Testing the Addition of the Pill Chemotherapy, Cabozantinib, to the Standard Immune Therapy Nivolumab Compared to Standard Chemotherapy for Non-small Cell Lung Cancer

A Randomized Phase II Trial of Cabozantinib and Cabozantinib Plus Nivolumab Versus Standard Chemotherapy in Patients With Previously Treated Non-Squamous NSCLC

This phase II trial compares cabozantinib alone and the combination of cabozantinib and nivolumab to standard chemotherapy in the treatment of patients with non-squamous non-small cell lung cancer (NSCLC). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ramucirumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as docetaxel, gemcitabine hydrochloride, paclitaxel, and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving cabozantinib alone or in combination with nivolumab may be more effective than standard chemotherapy in treating patients with non-small cell lung cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Stage IV Lung Cancer AJCC v8; Metastatic Lung Non-Squamous Non-Small Cell Carcinoma; Recurrent Lung Non-Squamous Non-Small Cell Carcinoma
• Intervention / Treatment: Biological: Nivolumab; Drug: Nab-paclitaxel; Drug: Paclitaxel; Drug: Docetaxel; Procedure: Computed Tomography; Drug: Cabozantinib S-malate; Procedure: Echocardiography; Procedure: Biospecimen Collection; Biological: Ramucirumab; Drug: Gemcitabine Hydrochloride

Detailed Description

PRIMARY OBJECTIVE:

I. To determine whether cabozantinib alone, or the combination of nivolumab and cabozantinib, as compared to standard chemotherapy alone, extends progression-free survival (PFS) for this patient population with non squamous NSCLC.

SECONDARY OBJECTIVES:

I. To determine the overall survival for each arm of the trial. II. To evaluate the best overall radiographic response rate for each arm of the trial.

III. To evaluate and describe the toxicity profile of monotherapy with cabozantinib, and the combination of nivolumab and cabozantinib in this patient population with non-squamous NSCLC.

EXPLORATORY IMAGING OBJECTIVES:

I. To describe time point tumor response assessment, overall best response, progression-free survival and overall survival using the conventional Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and the exploratory revised CHOI criteria with all measurements performed by the central review.

II. To compare the progression-free survival using the RECIST1.1 imaging response assessment measurements by site study personnel to those performed by central review.

EXPLORATORY CORRELATIVE OBJECTIVE:

I. To perform correlative biomarker research on tissue and blood biospecimens collected within this trial.

OUTLINE:

STEP 1: Patients are randomized to 1 of 3 arms.

ARM A: Patients receive cabozantinib S-malate orally (PO) once daily (QD). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit.

ARM B: Patients receive cabozantinib S-malate PO QD and nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit.

ARM C: Patients receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician.

STEP 2: Patients in Arm C experiencing disease progression are assigned to Arm Z.

ARM Z: Patients receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit.

Patients in all arms undergo echocardiogram (ECHO) as clinically indicated, computed tomography (CT) throughout the trial, and collection of blood on study.

After the completion of study treatment, patients are followed up every 3 months for up to 3 years.

