NeoTRIPaPDL1: Neoadjuvant Therapy in TRIPle Negative Breast Cancer With antiPDL1

Sponsor

Fondazione Michelangelo (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02620280

Collaborator

(none)

278

Enrollment

Locations

Arms

Duration (Months)

6.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study that aims to evaluate the addition of MPDL3280A (atezolizumab) to carboplatin and nab-paclitaxel in patients with early high-risk and locally advanced triple negative breast cancer. compared to the control arm of carboplatin and abraxane. Half of participants will receive MPDL3280A in combination with carboplatin and abraxane, while the other half will receive only carboplatin and abraxane.

Condition or Disease	Intervention/Treatment	Phase
Invasive Ductal Breast Carcinoma	Drug: Carboplatin Drug: Abraxane Drug: MPDL3280A Procedure: Surgery Drug: Anthra	Phase 3

Detailed Description

Emerging evidence shows that many breast cancers with triple negative and basal like features have infiltration by mononuclear cells and lymphocytes. Irrespective of the entity of tumor infiltration by mononuclear cells, expression of immune regulatory checkpoints such as PD-1 and its ligand B7-H1 (or PD-L1) negatively affect the results of treatments. These data suggest that a subset of patients have an ongoing immune response within the tumor micro-environment, and that PD-L1 expression is an adaptive method of tumor resistance to tumor infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, the data suggests a role for immune regulation of response to chemotherapy, and support the concept that blockade of immune check-points may favor the achievement of durable response by immune mechanisms themselves, and in combination with classical chemotherapy.

MPDL3280A (atezolizumab) is a human monoclonal antibody containing an engineered Fc-domain to optimize efficacy and safety that targets PD-L1 and blocks binding of its receptors, including PD-1 and B7.1. Based on these considerations, we plan to conduct a study of the combination of abraxane and carboplatin with or without PDL1-directed antibody in women with locally advanced breast cancer suitable for neoadjuvant therapy with the aim to improve event-free survival

Study Design

Study Type:

Interventional

Actual Enrollment :

278 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Neo-Adjuvant Study With the PDL1-directed Antibody in Triple Negative Locally Advanced Breast Cancer Undergoing Treatment With Nab-paclitaxel and Carboplatin

Study Start Date :

Apr 1, 2016

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Oct 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Carbo-abrax, surgery, anthra Patients will receive a combination of carboplatin and abraxane as neoadjuvant treatment. Definite surgery will be performed not later than 6 weeks after the last dose of neoadjuvant therapy. Four cycles of AC or EC or FEC will then be delivered as adjuvant chemotherapy	Drug: Carboplatin Carboplatin AUC 2 will be given i.v. on day 1 and day 8 q 3 weeks for a total of 8 cycles Other Names: Carboplatin Teva Drug: Abraxane Abraxane, 125 mg/m2 will be given i.v. on day 1 and day 8 q 3 weeks for a total of 8 cycles Other Names: nab-paclitaxel Procedure: Surgery Breast cancer surgery (breast and axilla) either conservative or radical not later than 6 weeks Drug: Anthra AC or EC (adriamycin or epirubicin and cyclophosphamide) or FEC (fluorouracil, epirubicin, and cyclophosphamide) on day 1 every three weeks for 4 cycles to be delivered after surgery
Experimental: Carbo-abrax-MPDL3280A, surgery, anthra Patients will receive a combination of carboplatin, abraxane and MPDL3280A as neoadjuvant treatment. Definite surgery will be performed not later than 6 weeks after the last dose of neoadjuvant therapy. Four cycles of AC or EC or FEC will then be delivered as adjuvant chemotherapy	Drug: Carboplatin Carboplatin AUC 2 will be given i.v. on day 1 and day 8 q 3 weeks for a total of 8 cycles Other Names: Carboplatin Teva Drug: Abraxane Abraxane, 125 mg/m2 will be given i.v. on day 1 and day 8 q 3 weeks for a total of 8 cycles Other Names: nab-paclitaxel Drug: MPDL3280A MPDL3280A, 1200 mg. will be given i.v. infusion on day 1 q 3 weeks for a total of 8 cycles Other Names: Atezolizumab Procedure: Surgery Breast cancer surgery (breast and axilla) either conservative or radical not later than 6 weeks Drug: Anthra AC or EC (adriamycin or epirubicin and cyclophosphamide) or FEC (fluorouracil, epirubicin, and cyclophosphamide) on day 1 every three weeks for 4 cycles to be delivered after surgery

Arm

Intervention/Treatment

Active Comparator: Carbo-abrax, surgery, anthra

Patients will receive a combination of carboplatin and abraxane as neoadjuvant treatment. Definite surgery will be performed not later than 6 weeks after the last dose of neoadjuvant therapy. Four cycles of AC or EC or FEC will then be delivered as adjuvant chemotherapy

Drug: Carboplatin

Carboplatin AUC 2 will be given i.v. on day 1 and day 8 q 3 weeks for a total of 8 cycles

Other Names:

Carboplatin Teva

Drug: Abraxane

Abraxane, 125 mg/m2 will be given i.v. on day 1 and day 8 q 3 weeks for a total of 8 cycles

