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Sponsored by: |
Park Nicollet Institute |
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Information provided by: | Park Nicollet Institute |
ClinicalTrials.gov Identifier: | NCT00466232 |
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 characterize the toxicities associated with the combination of topotecan and sorafenib in this patient population
Condition | Intervention | Phase |
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Small Cell Carcinoma Lung Cancer |
Drug: Topotecan Drug: Sorafenib |
Phase I |
Study Type: | Interventional |
Study Design: | Treatment, Non-Randomized, Open Label, Active Control, Single Group Assignment, Safety Study |
Official Title: | Phase I Study of Weekly Topotecan in Combination With Sorafenib in Treatment of Relapsed Small Cell Lung Cancer |
Estimated Enrollment: | 21 |
Study Start Date: | April 2007 |
Estimated Study Completion Date: | March 2009 |
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 recurrent SCLC.
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.
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Adequate organ function within 14 days of study enrollment as defined by the following:
Exclusion Criteria:
Contact: Elsie Anderson, RN, BAE | 952-993-6723 | Elsie.Anderson@parknicollet.com |
Contact: Karen K Swenson, RN, PhD | 952-993-6071 | Karen.Swenson@parknicollet.com |
United States, Minnesota | |
Park Nicollet Institute | Recruiting |
St. Louis Park, Minnesota, United States, 55416 | |
Contact: Karen K Swenson, RN, PhD 952-993-6071 Karen.Swenson@parknicollet.com | |
Principal Investigator: Joseph W Leach, MD |
Principal Investigator: | Joseph Leach, MD | Park Nicollet Institute |
Study ID Numbers: | 3557-07-C |
Study First Received: | April 24, 2007 |
Last Updated: | April 25, 2007 |
ClinicalTrials.gov Identifier: | NCT00466232 |
Health Authority: | United States: Institutional Review Board |
Small Cell Lung Cancer Treatment |
Thoracic Neoplasms Carcinoma, Neuroendocrine Carcinoma Neuroendocrine Tumors Carcinoma, Small Cell Neuroectodermal Tumors Respiratory Tract Diseases Lung Neoplasms |
Lung Diseases Neoplasms, Germ Cell and Embryonal Neuroepithelioma Topotecan Adenocarcinoma Sorafenib Neoplasms, Glandular and Epithelial |
Respiratory Tract Neoplasms Neoplasms Neoplasms by Site Neoplasms by Histologic Type Molecular Mechanisms of Pharmacological Action Antineoplastic Agents |
Therapeutic Uses Neoplasms, Nerve Tissue Enzyme Inhibitors Protein Kinase Inhibitors Pharmacologic Actions |