A Pilot Trial of Oral Topotecan for the Treatment of Refractory Advanced Solid Neoplasms Expressing HIF-1 Alpha
HIF-1 is a common mediator of hypoxic and non-hypoxic pathways that affects a
transcriptional program leading to survival, angiogenesis, migration and invasion of cancer
cells. We have demonstrated that chronic administration of topotecan inhibits HIF-1alpha
expression, angiogenesis and tumor growth in human xenografts. Notably, the mechanism by
which topotecan inhibits HIF-1alpha protein expression is independent of
replication-mediated DNA damage, suggested a mechanism of action distinct from its cytotoxic
This clinical trial is designed to explore the hypothesis that chronic administration of
topotecan (TPT) inhibits Hypoxia Inducible factor 1alpha (HIF-1alpha) expression and
angiogenesis in patients with metastatic tumors over-expressing HIF-1alpha.
Adult patients with metastatic solid tumors expressing HIF-1alpha, for whom standard therapy
does not exist or would likely not be effective, will be evaluated for study eligibility.
Due to safety concerns, pregnant women and HIV-infected individuals are excluded from this
study. Prior to enrollment, archival tumor tissue wil be evaluated for the expression of
HIF-1alpha as assessed by IHC. Only patients who have tumors that express HIF-1alpha and who
meet all eligibility criteria will be enrolled on this study. Patients will be asked to
undergo a biopsy to evaluate HIF-1alpha expression before starting treatment and at the end
of treatment on cycle 2 (day 12 or 13 cycle 2).
Topotecan at the dose of 1.2 mg/m(2) will be administered orally daily x 5 for 2 weeks,
during a 28 days cycle. Imaging studies including CT and DCE-MRI will be performed at
baseline, at the end of treatment on cycle 1 (day 9 or 10), end of treatment on cycle 2 (day
12 or 13) and will provide information on clinical response as well as tumor angiogenesis.
The repeat scans on day 9 or 10 of cycle 1 will be performed solely for research purposes to
evaluate for early changes in tumor angiogenesis. Additional correlative studies include
evaluation of mRNA expression of HIF-1 target genes in tumor tissue, circulating markers of
angiogenesis, and measurement of circulating endothelial precursor cells (CEP). The goal of
this trial is to establish whether topotecan inhibits HIF-1alpha and angiogenesis in human
Primary Purpose: Treatment
To determine whether chronic oral administration of topotecan inhibits HIF-1alpha expression.
United States: Federal Government
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