Testing the Use of the Combination of Selumetinib and Olaparib or Selumetinib Alone Targeted Treatment for RAS Pathway Mutant Recurrent or Persistent Ovarian and Endometrial Cancers, A ComboMATCH Treatment Trial

Recurrent Ovarian Carcinoma Clinical Trial

Official title:

A Randomized Trial of Selumetinib and Olaparib or Selumetinib Alone in Patients With Recurrent or Persistent RAS Pathway Mutant Ovarian and Endometrial Cancers: A ComboMATCH Treatment Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05554328
• Other study ID #: NCI-2022-06841
• Secondary ID: NCI-2022-06841EA
• Status: Recruiting
• Phase: Phase 2
• Start date: April 25, 2023
• Est. completion date: October 1, 2028

Study information

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

Clinical Trial Summary

This phase II ComboMATCH treatment trial compares selumetinib plus olaparib to selumetinib alone in women with endometrial or ovarian (fallopian tube and primary peritoneal) cancer that has come back (recurrent) or that remains despite treatment (persistent) and harbors a mutation in the RAS pathway. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Olaparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. The addition of olaparib to selumetinib could increase the percentage of tumors that shrink as well as lengthen the time that the tumors remain stable (without progression) as compared to selumetinib alone.

Description:

PRIMARY OBJECTIVES:

I. Compare progression free survival of combination of olaparib and selumetinib sulfate (selumetinib) to selumetinib alone in patients with RAS mutant ovarian cancer. (Cohort 1) II. Compare progression free survival of combination of olaparib and selumetinib to selumetinib alone in patients with RAS mutant endometrial cancer. (Cohort 2)

SECONDARY OBJECTIVES:

I. Determine safety of both arms per Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.

II. Compare objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 between the two arms.

III. Determine rate of objective response per RECIST 1.1 in those patients that crossover from the single agent arm to the combination arm.

IV. Report duration of response of the two treatment arms. V. Collect tissue and provide it to the ComboMATCH Registration protocol to assess concordance between the diagnostic tumor mutation profile generated by the designated laboratories, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor (ct)DNA mutation profile from plasma, as described in ComboMATCH Registration protocol. For this treatment substudy, the outcome objective will be to report the proportion of cases providing sufficient tissue for that integrated scientific activity in the ComboMATCH Registration protocol.

TRANSLATIONAL OBJECTIVE:

I. To assess association of baseline genomic and transcriptomic status with response and resistance to therapy.

OUTLINE: Patients in both cohorts are randomized to 1 of 2 arms.

ARM I: Patients receive selumetinib orally (PO) twice daily (BID) and olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo a tumor biopsy and blood collection during screening and on study, as well as echocardiogram (ECHO) or multigated acquisition (MUGA), and computed tomography (CT) scans throughout the trial. Patients may undergo bone marrow aspiration or biopsy as clinically indicated.

ARM II: Patients receive selumetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience progression may elect to cross over to Arm I provided they have not had dose limiting toxicities to monotherapy selumetinib. Patients also undergo a tumor biopsy and blood collection during screening and on study, as well as ECHO or MUGA, and CT scans throughout the trial. Patients may undergo bone marrow aspiration or biopsy as clinically indicated.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 165
• Est. completion date: October 1, 2028
• Est. primary completion date: October 1, 2028
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patient must have enrolled onto EAY191 and must have been given a treatment assignment to ComboMATCH to EAY191-N4 based on the presence of an actionable mutation as defined in EAY191

• Patients must be enrolled on the ComboMATCH Master Registration Trial EAY191

• Patients must have RAS pathway mutations as determined by the ComboMATCH screening assessment

• Cohort 1: Patients with histologically confirmed RAS pathway mutant ovarian, primary peritoneal, or fallopian tube ("ovarian") cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1)

• Cohort 2: Patients with histologically confirmed RAS pathway mutant endometrial cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1).

• Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy, if disease cannot be safely biopsied, or have archival tissue available from within 12 months prior to registration on the ComboMATCH Registration Trial (EAY191)

• Patients must have progressed after first-line treatment for recurrent or persistent disease

• Patients with ovarian cancer should not be eligible for further platinum-based therapy

• Patients with endometrial cancer must have received or been offered an immune oncology agent (alone or in combination with lenvatinib) unless there are existing contraindications for immune oncology agents or lenvatinib

• Patients may have received unlimited prior therapy

• Patients must have measurable and biopsiable disease. Measurable disease is defined by RECIST 1.1 as at least one 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 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

• Patients must have at least one "target lesion" separate from the lesion to be biopsied to be used to assess response on this protocol as defined by RECIST version 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy

• Prior therapy must have been completed at least four weeks prior to registration

• Age >= 18

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

• Hemoglobin (Hgb) >= 9.5 g/dL with no blood transfusion in the past 28 days (within 14 days prior to registration)

• Platelets >= 100,000/mcl (within 14 days prior to registration)

• Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to registration)

• Patients must have creatinine clearance estimated of >= 50 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test (within 14 days prior to registration)

• Total bilirubin level =< 1.5 x institutional upper limit of normal (ULN) or =< 3 x ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) (within 14 days prior to registration)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to registration)

• Patients must be able to swallow and retain oral medications and be without gastrointestinal illnesses that would preclude absorption of selumetinib or olaparib

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better

• Women of childbearing potential (WOCBP) must agree to use two forms of birth control (hormonal or barrier method of birth control; abstinence) during the study and for 12 weeks after completing treatment

• Non-sterilized male partners of WOCBP (including males sterilized by a method other than bilateral orchidectomy e.g., vasectomy) who intend to be sexually active with a female partner must be using an acceptable method of contraception such as male condom plus spermicide (condom alone in countries where spermicides are not approved) from the time of screening throughout the total duration of the study and the drug washout period (at least 16 weeks after the last dose of study intervention) to prevent pregnancy in a partner. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Vasectomized (i.e., sterile) males are considered fertile and should still use a male condom plus spermicide as indicated above during the clinical study

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial

• Patients with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required during the first cycle of therapy

• Patients with treated brain metastases are eligible if follow-up brain imaging after CNS-directed therapy shows no evidence of progression

• Extra caution should be taken with olaparib, as it crosses the blood brain barrier and can cause edema in brain metastases

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Patients who have received any MEK inhibitors

• Patients who have progressed while receiving a PARP inhibitor

• Patients who have received chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia

• Patients with uncontrolled intercurrent illness

• Patients with >= grade 2 neuropathy within 14 days of registration

• Patients with severe (Child-Pugh C) liver dysfunction

• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib and selumetinib or any excipients thereof

• Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents

• Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment even if less than 100% of the daily recommended dosing for vitamin E

• Vitamin E must not be taken in the 7 days prior to initiation of treatment with selumetinib

• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or known moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, Fluconazole, verapamil). The required washout period prior to starting olaparib is at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication

• Concomitant use of strong CYP2C19 inhibitors (e.g., ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole). The required washout period prior to starting selumetinib is at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication

• Have received or are receiving an investigational medicinal product (IMP) or other systemic anti-cancer treatment (including chemotherapy, immunotherapy, targeted therapy, biologic therapy, tumor embolization, or monoclonal antibodies) within 4 weeks prior to registration, or within a period during which the IMP or systemic target treatment has not been cleared from the body (e.g., a period of 5 'half-lives'), whichever is longer

• Known myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

• Patients who have had previous organ transplant, allogenic bone marrow transplant or double umbilical cord blood transplantation

• Patients who have had whole blood transfusion within 28 days prior to registration

• Patients with ophthalmological conditions as follows:

• Current or past history of retinal pigment epithelial detachment/central serous retinopathy or retinal vein occlusion.

• Intraocular pressure >21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of intraocular pressure [IOP]). Subjects with known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the study chair

• Patients with any other significant abnormality on ophthalmic examination should be discussed with the study chair for potential eligibility

• Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or longstanding orbito-temporal plexiform neurofibroma (PN) (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study

• Patients with severe, active co-morbidity defined as any of the following:

• History and/or confirmed pneumonitis

• Uncontrolled hypertension (blood pressure [BP] >= 150/90 mmHg despite medical therapy)

• Acute coronary syndrome within 6 months prior to registration

• Uncontrolled atrial fibrillation

• Known family history of long QT syndrome

• Women who are pregnant or unwilling to discontinue nursing

Related Conditions & MeSH terms

• Carcinoma
• Endometrial Neoplasms
• Recurrence
• Recurrent Endometrial Carcinoma
• Recurrent Fallopian Tube Carcinoma
• Recurrent Ovarian Carcinoma
• Recurrent Primary Peritoneal Carcinoma

Intervention

Procedure:
• Biopsy
Undergo tumor biopsy
• Biospecimen Collection
Undergo blood collection
• Bone Marrow Aspiration and Biopsy
Undergo bone marrow aspiration or biopsy
• Computed Tomography
Undergo CT scan
• Echocardiography
Undergo ECHO
• Multigated Acquisition Scan
Undergo MUGA

