Clinical trial NCT01099436: Neo-Adjuvant Chemotherapy (TAC) With or Without Zoledronic Acid in Treating HER2-negative Breast Cancer Patients
Official title: A Phase III Randomized Trial With NEOadjuvant Chemotherapy (TAC) With or Without ZOledronic Acid for Patients With HER2- Negative Large Resectable or Locally Advanced Breast Cancer(NEO-ZOTAC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: HER2-negative breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
Lead sponsor: Borstkanker Onderzoek Groep
Sponsor class: NETWORK
Collaborators: name: Dutch Cancer Society
name: Amgen
name: Sanofi
name: Novartis
First posted: 2010-04-07
Enrollment: 250
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, docetaxel, and zoledronic acid, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known whether combination chemotherapy is more effective when given together with zoledronic acid in treating patients with breast cancer.

PURPOSE: This randomized phase III trial is studying giving doxorubicin hydrochloride together with cyclophosphamide and docetaxel to see how well it works with or without zoledronic acid in treating patients with large resectable or locally advanced breast cancer.

Detailed description: OBJECTIVES:

Primary

* To determine the value of neoadjuvant chemotherapy comprising doxorubicin hydrochloride, cyclophosphamide, and docetaxel with or without zoledronic acid in patients with HER2-negative large resectable or locally advanced breast cancer.

Secondary

* To correlate clinical response with pathological responses in both treatment arms.
* To evaluate the disease-free survival and overall survival of patients treated with this regimen.
* To evaluate the safety and tolerability of adding zoledronic acid to neoadjuvant chemotherapy.
* To evaluate heterogeneity of the ER/PR and HER2 measurement in core biopsy and the surgical specimen.

OUTLINE: Patients are randomized between 2 treatment arms.

* Arm I: Patients receive doxorubicin hydrochloride IV, cyclophosphamide IV, and docetaxel IV on day 1. Patients also receive zoledronic acid IV over 15 minutes on day 1. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive doxorubicin hydrochloride IV, cyclophosphamide IV, and docetaxel IV as in arm I. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed breast cancer

  * Large resectable or locally advanced disease

    * T2 (≥ 2 cm and positive lymph nodes), T2 (≥ 3 cm), ≥ T3, T4, any N, M0 disease
* Measurable disease (breast and/or lymph nodes)
* HER2-negative disease by core biopsy
* No evidence of distant metastases (M1)
* No prior breast cancer

PATIENT CHARACTERISTICS:

* Female
* Menopausal status unspecified
* WHO performance status 0-2
* Not pregnant or nursing
* WBC ≥ 3.0 x 10\^9/L
* Neutrophil count ≥ 1.5 x 10\^9/L
* Platelet count ≥ 100 x 10\^9/L
* Bilirubin ≤ 1.5 times upper limit of normal (UNL)
* ALT and/or AST ≤ 2.5 times UNL
* Alkaline phosphatase ≤ 5 times UNL
* Creatinine clearance ≥ 50 mL/min
* Accessible for treatment and follow-up
* No previous malignancy within the past 5 years except basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix
* No peripheral neuropathy \> grade 2 (of any cause)
* No other serious diseases including recent myocardial infarction, clinical signs of cardiac failure, or clinically significant arrhythmias
* No poor dental health
* No known hypersensitivity reaction to any of the components of the treatment
* No medical or psychological condition that, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent

PRIOR CONCURRENT THERAPY:

* No prior breast surgery except for biopsy
* No prior chemotherapy or radiotherapy
* No prior bisphosphonates

Primary outcomes:
measure: Pathologic complete response after neoadjuvant chemotherapy with or without zoledronic
timeFrame: after surgery
Secondary outcomes:
measure: Correlation of clinical response with pathological responses of both treatment arms
timeFrame: after surgery
measure: Disease-free survival
timeFrame: 3 and 5 years
measure: Overall survival
timeFrame: 3 and 5 years
measure: Safety and tolerability
timeFrame: during treatment
measure: Heterogeneity of the ER/PR and HER2 measurement in core biopsy and the surgical specimen
timeFrame: at surgery
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
Study officials:
affiliation: Leiden University Medical Center
name: Judith Kroep, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Groot S, Pijl H, Charehbili A, van de Ven S, Smit VTHBM, Meershoek-Klein Kranenbarg E, Heijns JB, van Warmerdam LJC, Kessels LW, Dercksen MW, Pepels MJAE, van Laarhoven HWM, Vriens BEPJ, Putter H, Fiocco M, Liefers GJ, van der Hoeven JJM, Nortier JWR, Kroep JR; Dutch Breast Cancer Research Group. Addition of zoledronic acid to neoadjuvant chemotherapy is not beneficial in patients with HER2-negative stage II/III breast cancer: 5-year survival analysis of the NEOZOTAC trial (BOOG 2010-01). Breast Cancer Res. 2019 Aug 28;21(1):97. doi: 10.1186/s13058-019-1180-6.
citation: de Groot S, Charehbili A, van Laarhoven HW, Mooyaart AL, Dekker-Ensink NG, van de Ven S, Janssen LG, Swen JJ, Smit VT, Heijns JB, Kessels LW, van der Straaten T, Bohringer S, Gelderblom H, van der Hoeven JJ, Guchelaar HJ, Pijl H, Kroep JR; Dutch Breast Cancer Research Group. Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01). Breast Cancer Res. 2016 Jan 6;18(1):3. doi: 10.1186/s13058-015-0663-3.