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Home > "A" Clinical Trials Conditions > A Phase I Trial of Bevacizumab in Refractory Solid Tumors  A Phase I Trial of Bevacizumab in Refractory Solid Tumors
A Phase I Trial of Bevacizumab in Refractory Solid Tumors
For Condition:
Status: Recruiting
Sponsor(s): National Cancer Institute (NCI) ,
Synopsis: The growth of solid tumors is dependent on the tumor's ability to induce the formation of new blood vessels through the process of angiogenesis. Tumors secrete proteins, including vascular endothelial growth factor (VEGF) that activate microvascular endothelial cells to proliferate, migrate and organize into capillary structures. Bevacizumab is a humanized monoclonal neutralizing antibody that binds all five isoforms of human VEGF. In laboratory models, bevacizumab selectively inhibits VEGF-mediated tumor angiogenesis in a variety of tumors including neuroblastoma, rhabdomysosarcoma, Wilms' tumor, and hepatoblastoma. In animal studies, bevacizumab toxicity included physeal dysplasia (regional cessation of bone growth in animals with open growth plates) that was partially reversible, delayed wound healing, irregular menses, and proteinuria. In clinical trials in adults with solid tumors, no maximum tolerated dose was established. Toxicities attributed to bevacizumab included bleeding, thrombosis, hypertension, and proteinuria. No patient developed anti-bevacizumab antibody. In patients with renal cell carcinoma, bevacizumab (10 mg/kg IV q 2 weeks) resulted in a statistically significant prolongation in time to progression vs. placebo (hazard ratio= 2.3, p=0.001). In a randomized clinical trial in adults with metastatic colon cancer (n=800) the addition of bevacizumab (5mg/kg IV) to irinotecan/5FU/leucovorin increased survival, progression free survival, and response rate compared to irninotecan/5FU/leucovorin alone. In women with metastatic breast cancer, the combination of bevacizumab and capectabine improved response rate but did not impact progression free or 12-month survival compared to capecitabine alone. In this phase I study in pediatric patients with refractory solid tumors, bevacizumab will be administered intravenously every 2 weeks (day 1 and day 15) on a 28-day cycle. The starting dose of bevacizumab (5 mg/kg/dose) is 50% of the dose administered to adults in ongoing phase III trials. Children can remain on study for up to 1 year (12 cycles) if they do not experience significant toxicity or progressive disease (RECIST criteria). All pediatric patients will have bone age and lower extremity scanogram to monitor for physeal dysplasia. Plasma pharmacokinetics of bevacizumab will be obtained during cycle 1. During therapy patients will be monitored for the development of anti-bevacizumab antibody, serum and urine VEGF, VCAM-1, ICAM-1, bFGF, and TSP-1, and circulating endothelial cells and endothelial cell precursors. When available, tumor tissue for VEGF RNA expression by immunohistochemistry and RT-PCR will be obtained.
