Testing the Addition of the Pill Chemotherapy, Cabozantinib, to the Standard Immune Therapy Nivolumab Compared to Standard Chemotherapy for Non-small Cell Lung Cancer
Metastatic Lung Non-Squamous Non-Small Cell Carcinoma, Recurrent Lung Non-Squamous Non-Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8
About this trial
This is an interventional treatment trial for Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
Eligibility Criteria
Inclusion Criteria:
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC)
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have stage IV disease (includes M1a, M1b, or recurrent earlier stage disease), according to the 8th edition of the lung cancer Tumor Node Metastasis (TNM) classification system
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have predominant non-squamous histology (patients with NSCLC no otherwise specified [NOS] are eligible). Mixed tumors will be categorized by the predominant cell type. If small cell elements are present the patient is ineligible
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient's tumor(s) must be tested and known negative for EGFR tyrosinase kinase inhibitor (TKI) sensitizing mutations (EGFR Exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements (by fluorescence in situ hybridization [FISH], next generation sequencing [NGS], or immunohistochemistry [IHC]) by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods. Negative circulating tumor deoxyribonucleic acid (DNA) results alone are not acceptable. Prior testing for tumor PD-L1 status is not required
ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patients WITHOUT tumors with known molecular alterations in ROS1, MET, RET, or must have progressed radiographically (per local investigator assessment) following one, but only one, line of platinum-based chemotherapy AND one, but only one, line of prior immunotherapy. Lines of therapy are defined by clinical or radiographic progression. Patients may have received chemotherapy and immunotherapy either concurrently or sequentially in either order. Patient must have received at least 2 prior doses of checkpoint inhibitor therapy in an every 2, 3, or 4 week schedule. No submission of molecular testing is required and patients may be registered for Step 0 then proceed directly to Step 1 screening OR Patients with tumors with known molecular alterations in ROS1, MET, and RET must have progressed radiographically (per local investigator clinical assessment) on at least one line of prior chemotherapy or targeted therapy, but there is no limit on number of prior number. Reciept of prior immunotherapy is allowed but not required.
- Known molecular alterations in ROS1 , MET, and RET are defined as below ROS1 gene rearrangement by FISH or DNA analysis. In addition to above requirements, these patients must have progressed on at least one prior ROS1 TKI therapy
- MET exon 14 splice mutations on DNA analysis. In addition to above requirements, prior MET directed TKI therapy is optional
- MET mutations predicted to be sensitive to MET inhibitor. In addition to above requirements, prior MET directed TKI therapy is optional
- High MET amplification by FISH (characterized by a fluorescence in situ hybridization MET/CEP7 ratio of 5 or greater); OR MET amplification by DNA NGS CLIA certified assay. In addition to above requirements, prior MET directed TKI therapy is optional
RET gene rearrangement by FISH or DNA analysis. In addition to above requirements, prior RET directed TKI therapy is optional
- During Step 0 screening, CLIA reports of the testing results must be submitted via Medidata Rave for central review for instructions. The central review will be performed by the study chair, co-chair, biology co-chair, and/or a delegate to determine that the results indicate a patient's eligibility for targeted therapy. CLIA reports that contain information pertaining to any of the above mutations will be uploaded to Medidata Rave for central review of documentation for determination of patient eligibility for targeted therapy (Arm T). Central testing of tissue will not be performed. Institutions will be notified of the patient's eligibility status for Arm T within two (2) business days of submission of the molecular testing reports. Patients with tumors with the above known molecular alterations are eligible for cohort Arm Z following Step 1 eligibility review. Patients without tumors with the above known molecular alterations for randomization to Arm A, B or C following Step 1 eligibility review
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): NOTE: 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
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents (such as anthracycline or human epidermal growth factor receptor (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
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Patient must have met the eligibility criteria outlined above
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Patient must have measurable disease as defined by RECIST version (v) 1.1 criteria. Measurements must be obtained within 4 weeks prior to randomization/registration
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Patient must have an anticipated life expectancy greater than 3 months
ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to randomization/registration:
- Chemotherapy/targeted oral therapy administered in a daily or weekly schedule must be completed >= 1 week prior to randomization/registration
- Any chemotherapy administered in an every 2 week or greater schedule must be completed >= 2 weeks prior to randomization/registration
- Additionally, patient should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless adverse events (AE[s]) are clinically non significant and/or stable on supportive therapy (as determined by the treating physician)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Leukocytes >= 3,000/mcL (obtained within 2 weeks prior to randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Absolute neutrophil count >= 1,500/mcL (obtained within 2 weeks prior to randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Platelets >= 100,000/mcL (obtained within 2 weeks prior to randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Hemoglobin >= 9 g/dL (obtained within 2 weeks prior to randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained within 2 weeks prior to randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR 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/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Creatinine =< 1.5 x ULN OR calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 m^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 >= 50 ml/min/1.73 m^2 (obtained within 2 weeks prior to randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Patient must have corrected QT interval calculated by the Fridericia formula QTc corrected by Fridericia (QTcF) =< 500 ms within 28 days prior to randomization/registration
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Patient must be able to swallow tablets
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Patients with new or progressive brain metastases (active brain metastases) are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of study treatment.
