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

Phase 2Active Not RecruitingNCT01898117

The Netherlands Cancer Institute304 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

304

Conditions

Breast Cancer

Interventions

Carbo/cycloDRUG

Carbo/cyclo + atezolizumabDRUG

PaclitaxelDRUG

Paclitaxel + AtezolizumabDRUG

Eligibility

Sex: ALL

Medical Language ↔ Plain English

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

Locations (49)

Outcomes

Primary Outcomes

Validate the BRCA1-like test

Validate the BRCA1-like test in predicting differential PFS with first line alkylating and platinum agents (+/- antibody add-on) when compared to paclitaxel (+/- antibody add-on) in TNBC

Time frame: assessed up to 120 months

Secondary Outcomes

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)

Compare the overal survival (OS), overall response rate (ORR), clinical benefit rate (CBR) and duration of response (DOR) between the groups

Time frame: Assessed up to 120 months

Determine whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide (PFS1)

Compare the overal survival (OS), overall response rate (ORR), clinical benefit rate (CBR) and duration of response (DOR) between the groups

Time frame: Assessed up to 120 months

Improvement of objective response by adding atezolizumab

Determine whether atezolizumab added to first line palliative 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

Time frame: assessed up to 120 months

PD-L1 status (immunohistochemistry) in tumor infiltrating immune cells

Analyze whether PD-L1 status (immunohistochemistry) in tumor infiltrating immune cells predicts for potential differential PFS benefit of atezolizumab added to first line palliative chemotherapy in TNBC

Time frame: Assessed up to 120 months

Intratumoral CD8 and/or tumor-infiltrating lymphocytes (TIL)

Data from ClinicalTrials.gov

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