Imatinib, Bevacizumab, and Cyclophosphamide in Patients With Refractory Metastatic Solid Tumors

This study has been completed.
Sponsor:
Collaborators:
Novartis
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00390156
First received: October 18, 2006
Last updated: October 9, 2013
Last verified: October 2013
  Purpose

RATIONALE: Imatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bevacizumab and cyclophosphamide may also stop the growth of tumor cells by blocking blood flow to the tumor. Imatinib and bevacizumab may help cyclophosphamide work better by making tumor cells more sensitive to the drug. Giving cyclophosphamide once a day together with imatinib and bevacizumab may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of imatinib when given together with bevacizumab and cyclophosphamide in treating patients with refractory metastatic solid tumors.


Condition Intervention Phase
Unspecified Adult Solid Tumor
Biological: bevacizumab
Drug: cyclophosphamide
Drug: imatinib
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of Imatinib, Bevacizumab, & Metronomic Cyclophosphamide as Antiangiogenic Therapy in Refractory Metastatic Solid Tumors

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Maximum tolerated dose of imatinib when given together with bevacizumab and metronomic cyclophosphamide [ Time Frame: Safety data will be assessed after 3 patients and 6 patients complete 42 days of study treatment to determine whether to dose escalate to the next cohort. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacokinetics of imatinib [ Time Frame: After the last patient completes PKs on Cycle 1 Day 16 ] [ Designated as safety issue: No ]
  • Safety of imatinib in combination with cyclophosphamide and bevacizumab [ Time Frame: After all patients have completed study therapy. Safety data will be monitored throughout the study. ] [ Designated as safety issue: Yes ]

Enrollment: 35
Study Start Date: August 2006
Study Completion Date: January 2011
Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
Intervention Details:
    Biological: bevacizumab
    5 mg/kg
    Other Name: Avastin
    Drug: cyclophosphamide
    Current dose 50 mg
    Other Name: Cytoxan
    Drug: imatinib
    Current dose 400 mg
    Other Name: Gleevec
Detailed Description:

OBJECTIVES:

Primary

  • Determine the maximum tolerated dose of imatinib when given together with bevacizumab and metronomic cyclophosphamide in patients with refractory metastatic solid tumors.
  • Determine the safety profile of this regimen in these patients.

Secondary

  • Determine the effects of cyclophosphamide and bevacizumab on imatinib pharmacokinetics.
  • Determine if patients treated with this regimen achieve plasma levels of cyclophosphamide that are predicted to be antiangiogenic.
  • Determine the effects of this regimen on the number of circulating endothelial cells, endothelial progenitor cells, activated endothelial cells, and circulating tumor cells.
  • Determine the effects of this regimen on parameters measured by CT scan perfusion (e.g., regional blood flow, blood volume, permeability-surface area product, and mean transit time).

OUTLINE: This is a nonrandomized, open-label, pilot, dose-escalation study of imatinib.

Patients receive oral cyclophosphamide and oral imatinib once daily on days 1-28 and bevacizumab IV on days 1 and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of imatinib 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. At least 6 patients are treated at the MTD.

PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of solid tumor

    • Advanced or metastatic disease* NOTE: *With the exception of colorectal and lung cancer patients, all patients must receive approval from the insurance carrier that allows for coverage/payment of the study drug bevacizumab
  • Refractory to standard therapy OR no standard therapy exists
  • No advanced ovarian cancer or peritoneal carcinomatosis
  • No metastases from any cancer causing significant ascites
  • No lung malignancy with any of the following characteristics:

    • In close proximity to a major vessel
    • Centrally located
    • Cavitary
    • Squamous histology
    • Hemoptysis > ½ teaspoon per day

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-1
  • Platelet count ≥ 100,000/mm^3
  • Absolute neutrophil count ≥ 1,500/mm^3
  • Bilirubin < 2 mg/dL
  • AST or ALT < 3 times upper limit of normal
  • Creatinine < 2 mg/dL
  • Urine protein:creatinine ratio ≤ 1.0
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Able to tolerate oral therapy
  • No bleeding diatheses or coagulopathy
  • No impairment of gastrointestinal (GI) function or GI disease that may affect or alter absorption of imatinib mesylate and/or cyclophosphamide (e.g., malabsorption syndrome, history of total gastrectomy/significant small bowel resection)
  • No abdominal fistula, GI perforation, or intra-abdominal abscess within the past 6 months
  • No uncontrolled hypertension (i.e., blood pressure > 150/100 mm Hg)
  • No uncontrolled cardiovascular disease, including any of the following:

    • Coronary artery disease
    • Uncontrolled cardiac arrhythmia
    • Symptomatic congestive heart failure (i.e., New York Heart Association class II-IV)
    • Unstable angina pectoris
    • Clinically significant peripheral vascular disease
  • No arterial thromboses within the past year, including any of the following:

    • Transient ischemic attack
    • Myocardial infarction
    • Cerebrovascular event
    • Unstable angina
    • Angina requiring medical or surgical intervention
    • Clinically significant peripheral artery disease
    • Any other arterial thromboembolic event
  • No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
  • No serious nonhealing wound, ulcer, or bone fracture
  • No other active second malignancy except nonmelanoma skin cancer or cervical carcinoma in situ unless therapy has been completed and < 30% risk for relapse exists
  • No active infection or known HIV infection
  • No history of allergic reactions (≥ grade 3 or 4) to compounds of similar chemical or biologic composition to cyclophosphamide (i.e., alkylating agents)
  • No history of noncompliance with medical regimens
  • No known intolerance or hypersensitivity reaction to bevacizumab, imatinib mesylate, or cyclophosphamide
  • No other significant medical illness, psychiatric illness, or social situation that, in the opinion of the investigator, would limit compliance with study requirements
  • No inability to grant reliable informed consent

PRIOR CONCURRENT THERAPY:

  • No major surgical procedure within the past 28 days or anticipated major surgery during study treatment except for placement of a venous access device or surgery for a diagnostic study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00390156

Locations
United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94143-1705
Sponsors and Collaborators
University of California, San Francisco
Novartis
Investigators
Study Chair: Emily K. Bergsland, MD University of California, San Francisco
  More Information

Additional Information:
No publications provided

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00390156     History of Changes
Other Study ID Numbers: 06991, P30CA082103, 06991, H9672-28868, CSTI571BUS245
Study First Received: October 18, 2006
Last Updated: October 9, 2013
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by University of California, San Francisco:
refractory
prior treatment
solid tumors
phase I
phase 1

Additional relevant MeSH terms:
Neoplasms
Cyclophosphamide
Imatinib
Bevacizumab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Protein Kinase Inhibitors
Enzyme Inhibitors
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on July 24, 2014