• Study Type: Interventional
• Enrollment (Estimated): 117
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Veterans Administration Medical Center - Birmingham
  • Alaska
    • Anchorage, Alaska, United States, 98508
      • Anchorage Associates in Radiation Medicine
    • Anchorage, Alaska, United States, 99508
      • Alaska Breast Care and Surgery LLC
    • Anchorage, Alaska, United States, 99508
      • Alaska Oncology and Hematology LLC
    • Anchorage, Alaska, United States, 99508
      • Alaska Women's Cancer Care
    • Anchorage, Alaska, United States, 99508
      • Anchorage Oncology Centre
    • Anchorage, Alaska, United States, 99508
      • Katmai Oncology Group
    • Anchorage, Alaska, United States, 99508
      • Providence Alaska Medical Center
    • Anchorage, Alaska, United States, 99504
      • Anchorage Radiation Therapy Center
    • Fairbanks, Alaska, United States, 99701
      • Fairbanks Memorial Hospital
  • Arizona
    • Goodyear, Arizona, United States, 85338
      • CTCA at Western Regional Medical Center
    • Kingman, Arizona, United States, 86401
      • Kingman Regional Medical Center
    • Phoenix, Arizona, United States, 85004
      • Cancer Center at Saint Joseph's
    • Tucson, Arizona, United States, 85719
      • Banner University Medical Center - Tucson
    • Tucson, Arizona, United States, 85719
      • University of Arizona Cancer Center-North Campus
  • Arkansas
    • Fort Smith, Arkansas, United States, 72903
      • Mercy Hospital Fort Smith
    • Hot Springs, Arkansas, United States, 71913
      • CHI Saint Vincent Cancer Center Hot Springs
  • California
    • Arroyo Grande, California, United States, 93420
      • PCR Oncology
    • Arroyo Grande, California, United States, 93420
      • Mission Hope Medical Oncology - Arroyo Grande
    • Burbank, California, United States, 91505
      • Providence Saint Joseph Medical Center/Disney Family Cancer Center
    • Carmichael, California, United States, 95608
      • Mercy San Juan Medical Center
    • Carmichael, California, United States, 95608
      • Mercy Cancer Center - Carmichael
    • Elk Grove, California, United States, 95758
      • Mercy Cancer Center - Elk Grove
    • Fremont, California, United States, 94538
      • Washington Hospital
    • Marysville, California, United States, 95901
      • Fremont - Rideout Cancer Center
    • Orange, California, United States, 92868
      • Saint Joseph Hospital - Orange
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Institute Palo Alto
    • Rocklin, California, United States, 95765
      • Mercy Cancer Center - Rocklin
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • Sacramento, California, United States, 95816
      • Mercy Cancer Center - Sacramento
    • San Luis Obispo, California, United States, 93401
      • Pacific Central Coast Health Center-San Luis Obispo
    • Santa Maria, California, United States, 93444
      • Mission Hope Medical Oncology - Santa Maria
    • Woodland, California, United States, 95695
      • Woodland Memorial Hospital
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers-Aurora
    • Aurora, Colorado, United States, 80012
      • The Medical Center of Aurora
    • Boulder, Colorado, United States, 80303
      • Boulder Community Foothills Hospital
    • Boulder, Colorado, United States, 80304
      • Rocky Mountain Cancer Centers-Boulder
    • Centennial, Colorado, United States, 80112
      • Rocky Mountain Cancer Centers - Centennial
    • Colorado Springs, Colorado, United States, 80907
      • Penrose-Saint Francis Healthcare
    • Colorado Springs, Colorado, United States, 80907
      • Rocky Mountain Cancer Centers-Penrose
    • Colorado Springs, Colorado, United States, 80923
      • Saint Francis Cancer Center
    • Denver, Colorado, United States, 80210
      • Porter Adventist Hospital
    • Denver, Colorado, United States, 80218
      • Presbyterian - Saint Lukes Medical Center - Health One
    • Denver, Colorado, United States, 80218
      • SCL Health Saint Joseph Hospital
    • Denver, Colorado, United States, 80220
      • Rose Medical Center
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Centers-Midtown
    • Denver, Colorado, United States, 80220
      • Rocky Mountain Cancer Centers-Rose
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
    • Denver, Colorado, United States, 80204
      • Cancer Center of Colorado at Sloan's Lake
    • Denver, Colorado, United States, 80209
      • The Women's Imaging Center
    • Denver, Colorado, United States, 80206
      • National Jewish Health-Main Campus
    • Denver, Colorado, United States, 80220
      • Western Surgical Care
    • Durango, Colorado, United States, 81301
      • Mercy Medical Center
    • Durango, Colorado, United States, 81301
      • Southwest Oncology PC
    • Englewood, Colorado, United States, 80113
      • Mountain Blue Cancer Care Center - Swedish
    • Englewood, Colorado, United States, 80113
      • Swedish Medical Center
    • Englewood, Colorado, United States, 80113
      • Rocky Mountain Cancer Centers - Swedish
    • Englewood, Colorado, United States, 80113
      • The Melanoma and Skin Cancer Institute
    • Fort Collins, Colorado, United States, 80524
      • Poudre Valley Hospital
    • Fort Collins, Colorado, United States, 80528
      • Cancer Care and Hematology-Fort Collins
    • Golden, Colorado, United States, 80401
      • National Jewish Health-Western Hematology Oncology
    • Grand Junction, Colorado, United States, 81501
      • Saint Mary's Hospital and Regional Medical Center
    • Greeley, Colorado, United States, 80631
      • North Colorado Medical Center
    • Greeley, Colorado, United States, 80631
      • UCHealth Greeley Hospital
    • Highlands Ranch, Colorado, United States, 80129
      • UCHealth Highlands Ranch Hospital
    • Lafayette, Colorado, United States, 80026
      • Good Samaritan Medical Center
    • Lakewood, Colorado, United States, 80228
      • Saint Anthony Hospital
    • Lakewood, Colorado, United States, 80228
      • Rocky Mountain Cancer Centers-Lakewood
    • Littleton, Colorado, United States, 80120
      • Rocky Mountain Cancer Centers-Littleton
    • Littleton, Colorado, United States, 80122
      • Littleton Adventist Hospital
    • Lone Tree, Colorado, United States, 80124
      • Sky Ridge Medical Center
    • Lone Tree, Colorado, United States, 80124
      • Rocky Mountain Cancer Centers-Sky Ridge
    • Longmont, Colorado, United States, 80501
      • Longmont United Hospital
    • Longmont, Colorado, United States, 80501
      • Rocky Mountain Cancer Centers-Longmont
    • Loveland, Colorado, United States, 80539
      • McKee Medical Center
    • Loveland, Colorado, United States, 80538
      • Medical Center of the Rockies
    • Parker, Colorado, United States, 80138
      • Parker Adventist Hospital
    • Pueblo, Colorado, United States, 81004
      • Saint Mary Corwin Medical Center
    • Thornton, Colorado, United States, 80260
      • Rocky Mountain Cancer Centers-Thornton
    • Thornton, Colorado, United States, 80260
      • National Jewish Health-Northern Hematology Oncology
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • Veterans Affairs Connecticut Healthcare System-West Haven Campus
  • Florida
    • Aventura, Florida, United States, 33180
      • Mount Sinai Comprehensive Cancer Center at Aventura
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Emory University Hospital Midtown
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital/Winship Cancer Institute
    • Savannah, Georgia, United States, 31405
      • Lewis Cancer and Research Pavilion at Saint Joseph's/Candler
  • Idaho
    • Boise, Idaho, United States, 83706
      • Saint Alphonsus Cancer Care Center-Boise
    • Boise, Idaho, United States, 83712
      • Saint Luke's Cancer Institute - Boise
    • Caldwell, Idaho, United States, 83605
      • Saint Alphonsus Cancer Care Center-Caldwell
    • Coeur d'Alene, Idaho, United States, 83814
      • Kootenai Health - Coeur d'Alene
    • Emmett, Idaho, United States, 83617
      • Walter Knox Memorial Hospital
    • Fruitland, Idaho, United States, 83619
      • Saint Luke's Cancer Institute - Fruitland
    • Meridian, Idaho, United States, 83642
      • Idaho Urologic Institute-Meridian
    • Meridian, Idaho, United States, 83642
      • Saint Luke's Cancer Institute - Meridian
    • Nampa, Idaho, United States, 83686
      • Saint Luke's Cancer Institute - Nampa
    • Nampa, Idaho, United States, 83687
      • Saint Alphonsus Cancer Care Center-Nampa
    • Post Falls, Idaho, United States, 83854
      • Kootenai Clinic Cancer Services - Post Falls
    • Sandpoint, Idaho, United States, 83864
      • Kootenai Cancer Clinic
    • Twin Falls, Idaho, United States, 83301
      • Saint Luke's Cancer Institute - Twin Falls
  • Illinois
    • Alton, Illinois, United States, 62002
      • Saint Anthony's Health
    • Aurora, Illinois, United States, 60504
      • Rush - Copley Medical Center
    • Barrington, Illinois, United States, 60010
      • Advocate Good Shepherd Hospital
    • Bloomington, Illinois, United States, 61704
      • Illinois CancerCare-Bloomington
    • Canton, Illinois, United States, 61520
      • Illinois CancerCare-Canton
    • Carbondale, Illinois, United States, 62902
      • Memorial Hospital of Carbondale
    • Carterville, Illinois, United States, 62918
      • SIH Cancer Institute
    • Carthage, Illinois, United States, 62321
      • Illinois CancerCare-Carthage
    • Centralia, Illinois, United States, 62801
      • Centralia Oncology Clinic
    • Centralia, Illinois, United States, 62801
      • Saint Mary's Hospital
    • Chicago, Illinois, United States, 60612
      • University of Illinois
    • Chicago, Illinois, United States, 60657
      • Advocate Illinois Masonic Medical Center
    • Crystal Lake, Illinois, United States, 60014
      • AMG Crystal Lake - Oncology
    • Danville, Illinois, United States, 61832
      • Carle at The Riverfront
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
    • Decatur, Illinois, United States, 62526
      • Cancer Care Specialists of Illinois - Decatur
    • Dixon, Illinois, United States, 61021
      • Illinois CancerCare-Dixon
    • Downers Grove, Illinois, United States, 60515
      • Advocate Good Samaritan Hospital
    • Effingham, Illinois, United States, 62401
      • Crossroads Cancer Center
    • Effingham, Illinois, United States, 62401
      • Carle Physician Group-Effingham
    • Elgin, Illinois, United States, 60123
      • Advocate Sherman Hospital
    • Eureka, Illinois, United States, 61530
      • Illinois CancerCare-Eureka
    • Galesburg, Illinois, United States, 61401
      • Western Illinois Cancer Treatment Center
    • Galesburg, Illinois, United States, 61401
      • Illinois CancerCare-Galesburg
    • Hazel Crest, Illinois, United States, 60429
      • Advocate South Suburban Hospital
    • Hines, Illinois, United States, 60141
      • Edward Hines Jr VA Hospital
    • Kewanee, Illinois, United States, 61443
      • Illinois CancerCare-Kewanee Clinic
    • Libertyville, Illinois, United States, 60048
      • Condell Memorial Hospital
    • Libertyville, Illinois, United States, 60048
      • AMG Libertyville - Oncology
    • Macomb, Illinois, United States, 61455
      • Illinois CancerCare-Macomb
    • Mattoon, Illinois, United States, 61938
      • Carle Physician Group-Mattoon/Charleston
    • Mount Vernon, Illinois, United States, 62864
      • Good Samaritan Regional Health Center
    • O'Fallon, Illinois, United States, 62269
      • Cancer Care Center of O'Fallon
    • Oak Lawn, Illinois, United States, 60453-2699
      • Advocate Christ Medical Center
    • Ottawa, Illinois, United States, 61350
      • Illinois CancerCare-Ottawa Clinic
    • Park Ridge, Illinois, United States, 60068
      • Advocate Lutheran General Hospital
    • Pekin, Illinois, United States, 61554
      • Illinois CancerCare-Pekin
    • Peoria, Illinois, United States, 61636
      • Methodist Medical Center of Illinois
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare-Peoria
    • Peru, Illinois, United States, 61354
      • Illinois CancerCare-Peru
    • Peru, Illinois, United States, 61354
      • Valley Radiation Oncology
    • Princeton, Illinois, United States, 61356
      • Illinois CancerCare-Princeton
    • Rockford, Illinois, United States, 61114
      • SwedishAmerican Regional Cancer Center/ACT
    • Springfield, Illinois, United States, 62781
      • Memorial Medical Center
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University School of Medicine
    • Springfield, Illinois, United States, 62702
      • Springfield Clinic
    • Swansea, Illinois, United States, 62226
      • Southwest Illinois Health Services LLP
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center
    • Urbana, Illinois, United States, 61801
      • The Carle Foundation Hospital
    • Washington, Illinois, United States, 61571
      • Illinois CancerCare - Washington
    • Yorkville, Illinois, United States, 60560
      • Rush-Copley Healthcare Center
  • Indiana
    • Richmond, Indiana, United States, 47374
      • Reid Health
    • South Bend, Indiana, United States, 46601
      • Memorial Hospital of South Bend
  • Iowa
    • Ames, Iowa, United States, 50010
      • Mary Greeley Medical Center
    • Ames, Iowa, United States, 50010
      • McFarland Clinic - Ames
    • Bettendorf, Iowa, United States, 52722
      • University of Iowa Healthcare Cancer Services Quad Cities
    • Boone, Iowa, United States, 50036
      • McFarland Clinic - Boone
    • Carroll, Iowa, United States, 51401
      • Saint Anthony Regional Hospital
    • Clive, Iowa, United States, 50325
      • Mercy Cancer Center-West Lakes
    • Clive, Iowa, United States, 50325
      • Medical Oncology and Hematology Associates-West Des Moines
    • Council Bluffs, Iowa, United States, 51503
      • Alegent Health Mercy Hospital
    • Council Bluffs, Iowa, United States, 51503
      • Heartland Oncology and Hematology LLP
    • Council Bluffs, Iowa, United States, 51503
      • Methodist Jennie Edmundson Hospital
    • Creston, Iowa, United States, 50801
      • Greater Regional Medical Center
    • Des Moines, Iowa, United States, 50309
      • Iowa Methodist Medical Center
    • Des Moines, Iowa, United States, 50314
      • Mercy Medical Center - Des Moines
    • Des Moines, Iowa, United States, 50309
      • Medical Oncology and Hematology Associates-Des Moines
    • Des Moines, Iowa, United States, 50314
      • Broadlawns Medical Center
    • Des Moines, Iowa, United States, 50314
      • Mission Cancer and Blood - Laurel
    • Des Moines, Iowa, United States, 50316
      • Iowa Lutheran Hospital
    • Fort Dodge, Iowa, United States, 50501
      • Trinity Regional Medical Center
    • Fort Dodge, Iowa, United States, 50501
      • McFarland Clinic - Trinity Cancer Center
    • Iowa City, Iowa, United States, 52242
      • University of Iowa/Holden Comprehensive Cancer Center
    • Jefferson, Iowa, United States, 50129
      • McFarland Clinic - Jefferson
    • Marshalltown, Iowa, United States, 50158
      • McFarland Clinic - Marshalltown
    • West Des Moines, Iowa, United States, 50266-7700
      • Methodist West Hospital
    • West Des Moines, Iowa, United States, 50266
      • Mercy Medical Center-West Lakes
  • Kansas
    • Garden City, Kansas, United States, 67846
      • Central Care Cancer Center - Garden City
    • Great Bend, Kansas, United States, 67530
      • Central Care Cancer Center - Great Bend
    • Hays, Kansas, United States, 67601
      • HaysMed University of Kansas Health System
    • Lawrence, Kansas, United States, 66044
      • Lawrence Memorial Hospital
    • Olathe, Kansas, United States, 66061
      • Olathe Health Cancer Center
    • Overland Park, Kansas, United States, 66213
      • Saint Luke's South Hospital
    • Pittsburg, Kansas, United States, 66762
      • Ascension Via Christi - Pittsburg
    • Pittsburg, Kansas, United States, 66762
      • Freeman Physician Group of Pittsburg
    • Salina, Kansas, United States, 67401
      • Salina Regional Health Center
    • Topeka, Kansas, United States, 66606
      • University of Kansas Health System Saint Francis Campus
  • Kentucky
    • Bardstown, Kentucky, United States, 40004
      • Flaget Memorial Hospital
    • Corbin, Kentucky, United States, 40701
      • Commonwealth Cancer Center-Corbin
    • Lexington, Kentucky, United States, 40504
      • Saint Joseph Radiation Oncology Resource Center
    • Lexington, Kentucky, United States, 40509
      • Saint Joseph Hospital East
    • Lexington, Kentucky, United States, 40504
      • Saint Joseph Hospital
    • London, Kentucky, United States, 40741
      • Saint Joseph London
    • Louisville, Kentucky, United States, 40202
      • Jewish Hospital
    • Louisville, Kentucky, United States, 40245
      • UofL Health Medical Center Northeast
    • Louisville, Kentucky, United States, 40215
      • Saints Mary and Elizabeth Hospital
    • Mount Sterling, Kentucky, United States, 40353
      • Saint Joseph Mount Sterling
    • Owensboro, Kentucky, United States, 42303
      • Owensboro Health Mitchell Memorial Cancer Center
    • Paducah, Kentucky, United States, 42003
      • Mercy Health - Paducah Medical Oncology and Hematology
    • Shepherdsville, Kentucky, United States, 40165
      • Jewish Hospital Medical Center South
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70805
      • LSU Health Baton Rouge-North Clinic
    • Baton Rouge, Louisiana, United States, 70809
      • Louisiana Hematology Oncology Associates LLC
    • Baton Rouge, Louisiana, United States, 70809
      • Mary Bird Perkins Cancer Center
    • Baton Rouge, Louisiana, United States, 70809
      • Our Lady of the Lake Physicians Group - Medical Oncology
    • Baton Rouge, Louisiana, United States, 70808
      • Our Lady of The Lake
    • Covington, Louisiana, United States, 70433
      • Northshore Oncology Associates-Covington
    • Houma, Louisiana, United States, 70360
      • Terrebonne General Medical Center
  • Maine
    • Augusta, Maine, United States, 04330
      • Harold Alfond Center for Cancer Care
    • Biddeford, Maine, United States, 04005
      • MaineHealth/SMHC Cancer Care and Blood Disorders-Biddeford
    • Sanford, Maine, United States, 04073
      • MaineHealth/SMHC Cancer Care and Blood Disorders-Sanford
    • South Portland, Maine, United States, 04106
      • Maine Medical Partners - South Portland
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • Saint Agnes Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Worcester, Massachusetts, United States, 01655
