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Hepatic Arterial Infusion of Floxuridine, Gemcitabine Hydrochloride, and Radiolabeled Monoclonal Antibody Therapy in Treating Liver Metastases in Patients With Metastatic Colorectal Cancer Previously Treated With Surgery

A Phase I/II Trial of Radioimmunotherapy (Y-90 cT84.66), Gemcitabine and Hepatic Arterial Infusion of Fudr for Metastatic Colorectal Carcinoma to the Liver

Status
Completed
Phases
Phase 1Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00645710
Enrollment
16
Registered
2008-03-28
Start date
2005-02-11
Completion date
2018-02-07
Last updated
2019-03-28

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Liver Metastases, Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

Brief summary

RATIONALE: Drugs used in chemotherapy, such as floxuridine and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Hepatic arterial infusion uses a catheter to carry cancer-killing substances directly into the liver. Radiolabeled monoclonal antibodies can find tumor cells and carry tumor-killing substances to them without harming normal cells. Giving hepatic arterial infusion of floxuridine together with gemcitabine hydrochloride and radiolabeled monoclonal antibody therapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase I/II trial is studying the side effects and best dose of floxuridine when given as a hepatic arterial infusion together with gemcitabine hydrochloride and radiolabeled monoclonal antibody therapy and to see how well it works in treating liver metastases in patients with metastatic colorectal cancer.

Detailed description

OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and associated toxicities of concurrent hepatic arterial infusion (HAI) fluorodeoxypyrimidine (FUdR)/Decadron and intravenous gemcitabine combined with intravenous yttrium-90 (\^90Y) chimeric T84.66 (cT84.66) in colorectal cancer patients after hepatic resection or maximum surgical debulking (to \< 3 cm) of liver metastases. II. To study the feasibility and toxicities of such adjuvant therapy following resection and/or ablation of liver metastases. III. To evaluate the biodistribution, clearance and metabolism of \^90Y and \^111In (indium-iii) chimeric T84.66 administered intravenously. IV. To estimate radiation doses to whole body, normal organs, and tumor through serial nuclear imaging. V. To correlate proteomic profiles pre and post-therapy with toxicities and anti-tumor effects. OUTLINE: This is a phase I, dose-escalation study of floxuridine followed by a phase II study. Patients receive floxuridine as a continuous hepatic arterial infusion on days 1-14 and gemcitabine hydrochloride IV over 30 minutes on days 9 and 11. Patients also receive yttrium Y 90 anti-CEA monoclonal antibody cT84.66 IV over 25 minutes on day 9. Treatment repeats every 6 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients may receive an additional course of floxuridine in combination with systemic therapy at the discretion of the treating physician. After completion of study treatment, patients are followed up at 3 and 6 months.

