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

A Phase I Trial of Imatinib, Bevacizumab, & Metronomic Cyclophosphamide as Antiangiogenic Therapy in Refractory Metastatic Solid Tumors

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.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor
• Intervention / Treatment: Biological: bevacizumab; Drug: cyclophosphamide; Drug: imatinib

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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143-1705
      • UCSF Helen Diller Family Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose of imatinib when given together with bevacizumab and metronomic cyclophosphamide	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.

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetics of imatinib	After the last patient completes PKs on Cycle 1 Day 16
Safety of imatinib in combination with cyclophosphamide and bevacizumab	After all patients have completed study therapy. Safety data will be monitored throughout the study.

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Novartis
• Investigators: Study Chair: Emily K. Bergsland, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: October 18, 2006
• First Submitted That Met QC Criteria: October 18, 2006
• First Posted (Estimate): October 19, 2006

Study Record Updates

• Last Update Posted (Actual): July 28, 2020
• Last Update Submitted That Met QC Criteria: July 24, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: phase 1; solid tumors; phase I; refractory; prior treatment
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Cyclophosphamide; Bevacizumab; Imatinib Mesylate
• Other Study ID Numbers: 06991 (Other Identifier: UCSF); H9672-28868 (Other Identifier: UCSF CHR); CSTI571BUS245 (Other Identifier: Novartis)