACT/GOG-Ntx subscale contains 4 items. Each item was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). According to the FACIT measurement system, the Ntx score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the scale. The Ntx score ranges 0-16 with a large score suggesting less peripheral neuropathy symptoms	Up to 52 weeks
Secondary	Progression Free Survival	Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan. RECIST v1.1 defines progression as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.	Time from study entry to time of progression or death, an average of 7 months for SOC and 13 months for the treatment (Trametinib) arm.
Secondary	pERK Expression	Will be quantified using the H-score derived from the immunohistochemistry analysis of patient tumor tissue and is expected to present as a continuous measure. will consider the prognostic and predictive abilities of pERK relative to objective response rate (ORR) or PFS. Analysis of the dichotomous markers will be supported by Kaplan Meier plots, and forest plots of the odds-ratio and hazard ratio estimates. Duration of response will be depicted using swimmer plots, with median duration estimated using Kaplan Meier methods. The multivariable models will include covariate adjustment for geographic region, performance status and number of prior regimens, presented using effect coding. The adjusted hazard- and odds- ratio estimates from the multivariable models will be supported by nominal p-values and 2-sided, 95% confidence intervals. Confidence intervals will be interpreted as the plausible range of values for the true (unobserved) ratio that is supported by the data.	Baseline