Phase I Study of Weekly Topotecan in Combination With Sorafenib in Treatment of Relapsed Small Cell Lung Cancer
Small cell lung cancer (SCLC) comprises approximately 15 percent of all lung cancers in the
United States. It is highly correlated with tobacco use and occurs almost exclusively in
smokers. SCLC is a particularly virulent malignancy characterized by rapid growth and a
tendency to metastasize early in the disease course. In first line treatment, SCLC has a
high response rate to cytotoxic chemotherapy. Unfortunately, the disease develops drug
resistance in almost all cases resulting in recurrence. In second line treatment, the
likelihood of response to treatment is considerably less. Multiple agents have been used in
this setting with response rates typically around 25% and median survival of less than 6
months1-3. There is clearly a great need for more effective treatments in this disease.
Topotecan is a semi-synthetic, water soluble derivative of camptothecin, a cytotoxic
alkaloid extracted from plants of the genus Camptotheca. Its mechanism of action is
inhibition of topoisomerase I, an enzyme necessary to relieve torsional strain of DNA which
is necessary to carry out replication. This results in DNA double-strand breaks and
ultimately cell death. Topotecan has demonstrated activity in a number of malignancies and
is currently indicated for the treatment of ovarian cancer, cervical cancer and recurrent
small cell lung cancer.
Topotecan has demonstrated single agent activity in recurrent small cell lung cancer in a
number of trials. Reported response rates range from 2 to 31%3-7. A phase III trial
compared topotecan to CAV (cyclophosphamide, doxorubicin and vincristine) in treatment of
recurrent SCLC5. Response rate, survival and time to progression were similar in both
groups. The topotecan group demonstrated significant improvement in symptoms including
anorexia, fatigue and dyspnea. This led to FDA approval of topotecan for treatment of
The dose limiting toxicity of topotecan is hematologic. The approved schedule of
administration is 1.5mg/m2 daily x 5 every 21 days. A modified schedule of weekly
administration at 4mg/m2 has been shown to have similar efficacy with less toxicity8 and
has been widely adopted in clinical practice.
Sorafenib is an oral multi-kinase inhibitor with effects on tumor proliferation and tumor
angiogenesis. It has several biochemically important mechanisms including inhibition of
Raf-1 and B-Raf which are pivotal components of the Ras/Raf/Mek/Erk signaling pathway. It
also has inhibitory activity against the tyrosine kinases for VEGF and PDGFR as well as
Flt-3 and c-kit.
Sorafenib has been safely combined with full dose cytotoxic chemotherapy in several Phase I
trials9-11. There is no data on the combination of topotecan and sorafenib to date.
Sorafenib is metabolized in the liver undergoing oxidation via CYP3A4 and glucuronidation
via UGT1A9. There is no evidence that topotecan affects activity of the cytochrome P450
pathways suggesting low likelihood of a drug-drug interaction. There are no significant
overlapping toxicities making this an ideal drug combination to investigate.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The primary objective of this study is to determine the maximum tolerated dose of sorafenib up to the full active dose when combined with standard weekly dosing of topotecan in patients with recurrent small cell lung cancer and to
Joseph Leach, MD
Park Nicollet Institute
United States: Institutional Review Board
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