Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

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. Read our disclaimer for details.
 
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

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.

Condition or disease Intervention/treatment Phase
Early-stage Breast Cancer HER2-positive Breast Cancer Drug: Docetaxel Drug: Carboplatin Drug: Trastuzumab Drug: Pertuzumab Drug: Epirubicin Drug: Cyclophosphamide Drug: Atezolizumab Drug: Trastuzumab emtansine Drug: Paclitaxel Phase 2

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
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
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
Actual Study Start Date : May 23, 2019
Actual Primary Completion Date : June 30, 2021
Actual Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Nepidermin

Arm Intervention/treatment
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.

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.

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.

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: 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.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. Overall survival [ Time Frame: During the study period up to 10 years ]
    Time from randomisation to death from any cause

  5. Rate of breast conserving surgery [ Time Frame: At surgery ]
    Rate

  6. 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

  7. 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)

  8. 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)

  9. 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. ])

  10. 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]

  11. 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)

  12. 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

  13. 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)

  14. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03894007


Locations
Layout table for location information
Sweden
Sahlgrenska universitetssjukhuset
Göteborg, Sweden
Skånes universitetssjukhus
Malmö, Sweden
Karolinska universitetssjukhuset
Stockholm, Sweden, SE-17176
S:t Görans sjukhus
Stockholm, Sweden
Södersjukhuset
Stockholm, Sweden
Länssjukhuset Sundsvall
Sundsvall, Sweden
Norrlands universitetssjukhus
Umeå, Sweden
Örebro universitetssjukhus
Örebro, Sweden
Sponsors and Collaborators
Renske Altena
Investigators
Layout table for investigator information
Principal Investigator: Renske Altena, MD, PhD Karolinska University Hospital
Study Director: Jonas Bergh, MD, PhD Karolinska Institutet
Layout table for additonal information
Responsible Party: Renske Altena, MD, PhD. Principal Investigator., Karolinska University Hospital
ClinicalTrials.gov Identifier: NCT03894007    
Other Study ID Numbers: PREDIX II HER2
2018-004457-24 ( EudraCT Number )
First Posted: March 28, 2019    Key Record Dates
Last Update Posted: September 23, 2021
Last Verified: September 2021

Layout table for additional information
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
Keywords provided by Renske Altena, Karolinska University Hospital:
Neoadjuvant therapy
PD-L1 positive breast cancer
Additional relevant MeSH terms:
Layout table for MeSH terms
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Maytansine
Docetaxel
Ado-Trastuzumab Emtansine
Cyclophosphamide
Carboplatin
Trastuzumab
Atezolizumab
Epirubicin
Pertuzumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors