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Metronomic Low-Dose Cyclophosphamide and Methotrexate With or Without Bevacizumab in Treating Women With Metastatic Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00083031
Recruitment Status : Completed
First Posted : May 17, 2004
Last Update Posted : May 21, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Genentech, Inc.
Information provided by (Responsible Party):
Harold J. Burstein, MD, PhD, Dana-Farber Cancer Institute

Brief Summary:
This randomized phase II trial is studying metronomic low-dose cyclophosphamide and methotrexate to see how well they work compared to metronomic low-dose cyclophosphamide, methotrexate, and bevacizumab in treating women with metastatic breast cancer.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: bevacizumab Drug: cyclophosphamide Drug: methotrexate Phase 2

Detailed Description:

This study uses an investigational drug called Bevacizumab. Investigational means that this drug is not approved by the Federal Drug Administration and is still being studied. Bevacizumab is the common name for the commercial drug Avastin. The Bevacizumab used in this trial, however, is for use in research studies only and may be made at locations different from those where Avastin is made. Although some differences may exist, bevacizumab for research use and the commercial drug, Avastin, are manufactured by a similar process, meet similar standards for final product testing, and are expected to be very similar in safety and effectiveness.

The purpose of this study is to find out what effects (good and bad) low-dose continuous chemotherapy (referred to as metronomic chemotherapy) using drugs Cytoxan (also called cyclophosphamide) and methotrexate (CM), with or without bevacizumab.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 57 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Metronomic Chemotherapy With Bevacizumab for Advanced Breast Cancer
Actual Study Start Date : July 2003
Actual Primary Completion Date : August 2006
Actual Study Completion Date : August 2009

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Arm A-Bevacizumab
  • Methotrexate- twice daily on predetermined days per each week per cycle
  • Cyclophosphamide- oral, daily, predetermined dose
  • Bevacizumab- Via IV on predetermined days per cycle
Drug: bevacizumab
Other Name: Avastin

Drug: cyclophosphamide
Other Names:
  • Cytoxan
  • Neosar

Drug: methotrexate
Other Names:
  • Otrexup™
  • Rasuvo®
  • Rheumatrex®
  • Trexall

Experimental: Arm B- Without Bevacizumab
  • Methotrexate- twice daily on predetermined days per each week per cycle
  • Cyclophosphamide- oral, daily, predetermined dose
Drug: cyclophosphamide
Other Names:
  • Cytoxan
  • Neosar

Drug: methotrexate
Other Names:
  • Otrexup™
  • Rasuvo®
  • Rheumatrex®
  • Trexall




Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: Disease evaluations occurred every 8 weeks for the first 6 cycles and every 12 weeks thereafter until progression, death or lost-to-follow-up. Patients were followed for ORR up to approximately 1 year. ]
    ORR is the proportion of patients achieving Complete Response (CR) or Partial Response (PR) based on RECIST 1.0 criteria: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Both require confirmation no fewer than 4 weeks apart. CR/PR assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.


Secondary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: Disease evaluations occurred every 8 weeks for the first 6 cycles and every 12 weeks thereafter until progression, death or lost-to-follow-up. Patients were followed for PFS up to approximately 1 year. ]
    PFS based on the Kaplan-Meier method is defined as the time from study entry and documented disease progression (PD) per RECIST 1.0 criteria or death. Patients alive without progression are censored at time of last disease assessment. Per RECIST 1.0 for target lesions, PD is at least a 20% increase in sum LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or appearance of new lesions. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

  2. Overall Survival (OS) [ Time Frame: Patients were followed until death or lost-to-follow-up. Patients were followed for OS up to approximately 4 years. ]
    OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed invasive breast cancer, with stage IV disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis by physical exam or radiologic study.
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan. The protocol will employ the RECIST criteria.
  • Prior Therapy:

    • Chemotherapy: early stage breast cancer. Patients may have received prior adjuvant chemotherapy and/or hormonal therapy for early stage breast cancer, including cyclophosphamide-based chemotherapy regimens.
    • Chemotherapy: metastatic breast cancer. Patients may have received 0-1 prior regimens for metastatic breast cancer. No prior oral cyclophosphamideor methotrexate-based therapy for metastatic disease is permitted.
    • Chemotherapy: anthracyclines. Patients without prior anthraycline (in either the metastatic or adjuvant setting) exposure are eligible provided that they do not have visceral (parenchymal lung or liver) metastases. Patients without prior anthracycline-based therapy are expected to have "low volume" tumor burden, deemed appropriate for non-standard chemotherapy in the estimation of the treating clinician.
    • Trastuzumab. Patients with HER2-positive breast tumors must have received prior trastuzumab therapy for advanced disease, or have had recurrence within 12 months of receiving (neo)adjuvant trastuzumab.
    • Radiation therapy. Patients may have received prior radiation therapy in either the metastatic or early stage settings. Radiation therapy may not be administered during the study. Lesions progressing after previous irradiation are measurable; lesions not progressing after previous irradiation are not measurable.
    • Hormonal therapy. Patients with estrogen- or progesterone-receptor positive disease must have received at least one prior hormonal therapy in the adjuvant and/or metastatic setting.

