RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing
so they stop growing or die. Combining more than one drug may kill more tumor cells.
Oblimersen may increase the effectiveness of chemotherapy by making tumor cells more
sensitive to the drugs.
PURPOSE: Phase I/II trial to study the effectiveness of combining oxaliplatin, fluorouracil,
and leucovorin with oblimersen in treating patients who have unresectable, metastatic, or
recurrent colorectal cancer.
- Determine the maximum tolerated dose of oblimersen when administered with oxaliplatin,
fluorouracil, and leucovorin calcium in patients with advanced colorectal cancer.
- Determine the quantitative and qualitative toxic effects of this regimen in these
- Determine the antitumor activity of this regimen in these patients.
- Determine the plasma pharmacokinetics of oblimersen and oxaliplatin in patients treated
with this regimen.
- Determine relevant predictive biomarkers of response in patients treated with this
OUTLINE: This is an open-label, phase I, dose-escalation study of oblimersen followed by a
non-randomized, phase II study.
- Phase I: Patients receive oblimersen IV continuously on days 1-5 and 15-19; leucovorin
calcium IV over 2 hours and fluorouracil IV over 22 hours on days 6, 7, 20, and 21; and
oxaliplatin IV over 2 hours on days 6 and 20.
Cohorts of 3-6 patients receive escalating doses of oblimersen until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the highest dose at which no more than 1 of
6 patients experiences dose-limiting toxicity.
- Phase II: Up to 35 additional patients are treated as in phase I, with oblimersen at
In both phases, courses repeat every 28 days in the absence of disease progression or
Patients are followed at 30 days.
PROJECTED ACCRUAL: A total of 6-53 patients (6-18 patients for phase I and 12-35 patients
for phase II) will be accrued for this study.
- Histologically or cytologically confirmed adenocarcinoma of the colon or rectum
- Unresectable, metastatic, or recurrent disease
- Measurable or evaluable disease (phase I)
- Measurable disease (phase II)
- No known brain metastases
- Patients with previously treated brain metastases who are not currently
receiving steroids and have a stable CT scan or MRI are eligible
- 18 and over
- ECOG 0-2 OR
- Karnofsky 60-100%
- At least 12 weeks
- Absolute neutrophil count at least 1,500/mm^3
- Platelet count at least 100,000/mm^3
- Hemoglobin at least 9 g/dL
- Bilirubin no greater than 1.5 mg/dL
- AST/ALT no greater than 2.5 times upper limit of normal (ULN) (5 times ULN if liver
metastases are present)
- INR no greater than 1.5 times ULN (unless currently receiving anticoagulant therapy)
- PT/PTT no greater than 1.5 times ULN (unless currently receiving anticoagulant
- Creatinine normal OR
- Creatinine clearance at least 60 mL/min
- No symptomatic congestive heart failure
- No unstable angina pectoris
- No cardiac arrhythmia
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No history of allergic reaction to compounds of similar chemical or biologic
composition to fluorouracil or oxaliplatin
- No other concurrent uncontrolled medical condition that would preclude study
- No ongoing or active infection
- No psychiatric illness or social situation that would preclude study compliance
- No known history of degenerative facet disease during prior fluorouracil therapy
- No HIV-positive patients receiving combination antiretroviral therapy
PRIOR CONCURRENT THERAPY:
- No concurrent epoetin alfa during course 1
- No concurrent routine filgrastim (G-CSF) or sargramostim (GM-CSF)
- No concurrent immunotherapy
- At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and
- No prior oxaliplatin
- No other concurrent chemotherapy
- See Disease Characteristics
- At least 4 weeks since prior radiotherapy and recovered
- No concurrent radiotherapy
- Not specified
- No prior oblimersen
- No other concurrent investigational agents
- No other concurrent antitumor therapy