Testing the Combination of Pevonedistat with Chemotherapy for Bile Duct Cancer of the Liver
Inclusion Criteria
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Patient must have a life expectancy >= 12 weeks
- Patient must have histologically confirmed intrahepatic cholangiocarcinoma or biphasic hepatocellular carcinoma and cholangiocarcinoma that is metastatic or unresectable and who have progressed on or been intolerant of one prior line of systemic gemcitabine containing chemotherapy regimen. * NOTE: Prior immunotherapy or targeted therapies are allowed and will not be considered a line of therapy unless administered with cytotoxic chemotherapy
- Patient must have measurable disease. For patients who have received localized therapy (embolization, chemoembolization, radiofrequency ablation or radiation) are eligible if measurable disease is not within the treatment field or the treated disease has clearly progressed since last localized therapy
- Leukocytes >= 3,000/mcL (obtained within 14 days prior to randomization)
- Absolute neutrophil count >= 1,500/mcL (obtained within 14 days prior to randomization)
- Platelets >= 100,000/mcL (obtained within 14 days prior to randomization)
- Total bilirubin =< institutional upper limit of normal (ULN) except in patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome may enroll if direct bilirubin =< 1.5 x ULN of the direct bilirubin (obtained within 14 days prior to randomization)
- Hemoglobin >= 9 g/dL (obtained within 14 days prior to randomization)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained within 14 days prior to randomization)
- Creatinine =< institutional ULN, OR glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 (obtained within 14 days prior to randomization)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Known HIV positive patients who meet the following criteria will be considered eligible: * CD4 count >= 350 cells/mm^3 * Undetectable viral load * Maintained on modern therapeutic regimens utilizing non-CYP interactive agents (i.e. excluding ritonavir) * No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- Patients who received prior platinum or taxane chemotherapy are eligible
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. In addition, patients with any of the known cardiopulmonary disease, defined as follows, would be ineligible for this trial: * Unstable angina * Congestive heart failure (New York Heart Association [NYHA] class III or IV;); * Myocardial infarction within 6 months prior to randomization (patients who had ischemic heart disease such as acute coronary syndrome [ACS], myocardial infarction, and/or revascularization greater than 6 months before randomization and who are without cardiac symptoms may enroll) * Symptomatic cardiomyopathy * Clinically symptomatic pulmonary hypertension requiring pharmacologic therapy * Clinically significant arrhythmia, defined as: ** History of polymorphic ventricular fibrillation or torsade de pointes, ** Permanent atrial fibrillation, defined as continuous atrial fibrillation for >= 6 months, ** Persistent atrial fibrillation, defined as sustained atrial fibrillation lasting > 7 days and/or requiring cardioversion in the 4 weeks before randomization, ** Grade 3 atrial fibrillation defined as symptomatic and incompletely controlled medically, or controlled with device (e.g., pacemaker), or ablation ** Patients with paroxysmal atrial fibrillation or grade < 3 atrial fibrillation for period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen
- Patients must have the ability to understand and the willingness to sign a written informed consent document
- Participants with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible
Exclusion Criteria
- Patients must not have had major surgery within 14 days before randomization. Patients with surgery planned during study period are ineligible
- Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and until at least 4 months after the last dose of study treatment. All females of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
- Women of childbearing potential and sexually active males must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and continue for at least 4 months after the last dose of protocol treatment
- Male patients must not donate sperm during the course of this study or within 4 months after receiving their last dose of protocol treatment
- Female patients must not donate eggs (ova) during the course of this study or within 4 months after receiving their last dose of protocol treatment
- Patient must not have a prolonged rate corrected QT (QTc) interval >= 480 msec calculated according to institutional guideline
- Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e. have residual toxicities > grade 1) are ineligible with the exception of alopecia
- Patients with persistent >= grade 2 diarrhea lasting more than 3 days within 14 weeks of randomization are ineligible
- Patients with known central nervous system (CNS) involvement are ineligible
- Patients must not be receiving any other investigational agents
- Patients must not have received chemotherapy or radiotherapy within 2 weeks prior to randomization. Prior treatment with radiation therapy involving >= 25% of hematopoietically active bone marrow will be ineligible
- Patients must not have received immunotherapy within 8 weeks prior to randomization
- Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to pevonedistat, carboplatin, or paclitaxel
