Trial Information

A Phase I Dose-Escalation Study of Topotecan and Ifosfamide in Patients With Refractory Non-Hematologic Malignancies.

OBJECTIVES: I. Determine the maximum tolerated doses and sequence of topotecan and
ifosfamide that can be administered daily for 3 days on an every 4 week schedule in patients
with refractory solid tumors. II. Evaluate toxicity of topotecan and ifosfamide when
administered on this schedule in this patient population. III. Evaluate the pharmacokinetics
related to sequencing of topotecan and ifosfamide and the more efficacious, less toxic
schedule of treatment. IV. Assess the evidence of antineoplastic activity for this
combination of agents.

OUTLINE: This is an open label, dose escalation study. Cohorts of 3-6 patients receive
ifosfamide at an initial fixed dose plus escalating doses of topotecan by 30 minute infusion
daily for 3 successive days. Cycle repeats every 28 days. After topotecan dosage is
escalated for a total of 3 dose levels, then ifosfamide dose is escalated by one dose level.
The first patient enrolled is treated with ifosfamide followed by topotecan for cycle 1, and
for cycle 2 the order of drugs is reversed. The second patient is treated with the same
drugs but with topotecan administered before ifosfamide in the first cycle and then reversed
in the second cycle. From the third cycle onward, ifosfamide is followed by topotecan, but
the first two cycles continue to alternate with each subsequent patient entered. Filgrastim
(granulocyte colony-stimulating factor; G-CSF) is given for all cycles on days 5-12 or until
the absolute granulocyte count has reached its nadir and recovered. If there is no dose
limiting toxicity (DLT) in a cohort, new patients are entered at the next highest dose
level. If 1 of 3 patients at any level experiences DLT, an additional 3 patients are treated
at that level before proceeding to a higher level. If 2 or more patients experience DLT at
any dose level, the level immediately preceding that level is defined as the maximum
tolerated dose (MTD). Three more patients are treated at the MTD to ensure that no DLT is
experienced at that level. After MTD is identified, 10 additional patients are accrued at
that level. Patients with minor response, stable disease, or symptomatic or marker
improvement may continue on treatment for up to 6 cycles. After 6 cycles, continuation on
treatment is at the investigator's discretion.

PROJECTED ACCRUAL: There will be a maximum of 24 patients accrued into this study over 8
months.