Studieoverzicht - 2013-01 Triple-B

 
Number 2013-01 Triple-B
Nickname Triple-B
Status Open Date: 10-10-2013
Inclusion closed
Other study number(s)
Participating parties/groups
Full 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
Phase and type Randomized Phase II
Age ≥18
Menopausal status Both pre- and postmenopausal
Indication Advanced/metastatic
Subindication TNBC
Target sample size 304
Actual accrual 119 Date: 01-05-2019
Estimated study completion date 01-12-2021
CCMO approval Yes Date: 18-04-2013 Nr: NL44403.031.13 BI
EudraCT nr. 2013-001484-23
Trial Register NCT01898117
METC approval Yes Date: 24-05-2013 METC: Nederlands Kanker Instituut Nr: PTC13.0503/M13TNB
Amendments Yes Date: 22-08-2018
KWF-CKS approval Not applicable Date: Nr: nvt
News item
Website https://www.boogstudycenter.nl/studie/265/triple-b.html
Sponsor BOOG Study Center
Principal Investigator(s) S.C. Linn, H.M. Oosterkamp en M. Kok
Study manager J. Rademaker-Lakhai, BOOG

Studiecoördinator:
Leonora de Boo / Annelot van Rossum
Phone 020 – 5126981 / 020-5126187
E-mail l.d.boo@nki.nl / a.v.rossum@nki.nl


Central datamanagement and randomization Randomization:
NKI Data Center, Trial Office
Phone +31 20 512 2668
Fax +31 20 512 2679
E-mail trial@nki.nl

Central contact NKI Data Center:
I. Mandjes
Phone +31 20 512 2880
E-mail i.mandjes@nki.nl
Monitoring NKI Data Center, Heleen Bussing
Phone +31 20 512 2655
E-mail h.bussing@nki.nl
Local datamanagement IKNL / Centrum zelf
Funding Roche grant
Extra Immunohubs (aangestelde centra voor extra bloedbuizen en biopten)(status 26nov2018): NKI-AvL Centrale en Lokale goedkeuring: RSC E-mail: rsc@rsconsultancy.nl

Design:

Design

Objectives:

Primary:

Validate the BRCA-like test* in predicting differential progression free survival (PFS) according to RECIST v1.1 definitions for measurable and non-measurable disease with first line alkylating and platinum agents (± antibody add-on) when compared to paclitaxel (± antibody add-on) in TNBC

 

Secondary

  1. Test whether the addition of atezolizumab to 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
  2. Analyze whether PD-L1 status (immunohistochemistry) in either tumor cells or tumor infiltrating immune cells predicts for potential differential PFS benefit of atezolizumab added to first line palliative chemotherapy in TNBC
  3. Analyze whether intratumoral CD8 and/or tumor-infiltrating lymphocytes (TIL) predict for differential PFS benefit of atezolizumab added to fist line palliative chemotherapy in TNBC
  4. Evaluate whether an alkylating-platinum regimen is more effective than paclitaxel as first line chemotherapy regarding PFS in BRCA-like TNBC
  5. Evaluate whether paclitaxel is more effective than an alkylating regimen as first line chemotherapy regarding PFS in non-BRCA-like TNBC
  6. To 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
  7. To define whether pretreatment LDH level predicts for differential PFS benefit of atezolizumab added to first line palliative chemotherapy in TNBC
  8. To define biomarkers that can predict for a PFS advantage of carboplatin-cyclophosphamide (CC) as first line palliative chemotherapy in TNBC
  9. To define biomarkers that can predict for a PFS advantage of paclitaxel as first line palliative chemotherapy in TNBC
  10. To define biomarkers that can predict for a benefit of addition of atezolizumab to first line palliative chemotherapy in TNBC

11.Evaluation of PFS after cross-over to the other chemotherapy regimen with atezolizumab (PFS2)

  1. Evaluation of ORR, 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

13.Evaluate whether addition of atezolizumab to chemotherapy in first line is more beneficial than when added in second line

