Neoadjuvant Therapy in TRIPle Negative Breast Cancer With antiPDL1

NCT ID: NCT02620280

Last Updated: 2024-03-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 278 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-04-30
• Study Completion Date: 2024-01-07

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.

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

Conditions

Invasive Ductal Breast Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

Carboplatin

Intervention Type: DRUG

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

Abraxane

Intervention Type: DRUG

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

Surgery

Intervention Type: PROCEDURE

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

Anthra

Intervention Type: DRUG

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

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

Group Type: EXPERIMENTAL

Carboplatin

Intervention Type: DRUG

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

Abraxane

Intervention Type: DRUG

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

MPDL3280A

Intervention Type: DRUG

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

Surgery

Intervention Type: PROCEDURE

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

Anthra

Intervention Type: DRUG

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

Interventions

Carboplatin

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

Intervention Type: 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

Intervention Type: DRUG

MPDL3280A

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

Intervention Type: DRUG

Surgery

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

Intervention Type: PROCEDURE

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

Intervention Type: DRUG

Other Intervention Names

Carboplatin Teva; nab-paclitaxel; Atezolizumab

Eligibility Criteria

Inclusion Criteria

1. Female patients aged 18 years or older with early high-risk and locally advanced or inflammatory breast cancers

2. Histologically confirmed unilateral breast cancer with invasive ductal histology not otherwise specified (NOS) of high proliferation or grade

3. HER2 negative disease

4. Negative estrogen receptor (ER) and progesterone receptor (PgR), both < 1% locally assessed

5. 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

6. ECOG performance status 0 or 1

7. 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

8. Willing and able to comply with the protocol

9. Consent to the collection of blood samples

10. 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

1. Evidence of bilateral breast cancer or metastatic disease (M1)

2. Cases with an histology different from invasive ductal NOS of high proliferation or grade

3. Patients with HER2-positive disease according to ASCO/CAP guidelines 2013

4. 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

5. Previous treatment with chemotherapy, hormonal therapy or an investigational drug for any type of malignancy

6. Previous investigational treatment for any condition within 4 weeks of randomization date

7. 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

8. 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

9. Pre-existing motor or sensory neuropathy of grade > 1 for any reason

10. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

11. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the MPDL3280A formulation

12. Patients with prior allogeneic stem cell or solid organ transplantation

13. 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

14. History of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with organizing pneumonia) or evidence of active pneumonitis on screening chest computed tomography scan

15. Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease

16. 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.

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• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Fondazione Michelangelo

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Luca Gianni, MD

Role: STUDY_CHAIR

Ospedale San Raffaele

Locations

Brustgesundheitzentrum Tirol, Univ. Frauenklinik Innsbruck

Innsbruck, , Austria

Universitätsklinik für Innere Medizin III, mit Hämatologie, internistischer Onkologie, Hämostaseologie, Infektiologie, Rheumatologie und Onkologisches Zentrum

Salzburg, , Austria

Klinikum Augsburg International Patient Service

Augsburg, , Germany

Frauenarzt-Zentrum-Zehlendorf

Berlin, , Germany

Augusta-Kranken-Anstalt gGmbH Klinik für Hämatologie, Onkologie & Palliativmedizin

Bochum, , Germany

Uniklinik Köln Klinik und Poliklinic für Frauenheilkunde und Geburtshilfe Brestzentrum

Cologne, , Germany

Brustzentrum St. Elisabeth-Krankenhaus

Cologne, , Germany

Bethanien-Krankenhaus Onkologisches Zentrum

Frankfurt, , Germany

Markus Krankenhaus Klinik für Gynäkologie und Geburtshilfe

Frankfurt, , Germany

Gynäkologisch-Onkologische Praxis

Hanover, , Germany

NCT Nationales Centrum für Tumorerkrankungen

Heidelberg, , Germany

Interdisciplinary Oncology Center (IOZ)

München, , Germany

Cork University Hospital

Cork, , Ireland

Beaumont Hospital

Dublin, , Ireland

Mater Misericordiae University Hospital

Dublin, , Ireland

St. James's Hospital

Dublin, , Ireland

University Hospital Waterford

Waterford, , Ireland

Policlinico S. Orsola Malpoghi

Bologna, , Italy

Istituto per la Ricerca sul Cancro

Candiolo, , Italy

IST San Martino

Genova, , Italy

Istituto Toscano Tumori Ospedale Misericordia

Grosseto, , Italy

Ospedale San Raffaele

Milan, , Italy

Fondazione IRCCS Istituto nazionale dei Tumori

Milan, , Italy

Istituto Europeo di Oncologia

Milan, , Italy

Ospedale Luigi Sacco

Milan, , Italy

Arcispedale Santa Maria Nuova - A.O. Reggio Emilia

Reggio Emilia, , Italy

Ospedale Santa Maria della Misericordia

Udine, , Italy

Russian Cancer Research Center named after N.N.Blokhin

Moscow, , Russia

Petrov Research Institute of Oncology, Department of Breast Cancer

Saint Petersburg, , Russia

Road clinical hospital of OJSC "Russian Railways

Saint Petersburg, , Russia

Hospital Duran i Reynal Institut Català d'Oncologia

L'Hospitalet de Llobregat, , Spain

Hospital Clínico San Carlos

Madrid, , Spain

Hospital Universitario 12 de octubre

Madrid, , Spain

Hospital Universitario HM Sanchinarro, Centro Integral Oncologico Clara Campal (CIOCC)

Madrid, , Spain

Hospital Clinico Universitario de Valencia Servicio de Onco-Hematologia

Valencia, , Spain

Hospital Miguel Servet

Zaragoza, , Spain

C. Christian Hospital Taiwan

Changhua, , Taiwan

Kaohsiung Medical University Hospital

Kaohsiung City, , Taiwan

China Medical University Hospital No.2

Taichung, , Taiwan

National Taiwan University Hospital

Taipei, , Taiwan

Veteran General Hospital Taipei

Taipei, , Taiwan

Countries

Austria; Germany; Ireland; Italy; Russia; Spain; Taiwan

References

Gianni L, Huang CS, Egle D, Bermejo B, Zamagni C, Thill M, Anton A, Zambelli S, Bianchini G, Russo S, Ciruelos EM, Greil R, Semiglazov V, Colleoni M, Kelly C, Mariani G, Del Mastro L, Maffeis I, Valagussa P, Viale G. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Ann Oncol. 2022 May;33(5):534-543. doi: 10.1016/j.annonc.2022.02.004. Epub 2022 Feb 17.

Reference Type: DERIVED

PMID: 35182721 (View on PubMed)

Perez-Garcia J, Soberino J, Racca F, Gion M, Stradella A, Cortes J. Atezolizumab in the treatment of metastatic triple-negative breast cancer. Expert Opin Biol Ther. 2020 Sep;20(9):981-989. doi: 10.1080/14712598.2020.1769063. Epub 2020 May 25.

Reference Type: DERIVED

PMID: 32450725 (View on PubMed)

Other Identifiers

2014-005017-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

FM-14-B02

Identifier Type: -

Identifier Source: org_study_id