Details: The growth of solid tumors is dependent on the tumor's ability to induce the formation of new blood vessels through the process of angiogenesis. Tumors secrete proteins, including vascular endothelial growth factor (VEGF) that activate microvascular endothelial cells to proliferate, migrate and organize into capillary structures. Bevacizumab is a humanized monoclonal neutralizing antibody that binds all five isoforms of human VEGF. In laboratory models, bevacizumab selectively inhibits VEGF-mediated tumor angiogenesis in a variety of tumors including neuroblastoma, rhabdomysosarcoma, Wilms' tumor, and hepatoblastoma. In animal studies, bevacizumab toxicity included physeal dysplasia (regional cessation of bone growth in animals with open growth plates) that was partially reversible, delayed wound healing, irregular menses, and proteinuria. In clinical trials in adults with solid tumors, no maximum tolerated dose was established. Toxicities attributed to bevacizumab included bleeding, thrombosis, hypertension, and proteinuria. No patient developed anti-bevacizumab antibody. In patients with renal cell carcinoma, bevacizumab (10 mg/kg IV q 2 weeks) resulted in a statistically significant prolongation in time to progression vs. placebo (hazard ratio= 2.3, p=0.001). In a randomized clinical trial in adults with metastatic colon cancer (n=800) the addition of bevacizumab (5mg/kg IV) to irinotecan/5FU/leucovorin increased survival, progression free survival, and response rate compared to irninotecan/5FU/leucovorin alone. In women with metastatic breast cancer, the combination of bevacizumab and capectabine improved response rate but did not impact progression free or 12-month survival compared to capecitabine alone. In this phase I study in pediatric patients with refractory solid tumors, bevacizumab will be administered intravenously every 2 weeks (day 1 and day 15) on a 28-day cycle. The starting dose of bevacizumab (5 mg/kg/dose) is 50% of the dose administered to adults in ongoing phase III trials. Children can remain on study for up to 1 year (12 cycles) if they do not experience significant toxicity or progressive disease (RECIST criteria). All pediatric patients will have bone age and lower extremity scanogram to monitor for physeal dysplasia. Plasma pharmacokinetics of bevacizumab will be obtained during cycle 1. During therapy patients will be monitored for the development of anti-bevacizumab antibody, serum and urine VEGF, VCAM-1, ICAM-1, bFGF, and TSP-1, and circulating endothelial cells and endothelial cell precursors. When available, tumor tissue for VEGF RNA expression by immunohistochemistry and RT-PCR will be obtained.
Eligibility:
Study Type: Interventional, Treatment, Safety
Minimum Age/Maximum Age: /
Genders: Both
Protocol Entry Criteria: All studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated below. The eligibility criteria listed below are interpreted literally and cannot be waived. INCLUSION CRITERIA: 1. Age Patients must be greater than 1 and equal to or less than 21. 2. Diagnosis Histologic Verification- Patients must have had histologic verification of the malignancy at original diagnosis. All solid tumors are eligible with the specific exclusions of lymphomas, primary CNS tumors or patients with a history of CNS metastasis. Disease Status Patients must have either measurable or evaluable disease. Evaluable disease is defined as an assessment of tumor that cannot be quantified using a ruler or calipers, but can be used to determined disease progression or complete response (e.g. disease detectable by bone scan, bone marrow disease, tumor marker, or presence of malignant pleural effusion). Therapeutic Options Patient's current disease state must be one for which there is no known curative therapy. 3. Performance Level Karnofsky greater than or equal to 50% for patients greater than 10 years of age and Lansky greater than or equal to 50 for patients less than or equal to 10 years of age. Patients who are unable to walk because of paralysis or orthopedic involvement but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score. 4. Life Expectancy Must be greater than or equal to 8 weeks. 5. Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. a. Myelosuppressive chemotherapy: Must not have received within 3 weeks of entry onto this study (6 weeks if prior nitrosourea). b. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. These patients must be discussed with the study chair on a case-by case basis. c. Monoclonal antibody therapy: At least 8 weeks must have elapsed prior to the first planned dose of bevacizumab. d. XRT: greater than or equal to 2 wks for local palliative XRT (small port); greater than or equal to 4 months must have elapsed if prior craniospinal XRT or if greater than or equal to 50% radiation of pelvis; greater than or equal to 6 wks must have elapsed if other substantial BM radiation. e. Stem Cell Transplant (SCT): No evidence of active graft vs. host disease and greater than or equal to 2 months must have elapsed. 