- Patient must not be receiving any treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of the study drug as below. Clinically significant metabolic enzyme inducers are not permitted during the study. Patients must not be receiving any medications or substances that are strong inducers of CYP3A4/5 (i.e. phenytoin, rifampin, St. Johns wort) or inhibitors of breast cancer resistance protein (BCRP) (i.e. cyclosporine). Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if a new medication need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. Inhibitors of CYP3A4/5 are allowed
- Patients must not have uncontrolled intercurrent illness
- Patients must not have uncontrolled coagulopathy or bleeding disorder
- Patients must not have active, uncontrolled infection or severe infectious disease such as severe pneumonia, meningitis, or septicemia
- Patients with known moderate chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis are ineligible
- Patients must not have psychiatric illness/social situations that would limit compliance with study requirements
- Participants must not have had prior pevonedistat treatment
Alaska
Anchorage
Arizona
Kingman
Phoenix
Arkansas
Hot Springs
California
Arroyo Grande
Auburn
Berkeley
Burbank
Cameron Park
Castro Valley
Davis
Duarte
Fremont
Modesto
Mountain View
Palo Alto
Roseville
Sacramento
San Francisco
San Mateo
Santa Cruz
Santa Maria
Santa Rosa
Sunnyvale
Vacaville
Vallejo
Colorado
Colorado Springs
Denver
Durango
Fort Collins
Greeley
Lakewood
Littleton
Longmont
Loveland
Parker
Pueblo
Florida
Fort Lauderdale
Miami
Plantation
Hawaii
Aiea
Honolulu
Lihue
Idaho
Boise
Caldwell
Coeur D'Alene
Emmett
Fruitland
Meridian
Nampa
Post Falls
Sandpoint
Twin Falls
Illinois
Chicago
Lake Forest
Indiana
Indianapolis
Mooresville
Richmond
Terre Haute
Iowa
Ames
Boone
Clive
Council Bluffs
Creston
Des Moines
Fort Dodge
Jefferson
Marshalltown
West Des Moines
Kansas
Fairway
Hays
Kansas City
Lawrence
Olathe
Overland Park
Pittsburg
Salina
Topeka
Westwood
Kentucky
Bardstown
Corbin
Lexington
London
Louisville
Shepherdsville
Maine
Brewer
Massachusetts
Springfield
Worcester
Michigan
Ann Arbor
Battle Creek
Bay City
Brighton
Canton
Caro
Chelsea
Clarkston
Detroit
East China
Farmington Hills
Flint
Grand Rapids
Grosse Pointe Woods
Kalamazoo
Lansing
Lapeer
Livonia
Macomb Township
Marlette
Mount Clemens
Mount Pleasant
Muskegon
Niles
Norton Shores
Petoskey
Pontiac
Port Huron
Reed City
Rochester Hills
Saginaw
Saint Joseph
Sterling Heights
Tawas City
Traverse City
Warren
West Branch
Wyoming
Ypsilanti
Minnesota
Burnsville
Cambridge
Coon Rapids
Edina
Fridley
Maple Grove
Maplewood
Minneapolis
Monticello
New Ulm
Princeton
Robbinsdale
Saint Louis Park
Saint Paul
Shakopee
Stillwater
Waconia
Willmar
Woodbury
Wyoming
Missouri
Kansas City
Lee's Summit
North Kansas City
Montana
Anaconda
Billings
Bozeman
Great Falls
Kalispell
Missoula
Nebraska
Grand Island
Kearney
Lincoln
Omaha
Papillion
Nevada
Carson City
Henderson
Las Vegas
Pahrump
Reno
New Hampshire
Lebanon
New Jersey
Teaneck
New York
Buffalo
Rochester
North Carolina
Chapel Hill
Greenville
Hillsborough
Ohio
Beavercreek
Boardman
Centerville
Cincinnati
Cleveland
Dayton
Findlay
Franklin
Greenville
Kettering
Mansfield
Mayfield Heights
Sandusky
Strongsville
Troy
Warren
Warrensville Heights
Wooster
Youngstown
Oklahoma
Lawton
Oklahoma City
Oregon
Baker City
Bend
Clackamas
Coos Bay
Newberg
Ontario
Portland
Redmond
Pennsylvania
Allentown
Bethlehem
East Stroudsburg
Hazleton
Philadelphia
Pittsburgh
South Carolina
Boiling Springs
Easley
Greenville
Greer
Seneca
South Dakota
Sioux Falls
Tennessee
Bristol
Franklin
Kingsport
Nashville
Texas
Bryan
Dallas
Fort Worth
Richardson
Virginia
Bristol
Martinsville
Norton
Washington
Aberdeen
Bellevue
Bellingham
Bremerton
Burien
Centralia
Edmonds
Enumclaw
Everett
Federal Way
Issaquah
Kennewick
Lacey
Lakewood
Longview
Poulsbo
Renton
Seattle
Sedro-Woolley
Shelton
Tacoma
Vancouver
Walla Walla
Yelm
Wisconsin
Madison
Menomonee Falls
Milwaukee
New Richmond
West Bend
Wyoming
Cody
Sheridan
PRIMARY OBJECTIVE:
I. To determine the objective response rate of pevonedistat as a single agent and in combination with carboplatin and paclitaxel in patients with unresectable intrahepatic cholangiocarcinoma.
SECONDARY OBJECTIVES:
I. To evaluate the safety profile of pevonedistat alone and in combination with carboplatin and paclitaxel in patients with intrahepatic cholangiocarcinoma.
II. To determine the clinical benefit rate of patients with advanced intrahepatic cholangiocarcinoma (ICC) treated with pevonedistat monotherapy and in combination with carboplatin and paclitaxel.
III. To determine progression-free survival of patients treated with pevonedistat monotherapy and in combination with carboplatin and paclitaxel.
IV. To determine overall survival of patients treated with pevonedistat monotherapy and in combination with carboplatin and paclitaxel.
EXPLORATORY OBJECTIVES:
I. To determine whether overexpression of NEDD8, NAE1, and UBC12 predict response to treatment.
II. To identify the mutation profile of those cholangiocarcinomas with overexpression of the neddylation pathway.
III. To bank specimens for further future investigations.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive pevonedistat intravenously (IV) over 60 minutes on days 1, 3, and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive pevonedistat IV over 1 hour on days 1, 3, and 5, paclitaxel IV over 3 hours on day 1, and carboplatin IV over 15-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Starting cycle 5, patients may receive pevonedistat monotherapy at the discretion of treating physician.
After completion of study treatment, patients are followed up at 30 days after last dose of study treatment, then every 3 months for the first year and every 6 months for years 2-3.
Trial Phase Phase II
Trial Type Treatment
Lead Organization
ECOG-ACRIN Cancer Research Group
Principal Investigator
Dustin Alan Deming
- Primary ID EA2187
- Secondary IDs NCI-2019-07769
- Clinicaltrials.gov ID NCT04175912