Advanced Clear Cell Renal Carcinoma Clinical Trial
Official title:
A Phase II Study of ZD6474 (Vandetanib) in Subjects With Advanced Clear Cell Renal Carcinoma
Background:
- One way tumors are able to grow is by forming new blood vessels that supply it with
nutrients and oxygen.
- Vandetanib (ZD6474) is an experimental drug that blocks certain proteins on the surface
of tumor and blood vessel cells that are involved with the formation of new blood
vessels.
- Blocking these proteins may prevent the tumor cells or blood vessels from continuing to
grow.
Objectives:
- To determine whether vandetanib can cause tumors to shrink or stabilize in patients
with advanced kidney cancer.
- To determine how vandetanib may work in people with kidney cancer and to develop tests
that may be helpful in studying kidney cancer.
Eligibility:
-Patients 18 years of age or older with advanced clear cell kidney cancer whose disease has
worsened after treatment with one or more of the following drugs: sunitinib, sorafenib,
interleukin-2 and temsirolimus; or patients who have had to stop treatment with these drugs
due to unacceptable side effects; or patients who are unable to receive standard treatment.
Design:
- Patients take a vandetanib pill once a day in 28-day cycles.
- Patients are followed in the clinic every 2 weeks during the first month of treatment
and then every 4 weeks for a physical examination, blood and urine tests,
electrocardiogram and a review of any drug side effects.
- Patients have imaging scans (computed tomography (CT) or magnetic resonance imaging
(MRI)) about every 8 weeks to monitor tumor growth. MRI scans are also done to look at
tumor blood flow when treatment begins, 24 hours after the first dose of treatment, and
again about 4 and 8 weeks after starting treatment
- Optional tumor biopsies (surgical removal of a sample of tumor tissue) may be done
before starting vandetanib treatment and after 4 weeks of treatment to look for drug
effects on the tumor.
| Status | Terminated |
| Enrollment | 3 |
| Est. completion date | June 2010 |
| Est. primary completion date | June 2010 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years and older |
| Eligibility |
- INCLUSION CRITERIA: Patients must meet all the following criteria to be eligible for study enrolment: Histologically confirmed clear cell renal cell carcinoma (to be confirmed at the Dept. of Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI)). Patients must have advanced disease (metastatic or unresectable) disease. Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT scan. See section 6.2 for the evaluation of measurable disease. Prior therapy: 1. All patients must have either received prior sunitinib or sorafenib (discontinued for disease progression or unacceptable toxicity) or be unable to receive these agents. Patients who have discontinued sunitinib or sorafenib for life threatening toxicities that are also known to occur with vandetanib (such as skin, GI toxicities, bowel perforation etc.) will not be eligible. 2. All patients must have failed high dose IL-2, be ineligible to receive this agent or decline this therapy. 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 3,000/microL, absolute neutrophil count greater than or equal to 1,500/microL, platelet count greater than or equal to 100,000/microL, 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 Gilbert's 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)) Recovery from acute toxicity of prior treatment for RCC (to less than or equal to grade 1 Common Terminology Criteria for Adverse Events (CTCAE) v3.0). At least 4 weeks from completion of major surgery and a healed surgical incision. Negative pregnancy test in female patients of childbearing potential within 7 days of enrollment. Ability to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Prior malignancy of other histology, with the exception of cervical carcinoma in situ or adequately treated basal or squamous cell carcinoma of the skin, or any other malignancy for which the patient has not required active treatment for more than three years. Patients with VHL disease will be excluded from this study. Patients may not be receiving any other investigational agents or have received treatment with a non-approved or investigational drug within 30 days before Day 1 of study treatment. Patients with known brain metastases (except when adequately treated greater than or equal to 6 months before enrollment with no evidence of recurrence). Use of 5HT-3 antagonists because of the potential effect on corrected Q wave, T wave (QTc) interval. Any concurrent medication that may cause QTc prolongation or induce Torsades de Pointes (Appendix C). Drugs listed in Appendix C, Table 2, that in the investigator's opinion cannot be discontinued, are allowed, but must be monitored closely. 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. Patients with a history a major cardiac event more than 3 months prior to enrolment will be evaluated by a cardiologist to assess cardiac status and potential for increased risk with ZD6474 therapy. 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 symptomatic/ 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 Bazett's correction that is unmeasurable, or greater than or equal to 480 msec on screening 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 electrocardiograms (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 (see Appendix C, Group/Table 2) 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. 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 ZD 6474 or other excipients of ZD6474. Concomitant medications that are potent inducers of cytochrome P450 3A4 (CYP3A4) function, such as rifampin, rifabutin, phenytoin, carbamazepine, barbiturates such as phenobarbital, or St. John's Wort. Inclusion of Women and Minorities: Both men and women and members of all races and ethnic groups are eligible for this trial. |
