A Pilot Trial of Oral Topotecan for the Treatment of Refractory Advanced Solid Neoplasms Expressing HIF-1a

Completed · Phase 1

Conditions studied: Neoplasms

In brief

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....

Key facts

Study ID

NCT00117013

Run by

National Cancer Institute (NCI)

People needed

16

Starts

2005-06-28

Expected to finish

2010-10-25

Last updated by the study team

2017-07-02

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may not qualify if…

• Patients who have had anticancer therapy (chemotherapy, radiotherapy, vaccines and hormone therapy with the exception of GnRH agonists) within the last 4 weeks (6 weeks for nitrosoureas or mitomycin C or UCN-01); or those who have not recovered from adverse events (reduce to grade 2 or less) due to agents administered more than 4 weeks earlier. Patients must be greater than or equal to 2 weeks since any investigational agent administered as part of a Phase 0 study.
• Prior therapy with topotecan.
• Patients may not be receiving any other investigational agents. Patients who are on androgen suppression for the treatment of prostate cancer are eligible and will be allowed to continue the androgen suppression therapy on study. No herbal/alternative medications will be allowed on this study other than one multivitamin a day.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. However, patients who have had treatment for their brain metastases and whose brain metastatic disease has remained stable for at least 4 months without steroids or anti-seizure medications may be enrolled at the discretion of the Principal Investigator.
• History of allergic reaction attributed to compounds of similar chemical or biologic composition to topotecan or history of allergic reaction to any component of the topotecan formulation.
• Active peptic ulcer or GI condition that could alter absorption or motility.
• Pregnant women are excluded from this study. Breastfeeding should be discontinued if the mother is treated with topotecan.
• Patients with known immune deficiency syndromes or who are HIV positive will be excluded from the study.

Where it is running

• National Institutes of Health Clinical Center, 9000 Rockville Pike — Bethesda, Maryland, United States

Full record on ClinicalTrials.gov

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