Refractory Classic Hodgkin Lymphoma Clinical Trial
Official title:
A Phase I Study With an Expansion Cohort/Randomized Phase II Study of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients With Relapsed/Refractory Hodgkin Lymphoma
| Verified date | March 2024 |
| Source | National Cancer Institute (NCI) |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
This phase I/II trial studies the side effects and best dose of ipilimumab and nivolumab when given together with brentuximab vedotin, and how well they work in treating patients with Hodgkin lymphoma that has returned after a period of improvement (recurrent) or has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to CD30 positive cancer cells in a targeted way and delivers vedotin to kill them. It is not known whether giving brentuximab vedotin and nivolumab with or without ipilimumab may kill more cancer cells.
| Status | Suspended |
| Enrollment | 146 |
| Est. completion date | March 20, 2025 |
| Est. primary completion date | March 20, 2025 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 12 Years and older |
| Eligibility | Inclusion Criteria: - PHASE I (ARMS A, B, C, D, E, F, G, H, I, X, Y, Z) - Age >= 18 years - Patients must have pathologically confirmed relapsed or refractory classical Hodgkin lymphoma (cHL); a biopsy at any relapse is acceptable; other histologies including lymphocyte predominant (LP) HL are not permitted - Patients must have relapsed after first line chemotherapy; may have relapsed after autologous or allogeneic stem cell transplant, or have primary refractory disease; no upper limit for number of prior therapies; if status post allogeneic stem cell transplant, no active graft versus host disease - Patients may have received prior brentuximab vedotin, but must not have received brentuximab vedotin within 6 months prior to registration, and must not have relapsed within 6 months of receiving previous brentuximab vedotin; patients may not have received prior nivolumab or PD1/PDL1 axis agents; patients in the nivolumab/brentuximab cohorts ONLY (D, E, F, Y) may have received prior ipilimumab - Patients may have received other prior activating immunotherapies (i.e. checkpoint inhibitors), but must not have received them within 6 months prior to registration, and there must be no serious unresolved complication of therapy at the time of registration; for the purposes of this study monoclonal antibodies and antibody drug conjugates are not considered to be activating immunotherapies and there are no additional time restrictions on prior exposure to these agents (except prior brentuximab vedotin) - Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging Network (ACRIN) performance status between 0-2 - Patients must have measurable disease; baseline measurements and evaluations must be obtained within 4 weeks of registration to the study; abnormal PET scans will not constitute evaluable disease unless verified by a diagnostic quality CT scan; patients must use the same imaging modality (CT or PET/CT) throughout the study - Patient must not be pregnant or breast-feeding due to risk of fetal harm by the chemotherapeutic agents prescribed in this protocol; all patients of childbearing potential must have a blood test or urine study within 2 weeks prior to 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 not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Patient of childbearing potential and/or sexually active patients must either abstain from sexual intercourse for the duration of their participation in the study or agree to use both single barrier contraception and birth control pills or implants for at least one week prior to the start of the study drug and continuing for 5 months after the last dose of study drug (for patients of childbearing potential) and for 7 months after the last dose of study drug (for patients who are sexually active with anyone of childbearing potential); should a patient become pregnant or suspect pregnancy while the patient or their partner is participating in this study, the patient (or the participating partner) should inform the treating physician immediately - Patients must have no evidence of dyspnea at rest and a pulse oximetry > 92% while breathing room air - Patients must have forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) > 60% by pulmonary function test (PFT), unless due to large mediastinal mass from HL; carbon monoxide diffusion capacity (DLCO), FEV1, and FVC all > 50% predicted value; all pulmonary function tests must be obtained within one month prior to registration - Absolute neutrophil count (ANC) >= 1500/mcL (1.5 x 10^9/L) (obtained within 2 weeks prior to registration) - Platelets >= 75,000/mcL (75 x 10^9/L) (obtained within 2 weeks prior to registration) - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) (obtained within 2 weeks prior to registration) - Bilirubin =< 2 x upper limit of normal (ULN) (unless documented Gilbert's syndrome, for which bilirubin =< 3 x upper limit of normal [ULN] is permitted) (obtained within 2 weeks prior to registration) - Calculated creatinine clearance by Cockcroft-Gault formula >= 30 ml/min (obtained within 2 weeks prior to registration) - No evidence of prior malignancy except adequately treated non-melanoma skin cancer, in situ cervical carcinoma or any surgically- or radiation-cured malignancy continuously disease free for >= 5 years so as not to interfere with interpretation of radiographic response - Patient must have no current or prior history of central nervous system (CNS) involvement - All prior therapy must have been completed at least 21 days prior to enrollment; no concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose of treatment of lymphoma are allowed; topical steroids are allowed - No history of Steven's Johnson's syndrome, toxic epidermal necrolysis (TEN)s syndrome, or motor neuropathy - Human immunodeficiency virus (HIV) positive patients are allowed on this study if they have a CD4 count > 400, and are on a stable antiviral regimen; patients with poorly controlled HIV or other chronic active viral infections will be excluded - Patients must not have autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids; a history of occasional (but not continuous) use of steroid inhalers is allowed - Replacement doses of steroids for patients with adrenal insufficiency are allowed; patients who discontinue use of these classes of medication for at least 2 weeks prior to initiation of study treatment are eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study - Exclusion from this study also includes patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjogren's syndrome, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia Gravis); other CNS autoimmune disease (e.g., Multiple sclerosis); patients with autoimmune hypothyroid disease or type I diabetes on replacement treatment are eligible - Patients must not have grade 2 or greater peripheral sensory neuropathy - Patients must not have New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia - Patients must not have previously existing hypersensitivity to brentuximab vedotin or ipilimumab - Patients must not have a serious medical or psychiatric illness likely to interfere with study participation - Patients must not be participating in any other clinical trial or taking any other experimental medications within 21 days prior to registration - Routine vaccinations, including seasonal influenza, should be given at least 2 weeks prior to study treatment; vaccines are not prohibited on study, but must be given at least 6 weeks after cycle 1 and not within 7 days of treatment - Patients registering to Arms D, E, F, G, H, I, X, Y must not currently be smoking tobacco or other substances and must not have smoked within the past 6 months - RANDOMIZED PHASE II (ARMS K AND L): Age >= 12 years - Pediatric patients will include any patients < 18 years of age - RANDOMIZED PHASE II (ARMS K AND L): Patients must have pathologically confirmed relapsed or refractory classical Hodgkin lymphoma (cHL); a biopsy at any relapse is acceptable; other histologies including lymphocyte predominant (LP) HL are not permitted - RANDOMIZED PHASE II (ARMS K AND L): Patients must have relapsed after first line chemotherapy; may