Drug:
• Olaparib
Given PO
• Selumetinib Sulfate
Given PO

Locations

Country	Name	City	State
Puerto Rico	Centro Comprensivo de Cancer de UPR	San Juan
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	UPMC Altoona	Altoona	Pennsylvania
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Mission Cancer and Blood - Ankeny	Ankeny	Iowa
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	PCR Oncology	Arroyo Grande	California
United States	Duluth Clinic Ashland	Ashland	Wisconsin
United States	UM Sylvester Comprehensive Cancer Center at Aventura	Aventura	Florida
United States	UH Seidman Cancer Center at UH Avon Health Center	Avon	Ohio
United States	Advocate Good Shepherd Hospital	Barrington	Illinois
United States	UHHS-Chagrin Highlands Medical Center	Beachwood	Ohio
United States	Strecker Cancer Center-Belpre	Belpre	Ohio
United States	National Institutes of Health Clinical Center	Bethesda	Maryland
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Billings Clinic Cancer Center	Billings	Montana
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Bozeman Health Deaconess Hospital	Bozeman	Montana
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Trinity Health Medical Center - Brighton	Brighton	Michigan
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Aultman Health Foundation	Canton	Ohio
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Trinity Health Medical Center - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Miami Valley Hospital South	Centerville	Ohio
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Chelsea Hospital	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Advocate Illinois Masonic Medical Center	Chicago	Illinois
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Case Western Reserve University	Cleveland	Ohio
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Mount Carmel East Hospital	Columbus	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	The Mark H Zangmeister Center	Columbus	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	MD Anderson in The Woodlands	Conroe	Texas
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida
United States	AMG Crystal Lake - Oncology	Crystal Lake	Illinois
United States	Aurora Saint Luke's South Shore	Cudahy	Wisconsin
United States	UPMC Western Maryland	Cumberland	Maryland
United States	Carle at The Riverfront	Danville	Illinois
United States	Dayton Physician LLC - Englewood	Dayton	Ohio
United States	Beaumont Hospital - Dearborn	Dearborn	Michigan
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Essentia Health - Deer River Clinic	Deer River	Minnesota
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Mission Cancer and Blood - Des Moines	Des Moines	Iowa
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	Advocate Good Samaritan Hospital	Downers Grove	Illinois
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Duke University Medical Center	Durham	North Carolina
United States	Pocono Medical Center	East Stroudsburg	Pennsylvania
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Swedish Cancer Institute-Edmonds	Edmonds	Washington
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Advocate Sherman Hospital	Elgin	Illinois
United States	UPMC Hillman Cancer Center Erie	Erie	Pennsylvania
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Beaumont Hospital - Farmington Hills	Farmington Hills	Michigan
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	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Aurora Health Care Germantown Health Center	Germantown	Wisconsin
United States	CTCA at Western Regional Medical Center	Goodyear	Arizona
United States	Aurora Cancer Care-Grafton	Grafton	Wisconsin
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	Advocate South Suburban Hospital	Hazel Crest	Illinois
United States	Essentia Health Hibbing Clinic	Hibbing	Minnesota
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Queen's Cancer Cenrer - POB I	Honolulu	Hawaii
United States	Queen's Cancer Center - Kuakini	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	M D Anderson Cancer Center	Houston	Texas
United States	MD Anderson West Houston	Houston	Texas
United States	Edwards Comprehensive Cancer Center	Huntington	West Virginia
United States	Swedish Cancer Institute-Issaquah	Issaquah	Washington
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin
United States	Kettering Medical Center	Kettering	Ohio
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Kingman Regional Medical Center	Kingman	Arizona
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Fairfield Medical Center	Lancaster	Ohio
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	OptumCare Cancer Care at Charleston	Las Vegas	Nevada
United States	OptumCare Cancer Care at Fort Apache	Las Vegas	Nevada
United States	MD Anderson League City	League City	Texas
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	AMG Libertyville - Oncology	Libertyville	Illinois
United States	Condell Memorial Hospital	Libertyville	Illinois
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Great Lakes Cancer Management Specialists-Macomb Medical Campus	Macomb	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	Aurora Bay Area Medical Group-Marinette	Marinette	Wisconsin
United States	Memorial Hospital	Marysville	Ohio
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion	Mechanicsburg	Pennsylvania
United States	Riddle Memorial Hospital	Media	Pennsylvania
United States	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	UM Sylvester Comprehensive Cancer Center at Kendall	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
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	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Community Medical Center	Missoula	Montana
United States	University of South Alabama Mitchell Cancer Institute	Mobile	Alabama
United States	UPMC Hillman Cancer Center - Monroeville	Monroeville	Pennsylvania
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Ochsner Baptist Medical Center	New Orleans	Louisiana
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Licking Memorial Hospital	Newark	Ohio
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	Advocate Christ Medical Center	Oak Lawn	Illinois
United States	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Saint Alphonsus Cancer Care Center-Ontario	Ontario	Oregon
United States	Saint Joseph Hospital - Orange	Orange	California
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	University of Chicago Medicine-Orland Park	Orland Park	Illinois
United States	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Advocate Lutheran General Hospital	Park Ridge	Illinois
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Mercy Health Perrysburg Cancer Center	Perrysburg	Ohio
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	UM Sylvester Comprehensive Cancer Center at Plantation	Plantation	Florida
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	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Women and Infants Hospital	Providence	Rhode Island