Interventions

DRUGgemcitabine hydrochloride

Given IV

DRUGfloxuridine

Given via hepatic arterial infusion

GENETICproteomic profiling

Correlative studies

Correlative studies

OTHERlaboratory biomarker analysis

Correlative studies

OTHERmass spectrometry

Correlative studies

OTHERpharmacological study

Correlative studies

Sponsors

City of Hope Medical Center
Lead SponsorOTHER

Study design

Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No

Inclusion criteria

Inclusion * Patients must have a Karnofsky performance status of \>= 60%; this must be met pre-surgery and pre-study therapy * Patients must have histological confirmation of colorectal carcinoma and present with potentially resectable or abatable metachronous or synchronous hepatic metastases * Patients must have colorectal tumors that produce CEA as documented by either immunohistochemistry or by an elevated serum CEA * Prior radiotherapy, immunotherapy, or chemotherapy must have been completed at least four weeks prior to start of FUdR/RIT therapy on this study (6 weeks if mitomycin-C or nitrosoureas were part of last therapy) and patients must have recovered from all expected side effects of the prior therapy * Laboratory values must be met pre-surgery and pre-study therapy * Hemoglobin \> 10 gm % (patients may be transfused to reach a hemoglobin \> 10 gm %) * WBC \> 4000/ul * Absolute granulocyte count of \> 1,500/mm\^3 * Platelets \> 150,000/ul * Patients may have history of prior malignancy for which the patient has been disease-free for five years with the exception of basal or squamous cell skin cancers or carcinoma in situ of the cervix * Patients must have no prior history of radiation therapy to the liver * Total bilirubin \< 1.5 (unless reversibly obstructed due to the metastatic tumor) * Serum creatinine of \< 2.0 * Patients must have evidence of intrahepatic metastases involving \< 60% of the functioning liver * Patients cannot have evidence of extrahepatic disease with the following exceptions: patients known to have a resectable anastomotic or local recurrence of their tumor; patients who undergoing their initial surgery for resection of their primary colorectal carcinoma can have potentially resectable porta hepatis and/or mesenteric lymph node involvement in addition to liver metastases; patients who have disease extension from the liver metastasis that can be resected en bloc (e.g., diaphragm, kidney, and abdominal wall); patients who have minimal, potentially resectable to less than 3 cm extrahepatic disease * The pre-operative eligibility checklist must be completed * If a patient has previously received murine or chimeric antibody, then serum anti-antibody testing must be negative (This must be met pre-surgery if possible) * Serum HIV testing and hepatitis B surface antigen and C antibody testing must be negative * Women of childbearing potential must have a negative serum pregnancy test prior to entry and while on study must be practicing an effective form of contraception (This must be met pre-surgery and pre-study therapy) * Patients must have resectable or abatable liver metastases as determined by the attending surgeon * Colorectal carcinoma must be confined to the liver except as noted above * Patients with limited extrahepatic disease as defined (primary, lymph node, or anastomotic recurrence) must have disease resected or debulked to less than 3 cm in greatest dimension * To receive study therapy, patients must be at least 3 weeks post-surgery but no more than 16 weeks post surgery and without evidence of post-operative complications, such as infection or poor wound healing * Patients must have \< 40% liver resected at the close of completion of the hepatic resection Exclusion * Patients that have received radiation therapy to greater than 50% of their bone marrow * Patients with any nonmalignant intercurrent illness (example cardiovascular, pulmonary, or central nervous system disease) which is either poorly controlled with currently available treatment or which is of such severity that the investigators deem it unwise to enter the patient on protocol shall be ineligible * Biopsy-proven chronic active hepatitis

Design outcomes

Primary

MeasureTime frameDescription
Number of Participants With at Least One Dose Limiting Toxicity4 weeks from start of treatment, up to 2 years.Dose Limiting Toxicity (DLT) defined as any treatment-related grade grade 3 nonhematologic toxicity not reversible to grade 2 or less within 24 hours, or any grade 4 toxicity.Up to three cycles of therapy were allowed with DLTs determined based on first cycle tolerance. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2.0.
Recommended Phase II Dose4 weeks from start of treatment, up to 2 years.The maximum tolerated dose (MTD) of HAI FUdR in combination with intravenous gemcitabine and 90Y-DTPA-cT84.66 is based on toxicities observed during the first cycle and is defined as the highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. Dose escalations proceeded according to a standard 3+3 design.

Secondary

MeasureTime frameDescription
Overall SurvivalUp to 5 yearsEstimated using the product-limit method of Kaplan and Meier. Event defined as death due to any cause.
Progression-free SurvivalUp to 5 yearsEstimated using the product-limit method of Kaplan and Meier. Progression is defined as a 25% increase in the sum of products of measurable lesions over the smallest sum observed, or appearance of any lesions that had disappeared, or appearance of any new lesion/site.

Countries

United States

Participant flow

Participants by arm

ArmCount
Dose Level 1 - FUdR 0.10 mg/kg/Day
Patients receive floxuridine as a continuous hepatic arterial infusion on days 1-14 (starting dose level 0.10 mg/kg/day) and gemcitabine hydrochloride IV (105 mg/m\^2) over 30 minutes on days 9 and 11. Patients also receive yttrium Y 90 anti-CEA monoclonal antibody cT84.66 IV (16.6 mCi/m\^2) over 25 minutes on day 9. Treatment repeats every 6 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients may receive an additional course of floxuridine in combination with systemic therapy at the discretion of the treating physician.
3
Dose Level 2 - FUdR 0.15 mg/kg/Day
Patients receive floxuridine as a continuous hepatic arterial infusion on days 1-14 (starting dose level 0.15 mg/kg/day) and gemcitabine hydrochloride IV (105 mg/m\^2) over 30 minutes on days 9 and 11. Patients also receive yttrium Y 90 anti-CEA monoclonal antibody cT84.66 IV (16.6 mCi/m\^2) over 25 minutes on day 9. Treatment repeats every 6 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients may receive an additional course of floxuridine in combination with systemic therapy at the discretion of the treating physician.
3
Dose Level 3 - FUdR 0.20 mg/kg/Day
Patients receive floxuridine as a continuous hepatic arterial infusion on days 1-14 (starting dose level 0.20 mg/kg/day) and gemcitabine hydrochloride IV (105 mg/m\^2) over 30 minutes on days 9 and 11. Patients also receive yttrium Y 90 anti-CEA monoclonal antibody cT84.66 IV (16.6 mCi/m\^2) over 25 minutes on day 9. Treatment repeats every 6 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients may receive an additional course of floxuridine in combination with systemic therapy at the discretion of the treating physician.
10
Total16

