Neo-Adjuvant Chemotherapy (TAC) With or Without Zoledronic Acid in Treating HER2-negative Breast Cancer Patients (NEO-ZOTAC)

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)

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: cyclophosphamide; Drug: docetaxel; Procedure: neoadjuvant therapy; Drug: doxorubicin hydrochloride; Drug: zoledronic acid

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.

• Study Type: Interventional
• Enrollment (Actual): 250
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands, 2300 RC
    • Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TAC + Zoledronic acid; six cycles of docetaxel (Taxotere®), Adriamycin® (endoxan) and Cyclofosfamide (TAC) and zoledronic acid (Zometa)	Drug: cyclophosphamide; Drug: docetaxel; Procedure: neoadjuvant therapy; Drug: doxorubicin hydrochloride; Drug: zoledronic acid
Active Comparator: TAC; six cycles of docetaxel (Taxotere®), Adriamycin® (endoxan) and Cyclofosfamide (TAC)	Drug: cyclophosphamide; Drug: docetaxel; Procedure: neoadjuvant therapy; Drug: doxorubicin hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pathologic complete response after neoadjuvant chemotherapy with or without zoledronic	after surgery

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	3 and 5 years
Correlation of clinical response with pathological responses of both treatment arms	after surgery
Disease-free survival	3 and 5 years
Safety and tolerability	during treatment
Heterogeneity of the ER/PR and HER2 measurement in core biopsy and the surgical specimen	at surgery

Collaborators and Investigators

• Sponsor: Borstkanker Onderzoek Groep
• Collaborators: Sanofi; Novartis; Amgen; Dutch Cancer Society
• Investigators: Principal Investigator: Judith Kroep, MD, Leiden University Medical Center

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Clinical trial summary BOOG website

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): April 1, 2012
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: April 6, 2010
• First Submitted That Met QC Criteria: April 6, 2010
• First Posted (Estimate): April 7, 2010

Study Record Updates

• Last Update Posted (Actual): January 21, 2020
• Last Update Submitted That Met QC Criteria: January 16, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer; stage IIIC breast cancer; HER2-negative breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Bone Density Conservation Agents; Docetaxel; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Zoledronic Acid
• Other Study ID Numbers: BOOG-2010-01; CDR0000669246 (Registry Identifier: PDQ (Physician Data Query)); BOOG-NEO-ZOTAC (Other Identifier: BOOG); 2009-016932-11 (EudraCT Number)