      • UMass Memorial Medical Center - University Campus
  • Michigan
    • Adrian, Michigan, United States, 49221
      • Hickman Cancer Center
    • Ann Arbor, Michigan, United States, 48106
      • Saint Joseph Mercy Hospital
    • Battle Creek, Michigan, United States, 49017
      • Bronson Battle Creek
    • Brighton, Michigan, United States, 48114
      • Saint Joseph Mercy Brighton
    • Brighton, Michigan, United States, 48114
      • Trinity Health IHA Medical Group Hematology Oncology - Brighton
    • Canton, Michigan, United States, 48188
      • Saint Joseph Mercy Canton
    • Canton, Michigan, United States, 48188
      • Trinity Health IHA Medical Group Hematology Oncology - Canton
    • Caro, Michigan, United States, 48723
      • Caro Cancer Center
    • Chelsea, Michigan, United States, 48118
      • Saint Joseph Mercy Chelsea
    • Chelsea, Michigan, United States, 48118
      • Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
    • Clarkston, Michigan, United States, 48346
      • Hematology Oncology Consultants-Clarkston
    • Clarkston, Michigan, United States, 48346
      • Newland Medical Associates-Clarkston
    • Detroit, Michigan, United States, 48236
      • Ascension Saint John Hospital
    • East China Township, Michigan, United States, 48054
      • Great Lakes Cancer Management Specialists-Doctors Park
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Flint, Michigan, United States, 48503
      • Genesee Cancer and Blood Disease Treatment Center
    • Flint, Michigan, United States, 48503
      • Genesee Hematology Oncology PC
    • Flint, Michigan, United States, 48503
      • Genesys Hurley Cancer Institute
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health at Butterworth Campus
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital at Spectrum Health
    • Grand Rapids, Michigan, United States, 49503
      • Trinity Health Grand Rapids Hospital
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Academic Hematology Oncology Specialists
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Great Lakes Cancer Management Specialists-Van Elslander Cancer Center
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Michigan Breast Specialists-Grosse Pointe Woods
    • Kalamazoo, Michigan, United States, 49007
      • West Michigan Cancer Center
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49048
      • Borgess Medical Center
    • Kalamazoo, Michigan, United States, 49009
      • Ascension Borgess Cancer Center
    • Lansing, Michigan, United States, 48912
      • University of Michigan Health - Sparrow Lansing
    • Livonia, Michigan, United States, 48154
      • Trinity Health Saint Mary Mercy Livonia Hospital
    • Livonia, Michigan, United States, 48154
      • Hope Cancer Clinic
    • Macomb, Michigan, United States, 48044
      • Great Lakes Cancer Management Specialists-Macomb Medical Campus
    • Macomb, Michigan, United States, 48044
      • Michigan Breast Specialists-Macomb Township
    • Marlette, Michigan, United States, 48453
      • Saint Mary's Oncology/Hematology Associates of Marlette
    • Monroe, Michigan, United States, 48162
      • Toledo Clinic Cancer Centers-Monroe
    • Muskegon, Michigan, United States, 49444
      • Trinity Health Muskegon Hospital
    • Niles, Michigan, United States, 49120
      • Corewell Health Lakeland Hospitals - Niles Hospital
    • Norton Shores, Michigan, United States, 49444
      • Cancer and Hematology Centers of Western Michigan - Norton Shores
    • Novi, Michigan, United States, 48374
      • Ascension Providence Hospitals - Novi
    • Pontiac, Michigan, United States, 48341
      • Saint Joseph Mercy Oakland
    • Pontiac, Michigan, United States, 48341
      • 21st Century Oncology-Pontiac
    • Pontiac, Michigan, United States, 48341
      • Hope Cancer Center
    • Pontiac, Michigan, United States, 48341
      • Newland Medical Associates-Pontiac
    • Reed City, Michigan, United States, 49677
      • Corewell Health Reed City Hospital
    • Rochester Hills, Michigan, United States, 48309
      • Great Lakes Cancer Management Specialists-Rochester Hills
    • Saginaw, Michigan, United States, 48601
      • Ascension Saint Mary's Hospital
    • Saginaw, Michigan, United States, 48604
      • Oncology Hematology Associates of Saginaw Valley PC
    • Saint Joseph, Michigan, United States, 49085
      • Lakeland Medical Center Saint Joseph
    • Saint Joseph, Michigan, United States, 49085
      • Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center
    • Southfield, Michigan, United States, 48075
      • Ascension Providence Hospitals - Southfield
    • Sterling Heights, Michigan, United States, 48312
      • Bhadresh Nayak MD PC-Sterling Heights
    • Tawas City, Michigan, United States, 48764
      • Ascension Saint Joseph Hospital
    • Traverse City, Michigan, United States, 49684
      • Munson Medical Center
    • Warren, Michigan, United States, 48093
      • Saint John Macomb-Oakland Hospital
    • Warren, Michigan, United States, 48088
      • Advanced Breast Care Center PLLC
    • Warren, Michigan, United States, 48093
      • Great Lakes Cancer Management Specialists-Macomb Professional Building
    • Warren, Michigan, United States, 48093
      • Macomb Hematology Oncology PC
    • Warren, Michigan, United States, 48093
      • Michigan Breast Specialists-Warren
    • West Branch, Michigan, United States, 48661
      • Saint Mary's Oncology/Hematology Associates of West Branch
    • Wyoming, Michigan, United States, 49519
      • University of Michigan Health - West
    • Ypsilanti, Michigan, United States, 48197
      • Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
    • Ypsilanti, Michigan, United States, 48106
      • Huron Gastroenterology PC
  • Minnesota
    • Aitkin, Minnesota, United States, 56431
      • Riverwood Healthcare Center
    • Baxter, Minnesota, United States, 56425
      • Essentia Health - Baxter Clinic
    • Brainerd, Minnesota, United States, 56401
      • Essentia Health Saint Joseph's Medical Center
    • Burnsville, Minnesota, United States, 55337
      • Fairview Ridges Hospital
    • Burnsville, Minnesota, United States, 55337
      • Minnesota Oncology - Burnsville
    • Cambridge, Minnesota, United States, 55008
      • Cambridge Medical Center
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy Hospital
    • Deer River, Minnesota, United States, 56636
      • Essentia Health - Deer River Clinic
    • Detroit Lakes, Minnesota, United States, 56501
      • Essentia Health Saint Mary's - Detroit Lakes Clinic
    • Duluth, Minnesota, United States, 55805
      • Essentia Health Cancer Center
    • Duluth, Minnesota, United States, 55805
      • Essentia Health Saint Mary's Medical Center
    • Duluth, Minnesota, United States, 55805
      • Miller-Dwan Hospital
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Ely, Minnesota, United States, 55731
      • Essentia Health - Ely Clinic
    • Fergus Falls, Minnesota, United States, 56537
      • Lake Region Healthcare Corporation-Cancer Care
    • Fosston, Minnesota, United States, 56542
      • Essentia Health - Fosston
    • Fridley, Minnesota, United States, 55432
      • Unity Hospital
    • Hibbing, Minnesota, United States, 55746
      • Essentia Health Hibbing Clinic
    • International Falls, Minnesota, United States, 56649
      • Essentia Health - International Falls Clinic
    • Maple Grove, Minnesota, United States, 55369
      • Fairview Clinics and Surgery Center Maple Grove
    • Maplewood, Minnesota, United States, 55109
      • Saint John's Hospital - Healtheast
    • Maplewood, Minnesota, United States, 55109
      • Minnesota Oncology Hematology PA-Maplewood
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Minneapolis, Minnesota, United States, 55407
      • Abbott-Northwestern Hospital
    • Minneapolis, Minnesota, United States, 55454
      • Health Partners Inc
    • Monticello, Minnesota, United States, 55362
      • Monticello Cancer Center
    • Moose Lake, Minnesota, United States, 55767
      • Essentia Health - Moose Lake Clinic
    • New Ulm, Minnesota, United States, 56073
      • New Ulm Medical Center
    • Park Rapids, Minnesota, United States, 56470
      • Essentia Health - Park Rapids
    • Princeton, Minnesota, United States, 55371
      • Fairview Northland Medical Center
    • Robbinsdale, Minnesota, United States, 55422
      • North Memorial Medical Health Center
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Clinic - Saint Louis Park
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Sandstone, Minnesota, United States, 55072
      • Essentia Health Sandstone
    • Shakopee, Minnesota, United States, 55379
      • Saint Francis Regional Medical Center
    • Stillwater, Minnesota, United States, 55082
      • Lakeview Hospital
    • Virginia, Minnesota, United States, 55792
      • Essentia Health Virginia Clinic
    • Waconia, Minnesota, United States, 55387
      • Ridgeview Medical Center
    • Willmar, Minnesota, United States, 56201
      • Rice Memorial Hospital
    • Woodbury, Minnesota, United States, 55125
      • Minnesota Oncology Hematology PA-Woodbury
    • Wyoming, Minnesota, United States, 55092
      • Fairview Lakes Medical Center
  • Missouri
    • Ballwin, Missouri, United States, 63011
      • Saint Louis Cancer and Breast Institute-Ballwin
    • Bolivar, Missouri, United States, 65613
      • Central Care Cancer Center - Bolivar
    • Branson, Missouri, United States, 65616
      • Cox Cancer Center Branson
    • Cape Girardeau, Missouri, United States, 63703
      • Saint Francis Medical Center
    • Cape Girardeau, Missouri, United States, 63703
      • Southeast Cancer Center
    • Columbia, Missouri, United States, 65212
      • MU Health - University Hospital/Ellis Fischel Cancer Center
    • Creve Coeur, Missouri, United States, 63141
      • Siteman Cancer Center at West County Hospital
    • Farmington, Missouri, United States, 63640
      • Parkland Health Center - Farmington
    • Jefferson City, Missouri, United States, 65109
      • Capital Region Southwest Campus
    • Joplin, Missouri, United States, 64804
      • Freeman Health System
    • Joplin, Missouri, United States, 64804
      • Mercy Hospital Joplin
    • Kansas City, Missouri, United States, 64111
      • Saint Luke'S Hospital of Kansas City
    • Kansas City, Missouri, United States, 64108
      • Truman Medical Centers
    • Lee's Summit, Missouri, United States, 64086
      • Saint Luke's East - Lee's Summit
    • Rolla, Missouri, United States, 65401
      • Delbert Day Cancer Institute at PCRMC
    • Rolla, Missouri, United States, 65401
      • Mercy Clinic-Rolla-Cancer and Hematology
    • Saint Joseph, Missouri, United States, 64506
      • Heartland Regional Medical Center
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63131
      • Missouri Baptist Medical Center
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis
    • Saint Louis, Missouri, United States, 63128
      • Mercy Hospital South
    • Saint Louis, Missouri, United States, 63129
      • Siteman Cancer Center-South County
    • Saint Louis, Missouri, United States, 63136
      • Siteman Cancer Center at Christian Hospital
    • Saint Louis, Missouri, United States, 63109
      • Saint Louis Cancer and Breast Institute-South City
    • Saint Peters, Missouri, United States, 63376
      • Siteman Cancer Center at Saint Peters Hospital
    • Sainte Genevieve, Missouri, United States, 63670
      • Sainte Genevieve County Memorial Hospital
    • Springfield, Missouri, United States, 65807
      • CoxHealth South Hospital
    • Springfield, Missouri, United States, 65804
      • Mercy Hospital Springfield
    • Sullivan, Missouri, United States, 63080
      • Missouri Baptist Sullivan Hospital
    • Sunset Hills, Missouri, United States, 63127
      • BJC Outpatient Center at Sunset Hills
    • Washington, Missouri, United States, 63090
      • Mercy Hospital Washington
  • Montana
    • Anaconda, Montana, United States, 59711
      • Community Hospital of Anaconda
    • Billings, Montana, United States, 59101
      • Billings Clinic Cancer Center
    • Billings, Montana, United States, 59101
      • Saint Vincent Healthcare
    • Billings, Montana, United States, 59102
      • Saint Vincent Frontier Cancer Center
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Hospital
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic
    • Great Falls, Montana, United States, 59405
      • Benefis Healthcare- Sletten Cancer Institute
    • Kalispell, Montana, United States, 59901
      • Kalispell Regional Medical Center
    • Missoula, Montana, United States, 59804
      • Community Medical Hospital
    • Missoula, Montana, United States, 59802
      • Saint Patrick Hospital - Community Hospital
  • Nebraska
    • Bellevue, Nebraska, United States, 68123
      • Nebraska Medicine-Bellevue
    • Grand Island, Nebraska, United States, 68803
      • CHI Health Saint Francis
    • Kearney, Nebraska, United States, 68847
      • CHI Health Good Samaritan
    • Lincoln, Nebraska, United States, 68510
      • Saint Elizabeth Regional Medical Center
    • Omaha, Nebraska, United States, 68114
      • Nebraska Methodist Hospital
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68124
      • Alegent Health Bergan Mercy Medical Center
    • Omaha, Nebraska, United States, 68118
      • Nebraska Medicine-Village Pointe
    • Omaha, Nebraska, United States, 68122
      • Alegent Health Immanuel Medical Center
    • Omaha, Nebraska, United States, 68130
      • Alegent Health Lakeside Hospital
    • Omaha, Nebraska, United States, 68131
      • Creighton University Medical Center
    • Omaha, Nebraska, United States, 68114
      • Oncology Associates PC
    • Omaha, Nebraska, United States, 68114
      • Nebraska Cancer Specialists/Oncology Hematology West PC - MECC
    • Papillion, Nebraska, United States, 68046
      • Midlands Community Hospital
  • Nevada
    • Carson City, Nevada, United States, 89703
      • Carson Tahoe Regional Medical Center
    • Henderson, Nevada, United States, 89052
      • Comprehensive Cancer Centers of Nevada - Henderson
    • Henderson, Nevada, United States, 89052
      • OptumCare Cancer Care at Seven Hills
    • Henderson, Nevada, United States, 89052
      • Cancer and Blood Specialists-Henderson
    • Henderson, Nevada, United States, 89052
      • Las Vegas Cancer Center-Henderson
    • Henderson, Nevada, United States, 89074
      • Comprehensive Cancer Centers of Nevada-Southeast Henderson
    • Henderson, Nevada, United States, 89074
      • GenesisCare USA - Henderson
    • Henderson, Nevada, United States, 89052
      • Comprehensive Cancer Centers of Nevada-Horizon Ridge
    • Henderson, Nevada, United States, 89074
      • Las Vegas Urology - Green Valley
    • Henderson, Nevada, United States, 89074
      • Las Vegas Urology - Pebble
    • Henderson, Nevada, United States, 89074
      • Urology Specialists of Nevada - Green Valley
    • Las Vegas, Nevada, United States, 89144
      • Summerlin Hospital Medical Center
    • Las Vegas, Nevada, United States, 89109
      • Sunrise Hospital and Medical Center
    • Las Vegas, Nevada, United States, 89102
      • OptumCare Cancer Care at Charleston
    • Las Vegas, Nevada, United States, 89106
      • Radiation Oncology Centers of Nevada Central
    • Las Vegas, Nevada, United States, 89109
      • GenesisCare USA - Las Vegas
    • Las Vegas, Nevada, United States, 89119
      • Radiation Oncology Centers of Nevada Southeast
    • Las Vegas, Nevada, United States, 89128
      • Comprehensive Cancer Centers of Nevada - Northwest
    • Las Vegas, Nevada, United States, 89128
      • OptumCare Cancer Care at MountainView
    • Las Vegas, Nevada, United States, 89135
      • Alliance for Childhood Diseases/Cure 4 the Kids Foundation
    • Las Vegas, Nevada, United States, 89144
      • Comprehensive Cancer Centers of Nevada - Town Center
    • Las Vegas, Nevada, United States, 89144
      • Comprehensive Cancer Centers of Nevada-Summerlin
    • Las Vegas, Nevada, United States, 89148
      • Comprehensive Cancer Centers of Nevada
    • Las Vegas, Nevada, United States, 89148
      • OptumCare Cancer Care at Fort Apache
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada - Central Valley
    • Las Vegas, Nevada, United States, 89102
      • University Medical Center of Southern Nevada
    • Las Vegas, Nevada, United States, 89106
      • Cancer and Blood Specialists-Shadow
    • Las Vegas, Nevada, United States, 89109
      • HealthCare Partners Medical Group Oncology/Hematology-Maryland Parkway
    • Las Vegas, Nevada, United States, 89113
      • HealthCare Partners Medical Group Oncology/Hematology-San Martin
    • Las Vegas, Nevada, United States, 89128
      • Cancer and Blood Specialists-Tenaya
    • Las Vegas, Nevada, United States, 89128
      • GenesisCare USA - Vegas Tenaya
    • Las Vegas, Nevada, United States, 89128
      • HealthCare Partners Medical Group Oncology/Hematology-Tenaya
    • Las Vegas, Nevada, United States, 89148-2405
      • Las Vegas Cancer Center-Medical Center
    • Las Vegas, Nevada, United States, 89148
      • GenesisCare USA - Fort Apache
    • Las Vegas, Nevada, United States, 89149
      • HealthCare Partners Medical Group Oncology/Hematology-Centennial Hills
    • Las Vegas, Nevada, United States, 89128
      • Ann M Wierman MD LTD
    • Las Vegas, Nevada, United States, 89074
      • Las Vegas Urology - Pecos
    • Las Vegas, Nevada, United States, 89102
      • Desert West Surgery
    • Las Vegas, Nevada, United States, 89103
      • Hope Cancer Care of Nevada
    • Las Vegas, Nevada, United States, 89106
      • Urology Specialists of Nevada - Central
    • Las Vegas, Nevada, United States, 89113
      • Las Vegas Prostate Cancer Center
    • Las Vegas, Nevada, United States, 89113
      • Las Vegas Urology - Sunset
    • Las Vegas, Nevada, United States, 89128
      • Las Vegas Urology - Cathedral Rock
    • Las Vegas, Nevada, United States, 89128
      • Las Vegas Urology - Smoke Ranch
    • Las Vegas, Nevada, United States, 89128
      • Urology Specialists of Nevada - Northwest
    • Las Vegas, Nevada, United States, 89169
      • University Cancer Center
    • Las Vegas, Nevada, United States, 89113
      • Urology Specialists of Nevada - Southwest
    • Pahrump, Nevada, United States, 89048
      • Hope Cancer Care of Nevada-Pahrump
    • Reno, Nevada, United States, 89502
      • Renown Regional Medical Center
