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

NCT00083031 | Completed Phase 2 DMC

• 3 other identifiers: 03-083P50CA089393P30CA006516
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 4

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.

Conditions

Breast Cancer

Keywords

recurrent breast cancer; stage IV breast cancer

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  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.

  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.

Secondary Outcomes (2)

• Progression-Free Survival (PFS)

  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.

• Overall Survival (OS)

  Patients were followed until death or lost-to-follow-up. Patients were followed for OS up to approximately 4 years.

Study Arms (2)

Arm A-Bevacizumab

EXPERIMENTAL

* 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; Drug: cyclophosphamide; Drug: methotrexate

Arm B- Without Bevacizumab

EXPERIMENTAL

* Methotrexate- twice daily on predetermined days per each week per cycle * Cyclophosphamide- oral, daily, predetermined dose

Drug: cyclophosphamide; Drug: methotrexate

Interventions

bevacizumab DRUG

Also known as: Avastin

Arm A-Bevacizumab

cyclophosphamide DRUG

Also known as: Cytoxan, Neosar

Arm A-Bevacizumab; Arm B- Without Bevacizumab

methotrexate DRUG

Also known as: Otrexup™, Rasuvo®, Rheumatrex®, Trexall

Arm A-Bevacizumab; Arm B- Without Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• National Cancer Institute (NCI): collaborator
• Genentech, Inc.: collaborator

Study Sites (4)

Massachusetts General Hosptial

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Related Publications (1)

• Mayer EL, Tayob N, Ren S, Savoie JJ, Spigel DR, Burris HA 3rd, Ryan PD, Harris LN, Winer EP, Burstein HJ. A randomized phase II study of metronomic cyclophosphamide and methotrexate (CM) with or without bevacizumab in patients with advanced breast cancer. Breast Cancer Res Treat. 2024 Feb;204(1):123-132. doi: 10.1007/s10549-023-07167-9. Epub 2023 Nov 29.

  PMID: 38019444 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Bevacizumab; Cyclophosphamide; Methotrexate

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Harold J. Burstein, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 14, 2004
• First Posted: May 17, 2004
• Study Start: July 1, 2003
• Primary Completion: August 1, 2006
• Study Completion: August 1, 2009
• Last Updated: May 21, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)