Hepatic Artery Infusion of Carfilzomib in Participants With Liver Metastatic Disease Previously Treated With Hepatic Artery Infusion Pump Therapy

Background:

• Targeting protein homeostasis with proteasome inhibitors has demonstrated excellent efficacy across multiple pre-clinical cancer models, although translation to patients with solid tumors has consistently failed to yield meaningful responses secondary to new protein synthesis rebound associated with intermittent dosing.
• Implantable pumps for outpatient continuous infusion were developed and culminated in a commercialized product in 1980, though the only drug used to date is floxuridine.
• Carfilzomib (CFZ), a second-generation irreversible 20S core particle proteasome inhibitor, can be delivered by the hepatic artery infusion pump to diminish extra-hepatic systemic clearance and feasibly direct a larger percentage of the total dose to the desired tissues at continuous concentrations.

Objective:

-To establish the safety of hepatic artery infusion (HAI) of carfilzomib (CFZ) in participants with liver metastatic disease who were previously treated with HAI pump therapy

Eligibility:

• Participants with colorectal cancer (CRC), intrahepatic cholangiocarcinoma (ICC), or adrenocortical carcinoma (ACC) with liver metastatic disease not amenable to resection
• Participants must have been treated with HAI floxuridine and already have a surgically inserted HAI pump in place
• Age >= 18 years
• Adequate organ function

Design:

• Open-label, single-center, non-randomized Phase I study
• Treatment with HAI infusion of CFZ will be delivered in cycles of 28 days for up to 6 cycles.

• INCLUSION CRITERIA:
• Participants must have a histologically or cytologically confirmed by pathology report diagnosis of colorectal cancer (CRC), intrahepatic cholangiocarcinoma (ICC), or adrenocortical carcinoma (ACC).
• Participants must have measurable liver-dominant metastatic disease. Note: liver-dominant metastatic disease is defined as >=75% of metastatic disease present in the liver as assessed by the principal investigator.
• Extrahepatic disease should be treated with anticancer therapy, if applicable, and should be stable by RECIST criteria for at least 6 weeks prior to study treatment initiation.
• Participants must have previously undergone hepatic artery infusion pump therapy and have a functioning hepatic artery infusion pump in place.
• Participants must have progressed on, been intolerant of, or have residual disease after HAI floxuridine and appropriate current standard-of-care treatment.
• Age >= 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status <= 2.
• Participants must have an adequate organ and marrow function as defined below:

Leukocytes > 3,000/mcL

Hemoglobin >= 9 mg/dL

Absolute neutrophil count > 1,500/mcL

Platelets > 100,000/mcL

Total bilirubin < 2 X institutional upper limit of normal (ULN)

Aspartate aminotransferase (AST) < 2.5 X institutional (ULN)

Alanine aminotransferase (ALT) < 2.5 X institutional (ULN)

Creatinine <2 X institutional (ULN)

• Participants positive for human immunodeficiency virus (HIV) 1/2 antibody must have a negative HIV viral load.
• Participants positive for Hepatitis C (HCV) antibody must have a negative HCV viral load.
• Participants positive for Hepatitis B (HBV) core antibody (HBcAb) must have a negative HBV viral load. Note: Participants positive for Hepatitis B surface antigen (HBsAg) are excluded.
• Women of childbearing potential (WOCBP) must agree to use effective contraception (barrier, hormonal, intrauterine device, abstinence, surgical sterilization) at the study entry and up to 6 months after the last dose of the study drug. A participant may request a male partner to use an effective form of contraception to fulfill this requirement (e.g., condom/barrier).

Men must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 3 months after the last dose of the study drug. A participant may request a female partner to use an effective form of contraception to fulfill this requirement (e.g., intrauterine device, hormonal contraceptives). Men must not freeze or donate sperm within the same period.

• Women who are breastfeeding or plan to breastfeed must agree to discontinue/postpone breastfeeding from study treatment initiation through 2 weeks after the last dose of the study drug.
• Ability of participant to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• Participants with liver metastases amenable to resection.
• Participants who received floxuridine within 6 weeks prior to the study treatment initiation.
• Participants who received any anticancer therapy within 2 weeks prior to the study treatment initiation.
• Participants who received any investigational agents within 4 weeks prior to the study treatment initiation.
• Participants with incontrovertible radiographic evidence of disease progression per the RECIST definition outside of the liver within 3 months prior to the study treatment initiation. Note: Pulmonary lesions less than 1 cm are allowed.
• Prior radiation to the liver (Yttrium-90 [Y-90] or External Beam Radiation Therapy [EBRT]).
• History of allergic reactions attributed to compounds of similar chemical composition to CFZ.
• Positive serum or urine Beta-human chorionic gonadotropin (Beta-HCG) pregnancy test performed at screening.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, evaluated by medical history, electrocardiogram (EKG), physical exam, and laboratory testing, or social situations that would unacceptably increase risk for the participant or impair the ability to evaluate the endpoints of the study or that would limit compliance with study requirements.