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

Primary Purpose

Early-stage Breast Cancer, HER2-positive Breast Cancer

Status
Terminated
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
Docetaxel
Carboplatin
Trastuzumab
Pertuzumab
Epirubicin
Cyclophosphamide
Atezolizumab
Trastuzumab emtansine
Paclitaxel
Sponsored by
Renske Altena
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Early-stage Breast Cancer focused on measuring Neoadjuvant therapy, PD-L1 positive breast cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • Sahlgrenska universitetssjukhuset
  • Skånes universitetssjukhus
  • Karolinska universitetssjukhuset
  • S:t Görans sjukhus
  • Södersjukhuset
  • Länssjukhuset Sundsvall
  • Norrlands universitetssjukhus
  • Örebro universitetssjukhus

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

A: Experimental

B: Standard

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Rate of pathological objective response to primary medical treatment
Efficacy measure at surgery that is performed 2-3 weeks after 7 cycles (each cycle lasts 21 days) of preoperative treatment.

Secondary Outcome Measures

Objective response rate
Proportion of patients with reduction in tumour burden ≥30% according to RECIST
Distant disease-free survival
Time from randomisation to distant metastases or death due to breast cancer
Event-free survival
Time from randomisation to breast cancer relapse, contralateral breast cancer, other malignant neoplasms, or death from any cause
Overall survival
Time from randomisation to death from any cause
Rate of breast conserving surgery
Rate
Incidence of treatment-emergent adverse events (Safety)
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
Health related Quality of Life using the EORTC C30 scale (EORTC Quality of Life questionnaire C30)
Differences in PROMs according to EORTC BR23
Health related Quality of Life using the EORTC BR23 scale (EORTC Quality of Life breast specific questionnaire BR23)
Differences in objective cognitive function
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
% of Programmed Death Ligand 1 expressing cells [tumour cells and tumour infiltrating lymphocytes]
Treatment prediction, TMB
Tumour-mutational burden (total number of nonsynonymous mutations per coding area of a tumor genome)
Treatment prediction, TILs
Percentage of tumour infiltrating lymphocytes
Treatment prediction, composition of faeces microbiome
Composition of bacterial strains in gastro-intestinal flora (% of different strains measured with DNA/RNA analysis and in microbiotic culture)
Differences in PROMs
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.

Full Information

First Posted
March 21, 2019
Last Updated
September 22, 2021
Sponsor
Renske Altena
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1. Study Identification

Unique Protocol Identification Number
NCT03894007
Brief Title
Improving Pre-operative Systemic Therapy for Human Epidermal Growth Factor Receptor 2 (HER2) Amplified Breast Cancer
Acronym
PREDIXIIHER2
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Terminated
Why Stopped
Security and effect data from another ongoing study.
Study Start Date
May 23, 2019 (Actual)
Primary Completion Date
June 30, 2021 (Actual)
Study Completion Date
June 30, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Renske Altena

