1: Clin Cancer Res. 2006 May 15;12(10):3092-8.
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II clinical trial results involving treatment with low-dose daily oral
cyclophosphamide, weekly vinblastine, and rofecoxib in patients with
advanced solid tumors.
Preclinical studies indicate that conventional chemotherapeutic agents
given continuously at low doses (metronomic chemotherapy) may provide
an improved therapeutic index. Cyclophosphamide and vinblastine have
been best studied in experimental models, where tumor growth inhibition
is achieved, at least in part, through antiangiogenic mechanisms.
EXPERIMENTAL DESIGN: Fifty patients with advanced solid tumors were
enrolled in this phase II trial, 43 of whom had received at least one
prior chemotherapy regimen. Patients were required to have Eastern
Cooperative Oncology Group performance status of < or = 2, a life
expectancy of >3 months, and at least one measurable lesion. All
patients received oral cyclophosphamide (50 mg) and rofecoxib (25 mg)
daily in addition to weekly injections of vinblastine (3 mg/m2). Half
of the patients also received minocycline (100 mg) orally twice daily
with the intent of further inhibiting tumor angiogenesis. The primary
end point of the study was clinical benefit, defined as the percentage
of patients experiencing an objective response or exhibiting stable
disease for at least 6 months.
RESULTS: For the 47 eligible patients,
there were two (4%) complete responses and four (9%) partial responses,
for an overall objective response rate of 13%. An additional eight
patients achieved disease stabilization (stable disease > or = 6
months) (17%). The primary end point of clinical benefit was therefore
30%, (95% confidence interval, 16-44%). The median progression-free
survival for all patients was 103 days and 289 days for patients
experiencing clinical benefit. The incidence of patients experiencing
grade 3/4 toxicities were as follows: neutropenia (10/2), anemia (2/0),
and thrombocytopenia (1/0). No patients developed grade 3 or 4 nausea,
vomiting, mucositis, or alopecia.
CONCLUSIONS: This low-dose regimen
consisting of daily oral cyclophosphamide and weekly vinblastine
injections given concurrently with rofecoxib is associated with minimal
toxicity and provides significant clinical benefit to patients with
advanced solid tumors. These results are particularly encouraging given
the nature of the study population and indicate that this approach
merits further investigation in specific disease site studies.