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

NCT03894007 | Terminated Phase 2 DMC FDA Drug

• 2 other identifiers: PREDIX II HER22018-004457-24
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 8

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.

Conditions

Early-stage Breast Cancer; HER2-positive Breast Cancer

Keywords

Neoadjuvant therapy; PD-L1 positive breast cancer

Outcome Measures

Primary Outcomes (1)

• 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.

  At surgery 2-3 weeks after the last (of 7) cycles of neo-adjuvant systemic therapy.

Secondary Outcomes (14)

• Objective response rate

  After the 4th and 7th cycle (each cycle is 21 days)

• Distant disease-free survival

  During the study period up to 10 years

• Event-free survival

  During the study period up to 10 years

• Overall survival

  During the study period up to 10 years

• Rate of breast conserving surgery

  At surgery

Study Arms (2)

A: Experimental

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; Drug: Carboplatin; Drug: Trastuzumab; Drug: Pertuzumab; Drug: Epirubicin; Drug: Cyclophosphamide; Drug: Atezolizumab; Drug: Trastuzumab emtansine; Drug: Paclitaxel

B: Standard

ACTIVE COMPARATOR

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; Drug: Carboplatin; Drug: Trastuzumab; Drug: Pertuzumab; Drug: Epirubicin; Drug: Cyclophosphamide; Drug: Trastuzumab emtansine; Drug: Paclitaxel

Interventions

Docetaxel DRUG

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

A: Experimental; B: Standard

Carboplatin DRUG

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

A: Experimental; B: Standard

Trastuzumab DRUG

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

Also known as: Herceptin

A: Experimental; B: Standard

Pertuzumab 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.

Also known as: Perjeta

A: Experimental; B: Standard

Epirubicin DRUG

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

A: Experimental; B: Standard

Cyclophosphamide DRUG

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

A: Experimental; B: Standard

Atezolizumab DRUG

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

Also known as: Tecentriq

A: Experimental

Trastuzumab emtansine DRUG

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

Also known as: Kadcyla

A: Experimental; B: Standard

Paclitaxel DRUG

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

A: Experimental; B: Standard

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Renske Altena: lead

Study Sites (8)

Sahlgrenska universitetssjukhuset

Gothenburg, Sweden

Location

Skånes universitetssjukhus

Malmo, Sweden

Location

Örebro universitetssjukhus

Örebro, Sweden

Location

Karolinska universitetssjukhuset

Stockholm, SE-17176, Sweden

Location

S:t Görans sjukhus

Stockholm, Sweden

Location

Södersjukhuset

Stockholm, Sweden

Location

Länssjukhuset Sundsvall

Sundsvall, Sweden

Location

Norrlands universitetssjukhus

Umeå, Sweden

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Docetaxel; Carboplatin; Trastuzumab; pertuzumab; Epirubicin; Cyclophosphamide; atezolizumab; Ado-Trastuzumab Emtansine; Paclitaxel

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Doxorubicin; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Maytansine; Macrolides; Lactones; Lactams, Macrocyclic; Macrocyclic Compounds

Study Officials

• Renske Altena, MD, PhD

  Karolinska University Hospital

  PRINCIPAL INVESTIGATOR

• Jonas Bergh, MD, PhD

  Karolinska Institutet

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, PhD. Principal Investigator.

Model Details: 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.

Study Record Dates

• First Submitted: March 21, 2019
• First Posted: March 28, 2019
• Study Start: May 23, 2019
• Primary Completion: June 30, 2021
• Study Completion: June 30, 2021
• Last Updated: September 23, 2021

Record last verified: 2021-09

Locations

SE (8)