Randomized Study of Doxorubicin and Cyclophosphamide With or Without Intermittent Sunitinib in the First-line Treatment of Locally Advanced or Metastatic Breast Cancer Patients With Measurable Primary Breast Tumor

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National University Hospital, Singapore
Sponsor:
Information provided by (Responsible Party):
National University Hospital, Singapore
ClinicalTrials.gov Identifier:
NCT01176799
First received: August 5, 2010
Last updated: July 23, 2014
Last verified: July 2014
  Purpose

This is a single-centre, phase II randomized study of doxorubicin and cyclophosphamide (AC) with or without intermittent sunitinib in patients with measurable primary breast cancer who are receiving pre-operative chemotherapy.

A lead-in phase I study was built into this protocol to determine the dose and duration of sunitinib that may achieve the desired effects of normalizing tumor vasculature prior to chemotherapy administration.

A total of 64 patients with measurable primary tumor will be enrolled for the Phase II part of the study. Eligible patients will be randomized 1:1 to either arm A or arm B. Patients will be stratified according to metastatic status (metastatic vs non-metastatic) and presence or absence of clinical T4 disease.

Arm A (Control arm):

Doxorubicin 60mg/m2 day 1 Cyclophosphamide 600mg/m2 day1, every 3 weeks x 4 cycles

Arm B (Experimental arm):

Days -13 (or -7) to day 0 (total 7 or 14 days) - oral sunitinib daily (duration and dose as determined from the lead-in phase I study) Cycle 1: day 1 - Cycle 1 AC (60/600mg/m2); days 15-21 - oral sunitinib daily Cycle 2: day 1 - Cycle 2 AC (60/600mg/m2); days 15-21 - oral sunitinib daily Cycle 3: day 1 - Cycle 3 AC (60/600mg/m2); days 15-21 - oral sunitinib daily Cycle 4: day 1 - Cycle 4 AC (60/600mg/m2)

DCE-MRI scan will be performed serially to determine tumor response and change in tumor vascular parameters for each enrolled subject:

Patient will be evaluated weekly for toxicity assessments and full blood count during cycle 1, and on days 1 and 15 of each subsequent cycle. In addition, patients in Arm B will be evaluated weekly during the first two weeks of sunitinib administration prior to cycle 1 AC.


Condition Intervention Phase
Breast Cancer
Drug: Arm A
Drug: Arm B
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Randomized Study of Doxorubicin and Cyclophosphamide With or Without Intermittent Sunitinib in the First-line Treatment of Locally Advanced or Metastatic Breast Cancer Patients With Measurable Primary Breast Tumor

Resource links provided by NLM:


Further study details as provided by National University Hospital, Singapore:

Primary Outcome Measures:
  • pathological complete response rate [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    To compare the pathological complete response rate of doxorubicin/cyclophosphamide with or without intermittent sunitinib in the first-line pre-operative setting in breast cancer in the Phase II part of the study.


Secondary Outcome Measures:
  • clinical response rate [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    To compare the clinical response rate (complete and partial response) and progression-free survival in patients treated with 4 cycles of doxorubicin/cyclophosphamide with or without intermittent sunitinib in the first-line pre-operative setting in breast cancer


Estimated Enrollment: 73
Study Start Date: August 2010
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A: Control Arm

Doxorubicin - 60mg/m2 day 1

Cyclophosphamide

-600mg/m2 day1, every 3 weeks x 4 cycles

Drug: Arm A
Doxorubicin 60mg/m2 day 1 Cyclophosphamide 600mg/m2 day1, every 3 weeks x 4 cycles
Other Names:
  • Control Arm
  • Doxorubicin and Cyclophosphamide
Experimental: Arm B: Experimental
Days -13 (or -7) to day 0 (total 7 or 14 days) - oral sunitinib daily Cycle 1: day 1 - Cycle 1 AC (60/600mg/m2); days 15-21 - oral sunitinib daily Cycle 2: day 1 - Cycle 2 AC (60/600mg/m2); days 15-21 - oral sunitinib daily Cycle 3: day 1 - Cycle 3 AC (60/600mg/m2); days 15-21 - oral sunitinib daily Cycle 4: day 1 - Cycle 4 AC (60/600mg/m2)
Drug: Arm B
Days -13 (or -7) to day 0 (total 7 or 14 days) - oral sunitinib daily Cycle 1: day 1 - Cycle 1 AC (60/600mg/m2); days 15-21 - oral sunitinib daily Cycle 2: day 1 - Cycle 2 AC (60/600mg/m2); days 15-21 - oral sunitinib daily Cycle 3: day 1 - Cycle 3 AC (60/600mg/m2); days 15-21 - oral sunitinib daily Cycle 4: day 1 - Cycle 4 AC (60/600mg/m2)
Other Names:
  • Experimental Arm:
  • Sunitinib and doxorubicin and cyclophosphamide (AC)

Detailed Description:

Special tests Blood sampling

  • Germline DNA at baseline for pharmacogenetics analysis.
  • Pharmacokinetic sampling for doxorubicin and cyclophosphamide on day 1, cycle 1 of AC administration.
  • Pharmacokinetic sampling for sunitinib at baseline and weekly during the first course of sunitinib for subjects in Arm B before the sunitinib dose on that day.
  • Serial plasma samples for proteomics analysis and for analysis of soluble angiogenic factors
  • Serial whole blood for gene expression analysis
  • Serial blood samples for circulating tumor and circulating endothelial cells
  • DNA will be extracted from collected snap-frozen and/or paraffin-embedded tumor tissue sections (pre- and post-treatment) and plasma (pre- and post-treatment taken for plasma biomarker analysis). Primary tumor and circulating tumor DNA will be genotyped for cancer genes of interest that may influence cancer prognosis and/or treatment response.

Tumor core biopsy Arm A: Performed at baseline, approximately 3 weekly after cycle 1 AC but before cycle 2 AC, and upon completion of 4 cycles of AC, for a total of 3 tumor core biopsies Arm B: Performed at baseline, after completing the first course of sunitinib and before cycle 1 AC, approximately 3 weekly after cycle 1 AC but before cycle 2 AC, and upon completion of 4 cycles of AC, for a total of 4 tumor core biopsies.

The final biopsy may be obtained at surgery if the patient is scheduled for lumpectomy or mastectomy. The tumor cores will be stored in liquid nitrogen for subsequent DNA, RNA and protein extraction for biomarker studies including gene expression and proteomics analyses. Three to four samples will be obtained at each time point, and one tumor core at each time point will be stored in formalin and paraffin-embedded for immunohistochemistry analysis of biomarkers.

Note: Tumor biopsies, imaging and blood collection that are to be conducted after completing the first course of sunitinib may be carried out as early as 2 days before the last dose of sunitinib in the first course for logistics reasons.

  Eligibility

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

Inclusion Criteria:

  • Female, age >= 18 years.
  • Histologic or cytologic diagnosis of breast carcinoma.
  • T2-4 breast cancer with measurable primary breast tumor, defined as palpable tumor with both diameters 2.0cm or greater as measured by caliper.
  • Patients must not have received prior chemotherapy or hormonal therapy for the treatment of breast cancer.
  • Karnofsky performance status of 70 or higher.
  • Estimated life expectancy of at least 12 weeks.
  • Adequate organ function including the following:

    • Bone marrow:
  • Absolute neutrophil (segmented and bands) count (ANC) >=1.5 x 109/L
  • Platelets >= 100 x 109/L

    • Hepatic:
  • Bilirubin <= 1.5 x upper limit of normal (ULN),
  • ALT or AST <= 2.5x ULN, (or <= 5 X with liver metastases)

    • Renal:
  • Creatinine <= 1.5x ULN
  • Left ventricular ejection fraction >=50%
  • Signed informed consent from patient or legal representative.
  • Patients with reproductive potential must use an approved contraceptive method if appropriate (e.g., intrauterine device, birth control pills, or barrier device) during and for three months after the study.Females with childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.

Exclusion Criteria:

  • Prior treatment for locally advanced or metastatic breast cancer.
  • Treatment within the last 30 days with any investigational drug.
  • Concurrent administration of any other tumor therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy.
  • Major surgery within 28 days of study drug administration.
  • Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
  • Pregnancy.
  • Breast feeding.
  • Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator.
  • Active bleeding disorder or bleeding site.
  • Non-healing wound.
  • Poorly controlled diabetes mellitus.
  • Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
  • Symptomatic brain metastasis.
  • History of significant neurological or mental disorder, including seizures or dementia.
  • Known history of systemic connective tissue diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis), vasculitides (e.g., giant cell arteritis, Kawasaki disease, Wegener's granulomatosis, Churg-Strauss disease) or sickle cell disease.
  • Known history of renal impairment, defined as a Glomerular Filtration Rate (GFR) of less than 30ml/minute.
  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: NCT01176799

Contacts
Contact: Soo Chin Lee, MBBS, MRCP 65 6772 4629 Soo_Chin_Lee@nuhs.edu.sg

Locations
Singapore
National University Hospital Recruiting
Singapore, Singapore, 119074
Contact: Soo Chin Lee, MBBS, MRCP    65 6772 4629    Soo_Chin_Lee@nuhs.edu.sg   
Principal Investigator: Soo Chin Lee, MBBS, MRCP         
National University Hospital Recruiting
Singapore, Singapore, 119228
Sponsors and Collaborators
National University Hospital, Singapore
Investigators
Principal Investigator: Soo Chin Lee, MBBS, MRCP National University Hospital, Singapore
  More Information

No publications provided

Responsible Party: National University Hospital, Singapore
ClinicalTrials.gov Identifier: NCT01176799     History of Changes
Other Study ID Numbers: BR01/09/10
Study First Received: August 5, 2010
Last Updated: July 23, 2014
Health Authority: Singapore: Domain Specific Review Boards

Keywords provided by National University Hospital, Singapore:
Breast cancer patients with measurable primary breast cancer tumor.

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Liposomal doxorubicin
Sunitinib
Doxorubicin
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
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on September 29, 2014