Clinical Trials /

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

NCT03894007

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: PREDIX II HER2
  • SECONDARY ID: 2018-004457-24
  • NCT ID: NCT03894007

Conditions

  • Early-stage Breast Cancer
  • HER2-positive Breast Cancer

Interventions

DrugSynonymsArms
DocetaxelA: Experimental
CarboplatinA: Experimental
TrastuzumabHerceptinA: Experimental
PertuzumabPerjetaA: Experimental
EpirubicinA: Experimental
CyclophosphamideA: Experimental
AtezolizumabTecentriqA: Experimental
Trastuzumab emtansineKadcylaA: Experimental

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
A: ExperimentalExperimentalFour courses of docetaxel + 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.
  • Docetaxel
  • Carboplatin
  • Trastuzumab
  • Pertuzumab
  • Epirubicin
  • Cyclophosphamide
  • Atezolizumab
  • Trastuzumab emtansine
B: StandardActive ComparatorFour courses of docetaxel + 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.
  • Docetaxel
  • Carboplatin
  • Trastuzumab
  • Pertuzumab
  • Epirubicin
  • Cyclophosphamide
  • Trastuzumab emtansine

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description:Efficacy measure at surgery that is performed 2-3 weeks after 7 cycles (each cycle lasts 21 days) of preoperative treatment.

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:After the 4th and 7th cycle (each cycle is 21 days)
Safety Issue:
Description:Proportion of patients with reduction in tumour burden ≥30% according to RECIST
Measure:Distant disease-free survival
Time Frame:During the study period up to 10 years
Safety Issue:
Description:Time from randomisation to distant metastases or death due to breast cancer
Measure:Event-free survival
Time Frame:During the study period up to 10 years
Safety Issue:
Description:Time from randomisation to breast cancer relapse, contralateral breast cancer, other malignant neoplasms, or death from any cause
Measure:Overall survival
Time Frame:During the study period up to 10 years
Safety Issue:
Description:Time from randomisation to death from any cause
Measure:Rate of breast conserving surgery
Time Frame:At surgery
Safety Issue:
Description:Rate
Measure: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
Safety Issue:
Description:Rate of grade 3-4 toxicity, rate of % of discontinuation of study medication due to toxicity, rate of AE's of special interest
Measure:Differences in PROMs
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
Safety Issue:
Description:Health related Quality of Life using the EORTC C30 scale (EORTC Quality of Life questionnaire C30)
Measure:Differences in PROMs
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
Safety Issue:
Description:Health related Quality of Life using the EORTC BR23 scale (EORTC Quality of Life breast specific questionnaire BR23)
Measure:Differences in objective cognitive function
Time Frame:At baseline, 3 months after surgery, one and five year after treatment start
Safety Issue:
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. ])
Measure:Treatment prediction, tumour
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
Safety Issue:
Description:% of Programmed Death Ligand 1 expressing cells [tumour cells and tumour infiltrating lymphocytes]
Measure:Treatment prediction, tumour
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
Safety Issue:
Description:Tumour-mutational burden (total number of nonsynonymous mutations per coding area of a tumor genome)
Measure:Treatment prediction, tumour
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
Safety Issue:
Description:Percentage of tumour infiltrating lymphocytes
Measure: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
Safety Issue:
Description:Composition of bacterial strains in gastro-intestinal flora (% of different strains measured with DNA/RNA analysis and in microbiotic culture)
Measure: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
Safety Issue:
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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Renske Altena

Trial Keywords

  • Neoadjuvant therapy
  • PD-L1 positive breast cancer

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