Pazopanib in Patients With Relapsed or Refractory Small Cell Lung Cancer

OBJECTIVES:

Primary

• To determine the progression-free survival rate in participants with relapsed or refractory small cell lung cancer who have received one prior regimen of systemic chemotherapy at 8 weeks

Secondary

• To determine the response rate (as measured by RECIST 1.1 criteria and changes in blood flow/perfusion as measured by perfusion CT)
• To determine median and overall survival
• To characterize the toxicity profile of pazopanib in this patient population.

Exploratory

• To analyze levels of circulating biomarkers from blood and urine samples obtained serially throughout the study and assess the utility of individual or subsets of these proteins to serve as a surrogate marker for treatment effect, treatment efficacy, and for tumor progression
• To measure and investigate the use of monocytes as surrogate markers of angiogenesis inhibition
• To analyze the subject population by identification of intra-tumoral biomarkers (such as c-kit, VEGF receptors, and microvessel density measured in available tumor biopsies) associated with the efficacy, safety and resistance to pazopanib
• To assess the utility of perfusion CT scan in evaluating changes in anti-angiogenic activity as a measure of treatment efficacy

STATISTICAL DESIGN: This study uses a two-stage design to evaluate efficacy of cetuximab based on progression-free rate (PFR) at week 8 defined as complete response (CR), partial response (PR) or stable disease (SD) per RECIST 1.1 criteria. The null and alternative PFR are 30% and 50%. If fewer than 4 patients enrolled in the stage one cohort (n=15 patients) achieve SD or better than accrual would not proceed to stage two (n=15 patients). If 13 or more patients are progression-free of the 30 patients then the null hypothesis will be rejected. The probability that the treatment will be considered promising if the true PFR rate was 30% is 8.4% and 82% if the true PFR rate was 50%.

Inclusion criteria

• Diagnosis of small cell neuroendocrine carcinoma based on either histology or cytology with radiologically-confirmed progressive disease.
• Participants should have received first-line chemotherapy and may have had up to two prior chemotherapy regimens. Radiation therapy may have been part of the permitted prior therapy.
• Participants with brain metastases will be allowed if they have been treated with surgery and/or radiation therapy more than 21 days prior, are asymptomatic, and are stable for at least one week off steroids.
• 18 years of age or older
• ECOG Performance status of 0, 1 or 2
• Ability to swallow and retain oral medication
• Disease must be measurable according to RECIST 1.1
• Adequate organ function as defined in the protocol

Exclusion criteria

• Prior malignancy except for participants that have been disease-free for 3 years or with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma
• History or clinical evidence of central nervous system metastases or leptomeningeal carcinomatosis except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for one week prior to first dose of study drug.
• Clinically significant gastrointestinal abnormalities
• Presence of uncontrolled infection
• Prolongation of corrected QT interval (QTc) > 480msecs
• History of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting; myocardial infarction; unstable angina; symptomatic peripheral vascular disease; Class III or IV congestive heart failure
• Poorly controlled hypertension
• History of cerebrovascular accident including transient ischemic attack, pulmonary embolism or insufficiently treated deep venous thrombosis within the past 6 months
• Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture or ulcer
• Evidence of active bleeding or bleeding diathesis
• Hemoptysis in excess of 2.5mL within 6 weeks of first dose of study drug
• Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures
• Use of any prohibited medication within the timeframes listed in the protocol
• Use of an investigational agent, including an investigational anti-cancer agent, within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug
• Prior use of an investigational or licensed drug that targets VEGF or VEGF receptors
• Is now undergoing and/or has undergone in the 14 days immediately prior to first dose of study drug, any cancer therapy
• Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is progressing in severity
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib