Background: One way to treat liver cancer is to deliver chemotherapy drugs only to the liver (and not to the whole body). Researchers want to see if adding the drug PDS01ADC can improve the treatment. The drug triggers the immune system to fight cancer.\<TAB\> Objective: To see if treatment with HAIPs to deliver liver-directed FUDR and Dexamethasone chemotherapy in combination with PDS01ADC is effective for certain cancers. Eligibility: People aged 18 and older who have cancer of the bile ducts that is only in the liver, or colorectal cancer that has spread to the liver, or cancer of the adrenal glands that has spread to the liver, who are also receiving or planning to receive standard systemic chemotherapy for their disease. Design: Participants will be screened with: Medical history Physical exam Blood tests Pregnancy test (if needed) Tumor biopsy (if needed) Electrocardiogram Computed tomography (CT) scans Participants will have an abdominal operation. A catheter will be placed into an artery that feeds blood to the liver. The catheter will then be attached to the HAIP. The HAIP will lay under the skin on the left side of the abdomen. All participants will have liver-directed FUDR and Dexamethasone chemotherapy drugs or heparin with saline infused into the HAIP every 2 weeks. PDS01ADC will be injected under the skin every 4 weeks. They will receive this treatment until their cancer gets worse or they have bad side effects. Participants will also receive standard systemic chemotherapy for their disease, assigned based on diagnosis, through an IV by their medical oncologist (at NIH or by a local provider) every 2 weeks. Participants will have 2 study visits at NIH each month. They will have CT scans every 8 weeks. At visits, they will repeat some screening tests. Participants will have a follow-up visit 1 month after treatment ends. Then they will be contacted every 6 months for 5 years.
Background: Regional chemotherapy for hepatic malignancies takes advantage of the fact that tumors are perfused almost exclusively by the hepatic artery and, that the agent used (Floxuridine, FUDR) has a 95% first-pass metabolism by the liver. Early clinical trials performed during the 1970's and 1980's demonstrated impressive response rates that led to the adoption of hepatic artery infusion pump chemotherapy (HAIP) at select centers; however, little has changed in the ensuing decades with respect to regional therapy for the liver, although there has been continued and even renewed interest. Dose reductions of FUDR are common after several treatments, which has limited both the magnitude and duration of treatment responses in many cases. We posit that the logical and much-needed "next step" in regional therapy is to take advantage of the FUDR-induced tumor necrosis with an agent able to activate local tumor immunity for a synergistic effect. PDS01ADC is an immunocytokine composed of two IL-12 heterodimers, each fused to the H-chain of the NHS76 antibody. The NHS76 IgG1 antibody has affinity for both single- and double-stranded DNA (dsDNA), and targets regions of tumor necrosis where DNA has become exposed. PDS01ADC targets necrotic areas of the tumor and activates immune cells in the tumor microenvironment to induce a Th1 polarization of lymphocytes and the release of IFN-gamma. IFN-gamma in turn induces a host of immunomodulatory effects that contribute to robust antitumor responses that are localized within the tumor microenvironment, with no systemic distribution or exposure to IL-12. Data from a recent Phase I study demonstrate that subcutaneous administration of PDS01ADC is safe and a MTD has been determined. Moreover, preclinical models indicate that PDS01ADC synergizes with therapies able to effectively induce tumor necrosis, which may also minimize toxicity by limiting off-target exposure. Objective: -To determine the objective response rate (ORR) in participants with unresectable metastatic colorectal cancer (mCRC), intrahepatic cholangiocarcinoma (ICC), or adrenocortical carcinoma (ACC) with liver dominant disease treated with PDS01ADC in combination with HAIP in participants receiving systemic therapy Eligibility: * Histologically or cytologically confirmed, unresectable, colorectal adenocarcinoma metastatic to the liver (Cohort 1), intrahepatic cholangiocarcinoma (Cohort 2) or adrenocortical carcinoma with liver dominant disease (Cohort 3) * No evidence of extrahepatic metastases * Participants must have received first-line systemic chemotherapy. * Age \>= 18 years Design: -Open label, single center, non-randomized Phase II study
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
70
HAIP FUDR and Dexamethasone treatment on D1 of every cycle. Dexamethasone: (1 mg/day X pump volume / pump flow rate)
PDS01ADC will be administered by subcutaneous injection on Day 15 of every cycle. Cycle 1 at 12 mcg/kg; Cycle 2 reduced to 8 mcg/kg with the addition of systemic chemotherapy, to continue for further cycles. Note: any dose reduction in FUDR = 50% due to liver enzyme elevations means that the dose of PDS01ADC will be reduced to 4 mcg/kg.
Intera 3000 HAIP will be filled with mixture of Floxuridine and Dexamethasone in 25,000 units heparin/saline (Heparin + 0.9% Sodium Chloride) on Day 1; Days 1-14 of every cycle pump will perfuse drugs to liver. On Day 15 of each cycle, the pump will be emptied and filled with 30,000 units heparin/saline (Heparin + 0.9% Sodium Chloride); Days 15-28 of every cycle will perfuse heparin/saline to liver.
HAIP FUDR and Dexamethasone treatment on D1 of every cycle. Floxuridine: (0.12 mg/kg x ideal average body weight in kg X 30 mL \[pump volume\] / Pump Flow Rate)
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
RECRUITINGDetermine overall response rates
Simon optimal two-stage Phase II trial design will be used to determine overall response using RECIST criteria. The clinical response rate (CR+PR) will be determined and reported along with a 95% confidence interval, separately by cohort.
Time frame: baseline, every 8 weeks while on treatment, and 4-8 weeks following initial documentation of objective response; an additional scan is performed at Week 12.
Determine overall survival (OS)
CT will be used for response criteria. Overall survival (OS) probability will be determined using Kaplan-Meier estimates for all participants, separately by cohort; the median OS will be reported along with a 95% confidence interval.
Time frame: date of enrollment until death from any cause, or after 5 years off treatment
Determine extra-hepatic progression-free survival (PFS)
CT will be used for response criteria. Extra-hepatic progression-free survival (PFS) probability will be determined using Kaplan-Meier estimates for all participants, separately by cohort; the median PFS will be reported along with a 95% confidence interval.
Time frame: date of operation to date of first observation of progressive disease within the liver or death, or after 5 years off treatment whichever comes first
Evaluate safety of PDS01ADC in combination with HAIP therapy
Safety will be assessed by analyzing the type, grade and frequency. Toxicities by grade and per participant will be determined and reported separately by disease cohort.
Time frame: on-going from treatment start through end of treatment visit
Determine hepatic progression-free survival (PFS)
CT will be used for response criteria. Hepatic progression-free survival (PFS) probability will be determined using Kaplan-Meier estimates for all participants, separately by cohort; the median PFS will be reported along with a 95% confidence interval.
Time frame: date of operation to date of first observation of progressive disease within the liver or death, or after 5 years off treatment whichever comes first
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