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Improving Pre-operative Systemic Therapy for Human Epidermal Growth Factor Receptor 2 (HER2) Amplified Breast Cancer (PREDIXIIHER2)

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ClinicalTrials.gov Identifier: NCT03894007
Recruitment Status : Terminated (Security and effect data from another ongoing study.)
First Posted : March 28, 2019
Last Update Posted : September 23, 2021
Sponsor:
Information provided by (Responsible Party):
Renske Altena, Karolinska University Hospital

Tracking Information
First Submitted Date  ICMJE March 21, 2019
First Posted Date  ICMJE March 28, 2019
Last Update Posted Date September 23, 2021
Actual Study Start Date  ICMJE May 23, 2019
Actual Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 26, 2019)
Rate of pathological objective response to primary medical treatment [ Time Frame: At surgery 2-3 weeks after the last (of 7) cycles of neo-adjuvant systemic therapy. ]
Efficacy measure at surgery that is performed 2-3 weeks after 7 cycles (each cycle lasts 21 days) of preoperative treatment.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2020)
  • Objective response rate [ Time Frame: After the 4th and 7th cycle (each cycle is 21 days) ]
    Proportion of patients with reduction in tumour burden ≥30% according to RECIST
  • Distant disease-free survival [ Time Frame: During the study period up to 10 years ]
    Time from randomisation to distant metastases or death due to breast cancer
  • Event-free survival [ Time Frame: During the study period up to 10 years ]
    Time from randomisation to breast cancer relapse, contralateral breast cancer, other malignant neoplasms, or death from any cause
  • Overall survival [ Time Frame: During the study period up to 10 years ]
    Time from randomisation to death from any cause
  • Rate of breast conserving surgery [ Time Frame: At surgery ]
    Rate
  • Incidence of treatment-emergent adverse events (Safety) [ Time Frame: During the 18-week period of treatment and until 30 days after termination and during the follow-up period up to ten years ]
    Rate of grade 3-4 toxicity, rate of % of discontinuation of study medication due to toxicity, rate of AE's of special interest
  • Differences in PROMs according to EORTC C30 [ Time Frame: At baseline, after cycle 4 (a cycle is 21 days), after cycle 7 (a cycle is 21 days), 2 months, 1 year and 5 years after surgery ]
    Health related Quality of Life using the EORTC C30 scale (EORTC Quality of Life questionnaire C30)
  • Differences in PROMs according to EORTC BR23 [ Time Frame: At baseline, after cycle 4 (a cycle is 21 days), after cycle 7 (a cycle is 21 days), 2 months, 1 year and 5 years after surgery ]
    Health related Quality of Life using the EORTC BR23 scale (EORTC Quality of Life breast specific questionnaire BR23)
  • Differences in objective cognitive function [ Time Frame: At baseline, 3 months after surgery, one and five year after treatment start ]
    Assessed by an online neuropsychological test (Amsterdam Cognition Scan, validated for use in breast cancer patients [Feenstra et al, J Clin Exp Neuropsychol. 2018 Apr;40(3):253-273. ])
  • Treatment prediction, PD-L1 [ Time Frame: At baseline, after the 4th cycle (each cycle is 21 days), at surgery and annually during the post-surgical follow-up period up to five years ]
    % of Programmed Death Ligand 1 expressing cells [tumour cells and tumour infiltrating lymphocytes]
  • Treatment prediction, TMB [ Time Frame: At baseline, after the 4th cycle (each cycle is 21 days), at surgery and annually during the post-surgical follow-up period up to five years ]
    Tumour-mutational burden (total number of nonsynonymous mutations per coding area of a tumor genome)
  • Treatment prediction, TILs [ Time Frame: At baseline, after the 4th cycle (each cycle is 21 days), at surgery and annually during the post-surgical follow-up period up to five years ]
    Percentage of tumour infiltrating lymphocytes
  • Treatment prediction, composition of faeces microbiome [ Time Frame: At baseline, after 7th cycle (each cycle is 21 days) before surgery, and one year after surgery ]
    Composition of bacterial strains in gastro-intestinal flora (% of different strains measured with DNA/RNA analysis and in microbiotic culture)
  • Differences in PROMs [ Time Frame: At baseline, after cycle 4 (each cycle is 21 days), after cycle 7 (each cycle is 21 days), 2 months, 1 year and 5 years after surgery ]
    Symptoms using the Memorial Symptoms Assessment Scale (MSAS). The 32-item MSAS scale includes occurrence, frequency, severity, and distress associated with each symptom using four- and five-point rating scales. Symptom burden is calculated as the average of frequency, severity and distress of each symptom. Higher scores indicates higher symptom burden.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 26, 2019)
  • Objective response rate [ Time Frame: After the 4th and 7th cycle (each cycle is 21 days) ]
    Proportion of patients with reduction in tumour burden ≥30% according to RECIST
  • Distant disease-free survival [ Time Frame: During the study period up to 10 years ]
    Time from randomisation to distant metastases or death due to breast cancer
  • Event-free survival [ Time Frame: During the study period up to 10 years ]
    Time from randomisation to breast cancer relapse, contralateral breast cancer, other malignant neoplasms, or death from any cause
  • Overall survival [ Time Frame: During the study period up to 10 years ]
    Time from randomisation to death from any cause
  • Rate of breast conserving surgery [ Time Frame: At surgery ]
    Rate
  • Incidence of treatment-emergent adverse events (Safety) [ Time Frame: During the 18-week period of treatment and until 30 days after termination and during the follow-up period up to ten years ]
    Rate of grade 3-4 toxicity, rate of % of discontinuation of study medication due to toxicity, rate of AE's of special interest
  • Differences in PROMs [ Time Frame: At baseline, after cycle 4 (a cycle is 21 days), after cycle 7 (a cycle is 21 days), 2 months, 1 year and 5 years after surgery ]
    Health related Quality of Life using the EORTC C30 scale (EORTC Quality of Life questionnaire C30)
  • Differences in PROMs [ Time Frame: At baseline, after cycle 4 (a cycle is 21 days), after cycle 7 (a cycle is 21 days), 2 months, 1 year and 5 years after surgery ]
    Health related Quality of Life using the EORTC BR23 scale (EORTC Quality of Life breast specific questionnaire BR23)
  • Differences in objective cognitive function [ Time Frame: At baseline, 3 months after surgery, one and five year after treatment start ]
    Assessed by an online neuropsychological test (Amsterdam Cognition Scan, validated for use in breast cancer patients [Feenstra et al, J Clin Exp Neuropsychol. 2018 Apr;40(3):253-273. ])
  • Treatment prediction, tumour [ Time Frame: At baseline, after the 4th cycle (each cycle is 21 days), at surgery and annually during the post-surgical follow-up period up to five years ]
    % of Programmed Death Ligand 1 expressing cells [tumour cells and tumour infiltrating lymphocytes]
  • Treatment prediction, tumour [ Time Frame: At baseline, after the 4th cycle (each cycle is 21 days), at surgery and annually during the post-surgical follow-up period up to five years ]
    Tumour-mutational burden (total number of nonsynonymous mutations per coding area of a tumor genome)
  • Treatment prediction, tumour [ Time Frame: At baseline, after the 4th cycle (each cycle is 21 days), at surgery and annually during the post-surgical follow-up period up to five years ]
    Percentage of tumour infiltrating lymphocytes
  • Treatment prediction, composition of faeces microbiome [ Time Frame: At baseline, after 7th cycle (each cycle is 21 days) before surgery, and one year after surgery ]
    Composition of bacterial strains in gastro-intestinal flora (% of different strains measured with DNA/RNA analysis and in microbiotic culture)
  • Differences in PROMs [ Time Frame: At baseline, after cycle 4 (each cycle is 21 days), after cycle 7 (each cycle is 21 days), 2 months, 1 year and 5 years after surgery ]
    Symptoms using the Memorial Symptoms Assessment Scale (MSAS). The 32-item MSAS scale includes occurrence, frequency, severity, and distress associated with each symptom using four- and five-point rating scales. Symptom burden is calculated as the average of frequency, severity and distress of each symptom. Higher scores indicates higher symptom burden.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Improving Pre-operative Systemic Therapy for Human Epidermal Growth Factor Receptor 2 (HER2) Amplified Breast Cancer
Official Title  ICMJE Improving Pre-operative Systemic Therapy for Human Epidermal Growth Factor Receptor 2 (HER2) Amplified Breast Cancer Part of a Platform of Translational Phase II Trials Based on Molecular Subtypes
Brief Summary This is a phase 2 study evaluating medical treatment before surgery in HER2-amplified early breast cancer patients. Patients receive chemotherapy with HER2-targeted antibodies and are randomised to receive the checkpoint inhibitor atezolizumab or not.
Detailed Description

