Sunitinib, Cyclophosphamide, and Methotrexate in Treating Patients With Metastatic Breast Cancer

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00616122
First received: February 14, 2008
Last updated: November 1, 2013
Last verified: November 2013
  Purpose

RATIONALE: Sunitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide and methotrexate, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sunitinib together with combination chemotherapy may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of sunitinib when given together with cyclophosphamide and methotrexate to see how well they work in treating patients with metastatic breast cancer.


Condition Intervention Phase
Breast Cancer
Drug: cyclophosphamide
Drug: methotrexate
Drug: sunitinib malate
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of SU11248 (Sutent) in Combination With Metronomic Dosing of Cyclophosphamide and Methotrexate in Patients With Metastatic Breast Cancer

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Maximum Tolerated Dose (Phase I) [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]

    Patients in each cohort were followed for DLT for at least 8 weeks (2 week lead-in with sunitinib and 6 weeks of treatment with sunitinib and metronomic cyclophosphamide and methotrexate) before opening accrual to the next dose level.

    Dose limiting toxicity (DLT):

    1. ≥ grade 3 anemia that does not resolve with appropriate growth factors afebrile grade 4 neutropenia that does not resolve with growth factor support after ≥ 7 days
    2. grade 4 neutropenia associated with fever (1 reading of oral temperature > 38.5 ºC or 3 readings of oral temperature > 38.0 ºC in a 24 hour period)
    3. ≥ grade 3 thrombocytopenia
    4. ≥ grade 3 non-hematologic toxicities, except those that can be controlled to grade 2 or less with appropriate treatment.
    5. Inability to resume treatment with any of the study medications within 14 days of stopping due to treatment related toxicity.

  • PFS Greater Than or Equal to 12 Weeks (Phase II) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    Per Response Evaluation Criteria in Solid Tumors (RECIST):

    Complete Response (CR): Complete disappearance of all measurable and evaluable disease. No new lesions. Partial Response (PR): greater than or equal to 50% decrease under baseline in the sum of the products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable: Does not qualify for complete response, partial response or progression. Progression: 25% increase or an increase of 10 sq. cm (whichever is smaller) in the sum of products of measurable lesions over smallest sum observed (over baseline if no decrease), OR appearance of any lesion which had disappeared, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to deteriorating condition (unless deterioration is clearly unrelated to this cancer).



Secondary Outcome Measures:
  • Response [ Time Frame: until disease progression up to 13 months post treatment ] [ Designated as safety issue: No ]

    Per Response Evaluation Criteria in Solid Tumors (RECIST):

    Complete Response (CR): Complete disappearance of all measurable and evaluable disease. No new lesions. Partial Response (PR): greater than or equal to 50% decrease under baseline in the sum of the products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable: Does not qualify for complete response, partial response or progression. Progression: 25% increase or an increase of 10 sq. cm (whichever is smaller) in the sum of products of measurable lesions over smallest sum observed (over baseline if no decrease), OR appearance of any lesion which had disappeared, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to deteriorating condition (unless deterioration is clearly unrelated to this cancer).


  • Duration of Response [ Time Frame: until disease progression up to 13 months post treatment ] [ Designated as safety issue: No ]
    duration of response refers to duration of single partial response observed per Response Evaluation Criteria in Solid Tumors (RECIST): Complete Response (CR): Complete disappearance of all measurable and evaluable disease. No new lesions. Partial Response (PR): greater than or equal to 50% decrease under baseline in the sum of the products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable: Does not qualify for complete response, partial response or progression. Progression: 25% increase or an increase of 10 sq. cm (whichever is smaller) in the sum of products of measurable lesions over smallest sum observed (over baseline if no decrease), OR appearance of any lesion which had disappeared, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to deteriorating condition (unless deterioration is clearly unrelated to this cancer).