    • Reno, Nevada, United States, 89503
      • Saint Mary's Regional Medical Center
    • Reno, Nevada, United States, 89509
      • Radiation Oncology Associates
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
      • New Hampshire Oncology Hematology PA-Concord
    • Manchester, New Hampshire, United States, 03103
      • Solinsky Center for Cancer Care
    • Manchester, New Hampshire, United States, 03103
      • Elliot Hospital
  • New Jersey
    • Moorestown, New Jersey, United States, 08057
      • Virtua Samson Cancer Center
    • Mount Holly, New Jersey, United States, 08060
      • Virtua Memorial
    • Voorhees, New Jersey, United States, 08043
      • Virtua Voorhees
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • University of New Mexico Cancer Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center-Einstein Campus
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center - Moses Campus
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center-Weiler Hospital
    • Glens Falls, New York, United States, 12801
      • Glens Falls Hospital
  • North Carolina
    • Kenansville, North Carolina, United States, 28349
      • Vidant Oncology-Kenansville
    • Kinston, North Carolina, United States, 28501
      • Vidant Oncology-Kinston
    • Pinehurst, North Carolina, United States, 28374
      • FirstHealth of the Carolinas-Moore Regional Hospital
    • Richlands, North Carolina, United States, 28574
      • Vidant Oncology-Richlands
    • Washington, North Carolina, United States, 27889
      • Marion L Shepard Cancer Center at Vidant Beaufort Hospital
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Essentia Health Cancer Center-South University Clinic
    • Jamestown, North Dakota, United States, 58401
      • Essentia Health - Jamestown Clinic
  • Ohio
    • Alliance, Ohio, United States, 44601
      • Aultman Alliance Community Hospital
    • Beavercreek, Ohio, United States, 45431
      • Indu and Raj Soin Medical Center
    • Boardman, Ohio, United States, 44512
      • Saint Elizabeth Boardman Hospital
    • Canton, Ohio, United States, 44708
      • Cleveland Clinic Mercy Hospital
    • Canton, Ohio, United States, 44710
      • Aultman Health Foundation
    • Canton, Ohio, United States, 44708
      • Mercy Hematology and Oncology Associates Inc
    • Centerville, Ohio, United States, 45459
      • Miami Valley Hospital South
    • Centerville, Ohio, United States, 45459
      • Dayton Physicians LLC-Miami Valley South
    • Cincinnati, Ohio, United States, 45220
      • Good Samaritan Hospital - Cincinnati
    • Cincinnati, Ohio, United States, 45242
      • Bethesda North Hospital
    • Cincinnati, Ohio, United States, 45236
      • Oncology Hematology Care Inc-Kenwood
    • Cincinnati, Ohio, United States, 45247
      • TriHealth Cancer Institute-Westside
    • Cincinnati, Ohio, United States, 45255
      • TriHealth Cancer Institute-Anderson
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44111
      • Cleveland Clinic Cancer Center/Fairview Hospital
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
    • Dayton, Ohio, United States, 45415
      • Dayton Physician LLC-Miami Valley Hospital North
    • Dayton, Ohio, United States, 45415
      • Miami Valley Hospital North
    • Dayton, Ohio, United States, 45409
      • Dayton Blood and Cancer Center
    • Findlay, Ohio, United States, 45840
      • Blanchard Valley Hospital
    • Findlay, Ohio, United States, 45840
      • Armes Family Cancer Center
    • Findlay, Ohio, United States, 45840
      • Orion Cancer Care
    • Franklin, Ohio, United States, 45005-1066
      • Atrium Medical Center-Middletown Regional Hospital
    • Franklin, Ohio, United States, 45005
      • Dayton Physicians LLC-Atrium
    • Greenville, Ohio, United States, 45331
      • Wayne Hospital
    • Greenville, Ohio, United States, 45331
      • Dayton Physicians LLC-Wayne
    • Greenville, Ohio, United States, 45331
      • Miami Valley Cancer Care and Infusion
    • Kettering, Ohio, United States, 45429
      • Kettering Medical Center
    • Kettering, Ohio, United States, 45409
      • Greater Dayton Cancer Center
    • Kettering, Ohio, United States, 45420
      • First Dayton Cancer Care
    • Mansfield, Ohio, United States, 44906
      • Cleveland Clinic Cancer Center Mansfield
    • Maumee, Ohio, United States, 43537
      • Toledo Clinic Cancer Centers-Maumee
    • Mayfield Heights, Ohio, United States, 44124
      • Hillcrest Hospital Cancer Center
    • Perrysburg, Ohio, United States, 43551
      • Mercy Health Perrysburg Cancer Center
    • Sandusky, Ohio, United States, 44870
      • North Coast Cancer Care
    • Springfield, Ohio, United States, 45505
      • Springfield Regional Medical Center
    • Springfield, Ohio, United States, 45504
      • Springfield Regional Cancer Center
    • Strongsville, Ohio, United States, 44136
      • Cleveland Clinic Cancer Center Strongsville
    • Toledo, Ohio, United States, 43623
      • Mercy Health - Saint Anne Hospital
    • Toledo, Ohio, United States, 43623
      • Toledo Clinic Cancer Centers-Toledo
    • Troy, Ohio, United States, 45373
      • Upper Valley Medical Center
    • Troy, Ohio, United States, 45373
      • Dayton Physicians LLC - Troy
    • Warren, Ohio, United States, 44484
      • Saint Joseph Warren Hospital
    • Warrensville Heights, Ohio, United States, 44122
      • South Pointe Hospital
    • Wooster, Ohio, United States, 44691
      • Cleveland Clinic Wooster Family Health and Surgery Center
    • Wright-Patterson Air Force Base, Ohio, United States, 45433
      • Wright-Patterson Medical Center
    • Youngstown, Ohio, United States, 44501
      • Saint Elizabeth Youngstown Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • Mercy Hospital Oklahoma City
  • Oregon
    • Baker City, Oregon, United States, 97814
      • Saint Alphonsus Medical Center-Baker City
    • Bend, Oregon, United States, 97701
      • Saint Charles Health System
    • Clackamas, Oregon, United States, 97015
      • Clackamas Radiation Oncology Center
    • Clackamas, Oregon, United States, 97015
      • Providence Cancer Institute Clackamas Clinic
    • Coos Bay, Oregon, United States, 97420
      • Bay Area Hospital
    • Newberg, Oregon, United States, 97132
      • Providence Newberg Medical Center
    • Ontario, Oregon, United States, 97914
      • Saint Alphonsus Medical Center-Ontario
    • Oregon City, Oregon, United States, 97045
      • Providence Willamette Falls Medical Center
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
    • Portland, Oregon, United States, 97225
      • Providence Saint Vincent Medical Center
    • Redmond, Oregon, United States, 97756
      • Saint Charles Health System-Redmond
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Hospital-Cedar Crest
    • Allentown, Pennsylvania, United States, 18104
      • Saint Luke's Cancer Center - Allentown
    • Bethlehem, Pennsylvania, United States, 18017
      • Lehigh Valley Hospital - Muhlenberg
    • Bethlehem, Pennsylvania, United States, 18015
      • Saint Luke's University Hospital-Bethlehem Campus
    • Bryn Mawr, Pennsylvania, United States, 19010
      • Bryn Mawr Hospital
    • Chambersburg, Pennsylvania, United States, 17201
      • Chambersburg Hospital
    • Chambersburg, Pennsylvania, United States, 17201
      • WellSpan Medical Oncology and Hematology
    • Collegeville, Pennsylvania, United States, 19426
      • Main Line Health Center-Collegeville
    • East Stroudsburg, Pennsylvania, United States, 18301
      • Pocono Medical Center
    • Easton, Pennsylvania, United States, 18045
      • Saint Luke's Hospital-Anderson Campus
    • Ephrata, Pennsylvania, United States, 17522
      • Ephrata Cancer Center
    • Exton, Pennsylvania, United States, 19341
      • Main Line Health Center-Exton
    • Gettysburg, Pennsylvania, United States, 17325
      • Adams Cancer Center
    • Hanover, Pennsylvania, United States, 17331
      • Cherry Tree Cancer Center
    • Hazleton, Pennsylvania, United States, 18201
      • Lehigh Valley Hospital-Hazleton
    • Lebanon, Pennsylvania, United States, 17042
      • Sechler Family Cancer Center
    • Media, Pennsylvania, United States, 19063
      • Riddle Memorial Hospital
    • Newtown Square, Pennsylvania, United States, 19073
      • Bryn Mawr Health Center
    • Paoli, Pennsylvania, United States, 19301
      • Paoli Memorial Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania/Abramson Cancer Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center
    • Pottstown, Pennsylvania, United States, 19464
      • Pottstown Hospital
    • Quakertown, Pennsylvania, United States, 18951
      • Saint Luke's Hospital-Quakertown Campus
    • Quakertown, Pennsylvania, United States, 18951
      • Saint Luke's Hospital - Upper Bucks Campus
    • Sayre, Pennsylvania, United States, 18840
      • Guthrie Medical Group PC-Robert Packer Hospital
    • Wynnewood, Pennsylvania, United States, 19096
      • Lankenau Medical Center
    • York, Pennsylvania, United States, 17403
      • WellSpan Health-York Cancer Center
    • York, Pennsylvania, United States, 17403
      • WellSpan Health-York Hospital
    • York, Pennsylvania, United States, 17403
      • Cancer Care Associates of York
  • South Carolina
    • Greenwood, South Carolina, United States, 29646
      • Self Regional Healthcare
  • Texas
    • Bryan, Texas, United States, 77802
      • Saint Joseph Regional Cancer Center
  • Virginia
    • Mechanicsville, Virginia, United States, 23116
      • Bon Secours Memorial Regional Medical Center
    • Midlothian, Virginia, United States, 23114
      • Bon Secours Saint Francis Medical Center
    • Midlothian, Virginia, United States, 23113
      • Bon Secours Westchester Emergency Center
    • Norfolk, Virginia, United States, 23505
      • Bon Secours DePaul Medical Center
    • Portsmouth, Virginia, United States, 23707
      • Bon Secours Maryview Medical Center
    • Richmond, Virginia, United States, 23235
      • VCU Massey Cancer Center at Stony Point
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center
    • Richmond, Virginia, United States, 23226
      • Bon Secours Saint Mary's Hospital
    • Richmond, Virginia, United States, 23230
      • Bon Secours Cancer Institute at Reynolds Crossing
    • Richmond, Virginia, United States, 23223
      • Bon Secours Richmond Community Hospital
    • Suffolk, Virginia, United States, 23435
      • Bon Secours Health Center at Harbour View
  • Washington
    • Aberdeen, Washington, United States, 98520
      • Providence Regional Cancer System-Aberdeen
    • Bellevue, Washington, United States, 98004
      • Overlake Medical Center
    • Bellingham, Washington, United States, 98225
      • PeaceHealth Saint Joseph Medical Center
    • Bremerton, Washington, United States, 98310
      • Harrison HealthPartners Hematology and Oncology-Bremerton
    • Bremerton, Washington, United States, 98310
      • Harrison Medical Center
    • Burien, Washington, United States, 98166
      • Highline Medical Center-Main Campus
    • Centralia, Washington, United States, 98531
      • Providence Regional Cancer System-Centralia
    • Edmonds, Washington, United States, 98026
      • Swedish Cancer Institute-Edmonds
    • Enumclaw, Washington, United States, 98022
      • Saint Elizabeth Hospital
    • Everett, Washington, United States, 98201
      • Providence Regional Cancer Partnership
    • Federal Way, Washington, United States, 98003
      • Saint Francis Hospital
    • Issaquah, Washington, United States, 98029
      • Swedish Cancer Institute-Issaquah
    • Kennewick, Washington, United States, 99336
      • Kadlec Clinic Hematology and Oncology
    • Lacey, Washington, United States, 98503
      • Providence Regional Cancer System-Lacey
    • Lakewood, Washington, United States, 98499
      • Saint Clare Hospital
    • Longview, Washington, United States, 98632
      • PeaceHealth Saint John Medical Center
    • Port Townsend, Washington, United States, 98368
      • Jefferson Healthcare
    • Poulsbo, Washington, United States, 98370
      • Harrison HealthPartners Hematology and Oncology-Poulsbo
    • Renton, Washington, United States, 98055
      • Valley Medical Center
    • Seattle, Washington, United States, 98107
      • Swedish Medical Center-Ballard Campus
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center-First Hill
    • Seattle, Washington, United States, 98104
      • Pacific Gynecology Specialists
    • Seattle, Washington, United States, 98122-5711
      • Swedish Medical Center-Cherry Hill
    • Sedro-Woolley, Washington, United States, 98284
      • PeaceHealth United General Medical Center
    • Shelton, Washington, United States, 98584
      • Providence Regional Cancer System-Shelton
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties PLLC
    • Tacoma, Washington, United States, 98405
      • Franciscan Research Center-Northwest Medical Plaza
    • Vancouver, Washington, United States, 98664
      • PeaceHealth Southwest Medical Center
    • Walla Walla, Washington, United States, 99362
      • Providence Saint Mary Regional Cancer Center
    • Yakima, Washington, United States, 98902
      • North Star Lodge Cancer Center at Yakima Valley Memorial Hospital
    • Yelm, Washington, United States, 98597
      • Providence Regional Cancer System-Yelm
  • West Virginia
    • Huntington, West Virginia, United States, 25701
      • Edwards Comprehensive Cancer Center
  • Wisconsin
    • Appleton, Wisconsin, United States, 54911
      • ThedaCare Regional Cancer Center
    • Ashland, Wisconsin, United States, 54806
      • Duluth Clinic Ashland
    • Ashland, Wisconsin, United States, 54806
      • Northwest Wisconsin Cancer Center
    • Berlin, Wisconsin, United States, 54923
      • ThedaCare Cancer Care - Berlin
    • Burlington, Wisconsin, United States, 53105
      • Aurora Cancer Care-Southern Lakes VLCC
    • Chippewa Falls, Wisconsin, United States, 54729
      • Marshfield Clinic-Chippewa Center
    • Cudahy, Wisconsin, United States, 53110
      • Aurora Saint Luke's South Shore
    • Eau Claire, Wisconsin, United States, 54701
      • Marshfield Medical Center-EC Cancer Center
    • Germantown, Wisconsin, United States, 53022
      • Aurora Health Care Germantown Health Center
    • Grafton, Wisconsin, United States, 53024
      • Aurora Cancer Care-Grafton
    • Green Bay, Wisconsin, United States, 54311
      • Aurora BayCare Medical Center
    • Hayward, Wisconsin, United States, 54843
      • Essentia Health-Hayward Clinic
    • Kenosha, Wisconsin, United States, 53142
      • Aurora Cancer Care-Kenosha South
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Medical Center
    • Ladysmith, Wisconsin, United States, 54848
      • Marshfield Clinic - Ladysmith Center
    • Marinette, Wisconsin, United States, 54143
      • Aurora Bay Area Medical Group-Marinette
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Medical Center-Marshfield
    • Milwaukee, Wisconsin, United States, 53209
      • Aurora Cancer Care-Milwaukee
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora Saint Luke's Medical Center
    • Milwaukee, Wisconsin, United States, 53233
      • Aurora Sinai Medical Center
    • Minocqua, Wisconsin, United States, 54548
      • Marshfield Clinic-Minocqua Center
    • Mukwonago, Wisconsin, United States, 53149
      • ProHealth D N Greenwald Center
    • New Richmond, Wisconsin, United States, 54017
      • Cancer Center of Western Wisconsin
    • Oconomowoc, Wisconsin, United States, 53066
      • ProHealth Oconomowoc Memorial Hospital
    • Oshkosh, Wisconsin, United States, 54904
      • Vince Lombardi Cancer Clinic - Oshkosh
    • Racine, Wisconsin, United States, 53406
      • Aurora Cancer Care-Racine
    • Rice Lake, Wisconsin, United States, 54868
      • Marshfield Medical Center-Rice Lake
    • Sheboygan, Wisconsin, United States, 53081
      • Vince Lombardi Cancer Clinic-Sheboygan
    • Spooner, Wisconsin, United States, 54801
      • Essentia Health-Spooner Clinic
    • Stevens Point, Wisconsin, United States, 54482
      • Marshfield Medical Center-River Region at Stevens Point
    • Summit, Wisconsin, United States, 53066
      • Aurora Medical Center in Summit
    • Superior, Wisconsin, United States, 54880
      • Essentia Health Saint Mary's Hospital - Superior
    • Two Rivers, Wisconsin, United States, 54241
      • Vince Lombardi Cancer Clinic-Two Rivers
    • Waukesha, Wisconsin, United States, 53188
      • UW Cancer Center at ProHealth Care
    • Waukesha, Wisconsin, United States, 53188
      • ProHealth Waukesha Memorial Hospital
    • Wausau, Wisconsin, United States, 54401
      • Marshfield Clinic-Wausau Center
    • Wauwatosa, Wisconsin, United States, 53226
      • Aurora Cancer Care-Milwaukee West
    • Weston, Wisconsin, United States, 54476
      • Marshfield Medical Center - Weston
    • Wisconsin Rapids, Wisconsin, United States, 54494
      • Marshfield Clinic - Wisconsin Rapids Center
  • Wyoming
    • Cheyenne, Wyoming, United States, 82001
      • Cheyenne Regional Medical Center-West
    • Cody, Wyoming, United States, 82414
      • Billings Clinic-Cody
    • Sheridan, Wyoming, United States, 82801
      • Welch Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• RANDOMIZATION (STEP 1): Patient must be >= 18 years of age
• RANDOMIZATION (STEP 1): Patient must have pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC). Patients with NSCLC not otherwise specified (NOS) are eligible. Mixed tumors will be categorized by predominant cell type. If small cell elements are present, the patient is ineligible
• RANDOMIZATION (STEP 1): Patient must have metastatic Stage IVA or IVB disease (includes M1a, M1b, and M1c), according to the 8th edition of the lung cancer TNM classification system. Recurrent metastatic NSCLC ineligible for curative therapy (in the treating investigator's opinion) is also allowed
• RANDOMIZATION (STEP 1): Patient's tumor must be known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (for example at a minimum, negative for EGFR Exon 19 deletions, EGFR exon 20 insertions, and Exon 21 L858R, L861Q mutations ) AND negative for ALK gene rearrangements (by fluorescence in situ hybridization [FISH], next generation sequencing [NGS], or immunohistochemistry [IHC]) by routine Clinical Laboratory Improvement Act (CLIA)- or Food and Drug Administration (FDA)-certified clinical testing methods. CLIA or FDA approved circulating tumor deoxyribonucleic acid (DNA) testing is acceptable as an alternative to tissue testing

