RATIONALE: Biological therapies such as gefitinib may interfere with the growth of tumor cells and slow the growth of the tumor. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug with gefitinib may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of gefitinib and oxaliplatin combined with leucovorin and fluorouracil in treating patients who have advanced solid tumors or colorectal cancer.

Condition	Treatment or Intervention	Phase
stage IV colon cancer Stage IV rectal cancer recurrent colon cancer recurrent rectal cancer adenocarcinoma of the colon adenocarcinoma of the rectum	Drug: fluorouracil  Drug: gefitinib  Drug: leucovorin calcium  Drug: oxaliplatin  Procedure: chemotherapy  Procedure: drug modulation  Procedure: enzyme inhibitor therapy  Procedure: protein tyrosine kinase inhibitor therapy	Phase II

Further Study Details: 

OBJECTIVES:

• Determine the maximum tolerated dose of gefitinib and oxaliplatin when combined with fluorouracil and leucovorin calcium in patients with advanced solid tumors. (Phase I) (Phase I closed as of 5/30/02)
• Determine the pharmacokinetics and pharmacodynamics of this regimen in these patients.
• Determine the dose-limiting toxic effects and other toxic effects of this regimen in these patients.
• Determine the antitumor response in patients with advanced colorectal adenocarcinoma treated with this regimen. (Phase II)
• Determine the overall survival and time to progression in patients with advanced colorectal adenocarcinoma treated with this regimen. (Phase II)
• Determine the presence of polymorphisms or other genetic alterations in genes implicated in the action of this regimen and determine their possible relationship with toxic effects of and antitumor response to this regimen in these patients.

OUTLINE: This is a dose-escalation study of gefitinib and oxaliplatin (L-OHP).

• Patients receive L-OHP IV over 2 hours on day 1 and leucovorin calcium (CF) IV over 2 hours followed by fluorouracil (5-FU) IV bolus and 5-FU IV over 22 hours on days 1 and 2 during all courses. Beginning with course 2, patients also receive oral gefitinib daily on days 1-14. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response (CR) receive 2 additional courses past CR. Sequential dose escalation of gefitinib is followed by sequential dose escalation of L-OHP. Cohorts of 3-6 patients receive escalating doses of gefitinib and L-OHP until the maximum tolerated dose (MTD) of the combination is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.
• Patients are stratified according to prior therapy:
• Stratum A: Received no prior therapy or received adjuvant 5-FU/CF or adjuvant 5-FU/CF/irinotecan at least 6 months ago
• Stratum B: Received prior therapy for metastatic disease or received adjuvant 5-FU/CF fewer than 6 months ago or prior irinotecan Patients receive therapy as in phase I (closed as of 5/30/02) with L-OHP and gefitinib at the recommended phase II dose.

PROJECTED ACCRUAL: Approximately 12-15 patients will be accrued for phase I of the study within 4-6 months (Phase I closed as of 5/30/02). A total of 30-81 patients (18-46 for stratum A and 12-35 for stratum B) will be accrued for phase II of the study within 18 months.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed metastatic or unresectable solid tumor for which standard curative or palliative measures do not exist or are no longer effective
• Histologically confirmed metastatic or unresectable colorectal adenocarcinoma
• Measurable disease or assessable but nonmeasurable disease (including ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT scan/MRI), or cystic lesions)
• Disease characterized only by elevated serum tumor marker allowed
• No known brain metastases

PATIENT CHARACTERISTICS: Age:

• 18 and over

Performance status:

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy:

• More than 3 months

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm ^3

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• AST/ALT no greater than 2.5 times upper limit of normal

Renal:

• Creatinine normal OR
• Creatinine clearance at least 60 mL/min

Cardiovascular:

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No ongoing or active infection
• No peripheral neuropathy
• No prior allergic reactions to compounds of similar chemical or biologic composition to gefitinib or other study agents
• No other concurrent uncontrolled illness
• No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY: Biologic therapy:

• No prior bone marrow or stem cell support with high-dose chemotherapy
• At least 24 hours since prior colony-stimulating growth factors

Chemotherapy:

• See Biologic therapy
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• No more than 3 prior chemotherapy regimens

Endocrine therapy:

• At least 2 weeks since prior hormonal therapy except megestrol for anorexia/cachexia

Radiotherapy:

• No prior pelvic or whole abdominal radiotherapy
• At least 4 weeks since other prior radiotherapy and recovered

Surgery:

• At least 4 weeks since prior major surgery (e.g., laparotomy) and recovered

Other:

• At least 4 weeks since prior investigational therapy
• No other concurrent investigational or commercial anticancer agents
• No concurrent combination antiretroviral therapy for HIV-positive patients

California
      Stanford Cancer Center at Stanford University Medical Center, Stanford,  California,  94305,  United States

Study chairs or principal investigators

Branimir Ivan Sikic, MD,  Study Chair,  Stanford University   

Study ID Numbers:  CDR0000068923; SUMC-670; NCI-4370; NCT00025142
Record last reviewed:  March 2005
Last Updated:  March 10, 2005
Record first received:  October 11, 2001
ClinicalTrials.gov Identifier:  NCT00025142
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08