The primary aim is to investigate whether the rate of pCR, after optimal neoadjuvant anti-HER2 based systemic therapy, can be increased by addition of atezolizumab.

Secondary aims are to assess safety and tolerability of this treatment combination, and to identify therapy predictive factors for the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab plus-minus atezolizumab with a backbone of chemotherapy, using modern molecular biological investigational procedures with analyses by repeated biopsies from an intra-patient longitudinal study design.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Both arms start with four cycles of docetaxel/paklitaxel+carboplatin+trastuzumab+pertuzumab. Thereafter arm A receives three cycles of epirubicin+cyclophosphamide+atezolizumab and arm B receives epirubicin+cyclophosphamide.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Early-stage Breast Cancer
  • HER2-positive Breast Cancer
Intervention  ICMJE
  • Drug: Docetaxel
    75 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 4 courses preoperatively.
  • Drug: Carboplatin
    AUC 6 iv, day 1 every third week, 4 courses preoperatively.
  • Drug: Trastuzumab
    600 mg sc, day 1 every third week, 4 courses preoperatively. 14 courses postoperatively if complete response.
    Other Name: Herceptin
  • Drug: Pertuzumab
    840 mg iv starting dose, thereafter 420 mg, day 1 every third week. 14 courses postoperatively if complete response in patients with baseline high risk tumours.
    Other Name: Perjeta
  • Drug: Epirubicin
    90 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 3 courses preoperatively
  • Drug: Cyclophosphamide
    600 mg/m2 iv, day 1 every third week, 3 courses preoperatively
  • Drug: Atezolizumab
    840 mg iv, day 1 every third week, 3 courses preoperatively if randomised to arm A.
    Other Name: Tecentriq
  • Drug: Trastuzumab emtansine
    3.6 mg/kg iv, day 1 every third week, 14 courses postoperatively if not complete response.
    Other Name: Kadcyla
  • Drug: Paclitaxel
    80 mg/m2 iv, day 1 weekly, 12 weeks (4 cycles), in case of (anticipated) unmanageable toxicity related to docetaxel.
Study Arms  ICMJE
  • Experimental: A: Experimental

    Four courses of docetaxel or paclitaxel + carboplatin + trastuzumab sc + pertuzumab given every third week followed by three courses of epirubicin + cyclophosphamide + atezolizumab. In total seven courses of preoperative treatment. Response evaluations after course four.

    Postoperatively, if pathologic complete response, patients receive 14 courses of adjuvant trastuzumab every third week. If no pCR patients receive 14 courses of T-DM1 every third week.

    Interventions:
    • Drug: Docetaxel
    • Drug: Carboplatin
    • Drug: Trastuzumab
    • Drug: Pertuzumab
    • Drug: Epirubicin
    • Drug: Cyclophosphamide
    • Drug: Atezolizumab
    • Drug: Trastuzumab emtansine
    • Drug: Paclitaxel
  • Active Comparator: B: Standard

    Four courses of docetaxel or paclitaxel + carboplatin + trastuzumab sc + pertuzumab given every third week followed by three courses of epirubicin + cyclophosphamide. In total seven courses of preoperative treatment. Response evaluations after course four.

    Postoperatively, if pathologic complete response patients receive 14 courses of adjuvant trastuzumab (combined with pertuzumab in case of high-risk disease features) every third week. If no pCR patients receive 14 courses of T-DM1 every third week.

    Interventions:
    • Drug: Docetaxel
    • Drug: Carboplatin
    • Drug: Trastuzumab
    • Drug: Pertuzumab
    • Drug: Epirubicin
    • Drug: Cyclophosphamide
    • Drug: Trastuzumab emtansine
    • Drug: Paclitaxel
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 Terminated
Actual Enrollment  ICMJE
 (submitted: September 22, 2021)
6
Original Estimated Enrollment  ICMJE
 (submitted: March 26, 2019)
190
Actual Study Completion Date  ICMJE June 30, 2021
Actual Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Confirmed PD-L1 expression ≥1% on tumour cells and/or TILs (prescreening phase)
  • Able to provide written informed consent
  • Female gender
  • Patients with breast cancer confirmed by histology, characterised by immunohistochemistry for ER, PR, HER2 and proliferation marker.
  • HER2 amplification, IHC 3+ and preferably confirmed by ISH
  • Tumor and blood samples available.
  • Age 18 years or older. Elderly patients in adequate condition for the planned therapy, which may be supported by a geriatric assessment (according to ASCO guideline; Mohile et al, JCO 2018)
  • Primary breast cancer >20 mm in diameter or verified lymph node metastases
  • Adequate bone marrow, renal and hepatic functions (see Table 1)
  • LVEF ≥50%
  • ECOG performance status 0-1

Exclusion Criteria:

  • Distant metastases without chance to cure, including node metastases in the contralateral thoracic region or in the mediastinum. An exception is presence of at most 2 morphologically characterized well-defined distant metastases accessible for stereotactic radiotherapy, provided that this treatment is available at the participating centre.
  • Other malignancy diagnosed within the last five years, except for radically treated basal or squamous cell carcinoma of the skin or CIS of the cervix
  • Patients in child-bearing age without adequate contraception
  • Pregnancy or lactation
  • Uncontrolled hypertension, heart-, liver-, or kidney-diseases or other medical/psychiatric disorders.
  • History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis

    • Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
    • Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g., no psoriatic arthritis) are permitted provided that they meet the following conditions:

      • Rash must cover less than 10% of body surface area (BSA)
      • Disease is well controlled at baseline and only requiring low potency topical steroids
      • No acute exacerbations of underlying condition within the last 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids).
  • Vaccination with a live vaccine within 30 days of the first dose of study treatment
  • A known history of Human Immunodeficiency Virus (HIV) infection, hepatitis B (HBsAg reactive) or hepatitis C (HCV RNA detected) infection or active tuberculosis.
  • Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial

    • Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study
    • Patients with a history of allergic reaction to IV contrast requiring steroid pre- treatment should have baseline and subsequent tumor assessments performed using MRI.
    • The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
  • Hypersensitivity to atezolizumab
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 information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03894007
Other Study ID Numbers  ICMJE PREDIX II HER2
2018-004457-24 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Renske Altena, Karolinska University Hospital
Study Sponsor  ICMJE Renske Altena
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Renske Altena, MD, PhD Karolinska University Hospital
Study Director: Jonas Bergh, MD, PhD Karolinska Institutet
PRS Account Karolinska University Hospital
Verification Date September 2021

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