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| United States | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland |
| Lead Sponsor | Collaborator |
|---|---|
| National Cancer Institute (NCI) |
United States,
Chow WH, Devesa SS, Warren JL, Fraumeni JF Jr. Rising incidence of renal cell cancer in the United States. JAMA. 1999 May 5;281(17):1628-31. — View Citation
Phillips JL, Pavlovich CP, Walther M, Ried T, Linehan WM. The genetic basis of renal epithelial tumors: advances in research and its impact on prognosis and therapy. Curr Opin Urol. 2001 Sep;11(5):463-9. Review. — View Citation
Zambrano NR, Lubensky IA, Merino MJ, Linehan WM, Walther MM. Histopathology and molecular genetics of renal tumors toward unification of a classification system. J Urol. 1999 Oct;162(4):1246-58. Review. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Number of Participants With a Clinical Response (Partial Response (PR) + Clinical Response (CR)) | Clinical response is the best response recorded from the start of treatment until disease progression. Clinical response is assessed by the Response Evaluation in Solid Tumors (RECIST) criteria. A partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD. A complete response (CR) is the disappearance of all target lesions. | 12 months | No |
| Secondary | Effect of Vandetanib on Plasma Biomarkers-vascular Endothelial Growth Factor (VEGF), Vascular Endothelial Growth Factor 2 (VEGFR2) | Plasma VEGFR and VEGFR2 would have been measured using the (enzyme-linked immunosorbent assay)ELISA at baseline and specified timepoints following initiation of therapy. | 12 months | No |
| Secondary | Number of Circulating Endothelial Progenitor Cells (CEP) Per 10^6 Mononuclear Cells or Per Microliter of Peripheral Blood Analyzed in Samples Taken Before and After Treatment | CEP cell concentrations are calculated as a percentage of the total number of mononuclear cells or as the number of cells/microliter of whole blood after an evaluation of a minimum of 10^5 cellular events, and preferably 10^6 cellular events. | 12 months | No |
| Secondary | Progression-free Survival as Defined by the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | Progression free survival is defined as the time from initiation of treatment to either progression or death. RECIST evaluates tumor response. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria. For detailed information about RECIST, see the protocol Link module. |
12 months | No |
| Secondary | Number of Participants With Adverse Events | Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module. | 11.5 months | Yes |
| Secondary | Number of Circulating Endothelial Cells (CEC) Per 10^6 Mononuclear Cells or Per Microliter of Peripheral Blood Analyzed in Samples Taken Before and After Treatment | CEC cell concentrations are calculated as a percentage of the total number of mononuclear cells or as the number of cells/microliter of whole blood after an evaluation of a minimum of 10^5 cellular events, and preferably 10^6 cellular events. | 12 months | No |
| Secondary | Number of Participants With Vandetanib (ZD6474) Effects on Tumor Vascular Flow and Permeability Using Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) | Flow dynamics within specific tumor sites will be evaluated based on the results of the DCE-MRI obtained first without contrast enhancement and then after contrast enhancement. The parameter to be measured is the forward contrast transfer rate (Ktrans), the reverse contrast transfer rate (Kep), and/or the extravascular extracellular space volume fraction (Ve). Flow dynamics are a measure of blood flow changes in the tumor and are determined using the parameters previously defined (Ktrans, Kep, etc.). | 12 months | No |
| Secondary | Tumor Tissue Used to Evaluate Von Hippel-Lindau (VHL) Status and/or Components of the Vascular Endothelial Growth Factor (VEGF)/Epidermal Growth Factor Receptor (EGFR) Pathway | Components of the VEGF and EGFR pathways were to be evaluated using Western blot analysis at baseline and specified timepoints following initiation of therapy when tumor tissue was available. | 12 months | No |
| Secondary | The Effects of ZD6474 (Vandetanib) on Tumor Microvessel Density | Tumor tissue sections were to be stained with hematoxylin and eosin (H and E) and endothelial cell markers at baseline and specified timepoints following initiation of therapy (when tumor tissue was available) | 12 months | No |
| Secondary | Evaluate The Correlation Between Von Hippel-Lindau (VHL) Mutational Status and Response to ZD6474 (Vandetanib) | If an adequate number of responses were seen, the relation of these responses to the presence/absence of inactivating VHL mutations in tumor tissue would have been assessed. | 12 months | No |