Pazopanib in Patients With Relapsed or Refractory Small Cell Lung Cancer

A Phase II Study of Pazopanib in Patients With Relapsed or Refractory Small Cell Lung Cancer (SCLC)

Pazopanib is a drug that inhibits proteins thought to be important for new blood vessel formation. This drug has been used in other cancer research studies and information from those studies suggests that pazopanib may help block proteins that are important for the growth, invasion, and spread of cancer cells.

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