Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III, Phase II	Treatment	Completed	any age	NCI	E-1193 NCCTG-923252, SWOG-9332, E-10292, E1193

Objectives

I.  Compare the objective response rate and time to progression of patients 
with metastatic breast cancer, who have not had prior therapy for advanced 
disease following treatment with doxorubicin (DOX) vs. paclitaxel (TAX) vs. 
DOX/TAX with granulocyte colony-stimulating factor (G-CSF).

II.  Compare the toxicity of these 3 regimens.

III.  Determine by means of a crossover design whether DOX and TAX exhibit 
cross-resistance.

IV.  Compare the quality of life of patients who receive DOX vs. TAX vs. 
TAX/DOX/G-CSF.

V.  Compare the quality of life of patients who receive DOX vs. TAX as 
second-line therapy.

VI.  Evaluate the relation of steady-state TAX levels to therapeutic response 
and toxicity.

Entry Criteria

Disease Characteristics:

Histologically confirmed adenocarcinoma of the breast that is regionally
progressing or metastatic

Measurable or evaluable disease required as follows (initial measurements
within 2 weeks prior to entry):
  Bidimensionally or unidimensionally measurable lesions, including:
     Malignant disease measurable in 2 dimensions by ruler or calipers
     (metastatic pulmonary nodules, lymph nodes, subcutaneous metastases)

     Lesions with sharply defined borders measurable on ultrasound or CT

     Mediastinal and hilar lesions on x-ray, provided a pre-involvement chest
     x-ray is available

     Hepatic metastases readily measurable on CT or MRI

     Malignant hepatomegaly with the sum of the measurements of the liver edge
     below the costal margin and below the tip of the xiphoid in the
     midclavicular line on quiet respiration at least 5 cm

  Evaluable lesions evident on clinical or radiologic exam but not measurable
  by ruler or calipers, including:
     Cytologically positive pleural and peritoneal effusions
        Local intracavitary treatment not allowed at beginning of protocol
        treatment

        Pleural effusions must not have been drained nor be sclerosed

     Blastic and mixed blastic/lytic osseous metastases only if accompanied by
     either an analgesic requirement or a decrease in performance status and
     proven on x-ray
        No requirement for radiotherapy during the first two courses of
        treatment

     Pure osteolytic lesions

     Intra-abdominal or pelvic mass visualized on CT

     Multinodular or confluent, nonmeasurable lung or skin metastases

Brain metastases must have responded to prior radiotherapy or surgery and
continue to be in response

  Other measurable disease required

Hormone receptor status:
  Not specified

Prior/Concurrent Therapy:

Biologic therapy:
  Not specified

Chemotherapy:
  No prior systemic anthracyclines (e.g., doxorubicin), anthracenes (e.g.,
     mitoxantrone), paclitaxel, or docetaxel (taxotere)
  No prior chemotherapy for overt metastatic disease
  At least 6 months since adjuvant chemotherapy or at least 6
     months between such therapy and diagnosis of metastatic
     disease

Endocrine therapy:
  At least 2 weeks since hormonal therapy for advanced disease
  Prior adjuvant hormonal therapy allowed

Radiotherapy:
  No prior radiotherapy except:
     Irradiation of the breast, chest wall, or axilla
     Limited-field irradiation of less than 25% of marrow-containing bone
  At least 2 weeks since radiotherapy

Surgery:
  At least 4 weeks since major surgery and fully recovered

Patient Characteristics:

Age:
  Any age

Sex:
  Women only

Menopausal status:
  Not specified

Performance status:
  ECOG 0-2

Life expectancy:
  At least 3 months

Hematopoietic:
  (obtained within 2 weeks prior to entry)
  AGC at least 1,500
  Platelets at least 100,000

Hepatic:
  (obtained within 2 weeks prior to entry)
  Bilirubin no greater than 2 times normal
  AST no greater than 2.5 times normal

Renal:
  (obtained within 2 weeks prior to entry)
  Creatinine no greater than 2 times normal

