Combination Chemotherapy with or without Atezolizumab in Treating Patients with Stage III Colon Cancer and Deficient DNA Mismatch Repair
Inclusion Criteria
- Histologically proven stage III colon adenocarcinoma (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C); tumors must be deemed to originate in the colon including tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve)
- Presence of deficient (d) DNA mismatch repair (dMMR); MMR status must be assessed by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR; dMMR may be determined either locally or by site-selected reference lab; Note: loss of MLH1 and PMS2 commonly occur together; formalin-fixed paraffin-embedded (FFPE) tumor tissue is required for subsequent retrospective central confirmation of dMMR status
- Patients with testing that did not show dMMR (loss of MMR protein) are not eligible to participate; patients whose tumors show MSI-H by polymerase chain reaction (PCR)-based assay are not eligible to participate unless they also have MMR testing by IHC and are found to have dMMR (i.e. loss of one or more MMR proteins)
- Patients who are known to have Lynch syndrome and have been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2) are eligible to participate
- Tumors must have been completely resected; in patients with tumor adherent to adjacent structures, en bloc R0 resection must be documented in the operative report or otherwise confirmed by the surgeon; near or positive radial margins are acceptable so long as en bloc resection was performed; proximal or distal margin positivity is not permitted
- Entire tumor must be in the colon (rectal involvement is an exclusion); surgeon confirmation that entire tumor was located in the colon is required only in cases where it is important to establish if the tumor is a colon versus (vs.) rectal primary; patients with more than one primary colon adenocarcinoma are eligible if the qualifying stage III tumor is confined to the colon, and not rectum, and the other cancers of lower stage are removed in the en bloc R0 resection
- Based upon the operative report and other source documentation, the location of the primary tumor will be categorized as proximal or distal to the splenic flexure (included with distal), and further categorization will be as follows: cecum/ascending, transverse, descending, sigmoid colon, or rectosigmoid colon
- No evidence of residual involved lymph node disease or metastatic disease at the time of registration based on clinician assessment of imaging; the treating physician will determine if incidental lesions on imaging require workup to exclude metastatic disease; if based on review of images, the treating physician determines the patient to be stage III, then the patient is eligible
- No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for the current colon cancer except for one cycle of mFOLFOX6
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- This study involves: 1) an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown; and 2) an agent that has known genotoxic, mutagenic, and teratogenic effects; therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required; a female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)
- Absolute neutrophil count (ANC) >= 1500 mm^3
- Platelet count >= 100,000 mm^3; platelets >= 75,000 required for patients who received cycle 1 of mFOLFOX6 prior to registration
- Creatinine =< 1.5 x upper limit of normal (ULN) or
- Calculated creatinine clearance >= 45 mL/min by Cockcroft-Gault equation
- Total bilirubin =< 1.5 x upper limit of normal (ULN) except in the case of Gilbert disease
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
- Thyroid-stimulating hormone (TSH) within normal limits (WNL); supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
- No active known autoimmune disease, including colitis, inflammatory bowel disease (i.e. ulcerative colitis or Crohn’s disease), rheumatoid arthritis, panhypopituitarism, adrenal insufficiency
- No known active hepatitis B or C * Active hepatitis B can be defined as: ** Hepatitis B virus surface antigen (HBsAg) detectable for > 6 months; ** Serum hepatitis B virus (HBV) DNA 20,000 IU/ml (105 copies/ml); lower values 2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B virus e antigen (HBeAg)-negative chronic hepatitis B ** Persistent or intermittent elevation in ALT/AST levels ** Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation * Active hepatitis C can be defined as: ** Hepatitis C antibody (AB) positive AND ** Presence of hepatitis C virus (HCV) RNA
- Excluded if known active pulmonary disease with hypoxia defined as: * Oxygen saturation < 85% on room air, or * Oxygen saturation < 88% despite supplemental oxygen
- No grade >= 2 peripheral motor or sensory neuropathy
- Patients positive for human immunodeficiency virus (HIV) are eligible only if they meet all of the following: * A stable regimen of highly active anti-retroviral therapy (HAART) * No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections * A CD4 count above 250 cells/mcL, and an undetectable HIV viral load on standard PCR-based tests
- No other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study
- No systemic daily treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration
- No known history of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins
- No known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the atezolizumab formulation
- No known allergy to 5-fluorouracil, oxaliplatin, or leucovorin
Alaska
Anchorage
Arizona
Phoenix
Scottsdale
Tucson
Arkansas
Hot Springs
California
Anaheim
Arroyo Grande
Auburn
Baldwin Park
Bellflower
Berkeley
Burbank
Burlingame
Cameron Park
Castro Valley
Clovis
Concord
Costa Mesa
Davis
Dublin
Emeryville
Fontana
Fremont
Harbor City
Irvine
Los Angeles
Martinez
Marysville
Modesto
Mountain View
Novato
Ontario
Orange
Palo Alto
Panorama City
Riverside
Roseville
Sacramento
Salinas
San Diego
San Francisco
San Marcos
Santa Cruz
Santa Rosa
Sunnyvale
Vacaville
Vallejo
West Covina
Woodland Hills
Colorado
Aurora
Boulder
Colorado Springs
Denver
Durango
Englewood
Fort Collins
Golden
Grand Junction
Greeley
Lafayette
Lakewood
Littleton
Lone Tree
Longmont
Loveland
Parker
Pueblo
Thornton
Wheat Ridge
Connecticut
Derby
Fairfield
Guilford
Hartford
Middletown
New Haven
North Haven
Torrington
Trumbull
Waterbury
Waterford
Delaware
Dover
Frankford
Lewes
Milford
Newark
Rehoboth Beach
Seaford
Wilmington
District of Columbia
Washington
Florida
Aventura
Daytona Beach
Fort Lauderdale
Fort Myers
Jacksonville
Miami Beach
Orlando
Georgia
Albany
Athens
Augusta
Hawaii
Aiea
Honolulu
Lihue
Idaho
Boise
Caldwell
Coeur D'Alene
Emmett
Fruitland
Meridian
Nampa
Post Falls
Sandpoint
Twin Falls
Illinois
Bloomington
Canton
Carbondale
Carterville
Carthage
Centralia
Chicago
Crystal Lake
Danville
DeKalb
Decatur
Dixon
Effingham
Eureka
Evanston
Freeport
Galesburg
Geneva
Glenview
Harvey
Highland Park
Kewanee
Lake Forest
Libertyville
Macomb
Mattoon
Maywood
Moline
Mount Vernon
New Lenox
O'Fallon
Orland Park
Ottawa
Park Ridge
Pekin
Peoria
Peru
Princeton
Silvis
Skokie
Springfield
Swansea
Urbana
Warrenville
Indiana
Carmel
Indianapolis
Mooresville
Richmond
Terre Haute
Iowa
Ames
Bettendorf
Boone
Cedar Rapids
Clive
Council Bluffs
Creston
Davenport
Des Moines
Fort Dodge
Iowa City
Jefferson
Marshalltown
Mason City
Sioux City
West Des Moines
Kansas
Coffeyville
Garden City
Great Bend
Hays
Kansas City
Lawrence
Lenexa
Liberal
Olathe
Overland Park
Pittsburg
Salina
Topeka
Wellington
Westwood
Wichita
Kentucky
Bardstown
Corbin
Edgewood
Fort Thomas
Lexington
London
Louisville
Madisonville
Shepherdsville
Louisiana
Baton Rouge
Covington
Houma
Kenner
New Orleans
Maine
Augusta
Bangor
Belfast
Biddeford
Brewer
Rockport
Sanford
South Portland
Maryland
Baltimore
Glen Burnie
Ocean Pines
Salisbury
Massachusetts
Boston
Lowell
Michigan
Adrian
Ann Arbor
Battle Creek
Bay City
Bloomfield
Brighton
Brownstown
Canton
Caro
Chelsea
Clarkston
Clinton Township
Dearborn
Detroit
East China
East Lansing
Farmington Hills
Flint
Grand Rapids
Grosse Pointe
Grosse Pointe Woods
Jackson
Kalamazoo
Lansing
Lapeer
Livonia
Macomb Township
Marlette
Monroe
Mount Clemens
Mount Pleasant
Novi
Petoskey
Pontiac
Port Huron
Reed City
Rochester Hills
Roseville
Royal Oak
Saginaw
Saint Joseph
Sterling Heights
Tawas City
Traverse City
Troy
Warren
West Bloomfield
West Branch
Wyoming
Ypsilanti
Minnesota
Albert Lea
Bemidji
Brainerd
Burnsville
Coon Rapids
Deer River
Duluth
Edina
Fergus Falls
Fridley
Hibbing
Mankato
Maple Grove
Maplewood
Minneapolis
New Ulm
Robbinsdale
Rochester
Saint Cloud
Saint Louis Park
Saint Paul
Sandstone
Shakopee
Stillwater
Virginia
Waconia
Willmar
Woodbury
Wyoming
Mississippi
Pascagoula
Missouri
Ballwin
Bolivar
Bonne Terre
Branson
Cape Girardeau
Columbia
Creve Coeur
Independence
Jefferson City
Joplin
Kansas City
Lee's Summit
Rolla
Saint Joseph
Saint Louis
Saint Peters
Sainte Genevieve
Springfield
Sullivan
Sunset Hills
Washington
Montana
Anaconda
Billings
Bozeman
Great Falls
Helena
Kalispell
Missoula
Nebraska
Grand Island
Kearney
Lincoln
Omaha
Papillion
Nevada
Carson City
Henderson
Las Vegas
Pahrump
Reno
New Hampshire
Concord
Exeter
Lebanon
Manchester
Nashua
New Jersey
Basking Ridge
Cape May Court House
Egg Harbor Township
Englewood
Hamilton
Middletown
Montvale
Morristown
Mullica Hill
New Brunswick
Newark
Paramus
Ridgewood
Somerville
Summit
Vineland
Westwood
New Mexico
Albuquerque
Rio Rancho
New York
Auburn
Brooklyn
Buffalo
Commack
Cooperstown
East Hills
East Syracuse
Elmira
New York
Poughkeepsie
Rochester
Stony Brook
Syracuse
Uniondale
West Harrison
White Plains
North Carolina
Albemarle
Asheboro
Asheville
Burlington
Chapel Hill
Charlotte
Clinton
Clyde
Concord
Durham
Gastonia
Goldsboro
Greensboro
Greenville
Hendersonville
Jacksonville
Kenansville
Kinston
Lincolnton
Monroe
Richlands
Shelby
Washington
Wilmington
North Dakota
Bismarck
Fargo
Grand Forks
Minot
Ohio
Beavercreek
Belpre
Canton
Centerville
Chillicothe
Cincinnati
Cleveland
Columbus
Dayton
Delaware
Findlay
Franklin
Greenville
Kettering
Lancaster
Mansfield
Marietta
Marion
Maumee
Mayfield Heights
Mount Vernon
Newark
Perrysburg
Portsmouth
Sandusky
Springfield
Strongsville
Sylvania
Toledo
Troy
Warrensville Heights
Westerville
Wooster
Youngstown
Zanesville
Oklahoma
Lawton
Oklahoma City
Tulsa
Oregon
Baker City
Bend
Clackamas
Coos Bay
Corvallis
Newberg
Ontario
Portland
Pennsylvania
Abington
Allentown
Bethlehem
Bryn Mawr
Chadds Ford
Chambersburg
Danville
Ephrata
Gettysburg
Hanover
Harrisburg
Hazleton
Jefferson Hills
Lebanon
Lewisburg
Lewistown
Media
Monroeville
Natrona Heights
Paoli
Philadelphia
Pittsburgh
Pottsville
Sayre
Scranton
Selinsgrove
State College
West Reading
Wilkes-Barre
Willow Grove
Wynnewood
York
Puerto Rico
Aguadilla
Arecibo
Bayamon
Caguas
Manati
Ponce
San Juan
Santa Isabel
Rhode Island
Providence
South Carolina
Anderson
Boiling Springs
Charleston
Clinton
Easley
Greenville
Greenwood
Greer
Rock Hill
Seneca
Spartanburg
South Dakota
Aberdeen
Rapid City
Sioux Falls
Tennessee
Bristol
Chattanooga
Cookeville
Hixson
Johnson City
Kingsport
Knoxville
Lenoir City
Nashville
Oak Ridge
Ooltewah
Texas
Amarillo
Austin
Bryan
Conroe
Dallas
Houston
League City
Round Rock
Sugar Land
Temple
Utah
American Fork
Cedar City
Farmington
Logan
Murray
Ogden
Provo
Saint George
Salt Lake City
South Jordan
Vermont
Saint Johnsbury
Virginia
Bristol
Charlottesville
Lynchburg
Martinsville
Mechanicsville
Midlothian
Norfolk
Norton
Richmond
South Hill
Winchester
Washington
Aberdeen
Bellingham
Bremerton
Burien
Centralia
Edmonds