have relapsed after autologous stem cell transplant, or have primary refractory disease; no upper limit for number of prior therapies; patient must not have received a prior allogeneic stem cell transplant (out of risk of reactivation of pulmonary graft versus host disease [GVHD]) - RANDOMIZED PHASE II (ARMS K AND L): Patients may have received prior brentuximab vedotin, but must not have received brentuximab vedotin within 6 months prior to registration, and must not have relapsed within 6 months of receiving previous brentuximab vedotin; patients may not have received prior nivolumab or PD1/PDL1 axis agents; patients may not have received prior ipilimumab - RANDOMIZED PHASE II (ARMS K AND L): Patients may not have received other prior activating immunotherapies (i.e. checkpoint inhibitor therapies); for the purposes of this study monoclonal antibodies and antibody drug conjugates are not considered to be activating immunotherapies and there are no additional time restrictions on prior exposure to these agents (except prior brentuximab vedotin) - RANDOMIZED PHASE II (ARMS K AND L): Adult patient (>= 18 years of age) ECOG-ACRIN performance status between 0-2 - Pediatric patients (16-17 years of age) must have a Karnofsky performance level >= 50% - Pediatric patients (12-15 years of age) must have a Lansky performance level >= 50 - RANDOMIZED PHASE II (ARMS K AND L): Patients must have measurable disease; baseline measurements and evaluations must be obtained within 4 weeks of registration to the study; abnormal PET scans will not constitute evaluable disease unless verified by a diagnostic quality CT scan; patients must use the same imaging modality (CT or PET/CT) throughout the study - RANDOMIZED PHASE II (ARMS K AND L): Patient must not be pregnant or breast-feeding due to risk of fetal harm by the chemotherapeutic agents prescribed in this protocol; all patients of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a patient of childbearing potential is defined as 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 2) 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) - RANDOMIZED PHASE II (ARMS K AND L): Patient of childbearing potential and/or sexually active patient must either abstain from sexual intercourse for the duration of their participation in the study or agree to use both double barrier contraception and birth control pills or implants for at least one week prior to the start of the study drug and continuing for 5 months after the last dose of study drug (for patients of childbearing potential) and for 7 months after the last dose of study drug (for patients who are sexually active with anyone of childbearing potential); should a patient become pregnant or suspect pregnancy while the patient or their partner is participating in this study, the patient (or the participating partner) should inform the treating physician immediately - RANDOMIZED PHASE II (ARMS K AND L): Patients with impaired decision-making capacity are eligible with legally authorized representative - RANDOMIZED PHASE II (ARMS K AND L): Patients must have no evidence of dyspnea at rest and a pulse oximetry > 92% while breathing room air - RANDOMIZED PHASE II (ARMS K AND L): Patients must have FEV1/FVC > 60% by pulmonary function test (PFT), unless due to large mediastinal mass from HL; carbon monoxide diffusion capacity (DLCO), FEV1, and FVC all > 50% predicted value; all pulmonary function tests must be obtained within one month prior to registration - RANDOMIZED PHASE II (ARMS K AND L): ANC >= 1500/mcL (1.5 x 0^9/L) (obtained within 2 weeks prior to registration) - RANDOMIZED PHASE II (ARMS K AND L): Platelets >= 75,000/mcL (75 x 10^9/L) (obtained within 2 weeks prior to registration) - RANDOMIZED PHASE II (ARMS K AND L): AST/ALT =< 2.5 x upper limit of normal (ULN) for age (obtained within 2 weeks prior to registration) - RANDOMIZED PHASE II (ARMS K AND L): Bilirubin =< 2 x upper limit of normal (ULN) (unless documented Gilbert's syndrome, for which bilirubin =< 3 x upper limit of normal [ULN] is permitted) (obtained within 2 weeks prior to registration) - RANDOMIZED PHASE II (ARMS K AND L): Adult patients (>= 18 years old) must have a calculated creatinine clearance by Cockcroft-Gault formula >= 30 ml/min (obtained within 2 weeks prior to registration) - RANDOMIZED PHASE II (ARMS K AND L): Pediatric patients (< 18 years old) must have a creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or serum creatinine based on age/gender as follows: - Age: maximum serum creatinine (mg/dL) - < 13 years: male (1.2), female (1.2) - 13 to < 16 years: male (1.5), female (1.4) - >= 16 years: male (1.7), female (1.4) - RANDOMIZED PHASE II (ARMS K AND L): No evidence of prior malignancy except adequately treated non-melanoma skin cancer, in situ cervical carcinoma or any surgically- or radiation-cured malignancy continuously disease free for >= 5 years so as not to interfere with interpretation of radiographic response - RANDOMIZED PHASE II (ARMS K AND L): Patient must have no current or prior history of CNS involvement - RANDOMIZED PHASE II (ARMS K AND L): All prior therapy must have been completed at least 21 days prior to enrollment (6 weeks for nitrosoureas or mitomycin C); no concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose of treatment of lymphoma are allowed; topical steroids are allowed - RANDOMIZED PHASE II (ARMS K AND L): No history of Steven's Johnson's syndrome, TENs syndrome, or motor neuropathy - RANDOMIZED PHASE II (ARMS K AND L): HIV positive patients are eligible provided they meet the other protocol criteria including the following: - Long term survival expected were it not for the cHL - HIV viral loads undetectable by standard clinical HIV testing - Willing to adhere to effective combination antiretroviral therapy - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have autoimmune disorders, prior solid organ transplant, or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids; a history of occasional (but not continuous) use of steroid inhalers is allowed; replacement doses of steroids for patients with adrenal insufficiency are allowed; patients who discontinue use of steroid medication for at least 2 weeks prior to initiation of therapy are eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study; exclusion from this study also includes patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjogren's syndrome, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia Gravis); other CNS autoimmune disease (e.g., Multiple sclerosis); patients with autoimmune hypothyroid disease or type I diabetes on replacement treatment are eligible - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have grade 2 or greater peripheral sensory neuropathy - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have NYHA class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have previously existing hypersensitivity to brentuximab vedotin or ipilimumab - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have a serious medical or psychiatric illness likely to interfere with study participation - RANDOMIZED PHASE II (ARMS K AND L): Patients must not be participating in any other clinical trial or taking any other experimental medications within 21 days prior to registration - RANDOMIZED PHASE II (ARMS K AND L): Routine vaccinations, including seasonal influenza, should be given at least 2 weeks prior to study treatment; vaccines are not prohibited on study, but must be given at least 6 weeks after cycle 1 and not within 7 days of treatment - RANDOMIZED PHASE II (ARMS K AND L): Patients must not currently be smoking tobacco or other agents; vaping is not allowed - RANDOMIZED PHASE II (ARMS K AND L): Patients must not have a history of or evidence of cardiovascular risks including any of the following: - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec at baseline - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to registration - History prior to registration or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system - Left ventricular ejection fraction (LVEF) =< lower limit of normal on cardiac echocardiogram (echo) or multigated acquisition scan (MUGA) - Intra-cardiac defibrillator - History of abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy |
| Country | Name | City | State |
|---|---|---|---|
| United States | Providence Regional Cancer System-Aberdeen | Aberdeen | Washington |
| United States | Riverwood Healthcare Center | Aitkin | Minnesota |
| United States | Children's Hospital Medical Center of Akron | Akron | Ohio |
| United States | Albany Medical Center | Albany | New York |
| United States | University of New Mexico Cancer Center | Albuquerque | New Mexico |
| United States | Saint Anthony's Health | Alton | Illinois |
| United States | American Fork Hospital / Huntsman Intermountain Cancer Center | American Fork | Utah |
| United States | Community Hospital of Anaconda | Anaconda | Montana |
| United States | Alaska Breast Care and Surgery LLC | Anchorage | Alaska |
| United States | Alaska Oncology and Hematology LLC | Anchorage | Alaska |
| United States | Alaska Women's Cancer Care | Anchorage | Alaska |
| United States | Anchorage Associates in Radiation Medicine | Anchorage | Alaska |
| United States | Anchorage Oncology Centre | Anchorage | Alaska |
| United States | Anchorage Radiation Therapy Center | Anchorage | Alaska |
| United States | Katmai Oncology Group | Anchorage | Alaska |
| United States | Providence Alaska Medical Center | Anchorage | Alaska |
| United States | Kaiser Permanente-Deer Valley Medical Center | Antioch | California |
| United States | Mission Hope Medical Oncology - Arroyo Grande | Arroyo Grande | California |
| United States | PCR Oncology | Arroyo Grande | California |
| United States | Duluth Clinic Ashland | Ashland | Wisconsin |
| United States | Northwest Wisconsin Cancer Center | Ashland | Wisconsin |
| United States | Children's Healthcare of Atlanta - Egleston | Atlanta | Georgia |
| United States | Emory University Hospital/Winship Cancer Institute | Atlanta | Georgia |
| United States | MultiCare Auburn Medical Center | Auburn | Washington |
| United States | Rocky Mountain Cancer Centers-Aurora | Aurora | Colorado |
| United States | Rush - Copley Medical Center | Aurora | Illinois |
| United States | The Medical Center of Aurora | Aurora | Colorado |
| United States | Dell Children's Medical Center of Central Texas | Austin | Texas |
| United States | Saint Alphonsus Cancer Care Center-Baker City | Baker City | Oregon |
| United States | Saint Louis Cancer and Breast Institute-Ballwin | Ballwin | Missouri |
| United States | Johns Hopkins University/Sidney Kimmel Cancer Center | Baltimore | Maryland |
| United States | Saint Agnes Hospital | Baltimore | Maryland |
| United States | Flaget Memorial Hospital | Bardstown | Kentucky |
| United States | Louisiana Hematology Oncology Associates LLC | Baton Rouge | Louisiana |
| United States | LSU Health Baton Rouge-North Clinic | Baton Rouge | Louisiana |
| United States | Mary Bird Perkins Cancer Center | Baton Rouge | Louisiana |
| United States | Our Lady of The Lake | Baton Rouge | Louisiana |
| United States | Our Lady of the Lake Physician Group | Baton Rouge | Louisiana |
| United States | Overlake Medical Center | Bellevue | Washington |
| United States | PeaceHealth Saint Joseph Medical Center | Bellingham | Washington |
| United States | Saint Charles Health System | Bend | Oregon |
| United States | Walter Reed National Military Medical Center | Bethesda | Maryland |
| United States | Billings Clinic Cancer Center | Billings | Montana |
| United States | Saint Vincent Frontier Cancer Center | Billings | Montana |
| United States | Saint Vincent Healthcare | Billings | Montana |
| United States | Children's Hospital of Alabama | Birmingham | Alabama |
| United States | University of Alabama at Birmingham Cancer Center | Birmingham | Alabama |
| United States | Illinois CancerCare-Bloomington | Bloomington | Illinois |
| United States | Prisma Health Cancer Institute - Spartanburg | Boiling Springs | South Carolina |
| United States | Saint Alphonsus Cancer Care Center-Boise | Boise | Idaho |
| United States | Saint Luke's Cancer Institute - Boise | Boise | Idaho |
| United States | Central Care Cancer Center - Bolivar | Bolivar | Missouri |
| United States | Parkland Health Center-Bonne Terre | Bonne Terre | Missouri |
| United States | Tufts Medical Center | Boston | Massachusetts |
| United States | Boulder Community Foothills Hospital | Boulder | Colorado |
| United States | Boulder Community Hospital | Boulder | Colorado |
| United States | Rocky Mountain Cancer Centers-Boulder | Boulder | Colorado |
| United States | Bozeman Health Deaconess Hospital | Bozeman | Montana |
| United States | Essentia Health Saint Joseph's Medical Center | Brainerd | Minnesota |
| United States | Cox Cancer Center Branson | Branson | Missouri |
| United States | Harrison HealthPartners Hematology and Oncology-Bremerton | Bremerton | Washington |
| United States | United Hospital Center | Bridgeport | West Virginia |
| United States | Montefiore Medical Center - Moses Campus | Bronx | New York |
| United States | Saint Joseph Regional Cancer Center | Bryan | Texas |
| United States | Roswell Park Cancer Institute | Buffalo | New York |
| United States | Providence Saint Joseph Medical Center/Disney Family Cancer Center | Burbank | California |
| United States | Highline Medical Center-Main Campus | Burien | Washington |
| United States | Aurora Cancer Care-Southern Lakes VLCC | Burlington | Wisconsin |
| United States | Saint James Community Hospital and Cancer Treatment Center | Butte | Montana |
| United States | Saint Alphonsus Cancer Care Center-Caldwell | Caldwell | Idaho |
| United States | Illinois CancerCare-Canton | Canton | Illinois |
| United States | Saint Francis Medical Center | Cape Girardeau | Missouri |
| United States | Southeast Cancer Center | Cape Girardeau | Missouri |
| United States | Memorial Hospital of Carbondale | Carbondale | Illinois |
| United States | Carson Tahoe Regional Medical Center | Carson City | Nevada |
| United States | SIH Cancer Institute | Carterville | Illinois |
| United States | Illinois CancerCare-Carthage | Carthage | Illinois |
| United States | Sandra L Maxwell Cancer Center | Cedar City | Utah |
| United States | Rocky Mountain Cancer Centers - Centennial | Centennial | Colorado |
| United States | Centralia Oncology Clinic | Centralia | Illinois |
| United States | Providence Regional Cancer System-Centralia | Centralia | Washington |
| United States | UNC Lineberger Comprehensive Cancer Center | Chapel Hill | North Carolina |
| United States | Carolinas Medical Center/Levine Cancer Institute | Charlotte | North Carolina |
| United States | Memorial Hospital | Chattanooga | Tennessee |
| United States | Saint Luke's Hospital | Chesterfield | Missouri |
| United States | Cheyenne Regional Medical Center-West | Cheyenne | Wyoming |
| United States | Northwestern University | Chicago | Illinois |
| United States | Rush University Medical Center | Chicago | Illinois |
| United States | University of Illinois | Chicago | Illinois |
| United States | Marshfield Clinic-Chippewa Center | Chippewa Falls | Wisconsin |
| United States | Bethesda North Hospital | Cincinnati | Ohio |
| United States | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio |
| United States | Good Samaritan Hospital - Cincinnati | Cincinnati | Ohio |
| United States | TriHealth Cancer Institute-Anderson | Cincinnati | Ohio |
| United States | TriHealth Cancer Institute-Westside | Cincinnati | Ohio |
| United States | Clackamas Radiation Oncology Center | Clackamas | Oregon |
| United States | Providence Cancer Institute Clackamas Clinic | Clackamas | Oregon |
| United States | MetroHealth Medical Center | Cleveland | Ohio |
| United States | Southeastern Medical Oncology Center-Clinton | Clinton | North Carolina |
| United States | Mercy Cancer Center-West Lakes | Clive | Iowa |
| United States | Mission Cancer and Blood - West Des Moines | Clive | Iowa |
| United States | Billings Clinic-Cody | Cody | Wyoming |
| United States | Kootenai Health - Coeur d'Alene | Coeur d'Alene | Idaho |
| United States | Penrose-Saint Francis Healthcare | Colorado Springs | Colorado |
| United States | Rocky Mountain Cancer Centers-Penrose | Colorado Springs | Colorado |
| United States | Prisma Health Richland Hospital | Columbia | South Carolina |
