A Pilot Trial of Oral Topotecan for the Treatment of Refractory Advanced Solid Neoplasms Expressing HIF-1 Alpha
18 Years
N/A
Both
Neoplasms
Trial Information
A Pilot Trial of Oral Topotecan for the Treatment of Refractory Advanced Solid Neoplasms Expressing HIF-1 Alpha
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 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
cancers.
Inclusion Criteria
- INCLUSION CRITERIA:
Patients must have a pathologically confirmed solid tumor that is metastatic or
unresectable and which has either progressed following standard therapy or for which there
is no recommended standard treatment.
Patients must have tumors that can be biopsied with a minimal to small amount of risk and
must have a malignancy that expresses HIF-1 alpha protein as measured by
immunohistochemistry (determined on archival tissue, at least greater than 10% of cells
show positive staining for HIF-1 alpha).
ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).
Life expectancy is greater than 3 months.
Age greater than or equal to 18 years.
Patients must have normal organ and marrow functions as defined below.
- leukocytes greater than or equal to 3000/mm(3).
- absolute neutrophils greater than or equal to 1500/mm(3).
- platelets greater than or equal to 100,000/mm(3).
- AST (SGOT)/ALT (SGPT) less than or equal to 2.5 x institutional upper limit of
normal.
- total bilirubin less than or equal to 1.5x institutional upper limit of normal.
- Serum Creatinine less than or equal to 1.5 mg/dL OR creatinine clearance greater than
or equal to 50 mL/min for patients with creatinine levels greater than 1.5 mg/dL.
- PT/PTT less than or equal to 1.5 x ULN.
Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation.
No unstable medical illness.
Ability to understand and the willingness to sign a written informed consent document.
EXCLUSION CRITERIA:
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.
Type of Study:
Interventional
Study Design:
Primary Purpose: Treatment
Outcome Measure:
To determine whether chronic oral administration of topotecan inhibits HIF-1alpha expression.
Authority:
United States: Federal Government
Study ID:
050186
NCT ID:
NCT00117013
Start Date:
June 2005
Completion Date:
October 2010
Related Keywords:
- Neoplasms
- Phase I
- Antiangiogenesis
- Targeted Therapy
- Chronic Schedule
- VEGF
- Cancer
- Metastatic Solid Tumor
- Neoplasms
Name | Location |
|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |
