Liposomal Doxorubicin Compared With Observation or Cyclophosphamide and Methotrexate in Treating Older Women Who Have Undergone Surgery for Breast Cancer (CASA)

This study has been terminated.
(Accrual rate was too low)
Sponsor:
Information provided by (Responsible Party):
International Breast Cancer Study Group
ClinicalTrials.gov Identifier:
NCT00296010
First received: February 23, 2006
Last updated: July 20, 2012
Last verified: July 2012
  Purpose

RATIONALE: Drugs used in chemotherapy, such as methotrexate, cyclophosphamide, and liposomal doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving liposomal doxorubicin after surgery is more effective than observation or cyclophosphamide and methotrexate in treating breast cancer.

PURPOSE: This randomized phase III trial is studying liposomal doxorubicin to see how well it works compared with observation or cyclophosphamide and methotrexate in treating older women who have undergone surgery for breast cancer.


Condition Intervention Phase
Breast Cancer
Drug: cyclophosphamide
Drug: methotrexate
Drug: pegylated liposomal doxorubicin hydrochloride
Procedure: adjuvant therapy
Radiation: radiation therapy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase III Trial Evaluating the Role of Adjuvant Pegylated Liposomal Doxorubicin (PLD, Caelyx, Doxil) for Women (Age 66 Years or Older) With Endocrine Nonresponsive Breast Cancer Who Are Not Suitable for Being Offered a " Standard Chemotherapy Regimen"

Resource links provided by NLM:


Further study details as provided by International Breast Cancer Study Group:

Primary Outcome Measures:
  • Breast cancer free interval by physical examination, laboratory tests, and investigations every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually as indicated after completion of study treatment [ Time Frame: 5 years after recruitment starts ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Adverse events assessed by CTCAE v3.0 every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually after completion of study treatment [ Time Frame: 5 years after recruitment starts ] [ Designated as safety issue: Yes ]
  • Quality of life assessed by Casa QL form, Mini-Cog, and VES-13 at baseline and at 2, 6, and 12 months after completion of study treatment [ Time Frame: 5 years after recruitment starts ] [ Designated as safety issue: No ]
  • Disease-free survival by physical examination, laboratory tests, and investigations every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually as indicated after completion of study treatment [ Time Frame: 5 years after recruitment starts ] [ Designated as safety issue: No ]
  • Overall survival by physical examination, laboratory tests, and investigations every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually as indicated after completion of study treatment [ Time Frame: 5 years after recruitment starts ] [ Designated as safety issue: No ]
  • Sites of failure by physical examination, laboratory tests, and investigations every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually as indicated after completion of study treatment [ Time Frame: 5 years after recruitment starts ] [ Designated as safety issue: No ]
  • Second (non-breast) malignancy by physical examination, laboratory tests, and investigations every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually as indicated after completion of study treatment [ Time Frame: 5 years after recruitment starts ] [ Designated as safety issue: No ]
  • Causes of death prior to breast cancer recurrence by physical examination, laboratory tests, and investigations every 2 wks for 16 wks during treatment, every 3-6 mo. for 5 yrs, then annually as indicated after completion of study treatment [ Time Frame: 5 years after recruitment starts ] [ Designated as safety issue: No ]

Enrollment: 77
Study Start Date: August 2005
Study Completion Date: December 2011
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: CASA-nil PLD
Adjuvant pegylated liposomal doxorubicin (PLD) for 16 weeks
Drug: pegylated liposomal doxorubicin hydrochloride
Caelyx (R) (Doxil (R)) 20 mg/m2 iv x 8 doses (delivered every 2 weeks)
Procedure: adjuvant therapy Radiation: radiation therapy
Radiation therapy should be used according to institutional accepted guidelines. Radiation therapy to the conserved breast is recommended. Radiation therapy to the chest wall following mastectomy is optional (if given, it may also include nodal fields). Radiation therapy may be given either during operation or after all chemotherapy.
Active Comparator: CASA-Nil
No adjuvant therapy
Radiation: radiation therapy
Radiation therapy should be used according to institutional accepted guidelines. Radiation therapy to the conserved breast is recommended. Radiation therapy to the chest wall following mastectomy is optional (if given, it may also include nodal fields). Radiation therapy may be given either during operation or after all chemotherapy.
Experimental: CASA-CM PLD
Adjuvant pegylated liposomal doxorubicin (PLD) for 16 weeks
Drug: pegylated liposomal doxorubicin hydrochloride
Caelyx (R) (Doxil (R)) 20 mg/m2 iv x 8 doses (delivered every 2 weeks)
Procedure: adjuvant therapy Radiation: radiation therapy
Radiation therapy should be used according to institutional accepted guidelines. Radiation therapy to the conserved breast is recommended. Radiation therapy to the chest wall following mastectomy is optional (if given, it may also include nodal fields). Radiation therapy may be given either during operation or after all chemotherapy.
Active Comparator: CASA-CM CM
Low-dose, metronomic cyclophosphamide and methotrexate (CM) for 16 weeks
Drug: cyclophosphamide
cyclophosphamide 50 mg/day orally continuously for 16 weeks
Drug: methotrexate
methotrexate 2.5 mg twice a day orally on days 1 and 4 of every week for 16 weeks
Procedure: adjuvant therapy Radiation: radiation therapy
Radiation therapy should be used according to institutional accepted guidelines. Radiation therapy to the conserved breast is recommended. Radiation therapy to the chest wall following mastectomy is optional (if given, it may also include nodal fields). Radiation therapy may be given either during operation or after all chemotherapy.

Detailed Description:

OBJECTIVES:

Primary

  • Compare the breast cancer-free interval in elderly women with resectable, hormone receptor-negative breast cancer treated with pegylated doxorubicin hydrochloride liposome (PDL) vs observation or PDL vs cyclophosphamide and methotrexate.

Secondary

  • Compare the tolerability of these regimens in these patients.
  • Compare the safety and toxic effects of these regimens in these patients.
  • Compare the overall and progression-free survival of patients treated with these regimens.
  • Compare the quality of life of patients treated with these regimens.
  • Compare the sites of failure in patients treated with these regimens.
  • Compare the competing causes of death in patients treated with these regimens.
  • Compare the rate of second non-breast malignancy in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center. Patients are assigned, based on patient preference, to 1 of 2 treatment groups.

  • Group 1: Patients are randomized to 1 of 2 arms (arms I and II).

    • Arm I: Patients receive pegylated doxorubicin hydrochloride liposome (PDL) IV over 1 hour on day 1. Treatment repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable toxicity.
    • Arm II: Patients undergo observation only.
  • Group 2: Patients are randomized to 1 of 2 treatment arms (arms III and IV).

    • Arm III: Patients receive PDL as in arm I.
    • Arm IV: Patients receive oral cyclophosphamide once daily on days 1-7 and oral methotrexate twice daily on days 1 and 4. Treatment repeats every week for 16 courses in the absence of disease progression or unacceptable toxicity.

All patients may undergo radiotherapy according to institutional standards either during surgery or after the completion of chemotherapy.

Quality of life is assessed at baseline and at 3, 6, and 12 months.

After completion of study treatment, patients are followed periodically for 1 year.

PROJECTED ACCRUAL: A total of 1,296 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   66 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed breast cancer

    • Disease must be confined to the breast and axillary nodes without detected masses elsewhere
    • No history of prior ipsilateral or contralateral invasive breast cancer
  • Resected disease

    • No more than 16 weeks since last surgery to remove the tumor
    • No known clinical residual locoregional disease
    • Margins must be negative for invasive breast cancer and ductal carcinoma in situ
  • No locally advanced, inoperable breast cancer including any of the following:

    • Inflammatory breast cancer
    • Supraclavicular node involvement
    • Enlarged internal mammary nodes unless pathologically negative
  • Synchronous bilateral invasive breast cancer (diagnosed in the past 2 months) allowed if all tumors are hormone receptor-negative
  • Must not be a candidate for endocrine therapy or standard chemotherapy
  • Hormone receptor-negative disease

PATIENT CHARACTERISTICS:

  • Female
  • Menopausal status: postmenopausal
  • ECOG performance status 0-2
  • Platelet count ≥ 100,000/mm^3
  • Granulocyte count ≥ 1,500/mm^3
  • WBC ≥ 3,000/mm^3
  • AST and ALT ≤ 1.5 times upper limit of normal (ULN)
  • Bilirubin normal
  • Creatinine clearance ≥ 50 mL/min
  • Creatinine < 1.35 mg/dL
  • No significant malabsorption syndrome or disease affecting gastrointestinal tract function
  • No myocardial infarction within the past 6 months
  • No pulmonary embolism within the past 6 months
  • No deep vein thrombosis within the past 6 months
  • No New York Heart Association class III or IV heart disease
  • LVEF ≥ 50% by echocardiography, radionucleotide ventriculography, or MUGA
  • No evidence of acute ischemia by ECG
  • No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or bladder, or ipsilateral or contralateral breast carcinoma in situ
  • No active, uncontrolled infection
  • No active hepatitis B or C virus infection
  • No other chronic infection
  • Patients must not have any of the following "geriatric syndromes":

    • Dementia
    • Delirium
    • Major depression (as diagnosed by a psychiatrist)
    • Recent falls
    • Spontaneous bone fractures
    • Neglect
    • Abuse
  • No evidence of medically relevant conduction system abnormalities that would preclude study entry
  • No other nonmalignant, uncontrolled systemic diseases, psychiatric illness, or addictive or cognitive disorder that would preclude study participation or compliance

PRIOR CONCURRENT THERAPY:

  • At least 4 weeks since prior raloxifene, tamoxifen citrate, or other selective estrogen receptor modulators (SERMs)
  • No concurrent recombinant human epoetin alfa or pegfilgrastim
  • No prior neoadjuvant or adjuvant therapy for breast cancer except radiotherapy
  • Concurrent trastuzumab (Herceptin®) allowed
  • No concurrent hormonal replacement therapy
  • No other concurrent hormonal therapy (including estrogen, progesterone, androgens, tamoxifen citrate, SERMs, or aromatase inhibitors) except for the following:

    • Steroids for adrenal failure
    • Hormones for non-disease-related conditions (e.g., insulin for diabetes)
    • Intermittent dexamethasone as an antiemetic
  • No other concurrent investigational agents
  • No concurrent bisphosphonates, except for the treatment of osteoporosis
  • For patients who received prior anthracyclines, the following criteria must be met:

    • Cumulative dose ≤ 240 mg/m² for conventional doxorubicin

      • ≤ 140 mg/m² in case of prior doxorubicin and left chest radiotherapy (LCRT)
    • Cumulative dose ≤ 400 mg/m² for epirubicin

      • ≤ 230 mg/m² in case of prior epirubicin and LCRT
  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: NCT00296010

  Show 33 Study Locations
Sponsors and Collaborators
International Breast Cancer Study Group
Investigators
Study Chair: Diana Crivellari, MD Centro di Riferimento Oncologico, Aviano (Italy)
Study Chair: Silvia Dellapasqua, MD European Institute of Oncology, Milano (Italy)
Study Chair: Anne Hamilton, MD Royal Prince Alfred Hospital, Camperdown (Australia)
  More Information

No publications provided

Responsible Party: International Breast Cancer Study Group
ClinicalTrials.gov Identifier: NCT00296010     History of Changes
Other Study ID Numbers: CDR0000463710, IBCSG-32-05, BIG-CASA, 2005-003434-18, BIG-1-05, EU-205112
Study First Received: February 23, 2006
Last Updated: July 20, 2012
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
Belgium: Federal Agency for Medicinal Products and Health Products
Hungary: National Institute of Pharmacy
Italy: The Italian Medicines Agency
Slovenia: Agency for Medicinal Products - Ministry of Health
Sweden: Medical Products Agency
Switzerland: Swissmedic

Keywords provided by International Breast Cancer Study Group:
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer

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

ClinicalTrials.gov processed this record on September 30, 2014