Pazopanib Hydrochloride in Treating Patients With Stage IV Kidney Cancer

A Phase II Study of Pazopanib in VEGF-TKI Refractory Metastatic Renal Cell Carcinoma (MRCC)

RATIONALE: Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial is studying how well pazopanib hydrochloride works in treating patients with stage IV kidney cancer.

PRIMARY OBJECTIVES:

I. To determine the response rate (RR) associated with pazopanib (pazopanib hydrochloride) as 3rd-line therapy in metastatic renal cell carcinoma (mRCC) patients who have failed therapy with a distinct vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (TKI).

SECONDARY OBJECTIVES:

I. To determine if baseline hepatocyte growth factor (HGF), endothelial selectin (E-selectin) and interleukin-6 (IL-6) are associated with progression-free survival (PFS).

II. To determine if pre-metastatic niche density in regional lymph nodes (LNs) is associated with PFS.

III. To determine an association between E-selectin, IL-6 and pre-metastatic niche density.

IV. To evaluate the prognostic effect of pre-metastatic niches as an independent factor in time to first relapse.

V. To determine if phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in tumor tissue is associated with PFS.

VI. To describe the toxicity associated with pazopanib in this patient population.

VII. To evaluate PFS and overall survival (OS). VIII. To compare, within patient, time to tumor progression of 2nd-line therapy with time to tumor progression on pazopanib as 3rd-line therapy.

OUTLINE:

Patients receive oral pazopanib hydrochloride once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months.

Inclusion

• Histologically confirmed diagnosis of metastatic clear cell RCC
• At least one measurable lesion at baseline as per RECIST 1.1 criteria; if skin lesions are reported as target lesions, they must be documented (at baseline and at every physical exam) using color photography and a measuring device (such as a caliper) in clear focus to allow the size of the lesion to be determined from the photograph
• 1 prior VEGF-TKI required
• 1 other prior systemic therapy allowed
• ECOG PS 0-1
• Resolution of grade >= 2 toxicity from prior therapy
• Subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow-up; procedures conducted as part of the subject's routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol
• A female is eligible to enter and participate in this study if she is of non-child bearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had (1) a hysterectomy, (2) a bilateral oophorectomy (ovariectomy), (3) a bilateral tubal ligation, or (4) is post-menopausal; subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for >= 1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value > 40 mIU/mL and an estradiol value < 40pg/mL (< 140 pmol/L); subjects using HRT must have experienced total cessation of menses for >= 1 year and be greater than 45 years of age OR have had documented evidence of menopause based on FSH and estradiol concentrations prior to initiation of HRT
• Patients with childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception; GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows: (1) complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product, (2) oral contraceptive, either combined or progestogen alone, (3) injectable progestogen, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year, (4) male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject, (6) double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository); female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug
• Absolute neutrophil count (ANC) >= 1.5 X 10^9/L
• Hemoglobin >= 9 g/dL (5.6 mmol/L)
• Platelets >= 100 X 10^9/L
• Prothrombin time (PT) or international normalized ratio (INR) =< 1.2 X ULN
• Activated partial thromboplastin time (aPTT) =< 1.2 X ULN
• Total bilirubin =< 1.5 X ULN
• Alanine amino transferase (ALT) =< 2.5 X ULN
• Aspartate aminotransferase (AST) =< 2.5 X ULN
• Serum creatinine =< 2.0 mg/dL (133 umol/L) or, if >2.0 mg/dL; calculated creatinine clearance (ClCR) by Cockroft-Gault formula >= 30 mL/min
• Urine Protein to Creatinine Ratio (UPC) < 1

Exclusion

• Concurrent use of other investigational agents
• Known history of allergic reactions to pazopanib or other VEGF-TKIs
• Presence of serious or uncontrolled infection
• Prior malignancy (Note: Subjects who have had another malignancy and have been disease-free for 3 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible)
• History or clinical evidence of central nervous system (CNS) 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 6 months prior to first dose of study drug; screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases
• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to (1) active peptic ulcer disease, (2) known intraluminal metastatic lesion/s with risk of bleeding, (3) inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), (4) other gastrointestinal conditions with increased risk of perforation, or (5) history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment
• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to (1) malabsorption syndrome or (2) major resection of the stomach or small bowel
• Corrected QT interval (QTc) > 480 msecs using Bazett's formula
• History of any one or more of the following cardiovascular conditions within the past 6 months: (1) cardiac angioplasty or stenting, (2) myocardial infarction, (3) unstable angina, (4) coronary artery bypass graft surgery, (5) symptomatic peripheral vascular disease, or (6) Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)
• Poorly controlled hypertension defined as systolic blood pressure (SBP) of >= 140 mmHg or diastolic blood pressure (DBP) of >= 90mmHg
• Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry; BP must be re-assessed on two occasions that are separated by a minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP values from each BP assessment must be < 140/90 mmHg in order for a subject to be eligible for the study
• History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months; (Note: subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible)
• 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 (procedures such as catheter placement not considered to be major)
• Evidence of active bleeding or bleeding diathesis
• Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels
• Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks prior to the 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
• Unable or unwilling to discontinue use of prohibited medications list as specified in the full protocol for at least 14 days of a drug prior to the first dose of study drug and for the duration of the study
• Treatment with any of the following anti-cancer therapies: (1) radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of pazopanib OR (2) chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of pazopanib
• Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is progressing in severity, except alopecia
• Non-Compliance: Patients, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
• Medications that inhibit CYP3A4 may result in increased plasma pazopanib concentrations; therefore, co-administration of strong CYP3A4 inhibitors is PROHIBITED beginning 14 days prior to the first dose of study drug until discontinuation from the study; strong CYP3A4 inhibitors include (but are not limited to): certain antibiotics (including clarithromycin, telithromycin, and troleandomycin), certain HIV protease inhibitors (including ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, and lopinavir), certain antifungals (including itraconazole, ketoconazole, voriconazole, and fluconazole) and certain antidepressants (including nefazodone)