Clinical Trials /

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

NCT03595592

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Treatment of HER2 Positive Early High-risk and Locally Advanced Breast Cancer
  • Official Title: Atezolizumab, Pertuzumab and Trastuzumab With Chemotherapy as Neoadjuvant Treatment of HER2 Positive Early High-risk and Locally Advanced Breast Cancer (APTneo)

Clinical Trial IDs

  • ORG STUDY ID: FM-17-B01
  • SECONDARY ID: 2017-000981-31
  • NCT ID: NCT03595592

Conditions

  • Invasive Breast Cancer

Interventions

DrugSynonymsArms
TrastuzumabHerceptinHPCT
PertuzumabPerjetaHPCT
CarboplatinCarboplatin HospiriaHPCT
PaclitaxelPaclitaxel HospiriaHPCT
DoxorubicinDoxorubicin PfizerACy followed by HPCT and atezolizumab
CyclophosphamideCyclophosphamide SandozACy followed by HPCT and atezolizumab
AtezolizumabTecentriqACy followed by HPCT and atezolizumab

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
HPCTActive ComparatorPatients 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.
  • Trastuzumab
  • Pertuzumab
  • Carboplatin
  • Paclitaxel
ACy followed by HPCT and atezolizumabExperimentalPatients 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.
  • Trastuzumab
  • Pertuzumab
  • Carboplatin
  • Paclitaxel
  • Doxorubicin
  • Cyclophosphamide
  • Atezolizumab
HPCT and atezolizumabExperimentalPatients 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.
  • Trastuzumab
  • Pertuzumab
  • Carboplatin
  • Paclitaxel
  • Atezolizumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event Free Survival (EFS)
Time Frame:5 years after the randomization of the last patient
Safety Issue:
Description:Assess EFS (disease progression while on neoadjuvant therapy or disease recurrence after surgery) in the study arms

Secondary Outcome Measures

Measure:Pathological complete response (pCR)
Time Frame:At surgery, an expected average of 26 weeks after the randomization of the last patients
Safety Issue:
Description:Assess the rate of pCR defined as absence of invasive cancer in both breast and axillary nodes (ypT0Tis ypN0)
Measure:Clinical objective response
Time Frame:Participants will be followed for the duration of neoadjuvant therapy, an expected average of 22 weeks
Safety Issue:
Description:Assess the rate of clinical response rate after neoadjuvant therapy
Measure:Distant Event Free Survival (DEFS)
Time Frame:5 years after the randomization of the last patients
Safety Issue:
Description:Assess DEFS (defined as the occurrence of distant disease progression while on neoadjuvant therapy or distant disease recurrence after surgery) in the study arms
Measure:Overall Survival (OS)
Time Frame:5 years after the randomization of the last patient
Safety Issue:
Description:Assess OS in all arms
Measure: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
Safety Issue:
Description:Number of participants with adverse events and related grades in all arms

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Fondazione Michelangelo

Trial Keywords

  • Unilateral, HER2 positive

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