Topotecan in Treating Patients With Gynecologic Cancer That Cannot Be Removed by Surgery

A Phase I Study of Weekly Oral Topotecan in Gynecologic Malignancies

RATIONALE: Drugs used in chemotherapy, such as topotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

PURPOSE: This phase I trial is studying the side effects and best dose of topotecan in treating patients with gynecologic cancer that cannot be removed by surgery.

OBJECTIVES:

Primary

• To establish the maximum tolerated dose (MTD) of oral topotecan hydrochloride in patients with unresectable gynecologic malignancies.
• To determine the safety and tolerability of this drug in these patients.
• To obtain pharmacokinetic data to assess plasma concentrations of this drug when administered at the MTD.

Secondary

• To explore the response in patients treated with this drug.

OUTLINE: Patients receive oral topotecan hydrochloride on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients treated at the maximum tolerated dose undergo blood sample collection periodically on day 1 of course 1 for pharmacokinetic studies.

DISEASE CHARACTERISTICS:

• Histologically* or cytologically confirmed unresectable gynecologic malignancy for which standard curative or palliative care is not available

  • All tumor types allowed NOTE: *Histologic confirmation of recurrence is not required

• Measurable or nonmeasurable disease

  • If CT scan was used to evaluate measurable disease, lesions must be clearly defined and be ≥ 10 mm on spiral CT scan

• No "borderline tumors" or tumors with low malignant potential

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%
• Life expectancy ≥ 12 weeks
• ANC ≥ 1,500/μL
• Platelet count ≥ 100,000/μL
• Hemoglobin ≥ 9 g/dL
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Creatinine clearance ≥ 60 mL/min
• AST/ALT ≤ 2.5 times ULN (< 5 times ULN if liver metastases are present)
• Alkaline phosphatase ≤ 2.5 times ULN (< 5 times ULN if liver metastases are present)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Adequate intestinal function (i.e., no gastrostomy tube or requirement for IV hydration or nutritional support)
• No severe gastrointestinal bleeding or intestinal obstruction
• No other condition that would affect gastrointestinal absorption and motility
• No septicemia, severe infection, or acute hepatitis
• No other malignancies requiring chemotherapy or radiotherapy within the past 5 years, except skin cancer
• No concurrent severe medical problem unrelated to the malignancy that would significantly limit full compliance with the study, expose the patient to extreme risk, or decrease life expectancy

PRIOR CONCURRENT THERAPY:

• At least 28 days since prior investigational drugs (including cytotoxic drugs)

• At least 4 weeks since prior chemotherapy, radiotherapy, biologic therapy, or surgery and recovered

• No more than 3 prior chemotherapy regimens

• No prior topotecan hydrochloride or other camptothecin analogs

• No prior radiotherapy to > 25% of the bone marrow

• No other concurrent chemotherapy, radiotherapy, biologic therapy, immunotherapy, or hormonal therapy for cancer

• No concurrent administration of any of the following:

  • P-glycoprotein (ABCB1, Pgp, MDR1) inhibitors or inducers
  • Breast cancer-resistant protein (ABCG2, BCRP, MXR) inhibitors or inducers

• No concurrent chronic H2 antagonists, proton pump inhibitors, or antacids for gastritis, gastroesophageal reflux disease, or gastric or duodenal ulcers

  • Intermittent antacid therapy is allowed provided it is given ≥ 6 hours prior to and ≥ 90 minutes after study drug administration