Carcinoma, Renal Cell
Conditions
Keywords
pazopanib, Renal Cell Carcinoma, Kidney, cancer, bevacizumab
Brief summary
This study will determine whether blood tests, tumour imaging and tumour tissue analysis can reveal effects of drugs that block blood vessel growth (angiogenesis) in patients with renal cancer.
Detailed description
This single-centre, two-part, open-label study is designed to evaluate pharmacodynamic (PD) effects of bevacizumab and pazopanib in subjects with renal cancer who experience disease progression following at least one prior therapy of documented clinical benefit. In Part I, subjects will receive 3 infusions of 10 mg/kg bevacizumab, administered at 2-week intervals. The PD response to bevacizumab will be evaluated over 6 weeks using imaging techniques (magnetic resonance imaging; computed tomography \[CT\]; and positron emission tomography), intratumoural VEGF signaling by immunohistochemisty, plasma and serum biomarkers, and circulating tumour cells. Subjects may continue into Part II if, in the opinion of the investigator, the subject would derive continued clinical benefit from anti-angiogenic therapy. In Part II, each subject will receive sequentially escalating doses of oral pazopanib in 3-week cycles as follows: 1) 200 mg twice weekly, 2) 200 mg every other day, 3) 200 mg daily, 4) 400 mg daily, 5) 800 mg daily, and 6) 1200 mg daily. Subjects entering Part II will be randomised to receive treatment either throughout each 3-week cycle (Group 1) or for the first 2 weeks of each cycle only, followed by a 1 week treatment holiday (Group 2). After completion of Part II dose escalation subjects will receive continuous pazopanib at a dose of 800 mg daily in repeating 3-week cycles. These subjects will receive pazopanib until loss of clinical benefit, death, unacceptable toxicity, or withdrawal from the study for other reasons.
Interventions
DRUGBevacizumab
Bevacizumab - 3 infusions of 10mg/kg administered at 2 week intervals - Part I
DRUGPazopanib 2 week
Pazopanib for first 2 weeks of each 3-week cycles as follows: 1) 200 mg twice weekly, 2) 200 mg every other day, 3) 200 mg qd, 4) 400 mg qd, 5) 800 mg qd, and 6) 1200 mg qd (Group 1). Maintenance pazopanib 800 mg qd for all 3 weeks throughout repeating 3-week cycles. Number of cycles: until death, loss of clinical benefit, unacceptable toxicity, or withdrawal from the study for other reasons.
DRUGPazopanib 3 week
Pazopanib throughout each 3-week cycle as follows: 1) 200 mg twice weekly, 2) 200 mg every other day, 3) 200 mg qd, 4) 400 mg qd, 5) 800 mg qd, and 6) 1200 mg qd (Group 1). Maintenance pazopanib 800 mg qd for all 3 weeks throughout repeating 3-week cycles. Number of cycles: until death, loss of clinical benefit, unacceptable toxicity, or withdrawal from the study for other reasons.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically (any histological subtype) or cytologically confirmed unresectable RCC with a clear cell component. * Experienced documented evidence of radiological progression based on Response Evaluation Criteria in Solid Tumors \[RECIST\] while on first line (or greater) RCC therapy and within 6 months prior to the first dose of study medication (bevacizumab). * Evidence of unidimensionally measurable disease (i.e., at least 1 malignant tumour mass that can be accurately measured in at least 1 dimension with the longest diameter greater than or equal to 20 mm with conventional CT or MRI or V10 mm with spiral CT scan \[if spiral CT scan is used, minimum lesion size should be twice the reconstruction interval used, e.g., if reconstruction size is 7 mm, lesion size should be greater than or equal to 14 mm\]) Note: Subject should be excluded if all baseline measurable lesions are within previously irradiated areas. * Free of any malignant disease other than RCC for at least 5 years prior to the first dose of study medication (bevacizumab) in this study, with the exception of the following: Cervical carcinoma in situ, Melanoma in situ, Basal or squamous cell carcinoma of the skin * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 * Resolution of all acute toxic effects of prior chemotherapy, radiotherapy, or surgical procedures to NCI CTCAE Grade 1 or less. * Adequate organ function as defined by laboratory ranges Note: Laboratory values just outside of these ranges may be included if in the view of the investigator and medical monitor, these findings will not interfere with the study or pose an unacceptable risk to the subject. * Capable of giving written informed consent, and willing and able to comply with the requirements and restrictions listed in the consent form. * Males and females greater than or equal to 18 years of age at screening. A female subject is eligible to participate if she is of non-childbearing potential (see below) or if she is of childbearing potential and agrees to use one of the defined contraception methods from the time of first dose of study medication (bevacizumab) until 4 months after the last dose of study medication (bevacizumab or pazopanib). Non-childbearing potential is defined as pre-menopausal females with a documented bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or postmenopausal females with 12 months of spontaneous amenorrhea. If the exact duration of amenorrhea is unknown, a blood sample with simultaneous follicle stimulating hormone (FSH) greater than or equal to 40 MIU/mL and estradiol less than or equal to 40 pg/mL (less than or equal to 140 pmol/L) will be required as confirmation. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the approved contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method. A male subject is eligible to participate if he agrees to use one of the contraception methods listed in from the time of first dose of study medication (bevacizumab) until 4 months after the last dose of study medication (bevacizumab or pazopanib). Inclusion criteria for progression to Part II * The subject met all eligibility criteria (inclusive of inclusion and
Exclusion criteria
) for participation in Part I of the study. * In the opinion of the Investigator, the subject would derive continued therapeutic benefit from anti-angiogenic therapy. * In the opinion of the Investigator, there are no safety concerns that would present an unacceptable benefit:risk profile for treatment with pazopanib. * The subject is able to swallow and retain oral medication.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Tumour size, as measured by the sum of the longest diameters of all target lesions on CT | 6 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Plasma levels of pharmacodynamic markers of study drug effect | 6 weeks Part I; 15 weeks Part II; 6 weeks during maintenance therapy |
Countries
United Kingdom
Outcome results
None listed