Enumclaw
Everett
Federal Way
Issaquah
Kennewick
Lacey
Lakewood
Longview
Port Townsend
Poulsbo
Seattle
Shelton
Spokane
Spokane Valley
Tacoma
Vancouver
Walla Walla
Yelm
West Virginia
Bridgeport
Charleston
Huntington
Martinsburg
Morgantown
Parkersburg
Wisconsin
Antigo
Appleton
Ashland
Brookfield
Burlington
Eau Claire
Fond Du Lac
Franklin
Germantown
Grafton
Green Bay
Kenosha
La Crosse
Marinette
Marshfield
Medford
Milwaukee
Minocqua
Mukwonago
New Richmond
Oconomowoc
Oconto Falls
Oshkosh
Racine
Sheboygan
Stevens Point
Sturgeon Bay
Summit
Two Rivers
Waukesha
Wausau
Wauwatosa
West Allis
Weston
Wisconsin Rapids
Wyoming
Cheyenne
Cody
Sheridan
PRIMARY OBJECTIVE:
I. To determine whether atezolizumab combined with oxaliplatin, leucovorin calcium, and fluorouracil (FOLFOX) and its continuation as monotherapy can significantly improve disease-free survival (DFS) compared to FOLFOX alone in patients with stage III colon cancers and deficient DNA mismatch repair (dMMR).
SECONDARY OBJECTIVES:
I. To determine whether atezolizumab combined with FOLFOX and its continuation as monotherapy can significantly improve overall survival compared to FOLFOX alone in patients with stage III colon cancers and dMMR.
II. To assess the adverse events (AE) profile and safety of each treatment arm, using the Common Terminology Criteria for Adverse Events (CTCAE) and patient related outcomes (PRO)-CTCAE.
QUALITY OF LIFE OBJECTIVE:
I. To determine the impact of the addition of atezolizumab to FOLFOX on patient-reported neuropathy, health-related quality of life (QOL), and functional domains of health-related QOL.
POTENTIAL CORRELATIVE SCIENCE OBJECTIVES:
I. To determine if the “immunoscore” can predict the efficacy of atezolizumab for disease-free survival among patients with stage III colon cancer.
II. To assess whether circulating immune cell populations can predict the efficacy of atezolizumab as adjuvant therapy for stage III colon cancer.
III. To explore the associations of genomic alterations identified in cell-free (cf)DNA with DFS in patients treated with FOLFOX with or without atezolizumab.
IV. To assess whether soluble markers of systemic inflammation in blood can predict the efficacy of atezolizumab as adjuvant therapy for stage III colon cancer.
V. To assess the relationship between baseline plasma 25(OH) D levels, change in 25(OH)D levels, and DFS and overall survival (OS) in patients with stage III colon cancer receiving FOLFOX +/- atezolizumab.
VI. To determine the ability of using fecal microbiota and their metabolic products to predict survival benefit from anti-PD-L1 antibody therapy in dMMR colon cancer patients.
VII. To determine if hypermutation or hyper-indel status is associated with response to atezolizumab.
VIII. To determine if unique messenger ribonucleic acid (mRNA) expression signatures are predictive of disease-free survival among patients receiving adjuvant chemotherapy for stage III colon cancer.
IX. To determine if the efficacy of atezolizumab differs among dMMR cancers due to germline MMR mutation (MLH1, MSH2, MSH6, PMS2) versus those with MLH1 hypermethylation and CIMP in patients with stage III colon cancer.
X. To identify overall mutational burden and number of putative tumor neoantigens in colon carcinoma specimens.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes starting on day 1 of cycle 1 or 2. Treatment repeats every 14 days for up to 25 cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for recurrence every 6 months for 2 years, then annually for 3 years. Patients are also followed up for survival every 6 months for up to 8 years.
Trial Phase Phase III
Trial Type Treatment
Lead Organization
Alliance for Clinical Trials in Oncology
Principal Investigator
Frank A. Sinicrope
- Primary ID A021502
- Secondary IDs NCI-2016-01417
- Clinicaltrials.gov ID NCT02912559