Phase II Study of Vandetanib in Individuals With Kidney Cancer
Raktažodžiai
Santrauka
apibūdinimas
Background:
Von Hippel Lindau disease is a hereditary cancer syndrome in which affected individuals are at risk for developing tumors in a number of organs, including the kidneys, brain, spine, adrenal glands, eyes and pancreas.
The molecular hallmark of VHL is inactivation of the VHL gene which leads to accumulation of proteins targeted for degradation through the ubiquitin pathway, which includes a group of transcriptionally active proteins called the hypoxia inducible factors (HIF), whose alpha subunits undergo degradation in a VHL-dependent fashion. Accumulation of HIFs results in overexpression of several genes including vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), transforming growth factor (TGF)-alpha, platelet- derived growth factor (PDGF), and erythropoietin, which are believed to play a role in tumorigenesis, tumor progression and metastasis.
ZD6474 is an orally administered receptor tyrosine kinase inhibitor with activity against the Kinase insert domain-containing receptor/vascular endothelial growth factor receptor 2 (KDR/VEGFR2) and the epidermal growth factor receptor (EGFR). Kinase insert domain receptor (KDR)/vascular growth factor receptor 2 (VEGFR2) is an endothelial cell receptor for vascular endothelial growth factor (VEGF) and plays a crucial role in mediating tumor angiogenesis, while epidermal growth factor receptor (EGFR) (a receptor for TGF-alpha and epidermal growth factor (EGF) is believed to mediate tumor growth and proliferation.
Objective:
Primary Objective
To assess the overall response rate in VHL patients with renal tumors treated with single agent ZD6474
Secondary Objectives:
To study the safety and tolerability of ZD6474
To evaluate time to progression and progression-free survival in VHL patients receiving ZD6474
To study the effect of ZD6474 treatment on non-renal tumors associated with von Hippel Lindau disease ( pancreatic tumors, pheochromocytoma, central nervous system (CNS) hemangioblastomas)
To investigate the effect of ZD6474 on circulating endothelial cells and endothelial progenitor cells and to explore the utility of these markers as surrogates of angiogenesis inhibition
To investigate the effect of ZD6474 on biomarkers of angiogenesis such as plasma VEGF and soluble VEGFR2
Eligibility:
Adults with clinical diagnosis of von Hippel Lindau disease
Presence of one or more measurable renal tumors
Age greater than or equal to 18 years
Adequate organ function, performance status (Eastern Cooperative Oncology Group (ECOG) 0-2) and life expectancy (greater than 3 months)
Design:
Single agent ZD6474 administered daily at a starting dose of 300mg per day
Patients will be evaluated for response every 12 weeks using Response Evaluation Criteria in Solid Tumors (RECIST) criteria
The study is based on an open label two-stage optimal phase II design
Accrual of a maximum of 37 patients.
Datos
Paskutinį kartą patikrinta: | 09/30/2018 |
Pirmasis pateikimas: | 11/30/2007 |
Numatytas registravimas pateiktas: | 11/30/2007 |
Pirmas paskelbtas: | 12/03/2007 |
Paskutinis atnaujinimas pateiktas: | 10/01/2018 |
Paskutinis atnaujinimas paskelbtas: | 10/29/2018 |
Pirmųjų rezultatų pateikimo data: | 02/11/2015 |
Pirmojo QC rezultatų pateikimo data: | 03/08/2015 |
Pirmųjų paskelbtų rezultatų data: | 03/10/2015 |
Faktinė studijų pradžios data: | 02/06/2008 |
Numatoma pirminio užbaigimo data: | 06/19/2014 |
Numatoma studijų užbaigimo data: | 02/28/2015 |
Būklė ar liga
Intervencija / gydymas
Drug: Vandetanib in Participants with Kidney Cancer
Fazė
Rankų grupės
Ranka | Intervencija / gydymas |
---|---|
Experimental: Vandetanib in Participants with Kidney Cancer 300 mg/day (starting dose) oral dose of vandetanib once a day for 28 days | Drug: Vandetanib in Participants with Kidney Cancer |
Tinkamumo kriterijai
Amžius, tinkami studijuoti | 18 Years Į 18 Years |
Tinkamos studijoms lytys | All |
Priima sveikus savanorius | Taip |
Kriterijai | - INCLUSION CRITERIA: Patients must satisfy all the following criteria to be eligible for study enrolment. Clinical diagnosis of von Hippel Lindau disease. The presence of at least one measurable (as defined by RECIST) renal tumor (renal cell carcinoma (RCC)). Patients with tumors localized to the kidney as well as those with metastatic RCC are eligible. Age greater than or equal to 18 years. Life expectancy greater than 3 months Performance status Eastern Cooperative Oncology Group (ECOG) 0-2. Patients must have normal organ and marrow function as defined below: white blood cell (WBC) count greater than or equal to 3,000micro/L, absolute neutrophil count greater than or equal to 1,500 micro/L platelet count greater than or equal to 100,000 micro/L, serum creatinine less than or equal to 1.5 times upper limit of reference range or measured 24 hr. creatinine clearance greater than or equal to 50 ml/min, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 2.5 times upper limit of reference range, total bilirubin less than 1.5 times upper limit of reference range (less than 3 times upper limit of reference range in patients with Gilberts disease), alkaline phosphatase less than or equal to 2.5 times upper limit of reference range (or less than or equal to 5 times upper limit of reference range if considered to be related to liver metastases by the principal investigator (PI)). No history of serious intercurrent medical illness. At least four weeks from completion of any other surgical