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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Carbo/cyclo
* Drug: Carbo/cyclo + atezolizumab
* Drug: Paclitaxel
* Drug: Paclitaxel + Atezolizumab


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Carbo/cyclo<br>Carboplatin AUC=5 Cyclophosphamide 600 mg/m2 Q 4 weeks | Drug: Carbo/cyclo<br> <br> * Other names: Cyclophosphamide;|
| Active Comparator: Carbo/cyclo + Atezolizumab<br>Carboplatin AUC=5 Cyclophosphamide 600 mg/m2 atezolizumab 840 mg d1,15 Q 4 weeks | Drug: Carbo/cyclo + atezolizumab<br> <br> * Other names: Atezolizumab;|
| Active Comparator: Paclitaxel<br>Paclitaxel 90 mg/m2 d1, 8, 15 Q 4 weeks | Drug: Paclitaxel<br> <br> |
| Active Comparator: Paclitaxel + atezolizumab<br>Paclitaxel 90 mg/m2 d1, 8, 15 atezolizumab 840 mg d1,15 Q 4 weeks | Drug: Paclitaxel + Atezolizumab<br> <br> * Other names: Atezolizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Overall survival (OS) | Evaluation of overall survival (OS) for all (sub)group comparisons as pre-specified for PFS | assessed up to 120 months | 
| Toxicity of all study regimens | Adverse events will be graded according to NCI Common Toxicity Criteria version 4.03 | Assessed at 1 year | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Triple negative, Metastatic