Phase I Clinical Trial Evaluating the Toxicity, Pharmacokinetics and Biological Effect of Intravenous Bevacizumab (Avastin TM) in Combination With Escalating Doses of Oral AZD2171 for Patients With Advanced Malignancies
Overview
- Phase
- Phase 1
- Intervention
- bevacizumab
- Conditions
- Adult Grade III Lymphomatoid Granulomatosis
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 57
- Locations
- 1
- Primary Endpoint
- Pharmacokinetic profile of oral cediranib maleate in combination with bevacizumab
- Status
- Completed
- Last Updated
- 12 years ago
Overview
Brief Summary
This phase I trial is studying the side effects and best dose of bevacizumab and cediranib maleate in treating patients with metastatic or unresectable solid tumor, lymphoma, intracranial glioblastoma, gliosarcoma or anaplastic astrocytoma. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Cediranib maleate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Bevacizumab and cediranib maleate may also stop the growth of cancer cells by blocking blood flow to the cancer. Giving bevacizumab together with cediranib maleate may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the safety and toxicity profile of intravenous bevacizumab (avastin) administered in combination with oral AZD2171 (cediranib maleate) for patients with advanced malignancies. II. To determine the pharmacokinetic profile of oral AZD2171 in combination with bevacizumab (avastin) administered to patients with advanced malignancies. SECONDARY OBJECTIVES: I. To evaluate the serum concentrations of Nitric Oxide (NO) and Nitric oxide synthase (NOS) among patients treated with this regimen and to correlate with VEGF expression. II. To determine changes in the tumor vasculature detected by DCE-MRI among patients treated with this combination of VEGF receptor blocking agents. III. To evaluate the potential predictive role of angiogenesis molecular endpoints in malignant effusion samples. IV. To assess in a descriptive fashion the efficacy of the studied regimen. OUTLINE: This is a dose-escalation study. Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral cediranib maleate once daily on days 1-21. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bevacizumab and cediranib maleate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Blood samples are acquired at baseline, on day 2, and after 2 courses of treatment for pharmacokinetic studies. Samples are analyzed by TUNEL, immunofluorescence staining, laser-scanning cytometry, flow cytometry, enzyme-linked immunosorbent assay, and immunohistochemistry to assess apoptosis in tumor and endothelial cells, microvessel density mean vessel volume, nitric oxide concentration, and signal transduction pathways (i.e., ERK ½, P38 mitogen-activated protein kinase, protein kinase B, circulating endothelial and progenitor cells, basic fibroblast growth factor, vascular endothelial growth factor (VEGF) receptor phosphorylation, VEGF, and hypoxia inducible factor-1α). Some patients also undergo tissue biopsy at baseline and after 2 courses of treatment for characterization of vascular and angiogenesis markers. Some patients also undergo DCE-MRI at baseline, once between days 22-24, and after every 2 courses of treatment to assess blood perfusion. After completion of study treatment, patients are followed for 6 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histological confirmation of Solid Tumor or Lymphoma that is metastatic or unresectable; if assessing a single target lesion, histological confirmation of that particular lesion MUST be carried out
- •Patients may have received an unlimited number of prior therapies; however, At least 4 weeks MUST have passed since the last chemotherapy to day 1 of registration (6 weeks for regimens containing nitrosoureas or Mitomycin C)
- •ECOG performance status =\< 2 (Karnofsky \>= 60%)
- •Leukocytes \>= 3,000/mcL
- •Absolute neutrophil count \>= 1,500/mcL
- •Platelets \>= 100,000/mcL
- •Total bilirubin =\< 2.0 mg/dL (does NOT apply to patients with Gilbert's Syndrome)
- •AST(SGOT)/ALT(SGPT) =\< 2.5 X institutional upper limit of normal (Patients with liver involvement will be allowed =\< 5.0 X institutional upper normal limit)
- •Serum creatinine =\< 2.0 mg/dL
- •Patients MUST have recovered from all treatment related toxicities to Grade 1 NCI CTC (v 4.0) in severity
Exclusion Criteria
- •Patients with squamous non-small cell lung carcinoma
- •Serious or non-healing wound, ulcer or bone fracture
- •History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days of day 1 of registration
- •Invasive procedures defined as follows:
- •Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 registration
- •Anticipation of need for major surgical procedures during the course of the study
- •Core biopsy within 7 days prior to day 1 of therapy
- •Patients may not be receiving any other investigational agents
- •Patients with bleeding diathesis (clinical bleeding, prothrombin time \>= 1.5 X upper institutional normal value, INR \>= 1.5, activated partial thromboplastin time aPTT \>= 1.5 X upper institutional normal value), active gastric or duodenal ulcer
- •Uncontrolled systemic vascular hypertension (Systolic blood pressure \> 140 mmHg, Diastolic Blood Pressure \> 90 mmHg)
Arms & Interventions
Treatment (cediranib maleate and bevacizumab)
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral cediranib maleate once daily on days 1-21. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bevacizumab and cediranib maleate until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Intervention: bevacizumab
Treatment (cediranib maleate and bevacizumab)
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral cediranib maleate once daily on days 1-21. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bevacizumab and cediranib maleate until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Intervention: cediranib maleate
Outcomes
Primary Outcomes
Pharmacokinetic profile of oral cediranib maleate in combination with bevacizumab
Time Frame: Baseline and at 1, 2, 3, 4, 6, 8, and 24 hours after cediranib maleate treatment
Safety and toxicity profile of combination bevacizumab and cediranib maleate
Time Frame: Up to 6 weeks post-treatment
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.