Triple-B Study;Carboplatin-cyclophosphamide Versus Paclitaxel With or Without Atezolizumab as First-line Treatment in Advanced Triple Negative Breast Cancer (Triple-B)

November 21, 2025 updated by: The Netherlands Cancer Institute

Biomarker Discovery Randomized Phase IIb Trial With Carboplatin-cyclophosphamide Versus Paclitaxel With or Without Atezolizumab as First-line Treatment in Advanced Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is a difficult to treat molecular subtype with a poor survival. TNBC can be divided into at least two molecular entities; BRCA-like and non-BRCA-like. In this trial we would like to investigate whether a molecular subgroup exists within TNBCs that derives a benefit from atezolizumab added to first line chemotherapy.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Atezolizumab, a humanized monoclonal antibody that targets human programmed death-ligand 1 (PD-L1) has shown activity in TNBC. Early clinical trials with anti-PD-(L)1 monotherapy have shown that the median duration to response in TNBC is remarkably long (18 weeks) compared to cytotoxic chemotherapy. Since advanced TNBC is characterized by rapid disease progression, most patients with TNBC may not have the opportunity to derive benefit from immunotherapy. We hypothesize that by combining atezolizumab with paclitaxel or carboplatin-cyclophosphamide the desired rapid tumor control will be obtained with chemotherapy and subsequently atezolizumab can result in durable responses in a significant subset of patients. It is unknown whether addition of atezolizumab to first line chemotherapy in TNBC is more beneficial than adding this antibody to a second line treatment schedule. Because of this and because of the poor outcome of patients with advanced TNBC experiencing disease progression after first line palliative chemotherapy, patients who were randomized to a chemotherapy only arm in this study will be offered the opportunity to cross over to the other chemotherapy regimen plus atezolizumab at disease progression.

Study Type

Interventional

Enrollment (Actual)

304

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Alkmaar, Netherlands, 1815 JD
        • MCA
      • Alkmaar, Netherlands
        • Noordwest Ziekenhuis Groep
      • Almelo, Netherlands, 7609 PP
        • ZGT
      • Amersfoort, Netherlands
        • Meander Medisch Centrum
      • Amsterdam, Netherlands
        • OLVG
      • Amsterdam, Netherlands, 1066 CX
        • Netherlands Cancer Institute
      • Amsterdam, Netherlands, 1081 HV
        • AZVU
      • Amsterdam, Netherlands, 1034 CS
        • BovenIJ
      • Apeldoorn, Netherlands
        • Gelre Ziekenhuis
      • Arnhem, Netherlands
        • Rijnstate
      • Bergen op Zoom, Netherlands, 4624 VT
        • Lievensberg ziekenhuis
      • Beverwijk, Netherlands, 1940 EB
        • Rode Kruis Ziekenhuis
      • Breda, Netherlands
        • Amphia
      • Capelle aan den IJssel, Netherlands, 2906 ZC
        • IJsselland Ziekenhuis
      • Delft, Netherlands
        • Reinier de Graaf Gasthuis
      • Deventer, Netherlands, 7416 SE
        • Deventer Ziekenhuis
      • Dordrecht, Netherlands
        • Albert Schweitzer Ziekenhuis
      • Drachten, Netherlands, 9202 NN
        • Nijsmellinghe
      • Ede, Netherlands, 6716 RP
        • Ziekenhuis Gelderse Vallei
      • Eindhoven, Netherlands
        • Catharina Ziekenhuis
      • Eindhoven, Netherlands, 5631 BM
        • Maxima Medisch Centrum
      • Eindhoven, Netherlands
        • Jeroen Bosch Ziekenhuis
      • Enschede, Netherlands
        • Medisch Spectrum Twente (MST)
      • Goes, Netherlands
        • Admiraal De Ruyter Ziekenhuis
      • Gouda, Netherlands
        • Groene Hart Ziekenhuis
      • Gouda, Netherlands, 2803 HH
        • Groene Hart
      • Groningen, Netherlands
        • Martini Ziekenhuis
      • Harderwijk, Netherlands
        • St. Jansdal
      • Hilversum, Netherlands
        • Tergooi ziekenhuizen
      • Hoofddorp, Netherlands, 2134 TM
        • Spaarne Gasthuis
      • Hoorn, Netherlands
        • Dijklander Ziekenhuis
      • Leeuwarden, Netherlands, 8934 AD
        • MCL
      • Leiden, Netherlands, 2333 ZA
        • LUMC
      • Leidschendam, Netherlands, 2262 BA
        • Haaglanden MC
      • Maastricht, Netherlands
        • MUMC
      • Nieuwegein, Netherlands
        • St. Antonius Ziekenhuis
      • Roosendaal, Netherlands
        • Bravis ziekenhuis
      • Rotterdam, Netherlands
        • Maasstad Ziekenhuis
      • Rotterdam, Netherlands, 3045 PM
        • St. Fransicus Gasthuis
      • Rotterdam, Netherlands, 3083 AN
        • Ikazia
      • Rotterdam, Netherlands
        • Stichting Franciscus Vlietland Groep locatie Gasthuis
      • Schiedam, Netherlands, 3118 JH
        • Vlietland Ziekenhuis
      • Sittard, Netherlands
        • Zuyderland
      • The Hague, Netherlands, 2545 CH
        • Haga
      • Tilburg, Netherlands, 5042 AD
        • Elisabeth Tweesteden Ziekenhuis
      • Utrecht, Netherlands
        • UMCU
      • Utrecht, Netherlands
        • Diakonessenziekenhuis
      • Venlo, Netherlands
        • VieCuri Medisch Centrum voor Noord-Limburg
      • Zwolle, Netherlands, 8025 AB
        • Isala Klinieken