14.Evaluation of overall survival (OS) for all (sub)group comparisons as pre-specified for PFS and evaluation of overall response rate (ORR), clinical benefit rate (CBR), and duration of response (DOR) for all atezolizumab-related questions

15.Evaluate clinically relevant toxicity of all study regimens

16.Evaluate preliminary efficacy by PFS and OS in subgroups of patients treated before amendment 3 with carboplatin/cyclophosphamide or paclitaxel with or without bevacizumab

17.Evaluate putative predictive potential of BRCA-like status in various subgroups defined by treatment regimen received before amendment 3 (to be analyzed only after the main outcome of the trial, to avoid an extra interim analysis on the primary outcome).

 

* BRCA-like status determined by array comparative genomic hybridization (aCGH), multiplex ligase-dependent probe amplification (MLPA), or next generation sequencing (NGS); BRCA-like test positive when the genomic profile resembles that of BRCA-mutated breast cancers (BRCA-like genomic profile, derived from BRCA1 or BRCA2 mutation), or when the tumor is BRCA1-mutated, BRCA2-mutated, the patient is a BRCA1 and/or BRCA2 germline mutation carrier, or has a BRCA1 promoter hypermethylation.

Endpoints:

Primary endpoint:

Primary Outcome Measure (2x2 factorial design):

  • Interaction test of BRCA-like status vs. treatment (carboplatin+cyclophosphamide (CC) vs. paclitaxel (both arms with or without atezolizumab or bevacizumab (patients before amendment 3)) and PFS according to RECIST v1.1 definitions 1-3.

 

Secondary Outcome Measures:

  • Test benefit of the addition of atezolizumab to chemotherapy using objective response rate (ORR), proportion of patients free of progression at 6 months and at 12 months, all determined using RECIST v1.1 and overall survival (OS)
  • Define whether PD-L1 status in either tumor cells or tumor infiltrating immune cells predicts for benefit of atezolizumab added to first line palliative chemotherapy in TNBC; test association between PD-L1 status

and ORR, proportion of patients free of progression at 6 months and at 12 months, all determined using RECIST v1.1.

  • Define whether intratumoral CD8 and/or tumor-infiltrating lymphocytes (TIL) predicts for benefit of atezolizumab added to first line palliative chemotherapy in TNBC; test association between CD8 level (cut off to be determined) and ORR, proportion of patients free of progression at 6 months and at 12 months, all determined using RECIST v1.1
  • Determine whether certain molecular subtypes of TNBC as defined by gene expression are predictive for benefit of atezolizumab to first line chemotherapy using ORR, proportion of patients free of progression at 6 months and at 12 months, all determined using RECIST v1.1
  • Discovery of predictive biomarkers for benefit of atezolizumab to first line chemotherapy using ORR, proportion of patients free of progression at 6 months and at 12 months, all determined using RECIST v1.1
  • Discovery of predictive biomarkers for PFS benefit of carboplatin-cyclophosphamide or paclitaxel chemotherapy stratified for antibody add-on using RECIST v1.1
  • Determine PFS using RECIST v1.1 regarding the efficacy of the two different first line chemotherapeutic regimens, regardless of antibody add-on yes or no, in the whole study group, and in the BRCA-like and non-BRCA-like TNBCs subgroups separately
  • Evaluation of overall survival (OS) for all (sub)group comparisons as pre-specified for PFS and evaluation of overall response rate (ORR), clinical benefit rate (CBR), and duration of response (DOR) for all atezolizumab-related questions
  • Clinically relevant toxicity of all study regimens using CTCAE v4.0

 

Main eligibility 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) 47

- 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 (neo)adjuvant paclitaxel or (neo)adjuvant platinum compound

- Disease-free interval of at least 6 months after completion of (neo) adjuvant docetaxel

- Measurable or evaluable disease according to RECIST v1.1

Documents (public):

Informatie voor patiënten over deze studie en de deelnemende ziekenhuizen kunt u vinden op:

https://www.kanker.nl/trials/440-boog-2013-01-triple-b-borstkanker

Documents (protected):
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