- Patient must meet one of the following criteria with respect to brain metastases: Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study randomization/registration not demonstrating brain metastases OR patients with known brain metastases must have baseline brain imaging and completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery; or complete neurosurgical resection >= 3 months prior to randomization/registration) >= 4 weeks prior to randomization/registration. They must be clinically stable. Known leptomeningeal disease is not allowed
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Known human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: For patients with known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy at time of registration/randomization, if indicated
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR 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 registration/randomization
- ADDITIONAL ELIGIBILITY CRITERIA FOR STEP 1 (REGISTRATION) TARGETED ARM T: Patient was registered to step 0, targeted arm and central review results report the patient is eligible for arm T
- ADDITIONAL ELIGIBILITY CRITERIA FOR STEP 1 (REGISTRATION) TARGETED ARM T: Patients with ROS1 gene rearrangements must have progressed on at least one prior ROS1 targeted therapy such as crizotinib
ADDITIONAL ELIGIBILITY CRITERIA FOR STEP 1 (REGISTRATION) TARGETED ARM T: Patient must have progressed radiographically (per local investigator clinical assessment) on at least one line of prior chemotherapy or targeted therapy, but there is no limit on number of prior number. Prior immunotherapy is allowed but not required. Prior bevacizumab with chemo is allowed.
- NOTE: The requirement for prior chemotherapy will be met if patients have recurrence within 6 months after prior adjuvant platinum based chemotherapy for early stage disease, or recurrence within 6 months after prior radiotherapy plus platinum based chemotherapy for locally advanced disease
- NOTE: Patients with unresectable stage III NSCLC who have received chemo and radiation then consolidation durvalumab, followed by progression are eligible if progression happens after > 2 doses of durvalumab. Prior bevacizumab with chemo is also allowed
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have met all eligibility requirements for Step 1 at time of registration to Step 1 to be eligible for Step 2
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have radiographic progressive disease per RECIST criteria after >= 2 cycles of therapy on arm C
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must be registered to step 2 within 4 weeks of the last dose of treatment administration from step 1
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have an ECOG performance status between 0-2
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have recovered to baseline (pre-step 1) or Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Leukocytes >= 3,000/mcL (obtained within 2 weeks prior to randomization/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Absolute neutrophil count >= 1,500/mcL (obtained within 2 weeks prior to randomization/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Platelets >= 100,000/mcL (obtained within 2 weeks prior to randomization/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Hemoglobin >= 9 g/dL (obtained within 2 weeks prior to randomization/registration)
- Total bilirubin =< 1.5 x institutional ULN (obtained within 2 weeks prior to randomization/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): 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/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Creatinine =< 1.5 x ULN OR calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 m^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 >= 50 ml/min/1.73 m^2 (obtained within 2 weeks prior to randomization/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before registration
