Edotecarin and Cisplatin in Treating Patients With Advanced or Metastatic Solid Tumors

OBJECTIVES:

Primary

• Determine the maximum tolerated dose and recommended phase II dose of edotecarin when administered with cisplatin (administered in 2 different schedules) in patients with advanced or metastatic solid tumors.

Secondary

• Determine the safety profile of this regimen in these patients.
• Determine the plasma pharmacokinetics of this regimen in these patients.
• Determine the antitumor activity of this regimen in these patients.

OUTLINE: This is an open-label, multicenter, dose-escalation study of edotecarin. Patients are assigned to 1 of 2 schedules.

• Schedule A: Patients receive cisplatin IV over 30 minutes and edotecarin IV over 1 hour on days 1 and 8.
• Schedule B: Patients receive cisplatin IV over 2 hours and edotecarin IV over 1 hour on day 1.

In both schedules, courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients in each schedule receive escalating doses of edotecarin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, 10 additional patients with metastatic esophageal or gastric cancer receive treatment as above at the MTD.

Patients are followed every 2 months for 1 year or until disease progression.

PROJECTED ACCRUAL: A maximum of 80 patients (40 per schedule) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of one of the following:

• Histologically or cytologically confirmed active solid tumor malignancy
• Histologically confirmed esophageal or gastric cancer* meeting all the following criteria:

• Previously untreated disease
• Metastatic disease
• Measurable disease

• At least 1 unidimensionally measurable lesion at least 20 mm by conventional techniques OR 10 mm by spiral CT scan NOTE: *Patients with esophageal or gastric cancer are enrolled after the maximum tolerated dose has been determined
• No known brain or leptomeningeal disease

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9.0 g/dL

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN) (regardless of liver involvement by tumor)
• SGOT no greater than 3 times ULN (5 times ULN if there is liver involvement by tumor)
• Albumin at least 3.0 g/dL

Renal

• Creatinine no greater than 1.5 mg/dL

Cardiovascular

• None of the following within the past 12 months:

• Myocardial infarction
• Severe/unstable angina
• Symptomatic congestive heart failure
• Cerebrovascular accident
• Transient ischemic attack
• Deep vein thrombosis
• Other significant thromboembolic event
• No ongoing grade 2 or greater cardiac dysrhythmia
• No atrial fibrillation

Pulmonary

• No pulmonary embolism within the past 12 months

Gastrointestinal

• No active inflammatory bowel disease
• No partial or complete bowel obstruction
• No chronic diarrhea

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No grade 2 or greater acute toxic effects
• No active infection
• No other concurrent acute or chronic medical or psychiatric condition or laboratory abnormality that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior treatment with any of the following systemic therapies for metastatic cancer*:

• Antibody therapy
• Immunotherapy
• Gene therapy
• Vaccine therapy
• Cytokine therapy
• Inhibitors of vascular endothelial growth factor/Flk-1 pathway
• No concurrent sargramostim (GM-CSF)
• No concurrent antibody therapy or immunotherapy NOTE: *Patients with esophageal or gastric cancer only

Chemotherapy

• No more than 1 prior chemotherapy regimen for metastatic disease*
• No prior high-dose chemotherapy requiring hematopoietic stem cell rescue
• No other concurrent chemotherapy NOTE: *No prior chemotherapy for metastatic disease for patients with esophageal or gastric cancer

Endocrine therapy

• No concurrent hormonal treatment

Radiotherapy

• No prior radiotherapy to more than 25% of bone marrow reserve
• No prior radiotherapy to the sole measurable lesion*
• No concurrent radiotherapy NOTE: *Patients with esophageal or gastric cancer only

Surgery

• More than 12 months since prior coronary/peripheral artery bypass graft surgery

Other

• Recovered from prior therapy
• More than 6 months since last dose of prior adjuvant therapy*
• No prior treatment with any of the following systemic therapies for metastatic cancer*:

• Cyclooxygenase-2 inhibitors
• Matrix metalloprotease inhibitors
• Epidermal growth factor receptor inhibitors
• Other experimental agents
• No other concurrent anticancer therapy
• No concurrent enrollment in another clinical trial
• No other concurrent experimental drugs NOTE: *Patients with esophageal or gastric cancer only