| United States | Nationwide Children's Hospital | Columbus | Ohio |
| United States | Bay Area Hospital | Coos Bay | Oregon |
| United States | Commonwealth Cancer Center-Corbin | Corbin | Kentucky |
| United States | Driscoll Children's Hospital | Corpus Christi | Texas |
| United States | Alegent Health Mercy Hospital | Council Bluffs | Iowa |
| United States | Northshore Oncology Associates-Covington | Covington | Louisiana |
| United States | Greater Regional Medical Center | Creston | Iowa |
| United States | Siteman Cancer Center at West County Hospital | Creve Coeur | Missouri |
| United States | Carle at The Riverfront | Danville | Illinois |
| United States | Cancer Care Specialists of Illinois - Decatur | Decatur | Illinois |
| United States | Decatur Memorial Hospital | Decatur | Illinois |
| United States | Essentia Health - Deer River Clinic | Deer River | Minnesota |
| United States | Cancer Center of Colorado at Sloan's Lake | Denver | Colorado |
| United States | Colorado Blood Cancer Institute | Denver | Colorado |
| United States | Denver Health Medical Center | Denver | Colorado |
| United States | National Jewish Health-Main Campus | Denver | Colorado |
| United States | Porter Adventist Hospital | Denver | Colorado |
| United States | Presbyterian - Saint Lukes Medical Center - Health One | Denver | Colorado |
| United States | Rocky Mountain Cancer Centers-Midtown | Denver | Colorado |
| United States | Rocky Mountain Cancer Centers-Rose | Denver | Colorado |
| United States | Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center | Denver | Colorado |
| United States | Rose Medical Center | Denver | Colorado |
| United States | SCL Health Saint Joseph Hospital | Denver | Colorado |
| United States | The Women's Imaging Center | Denver | Colorado |
| United States | Western Surgical Care | Denver | Colorado |
| United States | Mercy Medical Center - Des Moines | Des Moines | Iowa |
| United States | Mission Cancer and Blood - Laurel | Des Moines | Iowa |
| United States | Essentia Health Saint Mary's - Detroit Lakes Clinic | Detroit Lakes | Minnesota |
| United States | Illinois CancerCare-Dixon | Dixon | Illinois |
| United States | Kaiser Permanente Dublin | Dublin | California |
| United States | Essentia Health Cancer Center | Duluth | Minnesota |
| United States | Essentia Health Saint Mary's Medical Center | Duluth | Minnesota |
| United States | Miller-Dwan Hospital | Duluth | Minnesota |
| United States | Mercy Medical Center | Durango | Colorado |
| United States | Southwest Oncology PC | Durango | Colorado |
| United States | Prisma Health Cancer Institute - Easley | Easley | South Carolina |
| United States | Marshfield Medical Center-EC Cancer Center | Eau Claire | Wisconsin |
| United States | Swedish Cancer Institute-Edmonds | Edmonds | Washington |
| United States | Carle Physician Group-Effingham | Effingham | Illinois |
| United States | Crossroads Cancer Center | Effingham | Illinois |
| United States | El Paso Children's Hospital | El Paso | Texas |
| United States | Walter Knox Memorial Hospital | Emmett | Idaho |
| United States | Mountain Blue Cancer Care Center - Swedish | Englewood | Colorado |
| United States | Rocky Mountain Cancer Centers - Swedish | Englewood | Colorado |
| United States | Swedish Medical Center | Englewood | Colorado |
| United States | Saint Elizabeth Hospital | Enumclaw | Washington |
| United States | Illinois CancerCare-Eureka | Eureka | Illinois |
| United States | Deaconess Clinic Downtown | Evansville | Indiana |
| United States | Providence Regional Cancer Partnership | Everett | Washington |
| United States | Fairbanks Memorial Hospital | Fairbanks | Alaska |
| United States | Essentia Health Cancer Center-South University Clinic | Fargo | North Dakota |
| United States | Parkland Health Center - Farmington | Farmington | Missouri |
| United States | Saint Francis Hospital | Federal Way | Washington |
| United States | Lake Region Healthcare Corporation-Cancer Care | Fergus Falls | Minnesota |
| United States | Aurora Health Center-Fond du Lac | Fond Du Lac | Wisconsin |
| United States | Golisano Children's Hospital of Southwest Florida | Fort Myers | Florida |
| United States | Regional Cancer Center-Lee Memorial Health System | Fort Myers | Florida |
| United States | Mercy Hospital Fort Smith | Fort Smith | Arkansas |
| United States | Cook Children's Medical Center | Fort Worth | Texas |
| United States | Essentia Health - Fosston | Fosston | Minnesota |
| United States | Kaiser Permanente-Fremont | Fremont | California |
| United States | Fresno Cancer Center | Fresno | California |
| United States | Kaiser Permanente-Fresno | Fresno | California |
| United States | Saint Luke's Cancer Institute - Fruitland | Fruitland | Idaho |
| United States | Illinois CancerCare-Galesburg | Galesburg | Illinois |
| United States | Western Illinois Cancer Treatment Center | Galesburg | Illinois |
| United States | Central Care Cancer Center - Garden City | Garden City | Kansas |
| United States | Aurora Health Care Germantown Health Center | Germantown | Wisconsin |
| United States | MultiCare Gig Harbor Medical Park | Gig Harbor | Washington |
| United States | Mountain Blue Cancer Care Center | Golden | Colorado |
| United States | National Jewish Health-Western Hematology Oncology | Golden | Colorado |
| United States | Southeastern Medical Oncology Center-Goldsboro | Goldsboro | North Carolina |
| United States | Wayne Memorial Hospital | Goldsboro | North Carolina |
| United States | Aurora Cancer Care-Grafton | Grafton | Wisconsin |
| United States | Nebraska Cancer Specialists/Oncology Hematology West PC | Grand Island | Nebraska |
| United States | Saint Mary's Hospital and Regional Medical Center | Grand Junction | Colorado |
| United States | Central Care Cancer Center - Great Bend | Great Bend | Kansas |
| United States | Benefis Sletten Cancer Institute | Great Falls | Montana |
| United States | Great Falls Clinic | Great Falls | Montana |
| United States | Banner North Colorado Medical Center | Greeley | Colorado |
| United States | Aurora BayCare Medical Center | Green Bay | Wisconsin |
| United States | BI-LO Charities Children's Cancer Center | Greenville | South Carolina |
| United States | Prisma Health Cancer Institute - Butternut | Greenville | South Carolina |
| United States | Prisma Health Cancer Institute - Eastside | Greenville | South Carolina |
| United States | Prisma Health Cancer Institute - Faris | Greenville | South Carolina |
| United States | Prisma Health Greenville Memorial Hospital | Greenville | South Carolina |
| United States | Saint Francis Cancer Center | Greenville | South Carolina |
| United States | Saint Francis Hospital | Greenville | South Carolina |
| United States | Prisma Health Cancer Institute - Greer | Greer | South Carolina |
| United States | Hackensack University Medical Center | Hackensack | New Jersey |
| United States | Saint Peter's Community Hospital | Helena | Montana |
| United States | Cancer and Blood Specialists-Henderson | Henderson | Nevada |
| United States | Comprehensive Cancer Centers of Nevada - Henderson | Henderson | Nevada |
| United States | Comprehensive Cancer Centers of Nevada-Horizon Ridge | Henderson | Nevada |
| United States | Comprehensive Cancer Centers of Nevada-Southeast Henderson | Henderson | Nevada |
| United States | GenesisCare USA - Henderson | Henderson | Nevada |
| United States | Las Vegas Cancer Center-Henderson | Henderson | Nevada |
| United States | Las Vegas Urology - Green Valley | Henderson | Nevada |
| United States | Las Vegas Urology - Pebble | Henderson | Nevada |
| United States | OptumCare Cancer Care at Seven Hills | Henderson | Nevada |
| United States | Urology Specialists of Nevada - Green Valley | Henderson | Nevada |
| United States | Penn State Milton S Hershey Medical Center | Hershey | Pennsylvania |
| United States | Essentia Health Hibbing Clinic | Hibbing | Minnesota |
| United States | Pulmonary Medicine Center of Chattanooga-Hixson | Hixson | Tennessee |
| United States | Kaiser Permanente Moanalua Medical Center | Honolulu | Hawaii |
| United States | CHI Saint Vincent Cancer Center Hot Springs | Hot Springs | Arkansas |
| United States | Oncology Center of The South Incorporated | Houma | Louisiana |
| United States | Terrebonne General Medical Center | Houma | Louisiana |
| United States | Indiana University/Melvin and Bren Simon Cancer Center | Indianapolis | Indiana |
| United States | Swedish Cancer Institute-Issaquah | Issaquah | Washington |
| United States | Onslow Memorial Hospital | Jacksonville | North Carolina |
| United States | Southeastern Medical Oncology Center-Jacksonville | Jacksonville | North Carolina |
| United States | Essentia Health - Jamestown Clinic | Jamestown | North Dakota |
| United States | MU Health Care Goldschmidt Cancer Center | Jefferson City | Missouri |
| United States | Duly Health and Care Joliet | Joliet | Illinois |
| United States | Freeman Health System | Joplin | Missouri |
| United States | Mercy Hospital Joplin | Joplin | Missouri |
| United States | Kalispell Regional Medical Center | Kalispell | Montana |
| United States | Children's Mercy Hospitals and Clinics | Kansas City | Missouri |
| United States | CHI Health Good Samaritan | Kearney | Nebraska |
| United States | Heartland Hematology and Oncology | Kearney | Nebraska |
| United States | Kadlec Clinic Hematology and Oncology | Kennewick | Washington |
| United States | Aurora Cancer Care-Kenosha South | Kenosha | Wisconsin |
| United States | Illinois CancerCare-Kewanee Clinic | Kewanee | Illinois |
| United States | Kingman Regional Medical Center | Kingman | Arizona |
| United States | East Tennessee Childrens Hospital | Knoxville | Tennessee |
| United States | Gundersen Lutheran Medical Center | La Crosse | Wisconsin |
| United States | Providence Regional Cancer System-Lacey | Lacey | Washington |
| United States | Marshfield Medical Center - Ladysmith | Ladysmith | Wisconsin |
| United States | Good Samaritan Medical Center | Lafayette | Colorado |
| United States | Monmouth Medical Center Southern Campus | Lakewood | New Jersey |
| United States | Rocky Mountain Cancer Centers-Lakewood | Lakewood | Colorado |
| United States | Saint Anthony Hospital | Lakewood | Colorado |
| United States | Saint Clare Hospital | Lakewood | Washington |
| United States | Alliance for Childhood Diseases/Cure 4 the Kids Foundation | Las Vegas | Nevada |
| United States | Ann M Wierman MD LTD | Las Vegas | Nevada |
| United States | Cancer and Blood Specialists-Shadow | Las Vegas | Nevada |
| United States | Cancer and Blood Specialists-Tenaya | Las Vegas | Nevada |
| United States | Comprehensive Cancer Centers of Nevada | Las Vegas | Nevada |
| United States | Comprehensive Cancer Centers of Nevada - Central Valley | Las Vegas | Nevada |
| United States | Comprehensive Cancer Centers of Nevada - Northwest | Las Vegas | Nevada |
| United States | Comprehensive Cancer Centers of Nevada - Town Center | Las Vegas | Nevada |
| United States | Comprehensive Cancer Centers of Nevada-Summerlin | Las Vegas | Nevada |
| United States | Desert West Surgery | Las Vegas | Nevada |
| United States | GenesisCare USA - Fort Apache | Las Vegas | Nevada |
| United States | GenesisCare USA - Las Vegas | Las Vegas | Nevada |
| United States | GenesisCare USA - Vegas Tenaya | Las Vegas | Nevada |
| United States | HealthCare Partners Medical Group Oncology/Hematology-Centennial Hills | Las Vegas | Nevada |
| United States | HealthCare Partners Medical Group Oncology/Hematology-Maryland Parkway | Las Vegas | Nevada |
| United States | HealthCare Partners Medical Group Oncology/Hematology-San Martin | Las Vegas | Nevada |
| United States | HealthCare Partners Medical Group Oncology/Hematology-Tenaya | Las Vegas | Nevada |
| United States | Hope Cancer Care of Nevada | Las Vegas | Nevada |
| United States | Las Vegas Cancer Center-Medical Center | Las Vegas | Nevada |
| United States | Las Vegas Prostate Cancer Center | Las Vegas | Nevada |
| United States | Las Vegas Urology - Cathedral Rock | Las Vegas | Nevada |
| United States | Las Vegas Urology - Pecos | Las Vegas | Nevada |
| United States | Las Vegas Urology - Smoke Ranch | Las Vegas | Nevada |
| United States | Las Vegas Urology - Sunset | Las Vegas | Nevada |
| United States | OptumCare Cancer Care at Charleston | Las Vegas | Nevada |
| United States | OptumCare Cancer Care at Fort Apache | Las Vegas | Nevada |
| United States | OptumCare Cancer Care at MountainView | Las Vegas | Nevada |
| United States | Radiation Oncology Centers of Nevada Central | Las Vegas | Nevada |
| United States | Radiation Oncology Centers of Nevada Southeast | Las Vegas | Nevada |
| United States | Summerlin Hospital Medical Center | Las Vegas | Nevada |
| United States | Sunrise Hospital and Medical Center | Las Vegas | Nevada |
| United States | University Cancer Center | Las Vegas | Nevada |
| United States | University Medical Center of Southern Nevada | Las Vegas | Nevada |
| United States | Urology Specialists of Nevada - Central | Las Vegas | Nevada |
| United States | Urology Specialists of Nevada - Northwest | Las Vegas | Nevada |
| United States | Urology Specialists of Nevada - Southwest | Las Vegas | Nevada |
| United States | Cancer Centers of Southwest Oklahoma Research | Lawton | Oklahoma |
| United States | Saint Joseph Hospital East | Lexington | Kentucky |
| United States | Saint Joseph Radiation Oncology Resource Center | Lexington | Kentucky |
| United States | Saint Elizabeth Regional Medical Center | Lincoln | Nebraska |
| United States | Littleton Adventist Hospital | Littleton | Colorado |
| United States | Rocky Mountain Cancer Centers-Littleton | Littleton | Colorado |
| United States | Logan Regional Hospital | Logan | Utah |
| United States | Saint Joseph London | London | Kentucky |
| United States | Rocky Mountain Cancer Centers-Sky Ridge | Lone Tree | Colorado |
| United States | Sky Ridge Medical Center | Lone Tree | Colorado |
| United States | Monmouth Medical Center | Long Branch | New Jersey |
| United States | Longmont United Hospital | Longmont | Colorado |
| United States | Rocky Mountain Cancer Centers-Longmont | Longmont | Colorado |
| United States | PeaceHealth Saint John Medical Center | Longview | Washington |
| United States | Jewish Hospital | Louisville | Kentucky |
| United States | Saints Mary and Elizabeth Hospital | Louisville | Kentucky |
| United States | UofL Health Medical Center Northeast | Louisville | Kentucky |
| United States | Banner McKee Medical Center | Loveland | Colorado |
| United States | Illinois CancerCare-Macomb | Macomb | Illinois |
| United States | University of Wisconsin Carbone Cancer Center - University Hospital | Madison | Wisconsin |
| United States | Aurora Bay Area Medical Group-Marinette | Marinette | Wisconsin |
| United States | Marshfield Medical Center-Marshfield | Marshfield | Wisconsin |
| United States | WVUH-Berkely Medical Center | Martinsburg | West Virginia |
| United States | Carle Physician Group-Mattoon/Charleston | Mattoon | Illinois |
| United States | Saint Jude Children's Research Hospital | Memphis | Tennessee |
| United States | Idaho Urologic Institute-Meridian | Meridian | Idaho |
| United States | Saint Luke's Cancer Institute - Meridian | Meridian | Idaho |
| United States | Aurora Cancer Care-Milwaukee | Milwaukee | Wisconsin |
| United States | Aurora Saint Luke's Medical Center | Milwaukee | Wisconsin |
| United States | Aurora Sinai Medical Center | Milwaukee | Wisconsin |
| United States | Medical College of Wisconsin | Milwaukee | Wisconsin |
| United States | Marshfield Clinic-Minocqua Center | Minocqua | Wisconsin |
| United States | Community Medical Center | Missoula | Montana |
| United States | Saint Patrick Hospital - Community Hospital | Missoula | Montana |
| United States | Kaiser Permanente-Modesto | Modesto | California |
| United States | West Virginia University Healthcare | Morgantown | West Virginia |
| United States | Morristown Medical Center | Morristown | New Jersey |
| United States | Good Samaritan Regional Health Center | Mount Vernon | Illinois |
| United States | Intermountain Medical Center | Murray | Utah |
| United States | Saint Alphonsus Cancer Care Center-Nampa | Nampa | Idaho |
| United States | Saint Luke's Cancer Institute - Nampa | Nampa | Idaho |
| United States | The Children's Hospital at TriStar Centennial | Nashville | Tennessee |
| United States | Vanderbilt University/Ingram Cancer Center | Nashville | Tennessee |
| United States | Rutgers Cancer Institute of New Jersey | New Brunswick | New Jersey |
| United States | Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital | New Brunswick | New Jersey |
| United States | Laura and Isaac Perlmutter Cancer Center at NYU Langone | New York | New York |
| United States | Memorial Sloan Kettering Cancer Center | New York | New York |
| United States | Mount Sinai Hospital | New York | New York |
| United States | NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center | New York | New York |
| United States | NYP/Weill Cornell Medical Center | New York | New York |
| United States | Providence Newberg Medical Center | Newberg | Oregon |
| United States | Chancellor Center for Oncology | Newburgh | Indiana |
| United States | Children's Hospital of The King's Daughters | Norfolk | Virginia |
| United States | Cancer Care Center of O'Fallon | O'Fallon | Illinois |
| United States | Kaiser Permanente Oakland-Broadway | Oakland | California |
| United States | Kaiser Permanente-Oakland | Oakland | California |
| United States | McKay-Dee Hospital Center | Ogden | Utah |
| United States | Mercy Hospital Oklahoma City | Oklahoma City | Oklahoma |
| United States | University of Oklahoma Health Sciences Center | Oklahoma City | Oklahoma |
| United States | Alegent Health Bergan Mercy Medical Center | Omaha | Nebraska |
| United States | Alegent Health Immanuel Medical Center | Omaha | Nebraska |
| United States | Alegent Health Lakeside Hospital | Omaha | Nebraska |
| United States | Creighton University Medical Center | Omaha | Nebraska |
| United States | Hematology and Oncology Consultants PC | Omaha | Nebraska |
| United States | Saint Alphonsus Cancer Care Center-Ontario | Ontario | Oregon |
| United States | Memorial GYN Plus | Ooltewah | Tennessee |
| United States | Children's Hospital of Orange County | Orange | California |
| United States | Providence Willamette Falls Medical Center | Oregon City | Oregon |
| United States | Vince Lombardi Cancer Clinic - Oshkosh | Oshkosh | Wisconsin |
| United States | Illinois CancerCare-Ottawa Clinic | Ottawa | Illinois |
| United States | Mercy Health - Paducah Medical Oncology and Hematology | Paducah | Kentucky |
| United States | Hope Cancer Care of Nevada-Pahrump | Pahrump | Nevada |
| United States | Stanford Cancer Institute Palo Alto | Palo Alto | California |
| United States | Midlands Community Hospital | Papillion | Nebraska |
| United States | Essentia Health - Park Rapids | Park Rapids | Minnesota |
| United States | Parker Adventist Hospital | Parker | Colorado |
| United States | Rocky Mountain Cancer Centers-Parker | Parker | Colorado |
| United States | Camden Clark Medical Center | Parkersburg | West Virginia |
| United States | Illinois CancerCare-Pekin | Pekin | Illinois |
| United States | Illinois CancerCare-Peoria | Peoria | Illinois |
| United States | Methodist Medical Center of Illinois | Peoria | Illinois |
| United States | Illinois CancerCare-Peru | Peru | Illinois |
| United States | Valley Radiation Oncology | Peru | Illinois |
| United States | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania |
| United States | Fox Chase Cancer Center | Philadelphia | Pennsylvania |
| United States | University of Pennsylvania/Abramson Cancer Center | Philadelphia | Pennsylvania |
| United States | Cancer Center at Saint Joseph's | Phoenix | Arizona |
| United States | Huron Medical Center PC | Port Huron | Michigan |
| United States | Lake Huron Medical Center | Port Huron | Michigan |
| United States | Jefferson Healthcare | Port Townsend | Washington |
| United States | Providence Portland Medical Center | Portland | Oregon |
| United States | Providence Saint Vincent Medical Center | Portland | Oregon |
| United States | Kootenai Clinic Cancer Services - Post Falls | Post Falls | Idaho |
| United States | Harrison HealthPartners Hematology and Oncology-Poulsbo | Poulsbo | Washington |
| United States | Illinois CancerCare-Princeton | Princeton | Illinois |
| United States | Rocky Mountain Cancer Centers - Pueblo | Pueblo | Colorado |
| United States | MultiCare Good Samaritan Hospital | Puyallup | Washington |
| United States | Aurora Cancer Care-Racine | Racine | Wisconsin |
| United States | Kaiser Permanente-Rancho Cordova Cancer Center | Rancho Cordova | California |
| United States | Saint Charles Health System-Redmond | Redmond | Oregon |
| United States | Kaiser Permanente-Redwood City | Redwood City | California |
| United States | Radiation Oncology Associates | Reno | Nevada |
| United States | Renown Regional Medical Center | Reno | Nevada |
| United States | Saint Mary's Regional Medical Center | Reno | Nevada |
| United States | Valley Medical Center | Renton | Washington |
| United States | Marshfield Medical Center-Rice Lake | Rice Lake | Wisconsin |
| United States | Kaiser Permanente-Richmond | Richmond | California |
| United States | Riverton Hospital | Riverton | Utah |
| United States | Mayo Clinic in Rochester | Rochester | Minnesota |
| United States | Rohnert Park Cancer Center | Rohnert Park | California |
| United States | Delbert Day Cancer Institute at PCRMC | Rolla | Missouri |
| United States | Mercy Clinic-Rolla-Cancer and Hematology | Rolla | Missouri |
| United States | Kaiser Permanente-Roseville | Roseville | California |
| United States | The Permanente Medical Group-Roseville Radiation Oncology | Roseville | California |
| United States | Kaiser Permanente - Sacramento | Sacramento | California |
| United States | Kaiser Permanente Downtown Commons | Sacramento | California |
| United States | Kaiser Permanente-South Sacramento | Sacramento | California |
| United States | South Sacramento Cancer Center | Sacramento | California |
| United States | Saint George Regional Medical Center | Saint George | Utah |
| United States | Heartland Regional Medical Center | Saint Joseph | Missouri |
| United States | Mercy Hospital Saint Louis | Saint Louis | Missouri |
| United States | Mercy Hospital South | Saint Louis | Missouri |
| United States | Missouri Baptist Medical Center | Saint Louis | Missouri |
| United States | Saint Louis Cancer and Breast Institute-South City | Saint Louis | Missouri |
| United States | Siteman Cancer Center at Christian Hospital | Saint Louis | Missouri |
| United States | Siteman Cancer Center-South County | Saint Louis | Missouri |
| United States | Washington University School of Medicine | Saint Louis | Missouri |
| United States | Siteman Cancer Center at Saint Peters Hospital | Saint Peters | Missouri |
| United States | Johns Hopkins All Children's Hospital | Saint Petersburg | Florida |
| United States | Sainte Genevieve County Memorial Hospital | Sainte Genevieve | Missouri |
| United States | LDS Hospital | Salt Lake City | Utah |
| United States | Utah Cancer Specialists-Salt Lake City | Salt Lake City | Utah |
| United States | Children's Hospital of San Antonio | San Antonio | Texas |
| United States | Kaiser Permanente-San Francisco | San Francisco | California |
| United States | UCSF Medical Center-Mission Bay | San Francisco | California |
| United States | Kaiser Permanente-Santa Teresa-San Jose | San Jose | California |
| United States | Kaiser Permanente San Leandro | San Leandro | California |
| United States | Pacific Central Coast Health Center-San Luis Obispo | San Luis Obispo | California |
| United States | Kaiser Permanente-San Rafael | San Rafael | California |
| United States | Kaiser San Rafael-Gallinas | San Rafael | California |
| United States | Kootenai Clinic Cancer Services - Sandpoint | Sandpoint | Idaho |
| United States | Essentia Health Sandstone | Sandstone | Minnesota |
| United States | Kaiser Permanente Medical Center - Santa Clara | Santa Clara | California |
| United States | Mission Hope Medical Oncology - Santa Maria | Santa Maria | California |
| United States | Kaiser Permanente-Santa Rosa | Santa Rosa | California |
| United States | Kaiser Permanente Washington | Seattle | Washington |
| United States | Pacific Gynecology Specialists | Seattle | Washington |
| United States | Seattle Children's Hospital | Seattle | Washington |
| United States | Swedish Medical Center-Ballard Campus | Seattle | Washington |