Exclusion Criteria:
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS: Patient must not have had any prior radiation therapy for bone metastasis within 2 weeks, or any other radiation therapy within 4 weeks prior to randomization/registration
- ELIGIBILITY CRITERIA FOR STEP
Sites / Locations
- Veterans Administration Medical Center - Birmingham
- Anchorage Associates in Radiation Medicine
- Anchorage Radiation Therapy Center
- Alaska Breast Care and Surgery LLC
- Alaska Oncology and Hematology LLC
- Alaska Women's Cancer Care
- Anchorage Oncology Centre
- Katmai Oncology Group
- Providence Alaska Medical Center
- Fairbanks Memorial Hospital
- CTCA at Western Regional Medical Center
- Kingman Regional Medical Center
- Cancer Center at Saint Joseph's
- Banner University Medical Center - Tucson
- University of Arizona Cancer Center-North Campus
- Mercy Hospital Fort Smith
- CHI Saint Vincent Cancer Center Hot Springs
- Mission Hope Medical Oncology - Arroyo Grande
- PCR Oncology
- Providence Saint Joseph Medical Center/Disney Family Cancer Center
- Mercy Cancer Center �� Carmichael
- Mercy San Juan Medical Center
- Mercy Cancer Center - Elk Grove
- Washington Hospital
- Fremont - Rideout Cancer Center
- Saint Joseph Hospital - Orange
- Stanford Cancer Institute Palo Alto
- Mercy Cancer Center - Rocklin
- Mercy Cancer Center - Sacramento
- University of California Davis Comprehensive Cancer Center
- Pacific Central Coast Health Center-San Luis Obispo
- Mission Hope Medical Oncology - Santa Maria
- Woodland Memorial Hospital
- Rocky Mountain Cancer Centers-Aurora
- The Medical Center of Aurora
- Boulder Community Foothills Hospital
- Rocky Mountain Cancer Centers-Boulder
- Rocky Mountain Cancer Centers - Centennial
- Penrose-Saint Francis Healthcare
- Rocky Mountain Cancer Centers-Penrose
- Saint Francis Cancer Center
- Cancer Center of Colorado at Sloan's Lake
- National Jewish Health-Main Campus
- The Women's Imaging Center
- Porter Adventist Hospital
- Colorado Blood Cancer Institute
- Presbyterian - Saint Lukes Medical Center - Health One
- Rocky Mountain Cancer Centers-Midtown
- SCL Health Saint Joseph Hospital
- Rocky Mountain Cancer Centers-Rose
- Rose Medical Center
- Western Surgical Care
- Mercy Medical Center
- Southwest Oncology PC
- Mountain Blue Cancer Care Center - Swedish
- Rocky Mountain Cancer Centers - Swedish
- Swedish Medical Center
- The Melanoma and Skin Cancer Institute
- Poudre Valley Hospital
- Cancer Care and Hematology-Fort Collins
- National Jewish Health-Western Hematology Oncology
- Saint Mary's Hospital and Regional Medical Center
- North Colorado Medical Center
- UCHealth Greeley Hospital
- UCHealth Highlands Ranch Hospital
- Good Samaritan Medical Center
- Rocky Mountain Cancer Centers-Lakewood
- Saint Anthony Hospital
- Rocky Mountain Cancer Centers-Littleton
- Littleton Adventist Hospital
- Rocky Mountain Cancer Centers-Sky Ridge
- Sky Ridge Medical Center
- Longmont United Hospital
- Rocky Mountain Cancer Centers-Longmont
- Medical Center of the Rockies
- McKee Medical Center
- Parker Adventist Hospital
- Saint Mary Corwin Medical Center
- National Jewish Health-Northern Hematology Oncology
- Rocky Mountain Cancer Centers-Thornton
- Veterans Affairs Connecticut Healthcare System-West Haven Campus
- Mount Sinai Comprehensive Cancer Center at Aventura
- Holy Cross Hospital
- Mount Sinai Medical Center
- Emory University Hospital Midtown
- Emory University Hospital/Winship Cancer Institute
- Lewis Cancer and Research Pavilion at Saint Joseph's/Candler
- Saint Alphonsus Cancer Care Center-Boise
- Saint Luke's Cancer Institute - Boise
- Saint Alphonsus Cancer Care Center-Caldwell
- Kootenai Health - Coeur d'Alene
- Walter Knox Memorial Hospital
- Saint Luke's Cancer Institute - Fruitland
- Idaho Urologic Institute-Meridian
- Saint Luke's Cancer Institute - Meridian
- Saint Luke's Cancer Institute - Nampa
- Saint Alphonsus Cancer Care Center-Nampa
- Kootenai Clinic Cancer Services - Post Falls
- Kootenai Cancer Clinic
- Saint Luke's Cancer Institute - Twin Falls
- Saint Anthony's Health
- Rush - Copley Medical Center
- Advocate Good Shepherd Hospital
- Illinois CancerCare-Bloomington
- Illinois CancerCare-Canton
- Memorial Hospital of Carbondale
- SIH Cancer Institute
- Illinois CancerCare-Carthage
- Centralia Oncology Clinic
- Saint Mary's Hospital
- University of Illinois
- Advocate Illinois Masonic Medical Center
- AMG Crystal Lake - Oncology
- Carle at The Riverfront
- Cancer Care Specialists of Illinois - Decatur
- Decatur Memorial Hospital
- Illinois CancerCare-Dixon
- Advocate Good Samaritan Hospital
- Carle Physician Group-Effingham
- Crossroads Cancer Center
- Advocate Sherman Hospital
- Illinois CancerCare-Eureka
- Illinois CancerCare-Galesburg
- Western Illinois Cancer Treatment Center
- Advocate South Suburban Hospital
- Edward Hines Jr VA Hospital
- Illinois CancerCare-Kewanee Clinic
- AMG Libertyville - Oncology
- Condell Memorial Hospital
- Illinois CancerCare-Macomb
- Carle Physician Group-Mattoon/Charleston
- Good Samaritan Regional Health Center
- Cancer Care Center of O'Fallon
- Advocate Christ Medical Center
- Illinois CancerCare-Ottawa Clinic
- Advocate Lutheran General Hospital
- Illinois CancerCare-Pekin
- Illinois CancerCare-Peoria
- Methodist Medical Center of Illinois
- Illinois CancerCare-Peru
- Valley Radiation Oncology
- Illinois CancerCare-Princeton
- SwedishAmerican Regional Cancer Center/ACT
- Southern Illinois University School of Medicine
- Springfield Clinic
- Memorial Medical Center
- Southwest Illinois Health Services LLP
- Carle Cancer Center
- The Carle Foundation Hospital
- Illinois CancerCare - Washington
- Rush-Copley Healthcare Center
- Reid Health
- Memorial Hospital of South Bend
- Mary Greeley Medical Center
- McFarland Clinic - Ames
- University of Iowa Healthcare Cancer Services Quad Cities
- McFarland Clinic - Boone
- Saint Anthony Regional Hospital
- Medical Oncology and Hematology Associates-West Des Moines
- Mercy Cancer Center-West Lakes
- Jennie Edmundson Memorial Hospital
- Alegent Health Mercy Hospital
- Heartland Oncology and Hematology LLP
- Greater Regional Medical Center
- Iowa Methodist Medical Center
- Medical Oncology and Hematology Associates-Des Moines
- Broadlawns Medical Center
- Mercy Medical Center - Des Moines
- Mission Cancer and Blood - Laurel
- Iowa Lutheran Hospital
- McFarland Clinic - Trinity Cancer Center
- Trinity Regional Medical Center
- University of Iowa/Holden Comprehensive Cancer Center
- McFarland Clinic - Jefferson
- McFarland Clinic - Marshalltown
- Methodist West Hospital
- Mercy Medical Center-West Lakes
- Central Care Cancer Center - Garden City
- Central Care Cancer Center - Great Bend
- HaysMed University of Kansas Health System
- Lawrence Memorial Hospital
- Olathe Health Cancer Center
- Saint Luke's South Hospital
- Ascension Via Christi - Pittsburg
- Freeman Physician Group of Pittsburg
- Salina Regional Health Center
- University of Kansas Health System Saint Francis Campus
- Flaget Memorial Hospital
- Commonwealth Cancer Center-Corbin
- Saint Joseph Hospital
- Saint Joseph Radiation Oncology Resource Center
- Saint Joseph Hospital East
- Saint Joseph London
- Jewish Hospital
- Saints Mary and Elizabeth Hospital
- UofL Health Medical Center Northeast
- Saint Joseph Mount Sterling
- Owensboro Health Mitchell Memorial Cancer Center
- Mercy Health - Paducah Medical Oncology and Hematology
- Jewish Hospital Medical Center South
- LSU Health Baton Rouge-North Clinic
- Our Lady of The Lake
- Louisiana Hematology Oncology Associates LLC
- Mary Bird Perkins Cancer Center
- Our Lady of the Lake Physicians Group - Medical Oncology
- Northshore Oncology Associates-Covington
- Terrebonne General Medical Center
- Harold Alfond Center for Cancer Care
- MaineHealth/SMHC Cancer Care and Blood Disorders-Biddeford
- MaineHealth/SMHC Cancer Care and Blood Disorders-Sanford
- Maine Medical Partners - South Portland
- Saint Agnes Hospital
- Boston Medical Center
- UMass Memorial Medical Center - University Campus
- Hickman Cancer Center
- Saint Joseph Mercy Hospital
- Bronson Battle Creek
- Saint Joseph Mercy Brighton
- Trinity Health IHA Medical Group Hematology Oncology - Brighton
- Saint Joseph Mercy Canton
- Trinity Health IHA Medical Group Hematology Oncology - Canton
- Caro Cancer Center
- Saint Joseph Mercy Chelsea
- Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
- Hematology Oncology Consultants-Clarkston
- Newland Medical Associates-Clarkston
- Ascension Saint John Hospital
- Great Lakes Cancer Management Specialists-Doctors Park
- Genesee Cancer and Blood Disease Treatment Center
- Genesee Hematology Oncology PC
- Genesys Hurley Cancer Institute
- Hurley Medical Center
- Helen DeVos Children's Hospital at Spectrum Health
- Spectrum Health at Butterworth Campus
- Trinity Health Grand Rapids Hospital
- Academic Hematology Oncology Specialists
- Great Lakes Cancer Management Specialists-Van Elslander Cancer Center
- Michigan Breast Specialists-Grosse Pointe Woods
- Bronson Methodist Hospital
- West Michigan Cancer Center
- Ascension Borgess Cancer Center
- Borgess Medical Center
- Sparrow Hospital
- Hope Cancer Clinic
- Trinity Health Saint Mary Mercy Livonia Hospital
- Great Lakes Cancer Management Specialists-Macomb Medical Campus
- Michigan Breast Specialists-Macomb Township
- Saint Mary's Oncology/Hematology Associates of Marlette
- Toledo Clinic Cancer Centers-Monroe
- Trinity Health Muskegon Hospital
- Lakeland Hospital Niles
- Cancer and Hematology Centers of Western Michigan - Norton Shores
- Ascension Providence Hospitals - Novi
- 21st Century Oncology-Pontiac
- Hope Cancer Center
- Newland Medical Associates-Pontiac
- Saint Joseph Mercy Oakland
- Spectrum Health Reed City Hospital
- Great Lakes Cancer Management Specialists-Rochester Hills
- Ascension Saint Mary's Hospital
- Oncology Hematology Associates of Saginaw Valley PC
- Lakeland Medical Center Saint Joseph
- Marie Yeager Cancer Center
- Ascension Providence Hospitals - Southfield
- Bhadresh Nayak MD PC-Sterling Heights
- Ascension Saint Joseph Hospital
- Munson Medical Center
- Advanced Breast Care Center PLLC
- Great Lakes Cancer Management Specialists-Macomb Professional Building
- Macomb Hematology Oncology PC
- Michigan Breast Specialists-Warren
- Saint John Macomb-Oakland Hospital
- Saint Mary's Oncology/Hematology Associates of West Branch
- University of Michigan Health - West
- Huron Gastroenterology PC
- Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
- Riverwood Healthcare Center
- Essentia Health - Baxter Clinic
- Essentia Health Saint Joseph's Medical Center
- Fairview Ridges Hospital
- Minnesota Oncology - Burnsville
- Cambridge Medical Center
- Mercy Hospital
- Essentia Health - Deer River Clinic
- Essentia Health Saint Mary's - Detroit Lakes Clinic
- Essentia Health Cancer Center
- Essentia Health Saint Mary's Medical Center
- Miller-Dwan Hospital
- Fairview Southdale Hospital
- Essentia Health - Ely Clinic
- Lake Region Healthcare Corporation-Cancer Care
- Essentia Health - Fosston
- Unity Hospital
- Essentia Health Hibbing Clinic
- Essentia Health - International Falls Clinic
- Fairview Clinics and Surgery Center Maple Grove
- Minnesota Oncology Hematology PA-Maplewood
- Saint John's Hospital - Healtheast
- Abbott-Northwestern Hospital
- Hennepin County Medical Center
- Health Partners Inc
- Monticello Cancer Center
- Essentia Health - Moose Lake Clinic
- New Ulm Medical Center
- Essentia Health - Park Rapids
- Fairview Northland Medical Center
- North Memorial Medical Health Center
- Park Nicollet Clinic - Saint Louis Park
- Regions Hospital
- United Hospital
- Essentia Health Sandstone
- Saint Francis Regional Medical Center
- Lakeview Hospital
- Essentia Health Virginia Clinic
- Ridgeview Medical Center
- Rice Memorial Hospital
- Minnesota Oncology Hematology PA-Woodbury
- Fairview Lakes Medical Center
- Saint Louis Cancer and Breast Institute-Ballwin
- Central Care Cancer Center - Bolivar
- Cox Cancer Center Branson
- Saint Francis Medical Center
- Southeast Cancer Center
- MU Health - University Hospital/Ellis Fischel Cancer Center
- Siteman Cancer Center at West County Hospital
- Parkland Health Center - Farmington
- Capital Region Southwest Campus
- Freeman Health System
- Mercy Hospital Joplin
- Truman Medical Centers
- Saint Luke's Hospital of Kansas City
- Saint Luke's East - Lee's Summit
- Delbert Day Cancer Institute at PCRMC
- Mercy Clinic-Rolla-Cancer and Hematology
- Heartland Regional Medical Center
- Saint Louis Cancer and Breast Institute-South City
- Washington University School of Medicine
- Mercy Hospital South
- Siteman Cancer Center-South County
- Missouri Baptist Medical Center
- Siteman Cancer Center at Christian Hospital
- Mercy Hospital Saint Louis
- Siteman Cancer Center at Saint Peters Hospital
- Sainte Genevieve County Memorial Hospital
- Mercy Hospital Springfield
- CoxHealth South Hospital
- Missouri Baptist Sullivan Hospital
- Missouri Baptist Outpatient Center-Sunset Hills
- Mercy Hospital Washington
- Community Hospital of Anaconda
- Billings Clinic Cancer Center
- Saint Vincent Healthcare
- Saint Vincent Frontier Cancer Center
- Bozeman Deaconess Hospital
- Benefis Healthcare- Sletten Cancer Institute
- Great Falls Clinic
- Kalispell Regional Medical Center
- Saint Patrick Hospital - Community Hospital
- Community Medical Hospital
- Nebraska Medicine-Bellevue
- CHI Health Saint Francis
- CHI Health Good Samaritan
- Saint Elizabeth Regional Medical Center
- Nebraska Cancer Specialists/Oncology Hematology West PC - MECC
- Nebraska Methodist Hospital
- Oncology Associates PC
- Nebraska Medicine-Village Pointe
- Alegent Health Immanuel Medical Center
- Alegent Health Bergan Mercy Medical Center
- Alegent Health Lakeside Hospital
- Creighton University Medical Center
- University of Nebraska Medical Center
- Midlands Community Hospital
- Carson Tahoe Regional Medical Center
- Cancer and Blood Specialists-Henderson
- Comprehensive Cancer Centers of Nevada - Henderson
- Comprehensive Cancer Centers of Nevada-Horizon Ridge
- Las Vegas Cancer Center-Henderson
- OptumCare Cancer Care at Seven Hills
- Comprehensive Cancer Centers of Nevada-Southeast Henderson
- GenesisCare USA - Henderson
- Las Vegas Urology - Green Valley
- Las Vegas Urology - Pebble
- Urology Specialists of Nevada - Green Valley
- Las Vegas Urology - Pecos
- Desert West Surgery
- OptumCare Cancer Care at Charleston
- University Medical Center of Southern Nevada
- Hope Cancer Care of Nevada
- Cancer and Blood Specialists-Shadow
- Radiation Oncology Centers of Nevada Central
- Urology Specialists of Nevada - Central
- GenesisCare USA - Las Vegas
- HealthCare Partners Medical Group Oncology/Hematology-Maryland Parkway
- Sunrise Hospital and Medical Center
- HealthCare Partners Medical Group Oncology/Hematology-San Martin
- Las Vegas Prostate Cancer Center
- Las Vegas Urology - Sunset
- Urology Specialists of Nevada - Southwest
- Radiation Oncology Centers of Nevada Southeast
- Ann M Wierman MD LTD
- Cancer and Blood Specialists-Tenaya
- Comprehensive Cancer Centers of Nevada - Northwest
- GenesisCare USA - Vegas Tenaya
- HealthCare Partners Medical Group Oncology/Hematology-Tenaya
- Las Vegas Urology - Cathedral Rock
- Las Vegas Urology - Smoke Ranch
- OptumCare Cancer Care at MountainView
- Urology Specialists of Nevada - Northwest
- Alliance for Childhood Diseases/Cure 4 the Kids Foundation
- Comprehensive Cancer Centers of Nevada - Town Center
- Comprehensive Cancer Centers of Nevada-Summerlin
- Summerlin Hospital Medical Center
- Las Vegas Cancer Center-Medical Center
- Comprehensive Cancer Centers of Nevada
- GenesisCare USA - Fort Apache
- OptumCare Cancer Care at Fort Apache
- HealthCare Partners Medical Group Oncology/Hematology-Centennial Hills
- Comprehensive Cancer Centers of Nevada - Central Valley
- University Cancer Center
- Hope Cancer Care of Nevada-Pahrump
- Renown Regional Medical Center
- Saint Mary's Regional Medical Center
- Radiation Oncology Associates
- New Hampshire Oncology Hematology PA-Concord
- Elliot Hospital
- Solinsky Center for Cancer Care
- Virtua Samson Cancer Center
- Virtua Memorial
- Virtua Voorhees
- University of New Mexico Cancer Center
- Montefiore Medical Center-Einstein Campus
- Montefiore Medical Center-Weiler Hospital
- Montefiore Medical Center - Moses Campus
- Glens Falls Hospital
- Vidant Oncology-Kenansville
- Vidant Oncology-Kinston
- FirstHealth of the Carolinas-Moore Regional Hospital
- Vidant Oncology-Richlands
- Marion L Shepard Cancer Center at Vidant Beaufort Hospital
- Essentia Health Cancer Center-South University Clinic
- Essentia Health - Jamestown Clinic
- Aultman Alliance Community Hospital
- Indu and Raj Soin Medical Center
- Saint Elizabeth Boardman Hospital
- Cleveland Clinic Mercy Hospital
- Mercy Hematology and Oncology Associates Inc
- Aultman Health Foundation
- Dayton Physicians LLC-Miami Valley South
- Miami Valley Hospital South
- Good Samaritan Hospital - Cincinnati
- Oncology Hematology Care Inc-Kenwood
- Bethesda North Hospital
- TriHealth Cancer Institute-Westside
- TriHealth Cancer Institute-Anderson
- Cleveland Clinic Cancer Center/Fairview Hospital
- Cleveland Clinic Foundation
- Dayton Blood and Cancer Center
- Miami Valley Hospital
- Dayton Physician LLC-Miami Valley Hospital North
- Miami Valley Hospital North
- Armes Family Cancer Center
- Blanchard Valley Hospital
- Orion Cancer Care
- Atrium Medical Center-Middletown Regional Hospital
- Dayton Physicians LLC-Atrium
- Dayton Physicians LLC-Wayne
- Miami Valley Cancer Care and Infusion
- Wayne Hospital
- Greater Dayton Cancer Center
- First Dayton Cancer Care
- Kettering Medical Center
- Cleveland Clinic Cancer Center Mansfield
- Toledo Clinic Cancer Centers-Maumee
- Hillcrest Hospital Cancer Center
- Mercy Health Perrysburg Cancer Center
- North Coast Cancer Care
- Springfield Regional Cancer Center
- Springfield Regional Medical Center
- Cleveland Clinic Cancer Center Strongsville
- Mercy Health - Saint Anne Hospital
- Toledo Clinic Cancer Centers-Toledo
- Dayton Physicians LLC - Troy
- Upper Valley Medical Center
- South Pointe Hospital
- Saint Joseph Warren Hospital
- Cleveland Clinic Wooster Family Health and Surgery Center
- Wright-Patterson Medical Center
- Saint Elizabeth Youngstown Hospital
- Mercy Hospital Oklahoma City
- Saint Alphonsus Medical Center-Baker City
- Saint Charles Health System
- Clackamas Radiation Oncology Center
- Providence Cancer Institute Clackamas Clinic
- Bay Area Hospital
- Providence Newberg Medical Center
- Saint Alphonsus Medical Center-Ontario
- Providence Willamette Falls Medical Center
- Providence Portland Medical Center
- Providence Saint Vincent Medical Center
- Oregon Health and Science University
- Saint Charles Health System-Redmond
- Lehigh Valley Hospital-Cedar Crest
- Saint Luke's Cancer Center - Allentown
- Saint Luke's University Hospital-Bethlehem Campus
- Lehigh Valley Hospital - Muhlenberg
- Bryn Mawr Hospital
- Chambersburg Hospital
- WellSpan Medical Oncology and Hematology
- Main Line Health Center-Collegeville
- Pocono Medical Center
- Saint Luke's Hospital-Anderson Campus
- Ephrata Cancer Center
- Main Line Health Center-Exton
- Adams Cancer Center
- Cherry Tree Cancer Center
- Lehigh Valley Hospital-Hazleton
- Sechler Family Cancer Center
- Riddle Memorial Hospital
- Bryn Mawr Health Center
- Paoli Memorial Hospital
- Penn Presbyterian Medical Center
- University of Pennsylvania/Abramson Cancer Center
- Pottstown Hospital
- Saint Luke's Hospital - Upper Bucks Campus
- Saint Luke's Hospital-Quakertown Campus
- Guthrie Medical Group PC-Robert Packer Hospital
