Clinical trial NCT03894007: Improving Pre-operative Systemic Therapy for Human Epidermal Growth Factor Receptor 2 (HER2) Amplified Breast Cancer
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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Early-stage Breast Cancer
HER2-positive Breast Cancer
Keywords: Neoadjuvant therapy
PD-L1 positive breast cancer
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
First posted: 2019-03-28
Enrollment: 6
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Rate of pathological objective response to primary medical treatment
timeFrame: At surgery 2-3 weeks after the last (of 7) cycles of neo-adjuvant systemic therapy.
Secondary outcomes:
measure: Objective response rate
timeFrame: After the 4th and 7th cycle (each cycle is 21 days)
measure: Distant disease-free survival
timeFrame: During the study period up to 10 years
measure: Event-free survival
timeFrame: During the study period up to 10 years
measure: Overall survival
timeFrame: During the study period up to 10 years
measure: Rate of breast conserving surgery
timeFrame: At surgery
measure: Incidence of treatment-emergent adverse events (Safety)
timeFrame: During the 18-week period of treatment and until 30 days after termination and during the follow-up period up to ten years
measure: Differences in PROMs according to EORTC C30
timeFrame: 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
measure: Differences in PROMs according to EORTC BR23
timeFrame: 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
measure: Differences in objective cognitive function
timeFrame: At baseline, 3 months after surgery, one and five year after treatment start
measure: Treatment prediction, PD-L1
timeFrame: 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
measure: Treatment prediction, TMB
timeFrame: 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
measure: Treatment prediction, TILs
timeFrame: 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
measure: Treatment prediction, composition of faeces microbiome
timeFrame: At baseline, after 7th cycle (each cycle is 21 days) before surgery, and one year after surgery
measure: Differences in PROMs
timeFrame: 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
Other outcomes:
Locations:
city: Göteborg
country: Sweden
facility: Sahlgrenska universitetssjukhuset
city: Malmö
country: Sweden
facility: Skånes universitetssjukhus
city: Stockholm
country: Sweden
facility: Karolinska universitetssjukhuset
city: Stockholm
country: Sweden
facility: S:t Görans sjukhus
city: Stockholm
country: Sweden
facility: Södersjukhuset
city: Sundsvall
country: Sweden
facility: Länssjukhuset Sundsvall
city: Umeå
country: Sweden
facility: Norrlands universitetssjukhus
city: Örebro
country: Sweden
facility: Örebro universitetssjukhus
Study officials:
affiliation: Karolinska University Hospital
name: Renske Altena, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Karolinska Institutet
name: Jonas Bergh, MD, PhD
role: STUDY_DIRECTOR
References: