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

Breast Cancer Clinical Trial

— Triple-B  

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01898117
• Other study ID #: M13TNB
• Secondary ID: 2013-001484-23NL
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 2013
• Est. completion date: December 2030

Study information

• Verified date: March 2024
• Source: The Netherlands Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 304
• Est. completion date: December 2030
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Triple Negative Breast Neoplasms

Intervention

Drug:
• Carbo/cyclo

• Carbo/cyclo + atezolizumab

• Paclitaxel

• Paclitaxel + Atezolizumab

Locations

Country	Name	City	State
Netherlands	MCA	Alkmaar
Netherlands	Noordwest Ziekenhuis Groep	Alkmaar
Netherlands	ZGT	Almelo
Netherlands	Meander Medisch Centrum	Amersfoort
Netherlands	AZVU	Amsterdam
Netherlands	BovenIJ	Amsterdam
Netherlands	Netherlands Cancer Institute	Amsterdam
Netherlands	OLVG	Amsterdam
Netherlands	Gelre Ziekenhuis	Apeldoorn
Netherlands	Rijnstate	Arnhem
Netherlands	Lievensberg ziekenhuis	Bergen op Zoom
Netherlands	Rode Kruis Ziekenhuis	Beverwijk
Netherlands	Amphia	Breda
Netherlands	IJsselland ziekenhuis	Capelle Aan Den IJssel
Netherlands	Reinier de Graaf Gasthuis	Delft
Netherlands	Haga	Den Haag
Netherlands	Deventer ziekenhuis	Deventer
Netherlands	Albert Schweitzer Ziekenhuis	Dordrecht
Netherlands	Nijsmellinghe	Drachten
Netherlands	Ziekenhuis Gelderse Vallei	Ede
Netherlands	Catharina ziekenhuis	Eindhoven
Netherlands	Jeroen Bosch ziekenhuis	Eindhoven
Netherlands	Maxima Medisch Centrum	Eindhoven
Netherlands	Medisch Spectrum Twente (MST)	Enschede
Netherlands	Admiraal de Ruyter ziekenhuis	Goes
Netherlands	Groene Hart	Gouda
Netherlands	Groene Hart Ziekenhuis	Gouda
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	St. Jansdal	Harderwijk
Netherlands	Tergooi ziekenhuizen	Hilversum
Netherlands	Spaarne Gasthuis	Hoofddorp
Netherlands	Dijklander ziekenhuis	Hoorn
Netherlands	MCL	Leeuwarden
Netherlands	LUMC	Leiden
Netherlands	Haaglanden MC	Leidschendam
Netherlands	MUMC	Maastricht
Netherlands	St. Antonius ziekenhuis	Nieuwegein
Netherlands	Bravis ziekenhuis	Roosendaal
Netherlands	Ikazia	Rotterdam
Netherlands	Maasstad Ziekenhuis	Rotterdam
Netherlands	St. Fransicus Gasthuis	Rotterdam
Netherlands	Stichting Franciscus Vlietland Groep locatie Gasthuis	Rotterdam
Netherlands	Vlietland ziekenhuis	Schiedam
Netherlands	Zuyderland	Sittard
Netherlands	Elisabeth Tweesteden ziekenhuis	Tilburg
Netherlands	Diakonessenziekenhuis	Utrecht
Netherlands	UMCU	Utrecht
Netherlands	VieCuri Medisch Centrum voor Noord-Limburg	Venlo
Netherlands	Isala Klinieken	Zwolle

Sponsors (3)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	Borstkanker Onderzoek Groep, Roche Pharma AG

Country where clinical trial is conducted

Netherlands, 

Outcome

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