      --- Patients must discontinue chemotherapy and/or hormonal therapy prior to study participation.

    • Concurrent Therapy. Patients may receive concurrent bisphosphonate therapy and/or erythropoietin growth factor support while on study. Patients may not receive other experimental treatments while on study. Bisphosphonate therapy and/or erythropoietin growth factor support therapy may commence at any point on study.
  • Patients may not have received prior experimental angiogenesis inhibitors.
  • Age ≥18 years.
  • Life expectancy greater than 6 months.
  • ECOG performance status ≤ 1 (Karnofsky ≥70%; see Appendix B).
  • Absence of poorly controlled hypertension (as defined by the treating clinician), proteinuria, prior history of either deep venous or arterial thrombosis, bleeding diatheses (including hemoptysis).
  • Radiologic exclusion of brain metastases (because of concern for potential CNS bleeding with therapy). All patients must have a brain CT or MRI no more than 6 weeks prior to enrollment.
  • Left ventricular function ≥ 45% as assessed by echocardiogram or nuclear medicine gated study.
  • Patients must have normal organ and marrow function as defined below. Labs should be completed within 4 weeks prior to registration.

    • absolute neutrophil count ≥1000/mm3
    • platelets ≥100,000/mm3
    • total bilirubin ≤ 2 x institutional upper limit of normal (ULN)
    • AST(SGOT)/ALT(SGPT) ≤ 4.0 x ULN
    • Alkaline phosphatase ≤ 5.0 x ULN
    • creatinine ≤ 2.0 mg/dl
    • 24 hr urine specimen < 500 mg protein/24 hr

      --- or

    • Protein on urinalysis < 1+
    • PT, PTT ≤ institutional upper limit of normal (ULN)
  • Fertility/reproduction. Patients must be neither pregnant nor expect becoming pregnant or conceiving a child while on study. Women of childbearing potential must have a negative pregnancy test. The effects of bevacizumab, methotrexate, and cyclophosphamide on the developing fetus are unknown. For this reason, women of childbearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Exclusion Criteria
  • Patients with less than stage IV disease or lack measurable disease.
  • Prior therapy that included any of the following:

    • Chemotherapy for metastatic breast cancer. Patients who have received ≥ 2 prior regimens for metastatic breast cancer; or who have received prior oral cyclophosphamide- or methotrexate-based therapy for metastatic disease.
    • Patients who have not recovered from reversible adverse events due to prior treatments.
    • Patients still on hormonal therapy - including LHRH agonist therapy.
  • Current use of anticoagulants or chronic aspirin therapy (> 325 mg/day) - excluding low-dose warfarin used for venous access patency (doses of 1 to 2 mg/d.)
  • History of grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide (such as other alkylating agents) or methotrexate (such as other antimetabolites.)
  • Patients with recent (within 6 months) arterial thromboembolic events, including transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina, or myocardial infarction (MI). Patients with clinically significant peripheral artery disease should also be excluded.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients with visceral metastases unless they have previously been treated with an anthraycline-based chemotherapy regimen in either the metastatic or adjuvant setting.
  • Patients may not receive other investigational agents while on study.
  • Non-healing wounds or major surgical procedures other than for venous access device or diagnostic study are not permitted within 28 days prior to enrollment (because of rare potential risk of delayed wound healing associated with bevacizumab).
  • Patients with large or rapidly accumulating pleural or abdominal effusions (based on clinician's judgment) because of the theoretical risk for methotrexate accumulation and related toxicity. --- If a patient's condition is deteriorating, laboratory evaluations should be repeated ≤ 48 hours prior to initiation of therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00083031


Locations
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United States, Massachusetts
Massachusetts General Hosptial
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Tennessee
Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
Dana-Farber Cancer Institute
National Cancer Institute (NCI)
Genentech, Inc.
Investigators
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Principal Investigator: Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute
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Responsible Party: Harold J. Burstein, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT00083031    
Other Study ID Numbers: 03-083
P50CA089393 ( U.S. NIH Grant/Contract )
P30CA006516 ( U.S. NIH Grant/Contract )
First Posted: May 17, 2004    Key Record Dates
Last Update Posted: May 21, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Harold J. Burstein, MD, PhD, Dana-Farber Cancer Institute:
recurrent breast cancer
stage IV breast cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Bevacizumab
Methotrexate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists