Trial Information

A Randomized Phase I/III Study Of Systematic Chemotherapy With Or Without Hepatic Chemoembolization For Liver-Dominant Metastatic Adenocarcinoma Of The Colon And Rectum

OBJECTIVES:

- Compare the survival of patients with liver-dominant metastatic colorectal
adenocarcinoma treated with irinotecan, fluorouracil, and leucovorin calcium with or
without hepatic chemoembolization.

- Compare response in the liver, time to hepatic tumor progression, and time to
extrahepatic tumor progression in patients treated with these regimens.

- Compare the possible treatment differences with respect to morbidity, toxic effects of
chemoembolization, toxic effects of chemotherapy, and death from cancer-related
complications in these patients.

OUTLINE: This is a phase I dose-escalation study followed by a phase III randomized,
multicenter study. (Phase I closed as of 10/14/02.)

- Phase I: Patients in phase I are sequentially enrolled to 1 of 3 treatment regimens.
(Phase I closed as of 10/14/02.)

- Regimen A: Patients receive irinotecan IV over 60-90 minutes, leucovorin calcium
IV, and fluorouracil IV over 10 minutes on days 1, 8, 15, and 22. Patients undergo
hepatic embolization with embolic suspension only on day 36.

- Regimen B: Patients receive chemotherapy as in regimen A. Patients undergo hepatic
chemoembolization with lower-dose cisplatin, doxorubicin, and mitomycin on day 36.

- Regimen C: Patients receive chemotherapy as in regimen A. Patients undergo hepatic
chemoembolization with higher-dose cisplatin, doxorubicin, and mitomycin on day
36.

After 1 week of rest, patients in all regimens receive a second 4-week course of systemic
chemotherapy.

Cohorts of 3-10 patients are sequentially enrolled until the maximum tolerated dose (MTD) of
chemotherapy and chemoembolization is determined. The MTD is defined as the dose preceding
that at which at least 4 of 10 patients experience dose-limiting toxicity.

- Phase III: Patients are stratified according to liver volume involvement (less than 25%
vs 25-50% vs more than 50% to less than 75%) and participating center. Patients are
randomized to 1 of 2 treatment arms.

- Arm I: Patients receive irinotecan IV over 60-90 minutes, leucovorin calcium IV,
and fluorouracil IV over 10 minutes on days 1, 8, 15, and 22. Courses repeat every
6 weeks in the absence of disease progression.

- Arm II: Patients receive chemotherapy as in arm I. Patients undergo hepatic
chemoembolization with cisplatin, doxorubicin, and mitomycin on day 36.
Chemotherapy repeats every 6 weeks in the absence of disease progression.
Chemoembolization may repeat every 6 weeks for 2-4 courses as necessary.

Patients in phase III are followed every 3 months for 2 years, every 6 months for 3 years,
and then annually thereafter.

PROJECTED ACCRUAL: A total of 9-18 patients will be accrued for phase I of this study.
(Phase I closed to accrual as of 10/14/02.) Approximately 315 patients will be accrued for
phase III of this study within 2.5 years.