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Bevacizumab and AZD2171 in Treating Patients With Metastatic or Unresectable Solid Tumor, Lymphoma, Intracranial Glioblastoma, Gliosarcoma or Anaplastic Astrocytoma
This study is ongoing, but not recruiting participants.

First Received on April 9, 2007.   Last Updated on December 15, 2011   History of Changes
Sponsor: M.D. Anderson Cancer Center
Collaborator: National Cancer Institute (NCI)
Information provided by (Responsible Party): M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT00458731
  Purpose

RATIONALE: 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. AZD2171 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Bevacizumab and AZD2171 may also stop the growth of cancer cells by blocking blood flow to the cancer. Giving bevacizumab together with AZD2171 may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of bevacizumab and AZD2171 in treating patients with metastatic or unresectable solid tumor, lymphoma, intracranial glioblastoma, gliosarcoma or anaplastic astrocytoma.


Condition Intervention Phase
Brain and Central Nervous System Tumors
Lymphoma
Intestinal Neoplasms
Unspecified Adult Solid Tumor, Protocol Specific
Biological: Bevacizumab (Avastin™)
Drug: AZD2171 (Cediranib Maleate)
Phase I

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Clinical Trial Evaluating the Toxicity, Pharmacokinetics and Biological Effect of Intravenous Bevacizumab (Avastin™) in Combination With Escalating Doses of Oral AZD2171 for Patients With Advanced Malignancies

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: Every 28 day cycle ] [ Designated as safety issue: Yes ]
  • Pharmacokinetics of Bevacizumab and AZD2171 [ Time Frame: Cycle 1 (beginning & end of 28 day cycle) ] [ Designated as safety issue: No ]
    Blood samples obtained at baseline (PRE-treatment), and 2, 4, (Day 1) and 24 hours (Day 2) after end of Avastin infusion and AZD2171 administration on the first cycle and once on Day 21.


Estimated Enrollment: 66
Study Start Date: May 2007
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bevacizumab + AZD2171 Biological: Bevacizumab (Avastin™)
Starting dose 3 mg/kg IV every two weeks (days 1 and 15)
Other Names:
  • Anti-VEGF monoclonal antibody
  • rhuMAb-VEGF
Drug: AZD2171 (Cediranib Maleate)
Starting dose 20 mg oral daily for 21 consecutive days (days 1-21)
Other Name: Cediranib

Detailed Description:

OBJECTIVES:

Primary

  • Determine the safety and toxicity of bevacizumab and AZD2171 in patients with metastatic or unresectable solid tumor, lymphoma, intracranial glioblastoma, gliosarcoma or anaplastic astrocytoma.
  • Determine the pharmacokinetic profile of this regimen in these patients.

Secondary

  • Correlate serum concentrations of nitric oxide (NO) and NO synthase with vascular endothelial growth factor (VEGF) expression in patients treated with this regimen.
  • Evaluate changes in tumor vasculature detected by dynamic contrast-enhanced MRI in patients treated with this regimen.
  • Determine the potential predictive role of angiogenesis molecular endpoints (e.g., VEGF) in malignant effusion samples.
  • Determine, preliminarily, the efficacy of this regimen in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral AZD2171 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 AZD2171 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.

PROJECTED ACCRUAL: A total of 66 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   15 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. 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).
  3. Age >/= 15 years
  4. ECOG performance status </= 2 (Karnofsky >/= 60%).
  5. Patients must have normal organ and marrow function as defined below: leukocytes >/= 3,000/mcL absolute neutrophil count >/=1,500/mcL; platelets >/= 100,000/mcL total bilirubin less than or equal to 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 less than or equal to 5.0 X institutional upper normal limit); serum creatinine </= 2.0 mg/dL
  6. Patients MUST have recovered from all treatment related toxicities to Grade 1 NCI CTC (v 4.0) in severity.
  7. Patients must be willing and able to review, understand, and provide written consent before starting therapy.
  8. Patients with stable brain metastasis (stable disease on one MRI assessment at least 4 weeks after completion of whole brain radiation, no evidence of progression on MRI assessment 4 weeks after stereotactic radiosurgery or complete surgical excision) will also be allowed to participate in this trial.
  9. Patients with histologically proven intracranial glioblastoma, gliosarcoma or anaplastic astrocytoma will be eligible. Patients must have shown unequivocal radiographic evidence for tumor progression by MRI scan as defined by Section 11.6. A scan should be performed within 14 days prior to registration and on a steroid dose that has been stable for at least 5 days. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI is required.

Exclusion Criteria:

  1. Patients with squamous non-small cell lung carcinoma.
  2. Serious or non-healing wound, ulcer or bone fracture.
  3. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days of day 1 of registration.
  4. Invasive procedures defined as follows: Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy; Anticipation of need for major surgical procedures during the course of the study; Core biopsy within 7 days prior to day 1 of registration.
  5. Patients may not be receiving any other investigational agents.
  6. 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.
  7. Uncontrolled systemic vascular hypertension (Systolic blood pressure > 140 mmHg, Diastolic Blood Pressure > 90 mmHg).
  8. Urine protein should be screened by dipstick or urine analysis. For proteinuria > 1+ or urine protein:creatinine ratio > 1.0, 24-hour urine protein should be obtained and the level should be < 1000 mg for patient enrollment.
  9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics on Day 1.
  10. Patients with clinically significant cardiovascular disease: History of CVA within 6 months; Myocardial Infarction or unstable angina within 6 months; New York Heart Association Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris; Clinically significant peripheral vascular disease: QTc prolongation >500msec or other significant ECG abnormality noted within 14 days of registration; Conditions requiring concurrent use of drugs or biologics with proarrhythmic potential.
  11. Pregnant women are excluded from this study because AZD-2171 is an angiogenesis inhibiting agent with potential teratogenic or abortifacient effects. Because of the potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD-2171, breastfeeding should be discontinued if the mother is treated with AZD-2171.These potential risks may also apply to other agents used in this study. Women of child-bearing potential and men must agree to use contraception prior to study entry and for the duration of study participation.
  12. (continued from exclusion criteria 11) Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00458731

Locations
United States, Texas
M. D. Anderson Cancer Center at University of Texas
Houston, Texas, United States, 77030-4009
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
Study Chair: David Hong, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT00458731     History of Changes
Other Study ID Numbers: 2005-0910, U01CA062461, P30CA016672, MDA-MDACC-2005-0910, CDR0000538277
Study First Received: April 9, 2007
Last Updated: December 15, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Advanced Cancer
Intravenous Bevacizumab
Avastin
Oral AZD2171
Cediranib Maleate
small intestine cancer
unspecified adult solid tumor, protocol specific
AIDS-related peripheral/systemic lymphoma
AIDS-related primary CNS lymphoma
anaplastic large cell lymphoma
angioimmunoblastic T-cell lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
intraocular lymphoma
nodal marginal zone B-cell lymphoma
primary central nervous system non-Hodgkin lymphoma
primary central nervous system Hodgkin lymphoma
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult Hodgkin lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent adult T-cell leukemia/lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma

Additional relevant MeSH terms:
Astrocytoma
Neoplasms
Glioblastoma
Intestinal Neoplasms
Lymphoma
Lymphoma, Non-Hodgkin
Nervous System Neoplasms
Lymphoma, Large-Cell, Immunoblastic
Central Nervous System Neoplasms
Lymphoma, Large-Cell, Anaplastic
Gliosarcoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Nervous System Diseases
Lymphoma, T-Cell

ClinicalTrials.gov processed this record on February 12, 2012