8 Continuous vs 8 Intermittent Cycles in First and Second Line in HER2/Neu Neg Metastatic Breast Cancer (Stop&Go)

8 Continuous vs 8 Intermittent Cycles in First and Second Line Treatment of Patients With HER2/Neu Negative, Incurable, Metastatic or Unresectable Locally Advanced Breast Cancer.

An open randomized phase III study to compare 8 continuous cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy in first line treatment, in combination with bevacizumab, and second line treatment of patients with HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer.

Study Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
• Intervention / Treatment: Drug: Paclitaxel, Bevacizumab, liposomal doxorubicin, Capecitabine; Drug: Paclitaxel, Bevacizumab, liposomal doxorubicin, Capecitabine

Detailed Description

The primary goal of this non-inferiority trial is to determine if the results obtained with a intermittent chemotherapy regimen (2 x 4 cycles of paclitaxel) are not inferior to the results of a continuous chemotherapy regimen (8 cycles of paclitaxel), both combined with bevacizumab in first line treatment of patients with HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer.

• Study Type: Interventional
• Enrollment (Actual): 420
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1006 AE
    • BOOG Study Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Female patients ≥ 18 years old.
• Patients with HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer, who are candidates for chemotherapy.
• Patients with measurable or evaluable-only (RECIST 1.1)
• Documented Estrogen Receptor (ER) / Progesteron Receptor (PR) status.
• HER2/neu-negative disease
• Patients with an ECOG Performance Status ≤ 2.
• Life expectancy of > 12 weeks.
• Signature of Informed Consent Form

Exclusion Criteria:

• Previous chemotherapy for HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer.
• Prior hormonal therapy for HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer that has not been discontinued 1 week before start of study treatment.
• Prior adjuvant/neo-adjuvant chemotherapy within 6 months prior to first study treatment. However, if the prior adjuvant/neo-adjuvant chemotherapy was taxane based, patients are excluded if they received their last chemotherapy within12 months prior to first study treatment.
• Prior radiotherapy covering more than 30% of marrow-bearing bone.
• Patients that have received recent radiation therapy that are not recovered from any significant (Grade ≥ 3) acute toxicity prior to study treatment.
• Prior therapy with bevacizumab, sorafenib, sunitinib, or other VEGF pathway-targeted therapy.
• Chronic daily treatment with aspirin
• Chronic daily treatment with corticosteroids, with the exception of inhaled steroids.
• Current or recent treatment with another investigational drug or participation in another investigational study.
• Inadequate bone marrow, liver, renal function
• INR > 1.5 or an aPTT > 1.5 x ULN within 7 days prior to first study treatment.
• Known CNS disease, except for treated brain metastases.
• Patients with concurrent active malignancy
• Pregnant or lactating
• Women of childbearing potential not using effective, non-hormonal means of contraception
• Major surgical procedure (including open biopsy) within 28 days prior to the first study treatment
• Core biopsy or other minor surgical procedure, within 7 days prior to day 1.
• Significant vascular disease within 6 months prior to day 1.
• Any previous venous thrombo-embolism > CTC Grade 3.
• History of haemoptysis
• History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
• Uncontrolled hypertension
• Clinically significant (i.e. active) cardiovasculair disease
• LVEF by MUGA or ECHO < 50%.
• History of abdominal fistula, Grade 4 bowel obstruction or GI perforation, intra-abdominal abscess within 6 months of randomization.
• Serious non-healing wound, peptic ulcer or bone fracture.
• Known hypersensitivity to any of the study drugs or excipients.
• Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
• Psychiatric illness, physical examination or laboratory findings that may interfer with protocol

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
Active Comparator: 8 cycles of Paclitaxel & bevacizumab; 8 cycles of Paclitaxel: 90 mg/m2 IV on days 1, 8 and 15 every 28 days & Bevacizumab: 10 mg/kg IV on days 1 and 15 every 28 days	Drug: Paclitaxel, Bevacizumab, liposomal doxorubicin, Capecitabine; st line:Paclitaxel and bevacizumab: 8 cycles, unless PD or unacceptable toxicity occurs earlier.Bevacizumab until PD or unacceptable toxicityAt PD patients will go to the 2nd treatment line.; nd line:Non-pegylated liposomal doxorubicin (Myocet®) (or capecitabine): 8 cycles, unless PD or unacceptable toxicity occurs earlier.At PD patients will go to the 3rd treatment line. If possible, it is advised to cross-over from 2nd line non-pegylated liposomal doxorubicin to 3rd line capecitabine.; Other Names: Non-pegylated liposomal doxorubicin (Myocet®); Drug: Paclitaxel, Bevacizumab, liposomal doxorubicin, Capecitabine; Arm B; st linePaclitaxel and bevacizumab: 4 cycles, unless PD or unacceptable toxicityBevacizumab until PD or unacceptable toxicityAt PD < 3 months after last paclitaxel start 2nd treatment line.At PD ≥ 3 months after last paclitaxel, start another 4 cyclesBevacizumab until the next PD or unacceptable toxicityAt the next PD start the 2nd treatment line.; nd line:Myocet® or capecitabine: 4 cycles, unless PD or unacceptable toxicityAt PD < 3 months start the 3rd treatment line. If possible, advised to cross-over from 2nd line Myocet® to 3rd line capecitabine.At PD ≥ 3 months after last administration of Myocet® or capecitabine, start another 4 cycles of Myocet® or capecitabineAt the next PD start 3rd treatment line.; Other Names: Non-pegylated liposomal doxorubicin (Myocet®):
Active Comparator: 2 x 4 cycles of Paclitaxel & bevacizumab; intermittent 2x4 cycles of Paclitaxel: 90 mg/m2 IV on days 1, 8 and 15 every 28 days & Bevacizumab: 10 mg/kg IV on days 1 and 15 every 28 days	Drug: Paclitaxel, Bevacizumab, liposomal doxorubicin, Capecitabine; st line:Paclitaxel and bevacizumab: 8 cycles, unless PD or unacceptable toxicity occurs earlier.Bevacizumab until PD or unacceptable toxicityAt PD patients will go to the 2nd treatment line.; nd line:Non-pegylated liposomal doxorubicin (Myocet®) (or capecitabine): 8 cycles, unless PD or unacceptable toxicity occurs earlier.At PD patients will go to the 3rd treatment line. If possible, it is advised to cross-over from 2nd line non-pegylated liposomal doxorubicin to 3rd line capecitabine.; Other Names: Non-pegylated liposomal doxorubicin (Myocet®); Drug: Paclitaxel, Bevacizumab, liposomal doxorubicin, Capecitabine; Arm B; st linePaclitaxel and bevacizumab: 4 cycles, unless PD or unacceptable toxicityBevacizumab until PD or unacceptable toxicityAt PD < 3 months after last paclitaxel start 2nd treatment line.At PD ≥ 3 months after last paclitaxel, start another 4 cyclesBevacizumab until the next PD or unacceptable toxicityAt the next PD start the 2nd treatment line.; nd line:Myocet® or capecitabine: 4 cycles, unless PD or unacceptable toxicityAt PD < 3 months start the 3rd treatment line. If possible, advised to cross-over from 2nd line Myocet® to 3rd line capecitabine.At PD ≥ 3 months after last administration of Myocet® or capecitabine, start another 4 cycles of Myocet® or capecitabineAt the next PD start 3rd treatment line.; Other Names: Non-pegylated liposomal doxorubicin (Myocet®):

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	PFS is defined as the time from start of treatment to the documented progression that requires the patient to switch to the next treatment line or to death due to any cause.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival second line treatment	To compare the PFS of second line treatment of 8 continuous cycles of chemotherapy with liposomal doxorubicin (or capecitabine) with 8 cycles of intermittent (2 times 4 cycles) chemotherapy with liposomal doxorubicin (or capecitabine);	1 year
Objective overall response rate	To compare the objective Overall Response Rate (ORR) between 8 continuous cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy in first treatment line, combined with bevacizumab, and in second treatment line. ORR calculated as the proportion of patients with a best overall response of confirmed Complete Response (CR) and Partial Response (PR).	1 year
Duration of objective response	To compare the Duration of Objective Response (DOR) between 8 continuous cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy in first treatment line, combined with bevacizumab, and second treatment line; For the intermittent chemotherapy schedule the first DOR and, if applicable, second DOR in the same treatment line will be accumulated DOR calculated as the time from the date of first documented CR or PR to the first documented progression or death due to underlying cancer	1 year
Overall survival	To compare Overall Survival (OS) between 8 continuous cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy. OS calculated as the time from the date of randomization to the date of death due to any cause or the date of last contact	1 year
Safety and tolerability. The total number of grade 3 and 4 adverse events will be analyzed.	To compare the Safety between 8 continuous cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy The total number of grade 3 and 4 adverse events will be analyzed as a measure of safety and tolerability	1 year
Quality of life measures	To compare the Quality of Life (QoL) between 8 continuous cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy. Changes in the RAND 36 quality of life scale will be measured	1 year
Pharmacoeconomics	To compare the Pharmacoeconomics between 8 continuous cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy. Direct medical costs will be calculated using a standard cost method.	1 year

Collaborators and Investigators

• Sponsor: Borstkanker Onderzoek Groep
• Collaborators: Roche Pharma AG; Teva Pharma
• Investigators: Principal Investigator: F.L.G. Erdkamp, PhD, Orbis Medical Centre; Principal Investigator: M.M.E.M. Bos, PhD, RdGG

Publications and helpful links

Helpful Links

• www.boogstudycenter.nl

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2010
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: November 26, 2010
• First Submitted That Met QC Criteria: September 2, 2013
• First Posted (Estimate): September 5, 2013

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 16, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: capecitabine; bevacizumab; paclitaxel; metastatic breast cancer; HER2/neu negative; liposomal doxorubicine
• 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; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibiotics, Antineoplastic; Paclitaxel; Capecitabine; Bevacizumab; Albumin-Bound Paclitaxel; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: BOOG 2010-02 Stop&Go study; NTR2589 (Registry Identifier: Nederlands Trialregister)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO