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

Sponsor

The Netherlands Cancer Institute (Other)

Overall Status

Recruiting

CT.gov ID

NCT01898117

Collaborator

Borstkanker Onderzoek Groep (Other), Roche Pharma AG (Industry)

304

Enrollment

Locations

Arms

209

Anticipated Duration (Months)

6.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Carbo/cyclo Drug: Carbo/cyclo + atezolizumab Drug: Paclitaxel Drug: Paclitaxel + Atezolizumab	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

304 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jul 1, 2013

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Dec 1, 2030

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Carbo/cyclo Carboplatin AUC=5 Cyclophosphamide 600 mg/m2 Q 4 weeks	Drug: Carbo/cyclo Other Names: Carboplatin Cyclophosphamide
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: Carboplatin Cyclophosphamide 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: Paclitaxel Atezolizumab

Outcome Measures

Primary Outcome Measures

Validate the BRCA-like test [assessed up to 120 months]
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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	MCA	Alkmaar	Netherlands	1815 JD
2	Noordwest Ziekenhuis Groep	Alkmaar	Netherlands
3	ZGT	Almelo	Netherlands	7609 PP
4	Meander Medisch Centrum	Amersfoort	Netherlands
5	BovenIJ	Amsterdam	Netherlands	1034 CS
6	Netherlands Cancer Institute	Amsterdam	Netherlands	1066 CX
7	AZVU	Amsterdam	Netherlands	1081 HV
8	OLVG	Amsterdam	Netherlands
9	Gelre Ziekenhuis	Apeldoorn	Netherlands
10	Rijnstate	Arnhem	Netherlands
11	Lievensberg ziekenhuis	Bergen op Zoom	Netherlands	4624 VT
12	Rode Kruis Ziekenhuis	Beverwijk	Netherlands	1940 EB
13	Amphia	Breda	Netherlands
14	IJsselland ziekenhuis	Capelle Aan Den IJssel	Netherlands	2906 ZC
15	Reinier de Graaf Gasthuis	Delft	Netherlands
16	Haga	Den Haag	Netherlands	2545 CH
17	Deventer ziekenhuis	Deventer	Netherlands	7416 SE
18	Albert Schweitzer Ziekenhuis	Dordrecht	Netherlands
19	Nijsmellinghe	Drachten	Netherlands	9202 NN
20	Ziekenhuis Gelderse Vallei	Ede	Netherlands	6716 RP
21	Maxima Medisch Centrum	Eindhoven	Netherlands	5631 BM
22	Catharina ziekenhuis	Eindhoven	Netherlands
23	Jeroen Bosch ziekenhuis	Eindhoven	Netherlands
24	Medisch Spectrum Twente (MST)	Enschede	Netherlands
25	Admiraal de Ruyter ziekenhuis	Goes	Netherlands
26	Groene Hart	Gouda	Netherlands	2803 HH
27	Groene Hart Ziekenhuis	Gouda	Netherlands
28	Martini Ziekenhuis	Groningen	Netherlands
29	St. Jansdal	Harderwijk	Netherlands
30	Tergooi ziekenhuizen	Hilversum	Netherlands
31	Spaarne Gasthuis	Hoofddorp	Netherlands	2134 TM
32	Dijklander ziekenhuis	Hoorn	Netherlands
33	MCL	Leeuwarden	Netherlands	8934 AD
34	LUMC	Leiden	Netherlands	2333 ZA
35	Haaglanden MC	Leidschendam	Netherlands	2262 BA
36	MUMC	Maastricht	Netherlands
37	St. Antonius ziekenhuis	Nieuwegein	Netherlands
38	Bravis ziekenhuis	Roosendaal	Netherlands
39	St. Fransicus Gasthuis	Rotterdam	Netherlands	3045 PM
40	Ikazia	Rotterdam	Netherlands	3083 AN
41	Maasstad Ziekenhuis	Rotterdam	Netherlands
42	Stichting Franciscus Vlietland Groep locatie Gasthuis	Rotterdam	Netherlands
43	Vlietland ziekenhuis	Schiedam	Netherlands	3118 JH
44	Zuyderland	Sittard	Netherlands
45	Elisabeth Tweesteden ziekenhuis	Tilburg	Netherlands	5042 AD
46	Diakonessenziekenhuis	Utrecht	Netherlands
47	UMCU	Utrecht	Netherlands
48	VieCuri Medisch Centrum voor Noord-Limburg	Venlo	Netherlands
49	Isala Klinieken	Zwolle	Netherlands	8025 AB