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Early-stage Breast Cancer, HER2-positive Breast Cancer
Keywords
Neoadjuvant therapy, PD-L1 positive breast cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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)
Allocation
Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A: Experimental
Arm Type
Experimental
Arm Description
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.
Arm Title
B: Standard
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Docetaxel
Intervention Description
75 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 4 courses preoperatively.
Intervention Type
Drug
Intervention Name(s)
Carboplatin
Intervention Description
AUC 6 iv, day 1 every third week, 4 courses preoperatively.
Intervention Type
Drug
Intervention Name(s)
Trastuzumab
Other Intervention Name(s)
Herceptin
Intervention Description
600 mg sc, day 1 every third week, 4 courses preoperatively. 14 courses postoperatively if complete response.
Intervention Type
Drug
Intervention Name(s)
Pertuzumab
Other Intervention Name(s)
Perjeta
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Epirubicin
Intervention Description
90 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 3 courses preoperatively
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
600 mg/m2 iv, day 1 every third week, 3 courses preoperatively
Intervention Type
Drug
Intervention Name(s)
Atezolizumab
Other Intervention Name(s)
Tecentriq
Intervention Description
840 mg iv, day 1 every third week, 3 courses preoperatively if randomised to arm A.
Intervention Type
Drug
Intervention Name(s)
Trastuzumab emtansine
Other Intervention Name(s)
Kadcyla
Intervention Description
3.6 mg/kg iv, day 1 every third week, 14 courses postoperatively if not complete response.
Intervention Type
Drug
Intervention Name(s)
Paclitaxel
Intervention Description
80 mg/m2 iv, day 1 weekly, 12 weeks (4 cycles), in case of (anticipated) unmanageable toxicity related to docetaxel.
Primary Outcome Measure Information:
Title
Rate of pathological objective response to primary medical treatment
Description
Efficacy measure at surgery that is performed 2-3 weeks after 7 cycles (each cycle lasts 21 days) of preoperative treatment.
Time Frame
At surgery 2-3 weeks after the last (of 7) cycles of neo-adjuvant systemic therapy.
Secondary Outcome Measure Information:
Title
Objective response rate
Description
Proportion of patients with reduction in tumour burden ≥30% according to RECIST
Time Frame
After the 4th and 7th cycle (each cycle is 21 days)
Title
Distant disease-free survival
Description
Time from randomisation to distant metastases or death due to breast cancer
Time Frame
During the study period up to 10 years
Title
Event-free survival
Description
Time from randomisation to breast cancer relapse, contralateral breast cancer, other malignant neoplasms, or death from any cause
Time Frame
During the study period up to 10 years
Title
Overall survival
Description
Time from randomisation to death from any cause
Time Frame
During the study period up to 10 years
Title
Rate of breast conserving surgery
Description
Rate
Time Frame
At surgery
Title
Incidence of treatment-emergent adverse events (Safety)
Description
Rate of grade 3-4 toxicity, rate of % of discontinuation of study medication due to toxicity, rate of AE's of special interest
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
Title
Differences in PROMs according to EORTC C30
Description
Health related Quality of Life using the EORTC C30 scale (EORTC Quality of Life questionnaire 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
Title
Differences in PROMs according to EORTC BR23
Description
Health related Quality of Life using the EORTC BR23 scale (EORTC Quality of Life breast specific questionnaire 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
Title
Differences in objective cognitive function
Description
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. ])
Time Frame
At baseline, 3 months after surgery, one and five year after treatment start
Title
Treatment prediction, PD-L1
Description
% of Programmed Death Ligand 1 expressing cells [tumour cells and tumour infiltrating lymphocytes]
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
Title
Treatment prediction, TMB
Description
Tumour-mutational burden (total number of nonsynonymous mutations per coding area of a tumor genome)
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
Title
Treatment prediction, TILs
Description
Percentage of tumour infiltrating lymphocytes
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
Title
Treatment prediction, composition of faeces microbiome
Description
Composition of bacterial strains in gastro-intestinal flora (% of different strains measured with DNA/RNA analysis and in microbiotic culture)
Time Frame
At baseline, after 7th cycle (each cycle is 21 days) before surgery, and one year after surgery
Title
Differences in PROMs
Description
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.
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

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Renske Altena, MD, PhD
Organizational Affiliation
Karolinska University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jonas Bergh, MD, PhD
Organizational Affiliation
Karolinska Institutet
Official's Role
Study Director
Facility Information:
Facility Name
Sahlgrenska universitetssjukhuset
City
Göteborg
Country
Sweden
Facility Name
Skånes universitetssjukhus
City
Malmö
Country
Sweden
Facility Name
Karolinska universitetssjukhuset
City
Stockholm
ZIP/Postal Code
SE-17176
Country
Sweden
Facility Name
S:t Görans sjukhus
City
Stockholm
Country
Sweden
Facility Name
Södersjukhuset
City
Stockholm
Country
Sweden
Facility Name
Länssjukhuset Sundsvall
City
Sundsvall
Country
Sweden
Facility Name
Norrlands universitetssjukhus
City
Umeå
Country
Sweden
Facility Name
Örebro universitetssjukhus
City
Örebro
Country
Sweden

12. IPD Sharing Statement

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

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