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Metastasized or locally advanced incurable triple negative breast cancer; patients with stage IV at diagnosis are eligible as well. If the primary lesion is the only measurable lesion according to RECIST criteria, every locoregional treatment must be mentioned to the investigators.
  • Histologically confirmed triple negative breast cancer (ER: < 10% nuclear staining of tumor cells on IHC; HER2: either score 0 or 1 at immunohistochemistry or negative at in situ hybridization [CISH or FISH] in case of score 2 or 3 on IHC)
  • Histological confirmation of triple negative breast cancer of a metastatic lesion is recommended
  • Histological or cytological confirmation of metastatic breast cancer is required in case of normal CA 15.3 levels
  • Primary tumor or metastasis tissue (10 x10 μm blank slides FFPE tumor material) sent to NKI-AVL for BRCA-like testing
  • Pretreatment histological biopsy of a metastatic lesion for the translational research questions (tumor tissue from bone metastases cannot be used).
  • No previous cytotoxic therapy for metastatic disease
  • Disease-free interval of at least 12 months after completion of adjuvant paclitaxel or platinum compound therapy
  • Disease-free interval of at least 6 months after completion of adjuvant docetaxel
  • Measurable disease according to RECIST v1.1
  • WHO performance status of 0 or 1
  • Adequate bone marrow function: neutrophils ≥ 1.5 x 10E9 cells/l, platelets ≥100 x 10E9 cells/l, Hb ≥ 6.2 mmol/l.
  • Normal liver function: bilirubin < 1.5 x upper limit of the normal range (ULN); alkaline phosphatase < 2.5 x ULN (< 5 x ULN in case of liver metastases, and < 7 x ULN in case of bone metastases); transaminases (ASAT/ALAT) < 2.5 x ULN (and < 5 x ULN in case of liver metastases).

  • Normal renal function:

    > calculated (Cockcroft-Gault) or measured creatinine clearance > 50 mL/min

  • INR < 1.5 and APTT normal, unless patient is on stable anti-coagulant treatment for at least two weeks with a low molecular weight heparin or coumarin, then an INR within the target range (usually between 2 and 3) is allowed.
  • Written informed consent

Exclusion Criteria:

  • Receptor conversion to hormone receptor positive (defined as >= 10% positive ER or PgR tumor cells) or HER2 positive
  • Another cancer except basal-cell carcinoma of the skin or in situ cervical cancer within the previous 5 years
  • Other antitumor therapy within the previous 21 days with the exception of endocrine therapy. The patient should have stopped any endocrine therapy before start study treatment.
  • Radiotherapy with palliative intent within the previous 7 days before randomization.
  • Known CNS disease except for treated brain metastases.
  • Uncontrolled serious medical or psychiatric illness
  • Pre-existing peripheral neuropathy > grade 1 (NCI-CTC AE (version 4.03)) at inclusion
  • Severe infection within 4 weeks prior to randomization
  • received antibiotocs within 2 weeks prior to cycle 1, day 1
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization or anticipation of need for major surgical procedure during the course of the study
  • New York Heart Association Class II or greater congestive heart failure. LVEF by MUGA, ultrasound or MRI must be ≥ 50% and should be performed within 4 weeks prior to randomization if cardiac failure is suspected.
  • History of myocardial infarction or unstable angina within 6 months prior to randomization
  • History of myocardial infarction or unstable angina or unstable arrhytmias within 3 months prior to randomization

futher criteria, see protocol

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Carbo/cyclo
Carboplatin AUC=5 Cyclophosphamide 600 mg/m2 Q 4 weeks
Drug: Carbo/cyclo
Other Names:
  • Cyclophosphamide
  • Carboplatin
Active Comparator: Carbo/cyclo + Atezolizumab
Carboplatin AUC=5 Cyclophosphamide 600 mg/m2 atezolizumab 840 mg d1,15 Q 4 weeks
Drug: Carbo/cyclo + atezolizumab
Other Names:
  • Cyclophosphamide
  • Carboplatin
  • Atezolizumab
Active Comparator: Paclitaxel
Paclitaxel 90 mg/m2 d1, 8, 15 Q 4 weeks
Drug: Paclitaxel
Active Comparator: Paclitaxel + atezolizumab
Paclitaxel 90 mg/m2 d1, 8, 15 atezolizumab 840 mg d1,15 Q 4 weeks
Drug: Paclitaxel + Atezolizumab
Other Names:
  • Atezolizumab
  • Paclitaxel

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Validate the BRCA1-like test
Time Frame: assessed up to 120 months
Validate the BRCA1-like test in predicting differential PFS with first line alkylating and platinum agents (+/- antibody add-on) when compared to paclitaxel (+/- antibody add-on) in TNBC
assessed up to 120 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Define predictive biomarkers for objective response gain
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 120 months
Define predictive biomarkers for objective response gain of the addition of atezolizumab to first line chemotherapy; e.g PD-L1, intratumoral CD8, TILs and pre-treatment LDH
From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 120 months
Determine PFS in BRCA like TNBC
Time Frame: From date of randomization until date of first documented progression or date of death, which ever comes first, assessed up to 120 months
Determine whether an alkylating platinum regimen is more effective then paclitaxel regarding PFS in BRCA like TNBC
From date of randomization until date of first documented progression or date of death, which ever comes first, assessed up to 120 months
Toxicity of all study regimens
Time Frame: Assessed at 1 year
Adverse events will be graded according to NCI Common Toxicity Criteria version 4.03
Assessed at 1 year
Determine whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide for patients with PD-L1 positive tumors defined as combined positive score (CPS) 10 or higher (PFS1)
Time Frame: Assessed up to 120 months
Compare the overal survival (OS), overall response rate (ORR), clinical benefit rate (CBR) and duration of response (DOR) between the groups
Assessed up to 120 months
Determine whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide (PFS1)
Time Frame: Assessed up to 120 months
Compare the overal survival (OS), overall response rate (ORR), clinical benefit rate (CBR) and duration of response (DOR) between the groups
Assessed up to 120 months
Improvement of objective response by adding atezolizumab
Time Frame: assessed up to 120 months
Determine whether atezolizumab added to first line palliative chemotherapy will result in more objective responses and a higher proportion of patients who are free of progression at 6 months and at 12 months
assessed up to 120 months
PD-L1 status (immunohistochemistry) in tumor infiltrating immune cells
Time Frame: Assessed up to 120 months
Analyze whether PD-L1 status (immunohistochemistry) in tumor infiltrating immune cells predicts for potential differential PFS benefit of atezolizumab added to first line palliative chemotherapy in TNBC
Assessed up to 120 months
Intratumoral CD8 and/or tumor-infiltrating lymphocytes (TIL)
Time Frame: Assessed up to 120 months
Analyze whether intratumoral CD8 and/or tumor-infiltrating lymphocytes (TIL) predict for differential PFS benefit of atezolizumab added to first line palliative chemotherapy in TNBC
Assessed up to 120 months
Compare PFS between alkylating-platinum regimen to paclitaxel as first line chemotherapy in BRCA1-like patients
Time Frame: Assessed up to 120 months
Evaluate whether an alkylating-platinum regimen is more effective than paclitaxel as first line chemotherapy regarding PFS in BRCA1-like TNBC
Assessed up to 120 months
Compare PFS between alkylating-platinum regimen to paclitaxel as first line chemotherapy in non BRCA1-like patients
Time Frame: Assessed up to 120 months
Evaluate whether an alkylating-platinum regimen is more effective than paclitaxel as first line chemotherapy regarding PFS in non BRCA1-like TNBC
Assessed up to 120 months
TNBC molecular subtypes- based on RNA -expression analysis
Time Frame: Assessed up to 120 months
define whether different TNBC molecular subtypes- based on RNA -expression analysis - predict for differential PFS benefit of atezolizumab added to first line palliative chemotherapy in TNBC
Assessed up to 120 months
pretreatment LDH level
Time Frame: Assessed up to 120 months
define whether pretreatment LDH level predicts for differential benefit of atezolizumab added to first line palliative chemotherapy in TNBC
Assessed up to 120 months
Define predictive biomarkers for PFS gain- chemotherapy
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 120 months
Define predictive biomarkers for PFS gain of carboplatin-cyclophosphamide or paclitaxel chemotherapy
From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 120 months
Define predictive biomarkers for PFS gain - atezolizumab
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 120 months
Define predictive biomarkers for PFS gain of addition of atezo lizumab to first line palliative chemotherapy in TNBC
From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 120 months
Determine PFS in cross over
Time Frame: At 6 and 12 months and up to 120 months
Determine the PFS and objective response after cross over to the other chemotherapy regimen with atezolizumab (PFS2)
At 6 and 12 months and up to 120 months
Overal Response Rate (ORR)
Time Frame: Assessed up to 120 months
proportion of patients that is free of progression at 6 months and at 12 months after cross-over to the other chemotherapy regimen with atezolizumab
Assessed up to 120 months
Benefit Atezolizumab
Time Frame: Assessed up to 120 months
Evaluate whether addition of atezolizumab to chemotherapy in first line is more beneficial than when added in second line
Assessed up to 120 months
Overall survival (OS)
Time Frame: assessed up to 120 months
Evaluation of overall survival (OS) for all (sub)group comparisons as pre-specified
assessed up to 120 months
Efficay in patients treated with or without Bevacizumab
Time Frame: Assessed up to 120 months
Evaluate preliminary efficacy by PFS and OS in subgroups of patients treated before amendment 3 with carboplatin/cyclophosphamide or paclitaxel with or without bevacizumab
Assessed up to 120 months
putative predictive potential of BRCA1-like status
Time Frame: Assessed up to 120 months
Evaluate putative predictive potential of BRCA1-like status in various subgroups defined by treatment regimen received before amendment 3.
Assessed up to 120 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Netherlands Cancer Institute

Collaborators

Roche Pharma AG
Borstkanker Onderzoek Groep

Investigators

  • Principal Investigator: Rianne Oosterkamp, MD, MC Haaglanden
  • Principal Investigator: Marleen Kok, MD, NKI-AvL

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2013

Primary Completion (Actual)

April 1, 2024

Study Completion (Estimated)

December 1, 2030

Study Registration Dates

First Submitted

June 27, 2013

First Submitted That Met QC Criteria

July 9, 2013

First Posted (Estimated)

July 12, 2013

Study Record Updates

Last Update Posted (Estimated)

November 26, 2025

Last Update Submitted That Met QC Criteria

November 21, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • M13TNB
  • 2013-001484-23 (EudraCT Number)
  • NL44403.031.13 (Other Identifier: CCMO)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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