- Lankenau Medical Center
- Cancer Care Associates of York
- WellSpan Health-York Cancer Center
- WellSpan Health-York Hospital
- Self Regional Healthcare
- Saint Joseph Regional Cancer Center
- Bon Secours Memorial Regional Medical Center
- Bon Secours Westchester Emergency Center
- Bon Secours Saint Francis Medical Center
- Bon Secours DePaul Medical Center
- Bon Secours Maryview Medical Center
- Bon Secours Richmond Community Hospital
- Bon Secours Saint Mary's Hospital
- Bon Secours Cancer Institute at Reynolds Crossing
- VCU Massey Cancer Center at Stony Point
- Virginia Commonwealth University/Massey Cancer Center
- Bon Secours Health Center at Harbour View
- Providence Regional Cancer System-Aberdeen
- Overlake Medical Center
- PeaceHealth Saint Joseph Medical Center
- Harrison HealthPartners Hematology and Oncology-Bremerton
- Harrison Medical Center
- Highline Medical Center-Main Campus
- Providence Regional Cancer System-Centralia
- Swedish Cancer Institute-Edmonds
- Saint Elizabeth Hospital
- Providence Regional Cancer Partnership
- Saint Francis Hospital
- Swedish Cancer Institute-Issaquah
- Kadlec Clinic Hematology and Oncology
- Providence Regional Cancer System-Lacey
- Saint Clare Hospital
- PeaceHealth Saint John Medical Center
- Jefferson Healthcare
- Harrison HealthPartners Hematology and Oncology-Poulsbo
- Valley Medical Center
- Pacific Gynecology Specialists
- Swedish Medical Center-Ballard Campus
- Swedish Medical Center-Cherry Hill
- Swedish Medical Center-First Hill
- PeaceHealth United General Medical Center
- Providence Regional Cancer System-Shelton
- Franciscan Research Center-Northwest Medical Plaza
- Northwest Medical Specialties PLLC
- PeaceHealth Southwest Medical Center
- Providence Saint Mary Regional Cancer Center
- North Star Lodge Cancer Center at Yakima Valley Memorial Hospital
- Providence Regional Cancer System-Yelm
- Edwards Comprehensive Cancer Center
- ThedaCare Regional Cancer Center
- Duluth Clinic Ashland
- Northwest Wisconsin Cancer Center
- ThedaCare Cancer Care - Berlin
- Aurora Cancer Care-Southern Lakes VLCC
- Marshfield Clinic-Chippewa Center
- Aurora Saint Luke's South Shore
- Marshfield Medical Center-EC Cancer Center
- Aurora Health Care Germantown Health Center
- Aurora Cancer Care-Grafton
- Aurora BayCare Medical Center
- Essentia Health-Hayward Clinic
- Aurora Cancer Care-Kenosha South
- Gundersen Lutheran Medical Center
- Marshfield Clinic - Ladysmith Center
- Aurora Bay Area Medical Group-Marinette
- Marshfield Medical Center-Marshfield
- Aurora Cancer Care-Milwaukee
- Aurora Saint Luke's Medical Center
- Aurora Sinai Medical Center
- Marshfield Clinic-Minocqua Center
- ProHealth D N Greenwald Center
- Cancer Center of Western Wisconsin
- ProHealth Oconomowoc Memorial Hospital
- Vince Lombardi Cancer Clinic - Oshkosh
- Aurora Cancer Care-Racine
- Marshfield Medical Center-Rice Lake
- Vince Lombardi Cancer Clinic-Sheboygan
- Essentia Health-Spooner Clinic
- Marshfield Medical Center-River Region at Stevens Point
- Aurora Medical Center in Summit
- Essentia Health Saint Mary's Hospital - Superior
- Vince Lombardi Cancer Clinic-Two Rivers
- ProHealth Waukesha Memorial Hospital
- UW Cancer Center at ProHealth Care
- Marshfield Clinic-Wausau Center
- Aurora Cancer Care-Milwaukee West
- Marshfield Medical Center - Weston
- Marshfield Clinic - Wisconsin Rapids Center
- Cheyenne Regional Medical Center-West
- Billings Clinic-Cody
- Welch Cancer Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Experimental
Experimental
Active Comparator
Experimental
Step 1, Arm A (cabozantinib S-malate)
Step 1, Arm B (cabozantinib S-malate, nivolumab)
Step 1, Arm C (standard chemotherapy)
Step 2, Arm Z (cabozantinib S-malate, nivolumab)
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.
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.
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.
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.