Cardiovascular:
  No history of congestive heart failure
  No myocardial infarction within the past 6 months
  No history of ischemic heart disease requiring medication
  No arrhythmia requiring medication
  No requirement for drugs known to alter cardiac conduction:
     Digoxin
     Propranolol
     Calcium channel blockers
  No venous thrombotic condition, including:
     Deep venous thrombophlebitis
     Pulmonary or other thromboembolism

Other:
  No history of allergic reaction to drugs using the vehicle
     Cremophor (e.g., anesthetics and muscle relaxants)
  No active, unresolved infection
     At least 7 days since parenteral antibiotics
  No second malignancy within 5 years except:
     Curatively treated nonmelanomatous skin cancer
     Curatively treated in situ cervical cancer
  No pregnant women
  Adequate contraception required of fertile patients
  Participation in a quality-of-life assessment optional

Expected Enrollment

A maximum of 733 patients will be entered over approximately 22 months; 220 
evaluable patients will be accrued to Arms A and B.  If at least 11 responses 
are seen in the first 40 patients entered on Arm C (phase II portion of the 
study), a total of 220 evaluable patients will be enrolled on that arm as well.

Outline

Randomized study.

Arm A:  Single-Agent Chemotherapy.  Doxorubicin, DOX, NSC-123127.

Arm B:  Single-Agent Chemotherapy.  Paclitaxel, TAX, NSC-673089.

Arm C:  2-Drug Combination Chemotherapy with Hematologic Toxicity Attenuation. 
 DOX; TAX; with Granulocyte Colony-Stimulating Factor (Amgen), G-CSF, 
NSC-614629.

Eton DT, Cella D, Yost KJ, et al.: Minimally important differences on the functional assessment of cancer therapy-breast (FACT-B) scale: results from ECOG study 1193 . [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-2142, 2003.

Sledge GW, Neuberg D, Bernardo P, et al.: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 21 (4): 588-92, 2003.[PUBMED Abstract]

Extermann M, Bonetti M, Sledge GW, et al.: MAX2: A convenient index to estimate the average per patient risk of severe toxicity from a chemotherapy regimen. Testing in ECOG studies. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1459, 2002.

Zon R, Neuberg D, Wood WC, et al.: Correlation of plasma VEGF(P-VEGF) with clinical outcome in patients with metastatic breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A712, 185a, 1998.

Neuberg D, Sledge GW, Fetting J, et al.: Changes in quality of life (QOL) during induction therapy in patients enrolled in a randomized trial of adriamycin, taxol, and adriamycin plus taxol in metastatic breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 16: A185, 54a, 1997.

Sledge GW, Neuberg D, Ingle J, et al.: Phase III trial of doxorubicin (A) vs. paclitaxel (T) vs. doxorubicin + paclitaxel (A+T) as first-line therapy for metastatic breast cancer (MBC). [Abstract] Proceedings of the American Society of Clinical Oncology 16: A-2, 1a, 1997.

Stender M, Neuberg D, Wood WC, et al.: Correlation of circulating c-erb B-2 extracelluar domain (her-2) with clinical outcome in patients with metastatic breast cancer (MBC). [Abstract] Proceedings of the American Society of Clinical Oncology 16: A541, 154a, 1997.

Extermann M, Bonetti M, Sledge GW, et al.: MAX2--a convenient index to estimate the average per patient risk for chemotherapy toxicity; validation in ECOG trials. Eur J Cancer 40 (8): 1193-8, 2004.[PUBMED Abstract]

Extermann M, Bonetti M, Sledge GW, et al.: MAX2: A convenient index to estimate the average per patient risk of severe toxicity from a chemotherapy regimen. Testing in ECOG studies. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1459, 2002.

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

George Sledge, MD, Protocol chair		Ph: 317-274-1690; 888-600-4822 Email: gsledge@iupui.edu

North Central Cancer Treatment Group

James Ingle, MD, Protocol chair		Ph: 507-284-3731 Email: ingle.james@mayo.edu

Southwest Oncology Group

Silvana Martino, DO, Protocol chair		Ph: 310-582-7900 Email: martinos@jwci.org