| United States | Swedish Medical Center-Cherry Hill | Seattle | Washington |
| United States | Swedish Medical Center-First Hill | Seattle | Washington |
| United States | PeaceHealth United General Medical Center | Sedro-Woolley | Washington |
| United States | Prisma Health Cancer Institute - Seneca | Seneca | South Carolina |
| United States | Vince Lombardi Cancer Clinic-Sheboygan | Sheboygan | Wisconsin |
| United States | Providence Regional Cancer System-Shelton | Shelton | Washington |
| United States | Jewish Hospital Medical Center South | Shepherdsville | Kentucky |
| United States | Welch Cancer Center | Sheridan | Wyoming |
| United States | Saint Michael Cancer Center | Silverdale | Washington |
| United States | Kaiser Permanente Cancer Treatment Center | South San Francisco | California |
| United States | Kaiser Permanente-South San Francisco | South San Francisco | California |
| United States | MultiCare Deaconess Cancer and Blood Specialty Center - Downtown | Spokane | Washington |
| United States | MultiCare Deaconess Cancer and Blood Specialty Center - North | Spokane | Washington |
| United States | Providence Sacred Heart Medical Center and Children's Hospital | Spokane | Washington |
| United States | MultiCare Deaconess Cancer and Blood Specialty Center - Valley | Spokane Valley | Washington |
| United States | CoxHealth South Hospital | Springfield | Missouri |
| United States | Memorial Medical Center | Springfield | Illinois |
| United States | Mercy Hospital Springfield | Springfield | Missouri |
| United States | Southern Illinois University School of Medicine | Springfield | Illinois |
| United States | Springfield Clinic | Springfield | Illinois |
| United States | Marshfield Medical Center-River Region at Stevens Point | Stevens Point | Wisconsin |
| United States | Kaiser Permanente-Stockton | Stockton | California |
| United States | Stony Brook University Medical Center | Stony Brook | New York |
| United States | Missouri Baptist Sullivan Hospital | Sullivan | Missouri |
| United States | Aurora Medical Center in Summit | Summit | Wisconsin |
| United States | BJC Outpatient Center at Sunset Hills | Sunset Hills | Missouri |
| United States | Southwest Illinois Health Services LLP | Swansea | Illinois |
| United States | State University of New York Upstate Medical University | Syracuse | New York |
| United States | Franciscan Research Center-Northwest Medical Plaza | Tacoma | Washington |
| United States | Madigan Army Medical Center | Tacoma | Washington |
| United States | Mary Bridge Children's Hospital and Health Center | Tacoma | Washington |
| United States | MultiCare Tacoma General Hospital | Tacoma | Washington |
| United States | Northwest Medical Specialties PLLC | Tacoma | Washington |
| United States | Saint Joseph's Hospital/Children's Hospital-Tampa | Tampa | Florida |
| United States | Tampa General Hospital | Tampa | Florida |
| United States | National Jewish Health-Northern Hematology Oncology | Thornton | Colorado |
| United States | Rocky Mountain Cancer Centers-Thornton | Thornton | Colorado |
| United States | Oklahoma Cancer Specialists and Research Institute-Tulsa | Tulsa | Oklahoma |
| United States | Saint Luke's Cancer Institute - Twin Falls | Twin Falls | Idaho |
| United States | Vince Lombardi Cancer Clinic-Two Rivers | Two Rivers | Wisconsin |
| United States | Carle Cancer Center | Urbana | Illinois |
| United States | The Carle Foundation Hospital | Urbana | Illinois |
| United States | Kaiser Permanente Medical Center-Vacaville | Vacaville | California |
| United States | Kaiser Permanente-Vallejo | Vallejo | California |
| United States | PeaceHealth Southwest Medical Center | Vancouver | Washington |
| United States | Essentia Health Virginia Clinic | Virginia | Minnesota |
| United States | Providence Saint Mary Regional Cancer Center | Walla Walla | Washington |
| United States | Kaiser Permanente-Walnut Creek | Walnut Creek | California |
| United States | Children's National Medical Center | Washington | District of Columbia |
| United States | Illinois CancerCare - Washington | Washington | Illinois |
| United States | Mercy Hospital Washington | Washington | Missouri |
| United States | Marshfield Clinic-Wausau Center | Wausau | Wisconsin |
| United States | Aurora Cancer Care-Milwaukee West | Wauwatosa | Wisconsin |
| United States | Aurora West Allis Medical Center | West Allis | Wisconsin |
| United States | Mercy Medical Center-West Lakes | West Des Moines | Iowa |
| United States | Marshfield Medical Center - Weston | Weston | Wisconsin |
| United States | SCL Health Lutheran Medical Center | Wheat Ridge | Colorado |
| United States | Marshfield Clinic - Wisconsin Rapids Center | Wisconsin Rapids | Wisconsin |
| United States | North Star Lodge Cancer Center at Yakima Valley Memorial Hospital | Yakima | Washington |
| United States | Providence Regional Cancer System-Yelm | Yelm | Washington |
| United States | Rush-Copley Healthcare Center | Yorkville | Illinois |
| Lead Sponsor | Collaborator |
|---|---|
| National Cancer Institute (NCI) |
United States,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Change in the percentage of activated T cells and natural killer cells (Phase I and II) | These quantities of interest will be calculated for each patient and the Wilcoxon signed-rank test will be used to test for significant difference between the time points. Using Wilcoxon rank sum test (two-sided type I error of 0.1), differences between those who progress or die within one year versus (vs.) those who are event-free at one year will be evaluated. | Baseline (Time 1) to 9 weeks (Time 3, time of first re-staging) | |
| Other | Change in the percentages of activated T cells and natural killer cells (Phase I and II) | These quantities of interest will be calculated for each patient and the Wilcoxon signed-rank test will be used to test for significant difference between the time points. Using the Wilcoxon rank sum test (two-sided type I error of 0.1), differences between those who progress or die within one year vs. those who are event-free at one year will be evaluated. | Day 1 of cycle 2 (Time 2) or 9 weeks (Time 3) to up to 6 weeks after completion of study treatment (Time 4, end of study) | |
| Other | Effects of combinations on systemic immunity (Phase I and II) | Baseline to up to 6 weeks after completion of study treatment | ||
| Other | Pre- and post-treatment levels of cytokines and T cell specific biomarkers (Phase I and II) | Pre- and post-treatment levels of these markers will be compared using the Wilcoxon signed-rank test with two-sided type I error of 0.1. Marker levels between patients who fail at 1-year vs. patients who are event-free at 1-year will be evaluated. Given limited data, the analyses of PD-1, co-expression of Tim-3 with PD-1, ICOS, sCD30, galectin-1 and the peripheral blood absolute lymphocyte to monocyte ratio will be mainly exploratory and will be summarized descriptively at the time-points described above. The association with PFS will be explored. | Baseline to up to 6 weeks after completion of study treatment | |
| Other | Differentially expressed genes between two groups (patients who fail at 1-year vs. patients who are event-free at 1-year or responders vs. non-responders) (Phase I and II) | Assessed using gene expression profiling (GEP). Differentially expressed genes will be identified using a rank-based method developed by Dr. Hong (RankProd, R package, Bioconductor Project) with multiple comparison adjustment using a false discovery rate approach. A two-way unsupervised hierarchical clustering analysis will be applied to both the genes and the samples to illustrate whether GEP can separate two groups or is associated with other clinical factors. The genes ranked as most significant will be assessed by gene ontology and pathway analysis for their potential functions in lymphoma biology and treatment failure. | 1 year | |
