Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Neoadjuvant Treatment of HER2 Positive Early High-risk and Locally Advanced Breast Cancer (APTneo)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03595592
Recruitment Status : Recruiting
First Posted : July 23, 2018
Last Update Posted : August 9, 2019
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Fondazione Michelangelo

Tracking Information
First Submitted Date  ICMJE July 11, 2018
First Posted Date  ICMJE July 23, 2018
Last Update Posted Date August 9, 2019
Actual Study Start Date  ICMJE September 7, 2018
Estimated Primary Completion Date December 15, 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 11, 2018)
Event Free Survival (EFS) [ Time Frame: 5 years after the randomization of the last patient ]
Assess EFS (disease progression while on neoadjuvant therapy or disease recurrence after surgery) in the study arms
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03595592 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 11, 2018)
  • Pathological complete response (pCR) [ Time Frame: At surgery, an expected average of 26 weeks after the randomization of the last patients ]
    Assess the rate of pCR defined as absence of invasive cancer in both breast and axillary nodes (ypT0Tis ypN0)
  • Clinical objective response [ Time Frame: Participants will be followed for the duration of neoadjuvant therapy, an expected average of 22 weeks ]
    Assess the rate of clinical response rate after neoadjuvant therapy
  • Distant Event Free Survival (DEFS) [ Time Frame: 5 years after the randomization of the last patients ]
    Assess DEFS (defined as the occurrence of distant disease progression while on neoadjuvant therapy or distant disease recurrence after surgery) in the study arms
  • Overall Survival (OS) [ Time Frame: 5 years after the randomization of the last patient ]
    Assess OS in all arms
  • Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: Participants will be followed for up to 5 years from the last randomized patient ]
    Number of participants with adverse events and related grades in all arms
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neoadjuvant Treatment of HER2 Positive Early High-risk and Locally Advanced Breast Cancer
Official Title  ICMJE Atezolizumab, Pertuzumab and Trastuzumab With Chemotherapy as Neoadjuvant Treatment of HER2 Positive Early High-risk and Locally Advanced Breast Cancer (APTneo)
Brief Summary n the present study the neoadjuvant approach with the anti-HER2 trastuzumab and pertuzumab combined with carboplatin and paclitaxel will be used to compare the Event-Free Survival (EFS) in regimens with and without atezolizumab. Following the neoadjuvant part of the study, after surgery all patients will continue to receive trastuzumab and pertuzumab to complete one year of anti-HER2 therapy. Similarly, patients allocated to receive atezolizumab will continue atezolizumab to complete one year In addition, several IHC and molecular assays will be performed before and during the period of chemotherapy administration and at surgery with the goal of defining a marker of efficacy to be later validated in a larger adjuvant setting.
Detailed Description

Dual targeting of HER2 with trastuzumab and pertuzumab in HER2-positive breast cancer is linked to clinical evidence of reversal of initial resistance to trastuzumab (Baselga J et al, J Clin Oncol 2010) in cases progressing on trastuzumab therapy, and in dramatic improvement in progression free and overall survival when the two monoclonal antibodies are used in combination with docetaxel (THP regimen) as first line therapy of metastatic disease as shown in the CLEOPATRA study (Swain S et al, ESMO abstract 2014). The randomized NeoSphere study showed that the same THP regimen given for 4 cycles as neoadjuvant treatment increased the rate of pathologic complete response (pCR) over that with conventional docetaxel and trastuzumab or docetaxel and pertuzumab (Gianni L et al, Lancet Oncol 2012).

Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that therapies focused on enhancing T cell responses against cancer can result in a significant survival benefit in patients with advanced malignancies (Hodi FS and Dranoff G, J Cutan Pathol 2010; Kantoff PW et al, New Engl J Med 2010; Chen DS et al, Clin Cancer Res 2012). Many human tumors have been found to overexpress PD L1, which acts to suppress anti tumor immunity. PD 1 is an inhibitory receptor expressed on T cells following T cell activation, which is sustained in states of chronic stimulation, such as in chronic infection or canc 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.

In addition to being involved in the natural progression of cancer, immunity can affect the activity of various anticancer agents. Accordingly, recent evidence suggests that some chemotherapeutic drugs, such as anthracyclines and oxaliplatin, rely on the induction of anticancer immune responses. Immune responses also play a major role in the efficacy of targeted therapies with monoclonal antibodies (Stagg J et al, Breast Care 2012). Studies have shown monoclonal antibodies such as trastuzumab and rituximab rely in part on immunemediated killing through antibody-dependent cellular cytotoxicity (ADCC). While innate immune responses appear to be important for tumor antigen-targeted monoclonal antibody therapies, recent studies in mice and correlative clinical evidence suggest that trastuzumab may also stimulate adaptive antitumor immunity. These studies raise the possibility that combination strategies may be used to capitalize on the adaptive tumor-specific immunity generated by anti-HER2 monoclonal antibodies.

