Clinical trial NCT01898117: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Triple negative
Metastatic
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: Borstkanker Onderzoek Groep
name: Roche Pharma AG
First posted: 2013-07-12
Enrollment: 304
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Validate the BRCA1-like test
timeFrame: assessed up to 120 months
Secondary outcomes:
measure: 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)
timeFrame: Assessed up to 120 months
measure: Determine whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide (PFS1)
timeFrame: Assessed up to 120 months
measure: Improvement of objective response by adding atezolizumab
timeFrame: assessed up to 120 months
measure: PD-L1 status (immunohistochemistry) in tumor infiltrating immune cells
timeFrame: Assessed up to 120 months
measure: Intratumoral CD8 and/or tumor-infiltrating lymphocytes (TIL)
timeFrame: Assessed up to 120 months
measure: Compare PFS between alkylating-platinum regimen to paclitaxel as first line chemotherapy in BRCA1-like patients
timeFrame: Assessed up to 120 months
measure: Compare PFS between alkylating-platinum regimen to paclitaxel as first line chemotherapy in non BRCA1-like patients
timeFrame: Assessed up to 120 months
measure: TNBC molecular subtypes- based on RNA -expression analysis
timeFrame: Assessed up to 120 months
measure: pretreatment LDH level
timeFrame: Assessed up to 120 months
measure: Define predictive biomarkers for objective response gain
timeFrame: 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
measure: Define predictive biomarkers for PFS gain- chemotherapy
timeFrame: 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
measure: Define predictive biomarkers for PFS gain - atezolizumab
timeFrame: 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
measure: Determine PFS in cross over
timeFrame: At 6 and 12 months and up to 120 months
measure: Overal Response Rate (ORR)
timeFrame: Assessed up to 120 months
measure: Benefit Atezolizumab
timeFrame: Assessed up to 120 months
measure: Overall survival (OS)
timeFrame: assessed up to 120 months
measure: Toxicity of all study regimens
timeFrame: Assessed at 1 year
measure: Efficay in patients treated with or without Bevacizumab
timeFrame: Assessed up to 120 months
measure: Determine PFS in BRCA like TNBC
timeFrame: From date of randomization until date of first documented progression or date of death, which ever comes first, assessed up to 120 months
measure: putative predictive potential of BRCA1-like status
timeFrame: Assessed up to 120 months
Other outcomes:
Locations:
city: Alkmaar
country: Netherlands
facility: MCA
city: Alkmaar
country: Netherlands
facility: Noordwest Ziekenhuis Groep
city: Almelo
country: Netherlands
facility: ZGT
city: Amersfoort
country: Netherlands
facility: Meander Medisch Centrum
city: Amsterdam
country: Netherlands
facility: BovenIJ
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute
city: Amsterdam
country: Netherlands
facility: AZVU
city: Amsterdam
country: Netherlands
facility: OLVG
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuis
city: Arnhem
country: Netherlands
facility: Rijnstate
city: Bergen op Zoom
country: Netherlands
facility: Lievensberg ziekenhuis
city: Beverwijk
country: Netherlands
facility: Rode Kruis Ziekenhuis
city: Breda
country: Netherlands
facility: Amphia
city: Capelle Aan Den IJssel
country: Netherlands
facility: IJsselland ziekenhuis
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
city: Den Haag
country: Netherlands
facility: Haga
city: Deventer
country: Netherlands
facility: Deventer ziekenhuis
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Ziekenhuis
city: Drachten
country: Netherlands
facility: Nijsmellinghe
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Eindhoven
country: Netherlands
facility: Catharina ziekenhuis
city: Eindhoven
country: Netherlands
facility: Jeroen Bosch ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente (MST)
city: Goes
country: Netherlands
facility: Admiraal de Ruyter ziekenhuis
city: Gouda
country: Netherlands
facility: Groene Hart
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Groningen
country: Netherlands
facility: Martini Ziekenhuis
city: Harderwijk
country: Netherlands
facility: St. Jansdal
city: Hilversum
country: Netherlands
facility: Tergooi ziekenhuizen
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
city: Hoorn
country: Netherlands
facility: Dijklander ziekenhuis
city: Leeuwarden
country: Netherlands
facility: MCL
city: Leiden
country: Netherlands
facility: LUMC
city: Leidschendam
country: Netherlands
facility: Haaglanden MC
city: Maastricht
country: Netherlands
facility: MUMC
city: Nieuwegein
country: Netherlands
facility: St. Antonius ziekenhuis
city: Roosendaal
country: Netherlands
facility: Bravis ziekenhuis
city: Rotterdam
country: Netherlands
facility: St. Fransicus Gasthuis
city: Rotterdam
country: Netherlands
facility: Ikazia
city: Rotterdam
country: Netherlands
facility: Maasstad Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Stichting Franciscus Vlietland Groep locatie Gasthuis
city: Schiedam
country: Netherlands
facility: Vlietland ziekenhuis
city: Sittard
country: Netherlands
facility: Zuyderland
city: Tilburg
country: Netherlands
facility: Elisabeth Tweesteden ziekenhuis
city: Utrecht
country: Netherlands
facility: Diakonessenziekenhuis
city: Utrecht
country: Netherlands
facility: UMCU
city: Venlo
country: Netherlands
facility: VieCuri Medisch Centrum voor Noord-Limburg
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: MC Haaglanden
name: Rianne Oosterkamp, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NKI-AvL
name: Marleen Kok, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Egger SJ, Chan MMK, Luo Q, Wilcken N. Platinum-containing regimens for triple-negative metastatic breast cancer. Cochrane Database Syst Rev. 2020 Oct 21;10(10):CD013750. doi: 10.1002/14651858.CD013750.