| Other | Microbiome analysis (Phase I and II) | Will compare the gut microbiome between Hodgkin lymphoma (HL) patients and healthy controls with respect to global diversity, taxonomic abundance, and bacterial functional pathways. The relative abundance of each taxon (phyla to genera) and functional pathways among different groups will be statistically compared in univariate analysis using t-test (or Wilcoxon test) and in multivariate analysis using logistic regression. Global diversity tests and multivariate analysis for taxonomic abundance and functional pathways will be adjusted for potential confounders (age, gender, race, and body mass index) in the comparisons of HL patients and controls, and further adjusted for stage and grade when examining the clinical response among HL patients. | Completion of study treatment | |
| Other | Absolute maximum standard uptake value (SUVmax) (Phase II) | Image data will be evaluated using Lugano response criteria with various D 5PS cut-offs in the entire cohort and in different therapy cohorts to determine if the existing set of criteria is sufficient to segregate the group into various response categories. Will correlate PFS, event free survival (EFS), OS 5PS in two reading settings (1-3 [negative] vs 4-5 [positive] and D 5PS 1-4 [negative] vs 5 [positive]) (Kaplan-Meier [KM] curve and log-rank testing). | Up to cycle 10 | |
| Other | Metabolic whole body tumor volume (MTV) and tumor lesion glycolysis (TLG) | Image data will be evaluated using Lugano response criteria with various D 5PS cut-offs in the entire cohort and in different therapy cohorts to determine if the existing set of criteria is sufficient to segregate the group into various response categories. Will correlate PFS, EFS, OS 5PS in two reading settings (1-3 [negative] vs 4-5 [positive] and D 5PS 1-4 [negative] vs 5 [positive]) (KM curve and log-rank testing). | Up to cycle 10 | |
| Other | Percent change in SUVmax, MTV and TLG between baseline and during therapy | Image data will be evaluated using Lugano response criteria with various D 5PS cut-offs in the entire cohort and in different therapy cohorts to determine if the existing set of criteria is sufficient to segregate the group into various response categories. Will correlate PFS, EFS, OS 5PS in two reading settings (1-3 [negative] vs 4-5 [positive] and D 5PS 1-4 [negative] vs 5 [positive]) (KM curve and log-rank testing). | Baseline up to cycle 10 | |
| Other | Percent change in size (sum of perpendicular diameters [SPD]) on computed tomography (CT) | Image data will be evaluated using Lugano response criteria with various D 5PS cut-offs in the entire cohort and in different therapy cohorts to determine if the existing set of criteria is sufficient to segregate the group into various response categories. Will correlate PFS, EFS, OS 5PS in two reading settings (1-3 [negative] vs 4-5 [positive] and D 5PS 1-4 [negative] vs 5 [positive]) (KM curve and log-rank testing). | Baseline up to cycle 10 | |
| Other | Absolute CT tumor volumes | Image data will be evaluated using Lugano response criteria with various D 5PS cut-offs in the entire cohort and in different therapy cohorts to determine if the existing set of criteria is sufficient to segregate the group into various response categories. Will correlate PFS, EFS, OS 5PS in two reading settings (1-3 [negative] vs 4-5 [positive] and D 5PS 1-4 [negative] vs 5 [positive]) (KM curve and log-rank testing). | Up to cycle 10 | |
| Other | Percent change in CT size (SPD) and in CT tumor volume between baseline and during therapy | Image data will be evaluated using Lugano response criteria with various D 5PS cut-offs in the entire cohort and in different therapy cohorts to determine if the existing set of criteria is sufficient to segregate the group into various response categories. Will correlate PFS, EFS, OS 5PS in two reading settings (1-3 [negative] vs 4-5 [positive] and D 5PS 1-4 [negative] vs 5 [positive]) (KM curve and log-rank testing). | Baseline up to cycle 10 | |
| Primary | Maximum tolerated dose (MTD) of each combination (Phase I) | MTD defined as the highest dose level at which less than 33% of 6 patients experience a dose limiting toxicity, will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Upon completion of the trial, frequency of subjects experiencing toxicities will be tabulated. Toxicities will be assessed and graded according to CTCAE version 4.0 terminology. Exact 95% confidence intervals (CI) around the toxicity proportions will be calculated. | 21 days | |
| Primary | CR rate (Phase II) | The analysis of CR between two arms will be performed using exact Cochran-Mantel-Haenszel (CMH) test stratifying on prior brentuximab vedotin (BV) (yes versus [vs.] no) and age (< 18 vs. >= 18). Multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. | Up to 10 years | |
| Secondary | Complete response (CR) rate (Phase I) | Assessed using the Revised Response Criteria for Malignant Lymphoma and reported along with the 95% CI. | Up to 3 years | |
| Secondary | Partial response (PR) rate (Phase I) | Assessed using the Revised Response Criteria for Malignant Lymphoma and reported along with the 95% CI. | Up to 3 years | |
| Secondary | Overall response rate (ORR) rate (Phase I) | Assessed using the Revised Response Criteria for Malignant Lymphoma and reported along with the 95% CI. | Up to 3 years | |
| Secondary | Duration of response (DOR) (Phase I) | DOR will be estimated using Kaplan-Meier methodology. Greenwood's formula will be used to calculate 95% CI for the Kaplan-Meier estimates. Descriptive statistics will be used to evaluate the DOR achieved with the protocol therapy and with the most recent prior systemic therapy. | From the documented beginning of response up to 3 years | |
| Secondary | Overall survival (OS) (Phase I) | OS will be estimated using Kaplan-Meier methodology. Greenwood's formula will be used to calculate 95% CI for the Kaplan-Meier estimates. | From the date of study entry up to 3 years | |
| Secondary | Progression-free survival (PFS) (Phase I) | PFS will be estimated using Kaplan-Meier methodology. Greenwood's formula will be used to calculate 95% CI for the Kaplan-Meier estimates. | From entry onto study up to 3 years | |
| Secondary | ORR (Phase II) | Assessed using Revised Response (Cheson) and Deauville criteria. The analysis of ORR between two arms will be performed using the CMH test stratifying on prior BV (yes vs. no) and age (< 18 vs. >= 18). Multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. | Up to 10 years | |
| Secondary | PFS (or modified PFS) (Phase II) | PFS will be estimated using Kaplan-Meier methodology and compared between arms using stratified log-rank test. Greenwood's formula will be used to calculate 95% confidence intervals for the Kaplan-Meier estimates. Cox proportional regression model will be used to estimate hazard ratios (95% CI) and assess the relationship between other prognostic factors with time-to-event outcome. Point estimates of all endpoints will be accompanied by the corresponding 95% confidence intervals. | From randomization up to 10 years | |
| Secondary | OS (Phase II) | OS will be estimated using Kaplan-Meier methodology and compared between arms using stratified log-rank test. Greenwood's formula will be used to calculate 95% confidence intervals for the Kaplan-Meier estimates. Cox proportional regression model will be used to estimate hazard ratios (95% CI) and assess the relationship between other prognostic factors with time-to-event outcome. Point estimates of all endpoints will be accompanied by the corresponding 95% confidence intervals. | From randomization up to 10 years | |
| Secondary | DOR (Phase II) | DOR, will be estimated using Kaplan-Meier methodology and compared between arms using stratified log-rank test. Greenwood's formula will be used to calculate 95% confidence intervals for the Kaplan-Meier estimates. Cox proportional regression model will be used to estimate hazard ratios (95% CI) and assess the relationship between other prognostic factors with time-to-event outcome. Point estimates of all endpoints will be accompanied by the corresponding 90% confidence intervals. The DOR achieved with the most recent prior systemic therapy will be collected on the case report forms, and descriptive statistics will be used to evaluate the DOR achieved with the protocol therapy and with the most recent prior systemic therapy. | From the documented beginning of response up to 10 years |
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