or investigational therapy for von Hippel Lindau and at least 4 weeks from any major surgical procedure. In addition, patients who have undergone recent major surgery should have well healed surgical incisions. All men and women of childbearing potential must use effective contraception. Negative pregnancy test in female patients of childbearing potential within 7 days prior to enrolment on study Ability to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Prior or concomitant non-von Hippel Lindau associated malignancy with the exception of adequately treated basal or squamous cell carcinoma of the skin, cervical carcinoma in situ or any other malignancy from which the patient has remained disease free for more than five years. Known brain metastases (unless adequately resected or irradiated with no evidence of recurrence for at least 6 months). Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events (to less than or equal to grade 1 Common Terminology Criteria in Adverse Events (CTCAE) v3.0) due to agents administered more than 4 weeks earlier. Patients may not be receiving any other investigational agents or have received treatment with a non-approved or investigational drug within 4 weeks prior to Day 1 of study treatment except those used for imaging studies. Use of 5HT-3 antagonists because of the potential effect on corrected QT interval (QTc) interval. Any concurrent medication that may cause QTc prolongation or induce Torsades de Pointes. Concomitant medications that are potent inducers of cytochrome P450 3A4 (CYP3A4) function, such as rifampin, rifabutin, phenytoin, carbamazepine, barbiturates such as phenobarbital, or St. Johns Wort. Clinically significant cardiac event (including symptomatic heart failure, myocardial infarction or angina) within 3 months of entry or presence of any cardiac disease that in the opinion of the Principal Investigator increases the risk of ventricular arrhythmia. History of clinically significant arrhythmia [including multifocal premature ventricular contraction (PVC), bigeminy, trigeminy, ventricular tachycardia] that is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia Uncontrolled atrial fibrillation. Atrial fibrillation controlled on medication is not excluded. Presence of Left bundle branch block. Previous history of QTc prolongation while taking other medications that required discontinuation of that medication. Congenital long QT syndrome or first degree relative with unexplained sudden death under the age of 40 years QTc with Bazetts correction that is unmeasurable, or greater than or equal to 480 msec on screening electrocardiogram (ECG). If a patient has QTc greater than or equal to 480 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be less than 480 msec in order for the patient to be eligible for the study). Patients who are receiving a drug that has a risk of QTc prolongation are excluded if QTc is greater than or equal to 460 msec. Potassium concentration less than 4.0 mEq/L, calcium (ionized calcium or adjusted for albumin), or magnesium concentrations outside normal limits despite optimal supplementation/correction Left ventricular ejection fraction less than 45 percent measured by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO) Hypertension not controlled by medical therapy (systolic blood pressure greater than 150 mmHg or diastolic blood pressure greater than 100 mmHg). Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patient known to be human immunodeficiency virus (HIV) positive and requiring antiretroviral therapy. Currently active diarrhea that may affect the ability of the patient to absorb ZD6474 or tolerate further diarrhea. Patients on therapeutic anticoagulation Patients with known bleeding disorders Pregnant women are excluded from this study because ZD6474 is an anti-angiogenic agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ZD6474, breastfeeding should be discontinued if the mother is treated with ZD6474. Any known hypersensitivity to ZD6474 or other excipients of ZD6474. |
Rezultatas
Pirminės rezultatų priemonės
1. Overall Response Rate. [Baseline and every 3 cycles, up to 2 years]
Antrinės rezultatų priemonės
1. Number of Participants With Adverse Events [72 months and 14 days]
2. Time To Progression (TTP) [Baseline and every 3 cycles while on study, up to 2 years.]
3. Progression Free Survival (PFS) [Baseline and every 3 cycles while on study, up to 2 years.]
4. Effect of Vandetanib (ZD6474) on Endothelial Progenitor Cells [Pre treatment, 4 hours after first treatment, and after one cycle of treatment (one cycle = 28 days)]
5. Effect of Vandetanib (ZD6474) on Circulating Endothelial Cells (CEC) [Pre treatment, 4 hours after first treatment, and after one cycle of treatment (one cycle = 28 days)]
6. Response in Pancreatic Tumors/Cysts Associated With Von Hippel Lindau (VHL) [Baseline and every 3 cycles while on study, up to 2 years.]
7. Response in Central Nervous System (CNS) Hemangioblastomas Associated With Von Hippel Lindau (VHL) [Baseline and every 3 cycles while on study, up to 2 years.]
8. Response in Pheochromocytomas Associated With Von Hippel Lindau (VHL) [Baseline and every 3 cycles while on study, up to 2 years.]
Kitos rezultato priemonės
1. Change in Plasma Biomarkers Vascular Endothelial Growth Factor (VEGF) and Soluble Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) Before and After Treatment With Vandetanib [Pre treatment, 4 hours after first treatment, and after one cycle of treatment (one cycle = 28 days)]