• RANDOMIZATION (STEP 1): Patient must have radiographic and/or clinical progression (per local investigator assessment) following one, but only one, line of platinum-based chemotherapy AND one, but only one, line of prior checkpoint inhibitor (anti-PD-1 or PD-L1) immunotherapy, either concurrently or sequentially in either order. A minimum of two doses of prior immunotherapy is required. Only one prior line of therapy is allowed if patients received chemotherapy and immunotherapy together (patients may not receive subsequent single agent chemotherapy), and greater than two prior lines of therapy are not allowed.

  • NOTE: Lines of therapy are defined by clinical or radiographic progression. For patients with recurrent metastatic NSCLC following treatment for stage 1-3 NSCLC, platinum-based chemotherapy received within 12 months of recurrence and/or immunotherapy received within 6 months of recurrence will meet the requirement for prior chemotherapy and/or immunotherapy but subsequent receipt of more immunotherapy and/or platinum-based chemotherapy is also allowed.
  • NOTE: Prior anti-VEGF antibody therapy (ie bevacizumab) is allowed. Prior ipilimumab, or investigational agents not excluded below, in combination with the required prior therapies above are allowed.
  • NOTE: Prior receipt of one or two lines of targeted therapy for ROS1, RET, MET, BRAF, ERBB2/HER2, or KRAS G12C positive NSCLC is allowed and will not count toward the line of therapy limit. However, progression is still required after chemotherapy and immunotherapy as above. Patients with ROS1, RET, MET positive NSCLC are strongly encouraged to get appropriate targeted therapy (such as crizotinib, entrectinib, lorlatinib, selpercatinib, pralsetinib, capmatinib, tepotinib, or another investigational, off-label, or approved agent directed against ROS1, RET, or MET positive NSCLC) prior to participation and will be stratified.
  • NOTE: No prior predominantly VEGFR directed TKI therapy (such as cabozantinib, lenvatinib, or sitravantinib) is allowed, except for the agents named above.
• RANDOMIZATION (STEP 1): The investigator must document the intended chemotherapy regimen should their patient be randomized to Arm C (docetaxel and ramucirumab, OR single agent chemotherapy - docetaxel, gemcitabine, paclitaxel, nab-paclitaxel). The patient must not have received the selected chemotherapy agent previously for metastatic disease

