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 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.

Inclusion Criteria:

- Patients must have histologically proven small cell carcinoma of bronchogenic origin.

- Must have received one course of systemic chemotherapy which included cisplatin or
carboplatin. Chemotherapy administered during radiation is allowable.

- Must have radiographically documented disease recurrence or progression by CT scan or
bone scan. CNS only recurrence is not sufficient. Measurable disease per RECIST
criteria is not required.

- ECOG Performance status of 0 to 2

- Adequate organ function within 14 days of study enrollment as defined by the
following:

- Absolute neutrophil count ≥ 1500/mm3

- Platelet count ≥ 100,000/mm3

- Hemoglobin ≥ 9 gm/dL

- Creatinine ≤ 1.5 mg/dL

- Bilirubin < 1.5 times upper limit of normal (x UNL)

- Alkaline phosphatase, aspartate transaminase and alanine transaminase < 3 x ULN
(may be <5 x ULN if hepatic metastases)

- Women of childbearing potential and sexually active males must use an effective
method of contraception during the study and for 3 months after the last dose of
study drug.

- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of treatment.

- Treated brain metastases that are stable for a minimum of 4 weeks following surgery
or radiation and off therapeutic glucocorticoids are allowed.

- INR<1.5 or a PT/PTT within normal limits. Patients receiving anti- coagulation
treatment with an agent such as warfarin or heparin may be allowed to participate.
For patients on warfarin, the INR should be measured prior to initiation of sorafenib
and monitored at least weekly, or as defined by the local standard of care, until INR
is stable.

- Ability to understand and the willingness to sign a written informed consent. A
signed informed consent must be obtained prior to any study specific procedures.

Exclusion Criteria:

- Pregnant or breast feeding.

- Myocardial infarction or cerebrovascular accident within 6 months.

- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic
blood pressure > 90 mmHg despite optimal medical management.

- History of other active invasive malignancy (except for basal cell or squamous cell
skin cancer) within 12 months.

- Major surgery within 4 weeks.

- Chemotherapy within 4 weeks.

- Cardiac disease: Congestive heart failure > NYHA Class II, unstable or new-onset
angina within prior 3 months.

- History of bleeding diathesis or coagulopathy.

- Active clinically serious infection > CTCAE Grade 2.

- Ventricular arrhythmias requiring anti-arrhythmic therapy.

- Serious non-healing wound, ulcer or fracture.

- Any hemorrhage or bleeding event > CTCAE Grade 3 within 4 weeks of study enrollment.

- Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of
study drug.

- Thrombotic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months.

- Known human immunodeficiency virus (HIV) or chronic hepatitis B or C infection.

- Any condition that impairs patient's ability to swallow whole pills.

- Any gastrointestinal malabsorption syndrome

- Use of St. John's wort or rifampin.