  • Correlation of Outcome Measures With Possible Surrogate Markers Including Serial Measurements of Circulating Tumor Cells and Circulating Endothelial Cells [ Time Frame: until disease progression up to 13 months post treatment ] [ Designated as safety issue: No ]

Enrollment: 32
Study Start Date: March 2006
Study Completion Date: December 2012
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sunitinib, Cyclophosphamide, and Methotrexate Drug: cyclophosphamide Drug: methotrexate Drug: sunitinib malate Other: laboratory biomarker analysis

Detailed Description:

OBJECTIVES:

Primary

  • To determine the maximum tolerated dose of the combination of metronomic dose cyclophosphamide and methotrexate with continuous dosing sunitinib malate. (Phase I)
  • To determine the time to disease progression in patients with metastatic breast cancer treated with metronomic dose chemotherapy with cyclophosphamide and methotrexate combined with continuous dosing of sunitinib malate. (Phase II)

Secondary

  • To determine the response rate in patients receiving this treatment.
  • To determine the duration of response in patients receiving this treatment.
  • To determine the toxicity of this regimen in these patients.
  • To determine the feasibility by assessment of toxicities of this regimen and number of voluntary withdrawals from the study.
  • To correlate outcome measures with possible surrogate markers including serial measurements of circulating tumor cells and circulating endothelial cells.

OUTLINE: This is a dose-escalation study of sunitinib malate.

  • Phase I: Patients receive oral sunitinib malate once daily. Beginning 14 days later, patients also receive oral cyclophosphamide once daily on days 1-21 and oral methotrexate twice daily on days 1, 2, 8, 9, 15, and 16. Treatment with sunitinib malate, cyclophosphamide, and methotrexate repeats every 21 days* in the absence of disease progression or unacceptable toxicity.
  • Phase II: Patients receive sunitinib malate at the maximum tolerated dose determined in phase I and cyclophosphamide and methotrexate as in phase I.

NOTE: *Course 1 includes 2 weeks of sunitinib malate alone followed by sunitinib malate, cyclophosphamide, and methotrexate for 21 days

Blood samples are collected periodically for measurement of circulating tumor cells, circulating endothelial cells, and VEGF levels.

After completion of study treatment, patients are followed for 30 days and then every 2 months for 1 year.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Pathologically confirmed diagnosis of breast cancer with documented progressive disease

    • Metastatic disease
  • Measurable disease as defined by RECIST criteria or evaluable disease
  • Must have received at least one prior chemotherapy regimen for metastatic breast cancer

    • Patients refusing all other chemotherapy for breast cancer may enroll without prior treatment
  • Patients with HER2-overexpression disease must have been previously treated with trastuzumab (Herceptin®)
  • Patients with stable brain metastases are eligible
  • Hormone receptor status not specified

PATIENT CHARACTERISTICS:

  • Menopausal status not specified
  • ECOG performance status 0-2
  • Life expectancy ≥ 12 weeks
  • ANC ≥ 1,000/mm³
  • Platelet count ≥ 100,000/mm³
  • Creatinine ≤ 1.5 times upper limit of normal (ULN)
  • AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver metastases)
  • Total bilirubin ≤ 1.5 times ULN
  • Able to take oral medications and maintain hydration
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 6 months after treatment
  • No severe concurrent illness including, but not limited to, any of the following:

    • Congestive heart failure
    • Significant cardiac disease
    • Uncontrolled hypertension
  • Must be able to read and speak English

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • At least 2 weeks since prior treatment, including chemotherapy, hormonal therapy, trastuzumab (Herceptin®), or other targeted therapies
  • Prior bevacizumab allowed if discontinued for any reason other than toxicity
  • No potent inducers or inhibitors of CYP3A4 enzymes that effect the metabolism of sunitinib malate
  • No prior sunitinib malate
  • No other concurrent investigational therapy
  • No concurrent radiotherapy
  • Concurrent bisphosphonates allowed
  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: NCT00616122

Locations
United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94115
Sponsors and Collaborators
University of California, San Francisco
Investigators
Principal Investigator: Hope S. Rugo, MD University of California, San Francisco
  More Information

Additional Information:
No publications provided

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00616122     History of Changes
Other Study ID Numbers: CDR0000583268, UCSF-057519
Study First Received: February 14, 2008
Results First Received: December 18, 2012
Last Updated: November 1, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of California, San Francisco:
recurrent breast cancer
stage IV breast cancer
male breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Methotrexate
Sunitinib
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
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Angiogenesis Inhibitors
Angiogenesis Modulating Agents

ClinicalTrials.gov processed this record on July 22, 2014