• RANDOMIZATION (STEP 1): Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to randomization:

  • FDA approved targeted oral therapy must be completed >= 1 week prior
  • Chemotherapy and/or immunotherapy must be completed >= 2 weeks prior
  • Prior investigational agents must be completed >= 4 weeks prior.
• RANDOMIZATION (STEP 1): Prior radiation therapy is allowed with a 2 week washout prior to randomization. Patient must not receive any systemic treatment with radionuclides within 6 weeks prior to randomization. Patient must have no clinically relevant ongoing complication from prior radiation therapy
• RANDOMIZATION (STEP 1): 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 (in the opinion of the treating physician) are eligible for this trial
• RANDOMIZATION (STEP 1): Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents (such as anthracycline or HER2-directed antibody therapy, but not prior checkpoint inhibitor therapy), must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients must be class 2B or better
• RANDOMIZATION (STEP 1): Patient must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have met the eligibility criteria outlined above
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have measurable disease as defined by RECIST v1.1. Measurements must be obtained within 4 weeks prior to randomization/registration
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have recovered to equal to or less than grade 1 toxicities related to prior treatment, unless toxicities are clinically non significant and/or stable on supportive therapy (as determined by the treating physician)
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Absolute neutrophil count >= 1,500/mcL (obtained within 2 weeks prior to randomization)
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Platelets >= 100,000/mcL (obtained within 2 weeks prior to randomization)
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Hemoglobin >= 9 g/dL (obtained within 2 weeks prior to randomization)
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (for patients with Gilbert's disease total bilirubin must be =< 3 x ULN) (obtained within 2 weeks prior to randomization)
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (obtained within 2 weeks prior to randomization)
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Creatinine =< 1.5 x ULN OR calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73m^2 (normalized to body surface area [BSA]) for patients with creatinine levels greater than 1.5 times the institutional normal creatinine =< 1.5 X ULN or creatinine clearance >= 50ml/min/1.73m^2 (obtained within 2 weeks prior to randomization)
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 msec within 28 days prior to Step 1 randomization
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must be able to swallow tablets

• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients with brain metastases are eligible as follows:

  • Previously treated brain metastases must have been treated with radiation > 2 weeks prior to randomization or surgery > 3 months prior to randomization OR
  • Untreated (active) brain metastases are allowed if they are clinically asymptomatic, < 1 cm, non-hemorrhagic, the patient is not on systemic anticoagulation, and the investigator believes that central nervous system (CNS) specific treatment is unlikely to be required during the first 3 months of study treatment.
  • NOTE: Symptomatic leptomeningeal disease is NOT allowed
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients with known history of human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients with known history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral at time of randomization (suppressive therapy is allowed, if indicated)
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients with a known 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 at time of randomization
• STEP 2 (CROSSOVER ARM Z): Patient must have met all eligibility requirements for Step 1 at time of registration to Step 1 to be eligible for Step 2
• STEP 2 (CROSSOVER ARM Z): Patient must have radiographic progressive disease per RECIST criteria after >= 2 cycles of therapy on Arm C. The scan showing progression must be completed within 6 weeks prior to Step 2 registration
• STEP 2 (CROSSOVER ARM Z): Patient must have an ECOG performance status 0-2
• STEP 2 (CROSSOVER ARM Z): Patient must have recovered to equal to or less than grade 1 toxicities related to prior treatment, unless the adverse event(s) are clinically non significant and/or stable on supportive therapy (as determined by the treating physician)
• STEP 2 (CROSSOVER ARM Z): Absolute neutrophil count >= 1,500/mcL (obtained within 2 weeks prior to registration to Step 2)
• STEP 2 (CROSSOVER ARM Z): Platelets >= 100,000/mcL (obtained within 2 weeks prior to registration to Step 2)
• STEP 2 (CROSSOVER ARM Z): Hemoglobin >= 9 g/dL (obtained within 2 weeks prior to registration to Step 2)
• STEP 2 (CROSSOVER ARM Z): Total bilirubin =< 1.5 x institutional ULN (for patients with Gilbert's disease total bilirubin must be =< 3 x ULN) (obtained within 2 weeks prior to registration to Step 2)
• STEP 2 (CROSSOVER ARM Z): AST(SGOT) and ALT(SGPT) =< 2.5 x ULN (obtained within 2 weeks prior to registration to Step 2)
• STEP 2 (CROSSOVER ARM Z): Creatinine =< 1.5 x ULN OR calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73m^2 (normalized to BSA) for patients with creatinine levels greater than 1.5 times the institutional normal creatinine =< 1.5 X ULN or creatinine clearance >= 50ml/min/1.73m^2 (obtained within 2 weeks prior to registration to Step 2)
• STEP 2 (CROSSOVER ARM Z): Patient must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days prior to Step 2 registration

Exclusion Criteria:

• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not be pregnant or breast-feeding due to the unknown effects of cabozantinib and nivolumab on human development and for the potential risk for adverse events in nursing infants with the treatment regimens being used.

  • All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization/registration to rule out pregnancy.
  • A patient of childbearing potential is anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for 6 months after completion of treatment on the study
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have clinically significant gastrointestinal bleeding within 6 months prior to randomization
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have pulmonary hemorrhage or hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months prior to randomization
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have active drug induced pneumonitis within 3 months prior to randomization. Prior immune mediated pneumonitis of grade 3 or 4 are not eligible regardless of time window
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have current radiographic evidence of tumor invading major blood vessel, evidence of tumor cavitation > 1 cm, evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or evidence of endotracheal or mainstem endobronchial tumor
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have peptic ulcer disease, known malabsorption syndrome, bowel obstruction or gastric outlet obstruction within 3 months prior to randomization
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months prior to randomization
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have grade 3 or greater infection, or infection requiring intravenous systemic treatment within 14 days prior to randomization. Patients must be off antibiotics at the time of randomization
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have serious non-healing wound/ulcer/bone fracture within 28 days prior to randomization
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have history of organ transplant
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have concurrent symptomatic untreated hypothyroidism
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have history of major surgery within 3 months prior to randomization, minor surgery within 28 days prior to randomization, other minor procedures within 7 days prior to randomization, or clinically relevant ongoing complications from prior procedures
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 160 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have unstable angina pectoris, clinically-significant cardiac arrhythmias, stroke (including transient ischemic attack [TIA]), or myocardial infarction within 6 months prior to randomization
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have a diagnosis of deep vein thrombosis/pulmonary embolism (DVT/PE) within 6 months of randomization unless stable, asymptomatic, and treated with low-molecular-weight heparin (LMWH) or a permitted oral anticoagulant for at least 7 days before randomization

• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not be receiving anticoagulants (i.e., warfarin, aspirin, clopidogrel) except:

  • Prophylactic use of low-dose aspirin (100 mg po daily or less) and/or low dose molecular weight heparin (LMWH) is permitted.
  • Therapeutic doses of low dose molecular weight heparin (LMWH) or specified direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban are allowed in patients without untreated brain metastases who are on a stable dose 7 days prior to study randomization, and without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not receive strong CYP3A4 inducers (e.g., dexamethasone (> 1 mg daily dosing), phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort) within 7 days prior to randomization

• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not be on continuous systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days prior to randomization, with the following exceptions:

  • Inhaled or topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  • Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption).
  • Physiologic replacement doses of systemic corticosteroids are permitted, if < 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not have known active autoimmune disease or known history of autoimmune disease for which recurrence may affect vital organ function or require immune suppressive treatment including systemic corticosteroids (e.g., immune-related neurologic disease, multiple sclerosis, autoimmune neuropathy, Guillain-Barre syndrome, etc.).
• RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not have had any prior allergic reaction or hypersensitivity to study drug components or related drugs (multitargeted small molecule tyrosine kinase inhibitors or checkpoint inhibitor monoclonal antibodies)
• STEP 2 (CROSSOVER ARM Z): Patient must not have intervening anticancer treatment or major surgical procedure(s) between Step 1 and Step 2, except palliative radiation which was completed >= 1 week prior to registration to Step 2
• STEP 2 (CROSSOVER ARM Z): Patient may not have central nervous system progression, but patients with stable CNS disease are allowed
• STEP 2 (CROSSOVER ARM Z): Patient must not have any intercurrent illness or disease complication that the investigator believes would limit the ability to safely tolerate the combination of cabozantinib and nivolumab

• STEP 2 (CROSSOVER ARM Z): Patient must not be pregnant or breast-feeding due to the unknown effects of cabozantinib and nivolumab on human development and for the potential risk for adverse events in nursing infants with the treatment regimens being used.

  • All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to Step 2 to rule out pregnancy.
  • A patient of childbearing potential is anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• STEP 2 (CROSSOVER ARM Z): Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for 6 months after completion of treatment on the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Step 1, Arm A (cabozantinib S-malate); Patients in Step 1, Arm A receive cabozantinib S-malate PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.	Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Drug: Cabozantinib S-malate; Given PO; Other Names: BMS-907351; Cabometyx; Cometriq; XL-184; XL184; Procedure: Echocardiography; Undergo ECHO; Other Names: EC; Procedure: Biospecimen Collection; Undergo blood collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection
Experimental: Step 1, Arm B (cabozantinib S-malate, nivolumab); Patients in Step 1, Arm B receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.	Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; CMAB819; Nivolumab Biosimilar CMAB819; ABP 206; Nivolumab Biosimilar ABP 206; BCD-263; Nivolumab Biosimilar BCD-263; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Drug: Cabozantinib S-malate; Given PO; Other Names: BMS-907351; Cabometyx; Cometriq; XL-184; XL184; Procedure: Echocardiography; Undergo ECHO; Other Names: EC; Procedure: Biospecimen Collection; Undergo blood collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection
Active Comparator: Step 1, Arm C (standard chemotherapy); Patients in Step 1, Arm C receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.	Drug: Nab-paclitaxel; Given IV; Other Names: ABI-007; Abraxane; Albumin-bound Paclitaxel; ABI 007; Albumin-Stabilized Nanoparticle Paclitaxel; Nanoparticle Albumin-bound Paclitaxel; Nanoparticle Paclitaxel; Paclitaxel Albumin; paclitaxel albumin-stabilized nanoparticle formulation; Protein-bound Paclitaxel; Paclitaxel Protein-Bound; Paclitaxel Nanoparticle Albumin-bound; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Drug: Docetaxel; Given IV; Other Names: Taxotere; Docecad; RP56976; Taxotere Injection Concentrate; RP 56976; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Procedure: Echocardiography; Undergo ECHO; Other Names: EC; Procedure: Biospecimen Collection; Undergo blood collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Biological: Ramucirumab; Given IV; Other Names: LY3009806; IMC-1121B; Cyramza; Anti-VEGFR-2 Fully Human Monoclonal Antibody IMC-1121B; Monoclonal Antibody HGS-ETR2; Drug: Gemcitabine Hydrochloride; Given PO; Other Names: Gemzar; dFdCyd; Difluorodeoxycytidine Hydrochloride; Gemcitabine HCI; LY-188011; LY188011
Experimental: Step 2, Arm Z (cabozantinib S-malate, nivolumab); Patients in Step 2, Arm Z receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.	Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; CMAB819; Nivolumab Biosimilar CMAB819; ABP 206; Nivolumab Biosimilar ABP 206; BCD-263; Nivolumab Biosimilar BCD-263; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Drug: Cabozantinib S-malate; Given PO; Other Names: BMS-907351; Cabometyx; Cometriq; XL-184; XL184; Procedure: Echocardiography; Undergo ECHO; Other Names: EC; Procedure: Biospecimen Collection; Undergo blood collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) for patient population with non-squamous no-small cell lung cancer (NSCLC)	The final analysis of PFS will be performed when the full information of PFS is reached (i.e., 58 events for each of the two primary comparisons). The two primary comparisons of PFS will each use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Estimates of PFS including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Cox proportional hazards models, stratified, on the same factors, will be used to estimate the treatment hazard ratios. At the final analyses, in the event that both primary PFS comparisons of the combination of nivolumab with cabozantinib and cabozantinib alone versus the standard chemotherapy are statistically significant, PFS will be compared between the two experimental arms (combination of nivolumab with cabozantinib versus [vs.] cabozantinib alone), using a stratified log rank test with a one-sided type I error rate of 10%.	After 58 events (From time of randomization to documented disease progression [site review of imaging] or death from any cause, whichever occurs first)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS) for each arm	The final analysis of OS will be performed when the full information of PFS is reached (i.e., 58 events for each of the two primary comparisons). OS will be tested in a hierarchical fashion if the primary comparison of PFS between treatment arms is statistically significant, using a log rank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Estimates of OS, including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Cox proportional hazards models, stratified, on the same factors, will be used to estimate the treatment hazard ratios. OS will be further tested in a hierarchical fashion if the comparison of PFS between the two experimental arms is statistically significant. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. Subset analyses of PFS and OS by treatment arm will be estimated and compared within subsets.	From time of randomization to documented disease progression (site review of imaging) or death from any cause, whichever occurs first, assessed up to 3 years
Best objective response for each arm	Will be evaluated via Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response rates (complete response [CR] + partial response [PR]) and toxicity will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Modeling procedures will implement backward selection; variables significant at the 0.10 level in the univariate setting will be chosen for inclusion in an initial full model, and at each step the least significant variable will be removed from the model. Only those covariates with p < 0.05 will remain in any final models, unless there are factors identified by the study team as crucial to model interpretation. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals.	Every 6 weeks for the first year on study, and then every 12 weeks after year one
Toxicity profile of monotherapy with cabozantinib, and the combination of nivolumab and cabozantinib	Will be determined using the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Response rates (complete response [CR] + pathologic response [PR]) and toxicity will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Modeling procedures will implement backward selection; variables significant at the 0.10 level in the univariate setting will be chosen for inclusion in an initial full model, and at each step the least significant variable will be removed from the model. Only those covariates with p < 0.05 will remain in any final models, unless there are factors identified by the study team as crucial to model interpretation. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals.	Up to 3 years after completion of study treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Agreement between central view and site review in terms of progression-free survival	The progression status and the progression time will be assessed in agreement. The progression status is a binary measurement and the agreement will be assessed using the Cohen's kappa coefficient. For progression time, will assess the temporal agreement using the method developed by Zeng et al.	After the completion of study treatment
Correlative biomarker research	Correlative biomarker research will be performed on tissue and blood specimens collected within this trial.	After the completion of study treatment
The RECIST1.1 response at each time point	The measurement of each time point will be performed using the revised CHOI criteria will be only applied to arms A and B, which will include anti-angiogenic therapy. Both the RECIST1.1 and revised CHOI criteria will assess the overall best response as CR, partial PR, stable disease (SD), or progressive disease (PD). Their concordance will be assessed using the weighted Cohen's kappa coefficient (k) with quadratic weights. As a rule of thumb, the level of concordance between the two criteria will be considered poor (k <0), slight (k 0-0.20), fair (k 0.21-0.40), moderate (k 0.41-0.60), substantial (k 0.61-0.80), and almost perfect (k 0.81 - 1).	Every 6 weeks for the first year on study, and then every 12 weeks after year one

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Joel W Neal, ECOG-ACRIN Cancer Research Group

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2020
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): September 30, 2024

Study Registration Dates

• First Submitted: March 16, 2020
• First Submitted That Met QC Criteria: March 16, 2020
• First Posted (Actual): March 17, 2020

Study Record Updates

• Last Update Posted (Estimated): April 15, 2024
• Last Update Submitted That Met QC Criteria: April 12, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Immune Checkpoint Inhibitors; Docetaxel; Paclitaxel; Antibodies; Nivolumab; Immunoglobulins; Albumin-Bound Paclitaxel; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Lexatumumab; Gemcitabine; Ramucirumab
• Other Study ID Numbers: NCI-2020-01541 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180820 (U.S. NIH Grant/Contract); EA5191 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No