Clinical trial NCT00072020: Chemotherapy and/or Hormone Therapy With or Without Zoledronate in Treating Women With Stage II or Stage III Breast Cancer
Official title: Does Adjuvant Zoledronic Acid Reduce Recurrence in Patients With High Risk Localized Breast Cancer?
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Breast Cancer
Metastatic Cancer
Keywords: bone metastases
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-11-06
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Zoledronate may delay or prevent the formation of bone metastases. It is not yet known whether chemotherapy and/or hormone therapy are more effective with or without zoledronate in preventing cancer recurrence and bone metastases in women with breast cancer.

PURPOSE: This randomized phase III trial is studying giving chemotherapy and/or hormone therapy together with zoledronate to see how well they work compared to chemotherapy and/or hormone therapy alone in preventing cancer recurrence and bone metastases in women with stage II or stage III breast cancer.

Detailed description: OBJECTIVES:

Primary

* Compare disease-free survival of women with stage II or III breast cancer at high risk of relapse treated with neoadjuvant or adjuvant chemotherapy and/or hormonal therapy with vs without zoledronate.

Secondary

* Compare time to bone metastases, as first recurrence, in patients treated with these regimens.
* Compare time to bone metastases, per se, in patients treated with these regimens.
* Compare time to distant metastases in patients treated with these regimens.
* Compare overall survival in patients treated with these regimens.
* Compare the reduction in skeletal-related events (fractures, spinal cord compression, radiotherapy to the bone, surgery to the bone, and hypercalcemia) before and after the development of bone metastases in patients treated with these regimens.
* Determine the safety and toxicity of zoledronate in patients treated with these regimens.
* Correlate prognostic factors, such as estrogen-receptor and progesterone-receptor status, TNM stage, tumor grade, HER2/neu status, and menopausal status with treatment outcome in patients treated with these regimens.
* Determine more specific prognostic indicators for the development of bone metastases and factors that are able to predict specific benefit from bisphosphonate treatment using proteomics, tissue micro-array, and other modern techniques in these patients.

OUTLINE: This is a randomized, open-label, parallel-group, multicenter study. Patients are stratified according to participating center. Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive neoadjuvant or adjuvant chemotherapy and/or hormonal therapy. Patients also receive concurrent zoledronate IV over 15 minutes every 3-4 weeks for 6 doses, every 3 months for 8 doses, and then every 6 months for 5 doses in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive neoadjuvant or adjuvant chemotherapy and/or hormonal therapy alone.

After completion of study treatment, patients are followed annually for 5 years.

PROJECTED ACCRUAL: A total of 3,300 patients (1,650 per treatment arm) will be accrued for this study within 3 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of primary breast cancer, meeting 1 of the following staging criteria:

  * Stage II
  * Stage III
  * T stage ≥ T1
* Receiving OR scheduled to receive chemotherapy and/or endocrine therapy

  * For patients receiving neoadjuvant therapy

    * Tumor \> 5 cm (T3), features of locally advanced disease (T4), OR biopsy-proven lymph node involvement (N1)
    * Scheduled to proceed to definitive surgery and/or radical radiotherapy with curative intent within 6 months of starting neoadjuvant therapy
    * No more than 30 days between initiation of neoadjuvant therapy and start of study drug
  * For patients receiving adjuvant therapy

    * Must have undergone complete primary tumor resection and treatment of axillary lymph nodes\*
    * Must have lymph node involvement
    * No prior neoadjuvant therapy\*\*
    * No more than 60 days since prior definitive surgery NOTE: \*Patients whose treatment plan includes further primary tumor resection and/or treatment of the axillary lymph nodes (e.g., clearance or radiotherapy) with curative intent after completion of chemotherapy are eligible provided the treatment is completed within 9 months of study entry

NOTE: \*\*Preoperative endocrine therapy with a duration of \< 30 days is not considered prior neoadjuvant therapy

* No evidence of recurrent or metastatic disease
* No history of breast cancer, except ductal carcinoma in situ or lobular carcinoma in situ
* Hormone receptor status:

  * Not specified

PATIENT CHARACTERISTICS:

Age

* 18 and over

Sex

* Female

Menopausal status

* Premenopausal or postmenopausal

Performance status

* Karnofsky 80-100% OR
* ECOG 0-1

Life expectancy

* Not specified

Hematopoietic

* Not specified

Hepatic

* Not specified

Renal

* Creatinine ≤ 1.5 times upper limit of normal

Other

* Not pregnant or nursing
* Fertile patients must use effective contraception
* No active dental problems, including dental abscess or infection of the jaw bone (e.g., maxilla or mandible)
* No prior or current diagnosis of osteonecrosis of the jaw
* No other malignancy within the past 5 years (including prior contralateral breast cancer) except nonmelanoma skin cancer or curatively treated carcinoma in situ of the cervix
* No history of disease with influence on bone metabolism, including any of the following:

  * Paget's disease of the bone
  * Primary hyperparathyroidism
  * Osteoporosis requiring treatment or likely to require treatment within the next 6 months
* No other severe physical or psychological disease that would preclude study compliance
* No known hypersensitivity to bisphosphonates

PRIOR CONCURRENT THERAPY:

Chemotherapy

* See Disease Characteristics

Endocrine therapy

* See Disease Characteristics

Radiotherapy

* See Disease Characteristics

Surgery

* See Disease Characteristics
* More than 4 weeks since prior and no concurrent dental or jaw surgery (e.g., extractions or implants)

  * Dental fillings, teeth scaling and polishing, or minor gingival surgery within the past 4 weeks are allowed

Other

* More than 1 year since prior bisphosphonates
* More than 30 days since prior investigational drugs
* No concurrent investigational drugs (i.e., not locally approved for any indication)

Primary outcomes:
measure: Disease-free survival as assessed annually for 10 years
Secondary outcomes:
measure: Time to bone metastases as first recurrence assessed annually for 10 years
measure: Time to bone metastases per se as assessed annually for 10 years
measure: Time to distant metastases as assessed annually for 10 years
measure: Overall survival as assessed by final analysis at 10 years
measure: Skeletal-related events prior to development of bone metastases as assessed annually for 10 years
measure: Skeletal-related events following development of bone metastases as assessed annually for 10 years
measure: Safety and toxicity of zoledronic acid as assessed annually for 10 years
measure: Evaluation of the influence of prognostic factors (e.g., estrogen receptor or progesterone receptor [ER/PR] status, TNM stage, tumor grade, HER2/neu, and menopausal status) on treatment outcome
measure: Analysis of tumor-specific mutations, proteomics and gene expression changes in tumor cells
Other outcomes:
Locations:
Study officials:
affiliation: Cancer Research Centre at Weston Park Hospital
name: Robert E. Coleman, MD, FRCP
affiliation: University of Leeds
name: Victoria Hiley
References:
citation: Marshall H, Gregory W, Bell R, et al.: Adjuvant therapy with zoledronic acid (AZURE-BIG 01/04): The influence of menopausal status and age on treatment effects. [Abstract] J Clin Oncol 30 (Suppl 15): A-502, 2012.
citation: Coleman RE, Marshall H, Cameron D, Dodwell D, Burkinshaw R, Keane M, Gil M, Houston SJ, Grieve RJ, Barrett-Lee PJ, Ritchie D, Pugh J, Gaunt C, Rea U, Peterson J, Davies C, Hiley V, Gregory W, Bell R; AZURE Investigators. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011 Oct 13;365(15):1396-405. doi: 10.1056/NEJMoa1105195. Epub 2011 Sep 25.
citation: Coleman R, Woodward E, Brown J, Cameron D, Bell R, Dodwell D, Keane M, Gil M, Davies C, Burkinshaw R, Houston SJ, Grieve RJ, Barrett-Lee PJ, Thorpe H. Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer. Breast Cancer Res Treat. 2011 Jun;127(2):429-38. doi: 10.1007/s10549-011-1429-y. Epub 2011 Mar 11.
citation: Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, Gil M, Ritchie D, Passos-Coelho JL, Wheatley D, Burkinshaw R, Marshall SJ, Thorpe H; AZURE (BIG01/04) Investigators. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer. 2010 Mar 30;102(7):1099-105. doi: 10.1038/sj.bjc.6605604. Epub 2010 Mar 16.
citation: Coleman R, Thorpe H, Cameron D, et al.: Zoledronic acid is well tolerated and can be safely administered with adjuvant chemotherapy first safety data from the AZURE trial (BIG01/04). [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-2080, S107, 2006.
citation: Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, Keane M, Gil M, Burkinshaw R, Grieve R, Barrett-Lee P, Ritchie D, Liversedge V, Hinsley S, Marshall H; AZURE investigators. Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol. 2014 Aug;15(9):997-1006. doi: 10.1016/S1470-2045(14)70302-X. Epub 2014 Jul 15.