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

Alternate Title

Paclitaxel With or Without Trastuzumab in Treating Women With Inoperable, Recurrent, or Metastatic Breast Cancer With or Without Overexpression of HER2/neu

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Closed 18 and over NCI CLB-9840 NCT00003440, CALGB-9840

Special Category: CTSU trial

Objectives

1. Compare the response rate in women with inoperable, recurrent, or metastatic breast cancer treated with paclitaxel via one-hour infusion every week vs 3-hour infusion every 3 weeks, regardless of HER2/neu status and assignment to trastuzumab (Herceptin®).
2. Compare the response rate and quality of life of patients with HER2/neu-nonoverexpressing disease treated with 1 of these 2 paclitaxel regimens with or without trastuzumab.
3. Correlate amplification and overexpression of the growth factor receptor ErbB2 by immunohistochemistry and fluorescent in situ hybridization (FISH) with response rate, time to progression, and overall survival of patients treated with these regimens.
4. Correlate ErbB2 shed extracellular domain (ECD) with response rate, time to progression, and overall survival of patients treated with these regimens.
5. Assess the patterns of ErbB2/ECD after treatment with these regimens and upon relapse in these patients.
6. Compare the time to progression and survival of patients with HER2/neu-overexpressing disease treated with these regimens.
7. Compare the time to progression and survival of patients with HER2/neu-nonoverexpressing disease treated with these regimens.
8. Compare the cardiac toxicity of these regimens as measured by changes in left ventricular ejection fraction from baseline to follow-up measurements in these patients.

Entry Criteria

Disease Characteristics:

• Histologically proven inoperable, recurrent, or metastatic adenocarcinoma of the breast



• Known HER2/neu status



• Measurable disease



• No CNS metastases unless at least 6 months since prior cranial radiotherapy and the patient is asymptomatic and not receiving corticosteroids for this condition at time of enrollment



• No leptomeningeal carcinoma (carcinomatous meningitis)



• Hormone receptor status:
  • Not specified

Prior/Concurrent Therapy:

Biologic therapy:

• No prior trastuzumab (Herceptin®)
• Concurrent epoetin alfa allowed

Chemotherapy:

• No more than 1 prior chemotherapy regimen for locally advanced or metastatic breast cancer
• No prior taxane for locally advanced or metastatic breast cancer
• No more than 1 prior adjuvant chemotherapy regimen
• At least 12 months since prior adjuvant taxane and recovered
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, melphalan, or mitomycin)
• No other concurrent chemotherapy

Endocrine therapy:

• See Disease Characteristics
• More than 4 weeks since prior hormonal therapy
• More than 1 week since prior hormonal therapy if documented tumor progression
• No concurrent hormonal therapy except any of the following:
  • Steroids for documented CNS metastases, adrenal failure, septic shock, or prevention of serious allergic reaction or emesis
  • Hormonal therapy for nonmalignant conditions (e.g., insulin for diabetes)

Radiotherapy:

• See Disease Characteristics
• No concurrent radiotherapy except whole brain irradiation for CNS disease

Surgery:

• More than 2 weeks since prior surgery, other than biopsy or placement of venous access device

Other:

• Concurrent bisphosphonate (e.g., pamidronate) therapy allowed

Patient Characteristics:

Age:

• 18 and over

Sex:

• Female

Menopausal status:

• Not specified

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Granulocyte count at least 1,500/mm³
• Platelet count at least 100,000/mm³

Hepatic:

• Bilirubin normal
• SGOT no greater than 3 times upper limit of normal

Renal:

• Creatinine no greater than 2.0 mg/dL

Cardiovascular:

• Left ventricular ejection fraction at least 45%

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception

Expected Enrollment

A total of 580 patients will be accrued for this study within 3 years.

Outline

This is a randomized study. Patients are stratified according to prior chemotherapy for metastatic disease (none or recurrence more than 6 months after adjuvant therapy vs one or none but recurrence less than 6 months after adjuvant therapy) and HER2/neu overexpression (yes vs no). Patients are assigned to 1 of 2 treatment groups based on HER2/neu status.

• Group A (HER2/neu-nonoverexpressing): Patients are randomized to 1 of 4 treatment arms.
  • Arm I: Patients receive paclitaxel IV over 3 hours on day 1.
  
  
  
  • Arm II: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15.
  
  
  
  • Arm III: Patients receive paclitaxel as in arm I. Patients receive an initial loading dose of trastuzumab (Herceptin®) IV over 90 minutes on day 1 of course 1 and maintenance dose of trastuzumab IV over 30 minutes on day 1 of subsequent courses and on days 8 and 15 of all courses. Trastuzumab is administered immediately after completion of paclitaxel infusion on weeks of concurrent administration.
  
  
  
  • Arm IV: Patients receive paclitaxel as in arm II and trastuzumab as in arm III.
  
  
  



• Group B: (HER2/neu-overexpressing): Patients are randomized to 1 of 2 treatment arms.
  • Arm I: Patients receive treatment as in arm III (group A).
  
  
  
  • Arm II: Patients receive treatment as in arm IV (group A).
  
  
  

In both groups, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and then at 3, 6, and 9 months.

Patients are followed at 6, 12, and 18 months and then annually for 5 years or until death.

Rimm DL, Broadwater G, Friedman P, et al.: Uniformly positive (>80%) HER2 expression maximizes sensitivity and specificity for prediction of response to trastuzumab in CALGB 9840. [Abstract] 31st Annual San Antonio Breast Cancer Symposium, December 10-14, 2008, San Antonio, Texas. A-6046, 2008.

Seidman AD, Berry D, Cirrincione C, et al.: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26 (10): 1642-9, 2008.[PUBMED Abstract]

Naughton MJ, Gu L, Wang XF, et al.: Quality of life (QOL) companion to CALGB 9840: a phase III study of paclitaxel (P) via weekly 1 hour (hr) versus standard 3 hour infusion every 3 weeks with trastuzumab in the treatment of patients with/without HER-2/neu-overexpressing metastatic breast cancer. [Abstract] J Clin Oncol 24 (Suppl 18): A-674, 2006.

Seidman AD, Broadwater G, Carney W, et al.: Serum HER2 extracellular domain (ECD) levels and efficacy of weekly (W) or every 3-weekly (q3W) paclitaxel (P) with or without trastuzumab (T) in patients (pts) with metastatic breast cancer (MBC): CALGB 150002/9840. [Abstract] J Clin Oncol 23 (Suppl 16): A-558, 18s, 2005.

Seidman AD, Berry D, Cirrincione C, et al.: CALGB 9840: phase III study of weekly (W) paclitaxel (P) via 1-hour(h) infusion versus standard (S) 3h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC. [Abstract] J Clin Oncol 22 (Suppl 14): A-512, 6s, 2004.

Polite BN, Cirrincione C, Fleming GF, et al.: Racial differences in clinical outcomes from metastatic breast cancer: a pooled analysis of CALGB 9342 and 9840--Cancer and Leukemia Group B. J Clin Oncol 26 (16): 2659-65, 2008.[PUBMED Abstract]

Kaufman PA, Broadwater G, Lezon-Geyda K, et al.: CALGB 150002: correlation of HER2 and chromosome 17 (ch17) copy number with trastuzumab (T) efficacy in CALGB 9840, paclitaxel (P) with or without T in HER2+ and HER2- metastatic breast cancer (MBC). [Abstract] J Clin Oncol 25 (Suppl 18): A-1009, 2007.

Polite BN, Cirrincione C, Fleming GF, et al.: Understanding racial differences in outcome from metastatic breast cancer (MBC): a pooled analysis of Cancer and Leukemia Group B (CALGB) 9342 and 9840. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-3097, 2005.

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Andrew Seidman, MD, Protocol chair		Ph: 212-639-5875; 800-525-2225

Registry Information
Official Title		A Phase III Study of Paclitaxel Via Weekly One Hour Infusion Versus Standard Three Hour Infusion Every Three Weeks in the Treatment of Patients With Metastatic Breast Cancer
Trial Start Date		1998-07-15
Registered in ClinicalTrials.gov		NCT00003440
Date Submitted to PDQ		1998-07-23
Information Last Verified		2003-12-10
NCI Grant/Contract Number		CA31946