Based on these considerations, we plan to conduct a randomized neoadjuvant study of the combination of trastuzumab, pertuzumab, carboplatin and paclitaxel with or without atezolizumab in women with early high-risk and locally advanced HER2-positive suitable for neoadjuvant therapy. One study arm will also include anthracycline and cyclophosphamide.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Parallel randomization to the study arms
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Invasive Breast Cancer
Intervention  ICMJE
  • Drug: Trastuzumab
    Trastuzumab will be given i.v. on day 1 every 3 weeks in arms HPCT, ACy followed by HPCT and atezolizumab and in arm HPCT and atezolizumab
    Other Name: Herceptin
  • Drug: Pertuzumab
    Pertuzumab will be given i.v. on day 1 every 3 weeks in arms HPCT, ACy followed by HPCT and atezolizumab and in arm HPCT and atezolizumab
    Other Name: Perjeta
  • Drug: Carboplatin
    Carboplatin will be given i.v. on day 1 and day 8 every 3 weeks in arms HPCT, ACy followed by HPCT and atezolizumab and in arm HPCT and atezolizumab
    Other Name: Carboplatin Hospiria
  • Drug: Paclitaxel
    Paclitaxel will be given i.v. on day 1 and day 8 every 3 weeks in arms HPCT, ACy followed by HPCT and atezolizumab and in arm HPCT and atezolizumab
    Other Name: Paclitaxel Hospiria
  • Drug: Doxorubicin
    Adriamycin will be delivered i.v. on day 1 every 3 weeks in arm ACy followed by HPCT for the first 3 cycles
    Other Name: Doxorubicin Pfizer
  • Drug: Cyclophosphamide
    Cyclophosphamide will be given i.v. on day 1 every 3 weeks in arm ACy followed by HPCT and atezolizumab for the first 3 cycles
    Other Name: Cyclophosphamide Sandoz
  • Drug: Atezolizumab
    Atezolizumab will be given i.v. on day 1 every 3 weeks in arm ACy followed by HPCT and atezolizumab and in arm HPCT and atezolizumab
    Other Name: Tecentriq
  • Procedure: Surgery
    Breast cancer surgery (breast and axilla) either conservative or radical not later than 4 weeks from the last dose of neoadjuvant therapy in all study arms
Study Arms  ICMJE
  • Active Comparator: HPCT
    Patients will receive a combination of trastuzumab, pertuzumab, carboplatin and paclitaxel as neoadjuvant therapy for 6 cycles every 3 weeks. Trastuzumab (H) will be delivered on day 1 at the dose of 8 mg/kg loading dose i.v., then 6 mg/kg i.v. Pertuzumab (P) will be delivered on day 1 at the dose of 840 mg loading dose i.v., then 420 mg i.v. Carboplatin (C) will be administered at AUC 2 i.v. on day 1 and day 8. Paclitaxel (T) will be given at 90 mg/m2 i.v. on day 1 and day 8. Definite surgery will be performed not later than 4 weeks after the last dose of neoadjuvant therapy. Trastuzumab and pertuzumab will then be delivered for 12 additional cycles as adjuvant therapy.
    Interventions:
    • Drug: Trastuzumab
    • Drug: Pertuzumab
    • Drug: Carboplatin
    • Drug: Paclitaxel
    • Procedure: Surgery
  • Experimental: ACy followed by HPCT and atezolizumab
    Patients will receive a combination of doxorubicin (A, 60 mg/m2 i.v.), cyclophosphamide (C, 600 mg/m2 i.v.) and atezolizumab (1200 mg i.v.) on day 1 every 3 week for 3 cycles. Subsequently they will be given trastuzumab on day 1 (H, at the loading dose of 8 mg/kg i.v. then 6 mg/kg i.v.), pertuzumab on day 1 (P, at the loading dose of 840 mg .v., then 420 mg i.v.), carboplatin (C) at AUC 2 i.v. on day 1 and day 8, paclitaxel (T) at 90 mg/m2 i.v. on day 1 and day 8, and atezolizumab 1200 mg i.v. on day 1 for 3 cycles every 3 weeks. Definite surgery will be performed not later than 4 weeks after the last dose of neoadjuvant therapy. Trastuzumab and pertuzumab will then be delivered for 15 additional cycles and atezolizumab for 12 additional cycles as adjuvant therapy.
    Interventions:
    • Drug: Trastuzumab
    • Drug: Pertuzumab
    • Drug: Carboplatin
    • Drug: Paclitaxel
    • Drug: Doxorubicin
    • Drug: Cyclophosphamide
    • Drug: Atezolizumab
    • Procedure: Surgery
  • Experimental: HPCT and atezolizumab
    Patients will receive a combination of trastuzumab, pertuzumab, carboplatin, paclitaxel and atezolizumab as neoadjuvant therapy for 6 cycles every 3 weeks. Trastuzumab (H) will be delivered on day 1 at the dose of 8 mg/kg loading dose i.v., then 6 mg/kg i.v. Pertuzumab (P) will be delivered on day 1 at the dose of 840 mg loading dose i.v., then 420 mg i.v. Carboplatin (C) will be administered at AUC 2 i.v. on day 1 and day 8; paclitaxel (T) will be given at 90 mg/m2 i.v. on day 1 and day 8; atezolizumab at the dose of 1200 mg i.v. on day 1. Definite surgery will be performed not later than 4 weeks after the last dose of neoadjuvant therapy. Trastuzumab, pertuzumab and atezolizumab will then be delivered for 12 additional cycles as adjuvant therapy.
    Interventions:
    • Drug: Trastuzumab
    • Drug: Pertuzumab
    • Drug: Carboplatin
    • Drug: Paclitaxel
    • Drug: Atezolizumab
    • Procedure: Surgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 11, 2018)
650
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 15, 2027
Estimated Primary Completion Date December 15, 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Female patients aged 18 years or older with early high-risk ((T1cN1; T2N1; T3N0) or locally advanced and inflammatory breast cancers (stage III A-C according to AJCC) suitable for neoadjuvant treatment
  2. Histologically confirmed unilateral invasive breast cancer
  3. HER2 positive disease according to ASCO/CAP guidelines 2013 [defined as IHC 3+ or ISH positive (by gene copy number or HER2 gene/CEP17 ratio of 2 or greater)]
  4. Known estrogen (ER) and progesterone receptor (PgR)
  5. Availability of a representative paraffin-embedded (FFPE) tumor block taken at diagnostic biopsy for central confirmation of HER2 eligibility, for assessment of ER, PgR, Ki67 and PD-L1 expression and for biomarker evaluation is mandatory. Note: the diagnostic biopsy of the breast lesion may have been taken before the required screening procedures. If diagnostic sentinel node biopsy if performed, an FFPE block must be available. An FFPE tumor block is also mandatory after the first cycle of therapy. Surgery tissue (residual tumor or tumor bed in case of pCR and axillary node material) is also mandatory.
  6. Consent to the collection of blood samples mandatorily before starting neoadjuvant treatment, after the first cycle of therapy, at the end of neoadjuvant treatment (before surgery), 6 months after surgery and at the end of all treatments.
  7. ECOG performance status 0 or 1
  8. 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 6 months after the last dose of study drugs. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Examples of contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide
  9. 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
  10. Willing and able to comply with the protocol

