A Pilot Trial of Oral Topotecan for the Treatment of Refractory Advanced Solid Neoplasms Expressing HIF-1a
Status:
Completed
Trial end date:
2010-10-25
Target enrollment:
Participant gender:
Summary
Background:
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 effects.
Objectives:
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.
Eligibility:
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).
Design:
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, FDG-PET 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 then every 2 cycles and will provide information on clinical response as
well as tumor metabolism and 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 metabolism and
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 cancers....