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

NCT ID: NCT03894007

Last Updated: 2021-09-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-23
• Study Completion Date: 2021-06-30

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.

Conditions

Early-stage Breast Cancer; HER2-positive Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Docetaxel

Intervention Type: DRUG

75 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 4 courses preoperatively.

Carboplatin

Intervention Type: DRUG

AUC 6 iv, day 1 every third week, 4 courses preoperatively.

Trastuzumab

Intervention Type: DRUG

600 mg sc, day 1 every third week, 4 courses preoperatively. 14 courses postoperatively if complete response.

Pertuzumab

Intervention Type: DRUG

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.

Epirubicin

Intervention Type: DRUG

90 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 3 courses preoperatively

Cyclophosphamide

Intervention Type: DRUG

600 mg/m2 iv, day 1 every third week, 3 courses preoperatively

Atezolizumab

Intervention Type: DRUG

840 mg iv, day 1 every third week, 3 courses preoperatively if randomised to arm A.

Trastuzumab emtansine

Intervention Type: DRUG

3.6 mg/kg iv, day 1 every third week, 14 courses postoperatively if not complete response.

Paclitaxel

Intervention Type: DRUG

80 mg/m2 iv, day 1 weekly, 12 weeks (4 cycles), in case of (anticipated) unmanageable toxicity related to docetaxel.

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.

Group Type: ACTIVE_COMPARATOR

Docetaxel

Intervention Type: DRUG

75 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 4 courses preoperatively.

Carboplatin

Intervention Type: DRUG

AUC 6 iv, day 1 every third week, 4 courses preoperatively.

Trastuzumab

Intervention Type: DRUG

600 mg sc, day 1 every third week, 4 courses preoperatively. 14 courses postoperatively if complete response.

Pertuzumab

Intervention Type: DRUG

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.

Epirubicin

Intervention Type: DRUG

90 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 3 courses preoperatively

Cyclophosphamide

Intervention Type: DRUG

600 mg/m2 iv, day 1 every third week, 3 courses preoperatively

Trastuzumab emtansine

Intervention Type: DRUG

3.6 mg/kg iv, day 1 every third week, 14 courses postoperatively if not complete response.

Paclitaxel

Intervention Type: DRUG

80 mg/m2 iv, day 1 weekly, 12 weeks (4 cycles), in case of (anticipated) unmanageable toxicity related to docetaxel.

Interventions

Docetaxel

75 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 4 courses preoperatively.

Intervention Type: DRUG

Carboplatin

AUC 6 iv, day 1 every third week, 4 courses preoperatively.

Intervention Type: DRUG

Trastuzumab

600 mg sc, day 1 every third week, 4 courses preoperatively. 14 courses postoperatively if complete response.

Intervention Type: 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.

Intervention Type: DRUG

Epirubicin

90 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 3 courses preoperatively

Intervention Type: DRUG

Cyclophosphamide

600 mg/m2 iv, day 1 every third week, 3 courses preoperatively

Intervention Type: DRUG

Atezolizumab

840 mg iv, day 1 every third week, 3 courses preoperatively if randomised to arm A.

Intervention Type: DRUG

Trastuzumab emtansine

3.6 mg/kg iv, day 1 every third week, 14 courses postoperatively if not complete response.

Intervention Type: DRUG

Paclitaxel

80 mg/m2 iv, day 1 weekly, 12 weeks (4 cycles), in case of (anticipated) unmanageable toxicity related to docetaxel.

Intervention Type: DRUG

Other Intervention Names

Herceptin; Perjeta; Tecentriq; Kadcyla

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Renske Altena

OTHER

Sponsor Role: lead

Responsible Party

Renske Altena

MD, PhD. Principal Investigator.

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Renske Altena, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Karolinska University Hospital

Jonas Bergh, MD, PhD

Role: STUDY_DIRECTOR

Karolinska Institutet

Locations

Sahlgrenska universitetssjukhuset

Gothenburg, , Sweden

Skånes universitetssjukhus

Malmo, , Sweden

Örebro universitetssjukhus

Örebro, , Sweden

Karolinska universitetssjukhuset

Stockholm, , Sweden

S:t Görans sjukhus

Stockholm, , Sweden

Södersjukhuset

Stockholm, , Sweden

Länssjukhuset Sundsvall

Sundsvall, , Sweden

Norrlands universitetssjukhus

Umeå, , Sweden

Countries

Sweden

Other Identifiers

2018-004457-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PREDIX II HER2

Identifier Type: -

Identifier Source: org_study_id