Exclusion Criteria:

  1. Evidence of bilateral breast cancer or metastatic disease (M1)
  2. Patients with HER2-negative defined as 0-1+ by immunohistochemistry or 2+ by immunohistochemistry without HER2 amplification by either In Situ Hybridization (ISH) or other amplification tests done locally are considered not eligible for the study
  3. 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
  4. Women with childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception, for example abstinence, an intra-uterine device, or double barrier method of contraception
  5. Previous treatment with chemotherapy, hormonal therapy or an investigational drug for any type of malignancy
  6. Previous investigational treatment for any condition other than malignancy within 4 weeks of randomization date
  7. Administration of a live, attenuated vaccine within 4 weeks before Day 1 or anticipation that such a live attenuated vaccine will be required during the study
  8. Previous or concomitant malignancy of any other type that could affect compliance with the protocol or interpretation of results. 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 atezolizumab 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 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 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 Day 1; evidence of transmural infarction on ECG; myocardial infarction stroke or transient ischemic attack (TIA) within 6 months prior to 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. Any of the following abnormal baseline hematological values:

    1. White blood count (WBC) < 2.5 x 109/L
    2. Absolute Neutrophil Count (ANC) < 1.5 x 109/L
    3. Lymphocyte count < 0.5 x 109/L
    4. Platelet count < 100 x 109/L
    5. Hemoglobin (Hb) < 10 g/dL
  24. Any of the following abnormal baseline laboratory tests

    1. Serum total bilirubin > 1.5 x ULN (upper limit of normal) (except for patients with clearly documented Gilbert's syndrome)
    2. Alanine transaminase (ALT) or aspartate transaminase (AST) > 1.25 x ULN
    3. Alkaline phosphatase > 2.5xx ULN
    4. Serum creatinine > 1.5 x ULN
    5. INR and aPTT > 1.5 × ULN within 2 weeks prior to enrollment. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
  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 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 Day 1 or at any time during the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Pinuccia Valagussa +39 02 870864 pinuccia.valagussa@fondazionemichelangelo.org
Contact: Irene Corradino +39 02 870864 irene.corradino@fondazionemichelangelo.org
Listed Location Countries  ICMJE Austria,   Germany,   Italy,   Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03595592
Other Study ID Numbers  ICMJE FM-17-B01
2017-000981-31 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Fondazione Michelangelo
Study Sponsor  ICMJE Fondazione Michelangelo
Collaborators  ICMJE Hoffmann-La Roche
Investigators  ICMJE
Study Chair: Luca Gianni, MD Ospedale San Raffaele
PRS Account Fondazione Michelangelo
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP