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


Phase 1
18 Years
N/A
Not Enrolling
Both
Unspecified Adult Solid Tumor

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Trial Information

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


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of imatinib when given together with bevacizumab and metronomic cyclophosphamide

Outcome 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.

Safety Issue:

Yes

Principal Investigator

Emily K. Bergsland, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of California, San Francisco

Authority:

United States: Institutional Review Board

Study ID:

06991

NCT ID:

NCT00390156

Start Date:

August 2006

Completion Date:

January 2011

Related Keywords:

  • Unspecified Adult Solid Tumor
  • refractory
  • prior treatment
  • solid tumors
  • phase I
  • phase 1
  • Neoplasms

Name

Location

UCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California  94115