Clinical Trials /

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

NCT01898117

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Triple-B Study;Carboplatin-cyclophosphamide Versus Paclitaxel With or Without Atezolizumab as First-line Treatment in Advanced Triple Negative Breast Cancer
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: M13TNB
  • SECONDARY ID: 2013-001484-23
  • SECONDARY ID: NL44403.031.13
  • NCT ID: NCT01898117

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
Carbo/cycloCarboplatin, CyclophosphamideCarbo/cyclo
Carbo/cyclo + atezolizumabCarboplatin, Cyclophosphamide, AtezolizumabCarbo/cyclo + Atezolizumab
PaclitaxelPaclitaxel
Paclitaxel + AtezolizumabPaclitaxel, AtezolizumabPaclitaxel + atezolizumab

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Carbo/cycloActive ComparatorCarboplatin AUC=5 Cyclophosphamide 600 mg/m2 Q 4 weeks
  • Carbo/cyclo
Carbo/cyclo + AtezolizumabActive ComparatorCarboplatin AUC=5 Cyclophosphamide 600 mg/m2 atezolizumab 840 mg d1,15 Q 4 weeks
  • Carbo/cyclo + atezolizumab
PaclitaxelActive ComparatorPaclitaxel 90 mg/m2 d1, 8, 15 Q 4 weeks
  • Paclitaxel
Paclitaxel + atezolizumabActive ComparatorPaclitaxel 90 mg/m2 d1, 8, 15 atezolizumab 840 mg d1,15 Q 4 weeks
  • Paclitaxel + Atezolizumab

Eligibility Criteria

        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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Validate the BRCA-like test
Time Frame:assessed up to 120 months
Safety Issue:
Description:Validate the BRCA-like test in predicting differential PFS with first line alkylating and platinum agents when compared to paclitaxel in TNBC

Secondary Outcome Measures

Measure:Improvement of objective response by adding atezolizumab
Time Frame:assessed up to 120 months
Safety Issue:
Description:Determine whether atezolizumab added to first line palliative chemotherapy improves objective response in TNBC
Measure: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
Safety Issue:
Description: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
Measure:Define predictive biomarkers for PFS 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
Safety Issue:
Description:Define predictive biomarkers for PFS gain of carboplatin-cyclophosphamide or paclitaxel chemotherapy
Measure: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
Safety Issue:
Description:Determine whether an alkylating platinum regimen is more effective then paclitaxel regarding PFS in BRCA like TNBC
Measure:Determine PFS in non 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
Safety Issue:
Description:Determine whether paclitaxel is more effective then an alkylating platinum regimen regarding PFS in non BRCA like TNBC
Measure:Overall survival (OS)
Time Frame:assessed up to 120 months
Safety Issue:
Description:Evaluation of overall survival (OS) for all (sub)group comparisons as pre-specified for PFS
Measure:Toxicity of all study regimens
Time Frame:Assessed at 1 year
Safety Issue:
Description:Adverse events will be graded according to NCI Common Toxicity Criteria version 4.03
Measure:Determine PFS in cross over
Time Frame:At 6 and 12 months and up to 120 months
Safety Issue:
Description:Determine the PFS and objective response after cross over to the other chemotherapy regimen with atezolizumab
Measure:Determine PFS in TNBC molecular subtypes
Time Frame:Assessed up to 120 months
Safety Issue:
Description:Determine whether TNBC molecular subtypes as defined by gene expression are predictive for differential PFS benefit of atezolizumab added to first line chemotherapy

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:The Netherlands Cancer Institute

Trial Keywords

  • Triple negative
  • Metastatic

Last Updated

January 17, 2018