Pazopanib Hydrochloride in Treating Patients With Von Hippel-Lindau Syndrome

This phase II trial studies the side effects and how well pazopanib hydrochloride works in treating patients with von Hippel-Lindau syndrome. Pazopanib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVE: I. Evaluate safety and efficacy of treatment with pazopanib hydrochloride (pazopanib) for 6 months in patients with von Hippel-Lindau syndrome (VHL) who have a measurable VHL related lesion. SECONDARY OBJECTIVES: I. Evaluate rate of growth over time in target lesions before and after pazopanib treatment. II. Evaluate need for surgical intervention over time in patients who receive pazopanib and compare to rate prior to receipt of drug. III. Create an annotated tissue resource from patients with VHL for use in future research related to cancer. PRECLINICAL OBJECTIVES: I. Evaluate circulating factors in patients with VHL undergoing treatment with pazopanib. II. Evaluate relationship between VHL genotype and response to pazopanib. OUTLINE: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Treatment repeats every 4 weeks for up to 24 weeks in the absence of disease progression or unacceptable toxicity. Patients benefitting from treatment may continue pazopanib hydrochloride in the absence of disease progression. After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 24 weeks.

Patients receive pazopanib hydrochloride PO QD on days 1-28. Treatment repeats every 4 weeks for up to 24 weeks in the absence of disease progression or unacceptable toxicity. Patients benefitting from treatment may continue pazopanib hydrochloride in the absence of disease progression.

Determined by the Response Evaluation Criteria in Solid Tumors. Estimated with its corresponding 95% posterior credible interval.

TTP will be estimated using the Kaplan-Meier method. Log-rank test will be performed to test the difference in survival between prognostic groups. Regression analyses of survival data based on the Cox proportional hazards model will be conducted on TTP. The proportional hazards assumption will be evaluated graphically and analytically, and regression diagnostics (e.g., martingale and Shoenfeld residuals) will be examined to ensure that the models are appropriate.

Summary statistics, including frequency tabulation, means, standard deviations, median, and range, will be used to describe subject characteristics and marker data. The chi-squared test or Fisher's exact test will be used to test the association between two categorical variables, such as response and prognostic factors and discrete markers. The association among various continuous and discrete markers and response may be assessed first by the exploratory data analysis graphically and tested using Wilcoxon rank sum test.

Inclusion Criteria: 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 Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 Genetically confirmed diagnosis of VHL or measurable disease consistent with the clinical diagnosis of VHL At least one measurable VHL related lesion, which is undergoing surveillance, and patient is not at immediate risk of needing intervention for this or other lesions; biopsy is not required given the known likely etiology and natural history in the setting of a positive genetic test Brain: asymptomatic hemangioblastoma, >= 0.5 cm Spine: asymptomatic hemangioblastoma, >= 0.5 cm Renal: solid mass suspicious for renal cell carcinoma (RCC) >= 1 cm or cystic mass (Bosniak 3-4) >= 1 cm Pancreas: solid mass >= 1 cm and =< 3 cm suspicious for neuroendocrine tumor, or neuroendocrine tumor > 3 cm but not considered operable Eye: asymptomatic peripapillary and/or macular hemangioblastoma, any size Adrenal: asymptomatic or controlled pheochromocytoma greater than 1 cm in size Patients may have received prior VHL-related systemic therapy, provided not within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of pazopanib Absolute neutrophil count (ANC) >= 1.5 X 10^9/L Hemoglobin >= 9 g/dL (5.6 mmol/L) Subjects may not have had a transfusion within 7 days of screening assessment Platelets >= 100 X 10^9/L Prothrombin time (PT) or international normalized ratio (INR) =< 1.2 X upper limit of normal (ULN) Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation or if they are on low molecular weight heparin Activated partial thromboplastin time (aPTT) =< 1.2 X ULN Total bilirubin =< 1.5 X ULN Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.0 X ULN Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are not permitted Serum creatinine =< 2.0 mg/dL (133 umol/L) OR, if > 2.0 mg/dL: calculated creatinine clearance (ClCR) >= 50 mL/min Urine protein to creatinine ratio (UPC) < 1 If UPC >= 1, then a 24-hour urine protein must be assessed. Subjects must have a 24-hour urine protein value < 1 g to be eligible A female is eligible to enter and participate in this study if she is of: non-childbearing potential including Any female who has had a surgical procedure rendering her incapable of becoming pregnant 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 < 40 pg/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; 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 GlaxoSmithKline (GSK) acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows: 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 Oral contraceptive Injectable progestogen Implants of levonorgestrel Estrogenic vaginal ring Percutaneous contraceptive patches Intrauterine device (IUD) Male partner sterilization 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 Exclusion Criteria: Prior malignancy. Subjects who have had another non VHL related malignancy and have been disease-free for 2 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to: Active peptic ulcer disease Known intraluminal metastatic lesion/s with risk of bleeding Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation 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: Malabsorption syndrome Major resection of the stomach or small bowel Presence of uncontrolled infection 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: Cardiac angioplasty or stenting Myocardial infarction Unstable angina Coronary artery bypass graft surgery Symptomatic peripheral vascular disease 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 >= 90 mmHg); Note: initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry; blood pressure (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 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 for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study Treatment with any of the following anti-cancer therapies: Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of pazopanib OR 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 investigational therapy that is > grade 1 and/or that is progressing in severity, except alopecia

Jonasch E, McCutcheon IE, Gombos DS, Ahrar K, Perrier ND, Liu D, Robichaux CC, Villarreal MF, Weldon JA, Woodson AH, Pilie PG, Fuller GN, Waguespack SG, Matin SF. Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial. Lancet Oncol. 2018 Oct;19(10):1351-1359. doi: 10.1016/S1470-2045(18)30487-X. Epub 2018 Sep 17.