6. Concomitant Medications a). Growth factor(s): Must not have received within 1 week of entry onto this study. b). Anticoagulants: Must not have current or recent use of full-dose anticoagulants including systemic thrombolytic agents, heparin, low molecular weight heparins or warfarin except as required to maintain patency of preexisting, permanent indwelling IV catheters. Last dose must be at least 1 week prior to study entry. c). Antipyretics and nonsteroidal anti-inflammatory medications: Must not have received medications known to inhibit platelet function or known to selectively inhibit cyclooxygenase-2 (COX-2) activity (i.e., all antipyretic and anti-inflammatory medications except acetaminophen) within 1 week prior to study entry. 7. Organ Function Requirements Adequate Bone Marrow Function Defined as: For patients with solid tumors without bone marrow involvement: -Peripheral absolute neutrophil count (ANC) greater than or equal to 1000/uL -Platelet count greater than or equal to 1000,000/uL (transfusion independent) -Hemoglobin greater than or equal to 8.0 gm/dL (may receive RBC transfusions); except as designated. Patients with tumor metastatic to bone marrow: -Baseline platelet count greater than or equal to 75,000/uL (transfusion independent) -Baseline granulocytopenia, anemia, and/or mild thrombocytopenia are eligible, but will not be evaluable for hematological toxicity. At least 2 of every cohort of 3 patients must be evaluable for hematologic toxicity. If dose limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity. Adequate Blood Clotting Defined as: -PT/PTT: less than or equal 1.2 x upper limit of normal Adequate Renal Function Defined as: -Negative urine dipstick for protein OR -Less than or equal to 500 mg protein/24 hour urine collection -Creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/m(2) OR -A serum creatinine based o age as follows: Age (Years) Maximum Serum Creatinine (mg/dL) Less than or equal to 5 0.8 5 less than age less than or equal to 10 1.0 10 less than age less than or equal to 15 1.2 Greater than 15 1.5 Adequate Liver Function Defined as: -Total bilirubin less than or equal to1.5 x upper limit of normal (ULN) for age, and -SGPT (ALT) less than or equal 5 x upper limit of normal (ULN) for age and albumin greater than or equal to 2 g/dL. EXCLUSION CRITERIA: 1. Pregnancy or Breast-Feeding: No information is available regarding human fetal or teratogenic toxicities. However, given the inhibitory effect of bevacizumab on VEGF, which is responsible for new vessel formation during the course of normal development, and the fact that antibodies can cross the placenta, the possibility of harm to the fetus is likely. Bevacizumab should not be administered to pregnant women. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. 2. Surgical Procedures and Serious or Non-healing Wounds: Patients with a documented, chronic non-healing wound, ulcer, or bone fracture or history of a major surgical procedure or significant traumatic injury within 28 days prior to beginning therapy should be excluded due to preclinical evidence supporting the potential for delayed wound healing. Minor surgical procedures for limited purposes of tissue retrieval will be allowed. For minor surgeries, patients should not receive the first planned dose of bevacizumab until the wound is healed and 7 days have elapsed. For procedures such as the placement of an indwelling IV catheter, it is recommended that bevacizumab be postponed for at least 24 hours after the procedure. 3. Known Bleeding Diathesis or Coagulopathy 4. Thrombosis: Patients must not have had a deep venous or arterial thrombosis (including pulmonary embolism) within the last three months prior to study entry, and must not have a known thrombophilic condition (i.e. protein S, protein C or antithrombin III deficiency, Factor V Leiden, Factor II G20210A mutation, homocysteinemia or antiphospholipid antibody syndrome). 5. Cardiac Disease or Hypertension: Patients must not have a history or myocardial infarction, severe or unstable angina, or severe peripheral vascular disease. Hypertension must be well controlled on stable doses of medication for at least two weeks. 6. Proteinuria: Patients must have either: (1) no proteinuria as assessed by urine dipstick; or (2) 24-hour urine collection demonstrating less than 500 mg of protein. 7. CNS Disease: History or clinical evidence of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastasis, or history of stroke. 8. Allergy: Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human bodies. 9. Patients Who Have an Uncontrolled Infection 10. Patients Who Have Previously Received Study Drug
Total Enrollment: 4
Location and Contact Information:
National Cancer Institute (NCI) *Recruiting*
Bethesda, Maryland, 20892
United States
Recruiting Patient and Public Liaison Office 1-800-411-1222
Additional Information:
Study ID Numbers: 040148; 04-C-0148
Study Start Date: April 2, 2004
Record last reviewed: March 19, 2004
Additional information available at: clinicaltrials.gov
Clinicaltrials.gov Reference link: NCT00080561
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A Phase I Trial of Bevacizumab in Refractory Solid Tumors
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