United States	Aurora Cancer Care-Racine	Racine	Wisconsin
United States	Duke Women's Cancer Care Raleigh	Raleigh	North Carolina
United States	Valley Medical Center	Renton	Washington
United States	VCU Massey Cancer Center at Stony Point	Richmond	Virginia
United States	Virginia Cancer Institute	Richmond	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Kootenai Clinic Cancer Services - Sandpoint	Sandpoint	Idaho
United States	Essentia Health Sandstone	Sandstone	Minnesota
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	Sidney Kimmel Cancer Center Washington Township	Sewell	New Jersey
United States	Saint Vincent Hospital Cancer Center at Sheboygan	Sheboygan	Wisconsin
United States	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin
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	VCU Community Memorial Health Center	South Hill	Virginia
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Memorial Medical Center	Springfield	Illinois
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Springfield Regional Cancer Center	Springfield	Ohio
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Saint Vincent Hospital Cancer Center at Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	MD Anderson in Sugar Land	Sugar Land	Texas
United States	Aurora Medical Center in Summit	Summit	Wisconsin
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Mercy Health - Saint Anne Hospital	Toledo	Ohio
United States	William Beaumont Hospital - Troy	Troy	Michigan
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	Carle Cancer Center	Urbana	Illinois
United States	Essentia Health Virginia Clinic	Virginia	Minnesota
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin
United States	Aurora West Allis Medical Center	West Allis	Wisconsin
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Asplundh Cancer Pavilion	Willow Grove	Pennsylvania
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington
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,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	ORR	Defined as the binomial proportion of patients with a best overall response of CR or PR. Defined using RECIST 1.1 criteria. Roughly 10 genomic and transcriptomic measures are expected to present as dichotomous factors. When 3 or more levels are presented, the relatively small sample sizes will likely require collapsing down to 2 levels. If presented as continuous variables, the median of the observed values will classify evaluable patients as having wild-type (WT) or mutated expression.	Up to 5 years
Other	Resistance to therapy	Defined as the proportion of patients with best overall response of disease progression. Defined using RECIST 1.1 criteria. Roughly 10 genomic and transcriptomic measures are expected to present as dichotomous factors. When 3 or more levels are presented, the relatively small sample sizes will likely require collapsing down to 2 levels. If presented as continuous variables, the median of the observed values will classify evaluable patients as having WT or mutated expression.	Up to 5 years
Other	Concordance between the diagnostic tumor mutation profile, biopsy mutations, and pre-treatment circulating tumor deoxyribonucleic acid (ctDNA) mutations	Assess the concordance of the diagnostic tumor mutation profile generated by the designated laboratory, the pre-treatment biopsy mutation profile, and the pre-treatment ctDNA mutation profile.	Up to 5 years
Primary	Progression-free survival (PFS)	Disease progression will be defined using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria, as determined by the treating physician. The primary analyses will be based on logrank tests stratified by the stratification factors as recorded at randomization. All enrolled patients will be included, regardless of compliance with their assigned study regimen. Patients will be grouped by their randomized treatment for intention-to-treat analyses. Treatment hazard ratios and 90% confidence intervals will be estimated using proportional hazards models specified with a main-effect for the randomized treatment assignment (experimental versus [vs] reference), and stratified using the stratification factors recorded at randomization. Treatment group differences will be graphed using Kaplan-Meier methods.	The duration of time from enrollment to the date of progression or death, whichever occurs first, assessed up to 5 years
Secondary	Incidence of adverse events (AE)	The safety population will support these analyses. The nature, frequency, and degree of toxicity will be tabulated at the System Organ Class and AE-specific term levels using Common Terminology Criteria for Adverse Events v5.0. Each patient will be represented according to the maximum grade observed for each term. Tabulations will show the number and percentage of patients by maximum grade, within the treatment group received, regardless of the randomized treatment assignment.	Up to 5 years
Secondary	Objective response rate (ORR) between two arms	ORR is defined as the binomial proportion of evaluable patients with a best overall response of complete response (CR) or partial response (PR) (by RECIST 1.1) within 6 months of the date of the last enrollment. Responses reported by the treating physician will be used for these analyses. The ORR estimates by treatment arm will be supported by their 2-sided, 95% Wilson-Score confidence intervals. The relative odds of response in the experimental arm (vs the reference arm) will be estimated using a multivariable logistic regression model specified with main effects for the randomized treatment assignment and covariate adjustments for the stratification factors reported at baseline.	Within 6 months of the date of last enrollment
Secondary	ORR in crossover patients	Determined by RECIST 1.1. The crossover population will support these analyses. The same evaluation criteria for ORR in the measurable disease population will be applied to the crossover population. These analyses will be done separately for each cohort.	Up to 5 years
Secondary	Duration of response of both arms	These analyses will be supported by patients in the measurable disease population who have a best overall response of PR or CR. Treatment group differences in response duration will be graphed using Kaplan-Meier methods and compared using logrank tests, stratified by the stratification factors defined at randomization. The relative hazards of progression or death in the experimental group (vs the reference group) will be estimated using a multivariable proportional hazards regression model specified with main effects for the treatment indicators and covariate adjustments for the stratification factors reported at baseline. These analyses will be done separately for each cohort.	The time from documentation of either PR or CR until disease progression or death, whichever is observed first, assessed up to 5 years