Baseline characteristics

CharacteristicTotalDose Level 1 - FUdR 0.10 mg/kg/DayDose Level 2 - FUdR 0.15 mg/kg/DayDose Level 3 - FUdR 0.20 mg/kg/Day
Age, Continuous56 years60 years54 years53 years
Karnofsky Performance Status for Assessment of Functional Impairment90 units on a scale90 units on a scale90 units on a scale90 units on a scale
Race/Ethnicity, Customized
Asian
3 Participants0 Participants1 Participants2 Participants
Race/Ethnicity, Customized
Caucasian
9 Participants2 Participants2 Participants5 Participants
Race/Ethnicity, Customized
Hispanic
3 Participants1 Participants0 Participants2 Participants
Race/Ethnicity, Customized
Unknown
1 Participants0 Participants0 Participants1 Participants
Region of Enrollment
United States
16 participants3 participants3 participants10 participants
Sex: Female, Male
Female
6 Participants1 Participants2 Participants3 Participants
Sex: Female, Male
Male
10 Participants2 Participants1 Participants7 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
deaths
Total, all-cause mortality
2 / 33 / 38 / 10
other
Total, other adverse events
3 / 33 / 310 / 10
serious
Total, serious adverse events
0 / 31 / 32 / 10

Outcome results

Primary

Number of Participants With at Least One Dose Limiting Toxicity

Dose Limiting Toxicity (DLT) defined as any treatment-related grade grade 3 nonhematologic toxicity not reversible to grade 2 or less within 24 hours, or any grade 4 toxicity.Up to three cycles of therapy were allowed with DLTs determined based on first cycle tolerance. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2.0.

Time frame: 4 weeks from start of treatment, up to 2 years.

Population: All patients receiving treatment were evaluated for DLT.

ArmMeasureValue (NUMBER)
Dose Level 1- FUdR 0.10 mg/kg/DayNumber of Participants With at Least One Dose Limiting Toxicity0 participants with DLTs
Dose Level 2 - FUdR 0.15 mg/kg/DayNumber of Participants With at Least One Dose Limiting Toxicity0 participants with DLTs
Dose Level 3 - FUdR 0.20 mg/kg/DayNumber of Participants With at Least One Dose Limiting Toxicity1 participants with DLTs
Primary

Recommended Phase II Dose

The maximum tolerated dose (MTD) of HAI FUdR in combination with intravenous gemcitabine and 90Y-DTPA-cT84.66 is based on toxicities observed during the first cycle and is defined as the highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. Dose escalations proceeded according to a standard 3+3 design.

Time frame: 4 weeks from start of treatment, up to 2 years.

Population: All patients observed for 56 days while receiving a full course of therapy or who experienced a DLT. Patients withdrawing before completion of the first course, for reasons other than DLT, were replaced.

ArmMeasureValue (NUMBER)
Dose Level 1- FUdR 0.10 mg/kg/DayRecommended Phase II Dose0.20 mg/kg/day
Secondary

Overall Survival

Estimated using the product-limit method of Kaplan and Meier. Event defined as death due to any cause.

Time frame: Up to 5 years

ArmMeasureValue (MEDIAN)
Dose Level 1- FUdR 0.10 mg/kg/DayOverall Survival23.2 Months
Dose Level 2 - FUdR 0.15 mg/kg/DayOverall Survival73.2 Months
Dose Level 3 - FUdR 0.20 mg/kg/DayOverall Survival41.2 Months
Secondary

Progression-free Survival

Estimated using the product-limit method of Kaplan and Meier. Progression is defined as a 25% increase in the sum of products of measurable lesions over the smallest sum observed, or appearance of any lesions that had disappeared, or appearance of any new lesion/site.

Time frame: Up to 5 years

ArmMeasureValue (MEDIAN)
Dose Level 1- FUdR 0.10 mg/kg/DayProgression-free Survival8.3 Months
Dose Level 2 - FUdR 0.15 mg/kg/DayProgression-free Survival11.5 Months
Dose Level 3 - FUdR 0.20 mg/kg/DayProgression-free Survival9.6 Months

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026