Other Names:

nab-paclitaxel

Procedure: Surgery

Breast cancer surgery (breast and axilla) either conservative or radical not later than 6 weeks

Drug: Anthra

AC or EC (adriamycin or epirubicin and cyclophosphamide) or FEC (fluorouracil, epirubicin, and cyclophosphamide) on day 1 every three weeks for 4 cycles to be delivered after surgery

Experimental: Carbo-abrax-MPDL3280A, surgery, anthra

Patients will receive a combination of carboplatin, abraxane and MPDL3280A as neoadjuvant treatment. Definite surgery will be performed not later than 6 weeks after the last dose of neoadjuvant therapy. Four cycles of AC or EC or FEC will then be delivered as adjuvant chemotherapy

Drug: Carboplatin

Carboplatin AUC 2 will be given i.v. on day 1 and day 8 q 3 weeks for a total of 8 cycles

Other Names:

Carboplatin Teva

Drug: Abraxane

Abraxane, 125 mg/m2 will be given i.v. on day 1 and day 8 q 3 weeks for a total of 8 cycles

Other Names:

nab-paclitaxel

Drug: MPDL3280A

MPDL3280A, 1200 mg. will be given i.v. infusion on day 1 q 3 weeks for a total of 8 cycles

Other Names:

Atezolizumab

Procedure: Surgery

Breast cancer surgery (breast and axilla) either conservative or radical not later than 6 weeks

Drug: Anthra

AC or EC (adriamycin or epirubicin and cyclophosphamide) or FEC (fluorouracil, epirubicin, and cyclophosphamide) on day 1 every three weeks for 4 cycles to be delivered after surgery

Outcome Measures

Primary Outcome Measures

Event Free Survival (EFS) [5 years after the randomization of the last patient]
To compare EFS (disease progression while on neoadjuvant therapy or disease recurrence after surgery) in the two study arms

Secondary Outcome Measures

Pathological complete response (pCR) [At surgery, an expected average of 34 weeks after the randomization of the last patient]
Assess the rate of pCR defined as ypT0-ypTis ypN0 at surgery in the two treatment arms
Clinical objective response [Participants will be followed for the duration of neoadjuvant therapy, an expected average of 26 weeks]
Assess the clinical response rate after neoadjuvant therapy
Distant Event Free Survival (DEFS) [5 years after the randomization of the last patients]
To compare the DEFS, defined as the occurrence of distant disease progression while on neoadjuvant therapy or distant recurrence after surgery in the two treatment arms
Number of participants with adverse events as a Measure of Safety and Tolerability [Participants wil be followed for up to 5 years from the last randomized patient]
Number of participants with Adverse Events and related grade

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Female patients aged 18 years or older with early high-risk and locally advanced or inflammatory breast cancers
Histologically confirmed unilateral breast cancer with invasive ductal histology not otherwise specified (NOS) of high proliferation or grade
HER2 negative disease
Negative estrogen receptor (ER) and progesterone receptor (PgR), both < 1% locally assessed
Representative paraffin-embedded (FFPE) tumor block taken at diagnostic biopsy for confirmation of HER2, ER and PgR eligibility, for assessment of PDL-1 expression and for further exploratory biomarker evaluation is mandatory
ECOG performance status 0 or 1
Written informed consent to participate in the trial (approved by the Institutional Review Board [IRB]/ Independent Ethics Committee [IEC]) obtained prior to any study specific screening procedures
Willing and able to comply with the protocol
Consent to the collection of blood samples
For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 90 days after the last dose of study drug.

Exclusion Criteria:

Evidence of bilateral breast cancer or metastatic disease (M1)
Cases with an histology different from invasive ductal NOS of high proliferation or grade
Patients with HER2-positive disease according to ASCO/CAP guidelines 2013
Pregnant or lactating women. Documentation of a negative pregnancy test must be available for premenopausal women with intact reproductive organs and for women less than one year after the last menstrual cycle
Previous treatment with chemotherapy, hormonal therapy or an investigational drug for any type of malignancy
Previous investigational treatment for any condition within 4 weeks of randomization date
Administration of a live, attenuated vaccine within 4 weeks before cycle 1 Day 1 or anticipation that such a live attenuated vaccine will be required during the study
Previous or concomitant invasive malignancy of any other type or previous invasive breast cancer. Patients with curatively treated basal cell carcinoma of the skin or in situ cervix cancer are generally eligible
Pre-existing motor or sensory neuropathy of grade > 1 for any reason
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the MPDL3280A formulation
Patients with prior allogeneic stem cell or solid organ transplantation
History of autoimmune disease including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
History of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with organizing pneumonia) or evidence of active pneumonitis on screening chest computed tomography scan
Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease
History of HIV infection, active hepatitis B (chronic or acute), or hepatitis C infection. Patients with past or resolved hepatitis B infection (defined as having a negative HBsAg test and a positive hepatitis B core antigen [anti-HBc] test) are eligible.

Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction assay (PCR) is negative for HCV RNA 17. Active tuberculosis 18. Severe infections within 4 weeks prior to cycle 1 Day 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. Signs or symptoms of significant infection within 2 weeks prior to cycle 1 Day 1 19. Received oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1 20. Other serious illness or medical condition including: history of documented congestive cardiac failure; New York Heart Association (NYHA) Class II or greater CHF; angina pectoris requiring anti-anginal medication or unstable angina within 6 months prior to cycle 1 Day 1; evidence of transmural infarction on ECG; myocardial infarction stroke or transient ischemic attack (TIA) within 6 months prior to cycle 1 Day 1; poorly controlled hypertension (e.g. systolic

180 mm Hg or diastolic >100 mm Hg; however, patients with hypertension which is well controlled on medication are eligible); clinically significant valvular heart disease; high-risk uncontrolled arrhythmias 21. Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and precluding informed consent or adversely affecting compliance with study drugs 22. Serious uncontrolled infections (bacterial or viral) or poorly controlled diabetes mellitus 23. Abnormal baseline hematological values 24. Abnormal baseline laboratory tests for serum total bilirubin, liver function tests, alkaline phosphatase, serum creatinine, INR and aPTT 25. Baseline left ventricular ejection fraction (LVEF) < 50% by echocardiography or multi-gated scintigraphic scan (MUGA) 26. Major surgical procedure within 28 days prior to cycle 1 Day 1 or anticipation of need for a major surgical procedure during the course of the study 27. Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to cycle 1 Day 1 or at any time during the study.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Brustgesundheitzentrum Tirol, Univ. Frauenklinik Innsbruck	Innsbruck	Austria	6020
2	Universitätsklinik für Innere Medizin III, mit Hämatologie, internistischer Onkologie, Hämostaseologie, Infektiologie, Rheumatologie und Onkologisches Zentrum	Salzburg	Austria	5020
3	Klinikum Augsburg International Patient Service	Augsburg	Germany	86156
4	Frauenarzt-Zentrum-Zehlendorf	Berlin	Germany	14169
5	Augusta-Kranken-Anstalt gGmbH Klinik für Hämatologie, Onkologie & Palliativmedizin	Bochum	Germany	447891
6	Bethanien-Krankenhaus Onkologisches Zentrum	Frankfurt	Germany	60389
7	Markus Krankenhaus Klinik für Gynäkologie und Geburtshilfe	Frankfurt	Germany	60431
8	Gynäkologisch-Onkologische Praxis	Hannover	Germany	30177
9	NCT Nationales Centrum für Tumorerkrankungen	Heidelberg	Germany	69120
10	Uniklinik Köln Klinik und Poliklinic für Frauenheilkunde und Geburtshilfe Brestzentrum	Köln	Germany	50931
11	Brustzentrum St. Elisabeth-Krankenhaus	Köln	Germany	50935
12	Interdisciplinary Oncology Center (IOZ)	Munchen	Germany	80336
13	Cork University Hospital	Cork	Ireland
14	Beaumont Hospital	Dublin	Ireland
15	Mater Misericordiae University Hospital	Dublin	Ireland
16	St. James's Hospital	Dublin	Ireland
17	University Hospital Waterford	Waterford	Ireland
18	Policlinico S. Orsola Malpoghi	Bologna	Italy	40138
19	Istituto per la Ricerca sul Cancro	Candiolo	Italy	10060
20	IST San Martino	Genova	Italy	16132
21	Istituto Toscano Tumori Ospedale Misericordia	Grosseto	Italy	58100
22	Ospedale San Raffaele	Milano	Italy	20132
23	Fondazione IRCCS Istituto nazionale dei Tumori	Milano	Italy	20133
24	Istituto Europeo di Oncologia	Milano	Italy	20141
25	Ospedale Luigi Sacco	Milano	Italy	20160
26	Arcispedale Santa Maria Nuova - A.O. Reggio Emilia	Reggio Emilia	Italy	42123
27	Ospedale Santa Maria della Misericordia	Udine	Italy	33100
28	Russian Cancer Research Center named after N.N.Blokhin	Moscow	Russian Federation
29	Petrov Research Institute of Oncology, Department of Breast Cancer	Saint Petersburg	Russian Federation
30	Road clinical hospital of OJSC "Russian Railways	Saint Petersburg	Russian Federation
31	Hospital Duran i Reynal Institut Català d'Oncologia	Hospitalet de Llobregat	Spain	08908
32	Hospital Clínico San Carlos	Madrid	Spain	28040
33	Hospital Universitario 12 de octubre	Madrid	Spain	28041
34	Hospital Universitario HM Sanchinarro, Centro Integral Oncologico Clara Campal (CIOCC)	Madrid	Spain	28050
35	Hospital Clinico Universitario de Valencia Servicio de Onco-Hematologia	Valencia	Spain	46010
36	Hospital Miguel Servet	Zaragoza	Spain	59009
37	C. Christian Hospital Taiwan	Changhua City	Taiwan
38	Kaohsiung Medical University Hospital	Kaohsiung	Taiwan
39	China Medical University Hospital No.2	Taichung City	Taiwan
40	National Taiwan University Hospital	Taipei	Taiwan
41	Veteran General Hospital Taipei	Taipei	Taiwan