Chemotherapy-Free pCR-Guided Strategy With Trastuzumab-pertuzumab and T-DM1 in HER2-positive Early Breast Cancer

Study Overview
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Brief Summary
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This is a multicenter, open-label, single-arm, one-stage, phase II study to assess the efficacy of a chemotherapy-free pathological complete response (pCR)-guided strategy with trastuzumab and pertuzumab (given as a subcutaneous fixed-dose combination) and T-DM1, for patients with previously untreated HER2-positive early breast cancer.

Official Title
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Chemotherapy-Free pCR-Guided Strategy With Subcutaneous Trastuzumab-pertuzumab and T-DM1 in HER2-positive Early Breast Cancer (PHERGAIN-2)

Conditions
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Early Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab and Pertuzumab (FDC SC) and T-DM1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient eligibility will be reviewed and documented by a suitable member of the investigator's study team before the patients are enrolled in the study. Patients must meet ALL the following inclusion criteria to be enrolled in the study: Written informed consent prior to beginning specific protocol procedures. Female or male patients ≥ 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Histologically proven invasive carcinoma of the breast. Tumor size between >5 to 25 mm by breast MRI and node-negative status by clinical exam, MRI and ultrasound. Centrally confirmed HER2[+] disease (IHC score 3+). Known estrogen receptor (ER) and progesterone receptor (PgR) status locally determined prior to study entry. Normal left ventricular function and diastolic function (left ventricular ejection fraction [LVEF] ≥55%) as assessed by echocardiogram or multiple-gated acquisition scan (MUGA) documented within ≤28 days prior to first dose of study treatment. Adequate bone marrow, liver, and renal function: Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L). 10) Hepatic: total bilirubin ≤ institutional upper limit of normal (ULN) (except for Gilbert's syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 times ULN. 11) Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 ×ULN Patient must be accessible for treatment and follow-up. Willingness and ability to provide blood samples at baseline, after 2 treatment cycles and at surgery. Willingness to provide tumor tissue samples at baseline and at surgery. All patients must be willing to undergo a pulmonary (X-ray or CT scan), hepatic (ultrasound or CT scan) and bone (PET or CT scan) assessment, to prove no evidence of metastatic disease. Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of nonhormonal contraception or 2 effective forms of nonhormonal contraception by the patient and/or partner and to continue its use for the duration of study treatment and for 7 months after the last dose of study treatment. Note: Acceptable forms of effective contraception should include 2 of the following: i. Placement of non-hormonal intrauterine device (IUD) ii. Condom with spermicidal foam/gel/film/cream/suppository iii. Diaphragm or cervical/vault caps with spermicidal foam/film/cream/suppository The above contraception methods are not a requirement in the case the male patient, or male partner of a female patient, is surgically sterilized, the female patient is > 45 years of age and is postmenopausal (has not menstruated for at least 12 consecutive months) or the patient remains abstinent and truly abstains from sexual activity (refrains from heterosexual intercourse). Negative serum pregnancy test for premenopausal women including women who have had a tubal ligation and for women less than 12 months after the onset of menopause Exclusion Criteria: Any patient meeting ANY of the following criteria will be excluded from the study: Any previous treatment, including chemotherapy, anti-HER2 therapy, radiation therapy, or ET for invasive breast cancer, except for breast carcinoma in situ of the contralateral breast cancer, in the last 5 years. HER2 0+, 1+ or 2+ despite in situ hybridization (ISH) positive. Node-positive HER2[+] breast cancer. Evidence of metastatic disease. Note: CT/MRI scan of thorax/abdomen/pelvis to rule out metastatic disease will be performed before enrolment. Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances. History of other malignancy within the last five years prior to first dose of study drug administration, except for curatively treated basal and squamous cell carcinoma of the skin and/or in situ cervical carcinoma. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment. Serious cardiac illness or medical conditions including, but not confined to, the following: History of NCI CTCAE v5.0 Grade ≥ 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) Class ≥ II. High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate ≥ 100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz II] or third-degree AV-block). Serious cardiac arrhythmia or severe conduction abnormality not controlled by adequate medication. Angina pectoris requiring anti-angina medication. Clinically significant valvular heart disease. Evidence of transmural infarction on electrocardiogram (ECG). Evidence of myocardial infarction within 12 months prior to randomization. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalaemia, hypomagnesemia, hypocalcaemia), or family history of sudden unexplained death or long QT syndrome. Active uncontrolled infection at the time of enrollment. Current known infection with HIV, hepatitis B virus, or hepatitis C virus. Patients with pulmonary disease requiring continuous oxygen therapy. Current NCI CTCAE (version v5.0) Grade 2 ≥ neuropathy. Previous history of bleeding diathesis. Patient is currently receiving chronic treatment with corticosteroids, or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed). Major surgical procedure or significant traumatic injury within 14 days prior to randomization or anticipation of need for major surgery within the course of the study treatment. LVEF below 55% as determined by multiple-gated acquisition (MUGA) scan or echocardiography (ECHO). Any other concurrent severe and/or uncontrolled medical condition that would contraindicate patient participation in the clinical study. History of receiving any investigational treatment within 28 days prior to randomization. Pregnant or breast-feeding women or patients not willing to apply highly effective contraception as defined in the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patient HER 2+ IHC 3+<br>Patients ≥18 years of age with previously untreated HER2-positive (HER2[+]) (Immunohistochemistry [IHC] 3+) invasive carcinoma according to the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria and tumor size between >5 to 25 mm by breast magnetic resonance imaging (MRI) and node-negative status by clinical exam, MRI, and ultrasound. Patients must have not been previously treated with chemotherapy, anti-HER2 therapy, radiation therapy, or endocrine therapy (ET) for invasive breast cancer. Patients with metastatic disease are not eligible. In patients with suspected axillary node involvement, a negative fine needle aspiration biopsy (FNAB) will be mandatory | Drug: Trastuzumab and Pertuzumab (FDC SC) and T-DM1<br>* Patients will receive Trastuzumab and Pertuzumab as a subcutaneous fixed-dose combination (PH FDC SC) (± ET depending on HR status) for 8 3-week cycles, on day 1 only. ET will consist of letrozole for post-menopausal women or tamoxifen ± ovarian function suppression (OFS) for pre-menopausal women administered continuously. Men will receive tamoxifen. After completing neoadjuvant therapy, a final breast MRI will be performed 2 weeks prior to surgery. Surgery will be performed within 4 weeks after completion of the last cycle of PH FDC SC. Adjuvant systemic therapy will start within 4 weeks from surgery. There will be three different cohorts depending on pathological report: Cohort A: PH FDC SC ± ET for 10 additional 3-week cycles Cohort B: T-DM1 ± ET for 10 cycles Cohort C: T-DM1 ± ET for 10 cycles, with possibility of physician's choice chemotherapy before adjuvant T-DM1.<br>* Other names: Kadcyla;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year recurrence-free interval (3y-RFI) | 3-year recurrence-free interval (3y-RFI) defined as time from start of treatment in adjuvant setting until recurrence, new invasive disease, or death from breast cancer. Recurrence will be defined in accordance with the standardized efficacy endpoints (STEEP) criteria. | 3 years | 
| Global health status decline | Global health status decline rate at 1 year from start of neoadjuvant treatment, defined as the rate of patients with a ≥10% global health status decline at 1 year from start of neoadjuvant treatment as assessed by the Global Health Status | 1 year | 
| Global health status decline QoL | Global health status decline rate at 1 year from start of neoadjuvant treatment, defined as the rate of patients with a ≥10% global health status decline at 1 year from start of neoadjuvant treatment as assessed by the QoL EORTC-QLC-C30 scale. | 1 year | 
| Global health status decline QLQ-BR23 | Global health status decline rate at 1 year from start of neoadjuvant treatment, defined as the rate of patients with a ≥10% global health status decline at 1 year from start of neoadjuvant treatment as assessed by the breast cancer module QLQ-BR23. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pathological complete response (pCR) | pCR rates in the overall population to assess overall efficacy | after neoadjuvant treatment (8 cycles, an average of 6months) | 
| pathological complete response (pCR) according to hormone receptor (HR) status | pCR rates according to HR status | after neoadjuvant treatment (8 cycles, an average of 6months) | 
| Residual cancer burden (RCB) | RCB -0, -I, -II, -III; (0:best outcome, III: worst outcome) | after neoadjuvant treatment (8 cycles, an average of 6months) | 
| Breast-conserving surgery (BCS) | Evaluate the rate of BCS | after neoadjuvant treatment (8 cycles, an average of 6months) | 
| Response rate BCS | Evaluate the correlation between final MRI-guide response rate results and breast-conserving surgery (BCS) | after neoadjuvant treatment (8 cycles, an average of 6months) | 
| Response rate pCR | Evaluate the correlation between final MRI- guide response rate and pCR | after neoadjuvant treatment (8 cycles, an average of 6months) | 
| Response rate RCB | Evaluate the correlation between final MRI -guide response rate and RCB at surgery | after neoadjuvant treatment (8 cycles, an average of 6months) | 
| Survival rates EFS | Analyze the event-free survival (EFS) | 3 years and 5 years | 
| Survival rates relapse-free survival (RFS) | Analyze RFS | 3 years and 5 years | 
| Survival rates invasive disease-free survival (iDFS) | Analyze iDFS | 3 years and 5 years | 
| Survival ratesdistant relapse-free survival (DRFS) | Analyze DRFS | 3 years and 5 years | 
| Survival rates disease-free survival (DFS) | Analyze DFS | 3 years and 5 years | 
| Survival rates overall survival (OS) | Analyze OS | 3 years and 5 years | 
| Survival ratesbreast cancer-specific survival (BCSS). | Analyze BCSS | 3 years and 5 years | 
| Survival rates relapse-free interval (RFI) | Analyze RFI | 5 years | 
| Safety adverse events (AEs) | Number of patients with treatment-related AEs (Grade 3 and 4 AEs and serious adverse events [SAEs]) by using the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. | Baseline up to 3 years | 
| Safety adverse events (AEs) | Number of patients with treatment-related AEs (Grade 3 and 4 AEs and serious adverse events [SAEs]) by using the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. | Baseline up to 5 years | 
| Health-Related Quality of Life (HRQoL) - QLQ-C30 | Change from baseline in scores using the European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (QLQ-C30) [with 5 functional and 3 symptom scales, a Global Health Status (GHS)/QoL scale, and 6 single items], at baseline, Day 1 of cycles 2-4, then on Day 1 of each subsequent cycle starting with cycle 6, and at the end-of-treatment. Responses to all items are converted to a 0-100 scale using a standard scoring algorithm. For functional scales, higher score represents a better level of functioning; for symptom scales, a higher score represents a higher severity of symptoms. | Baseline up to 5 years | 
| Health-Related Quality of Life (HRQoL) - QLQ-BR23 | Change from baseline in scores using the European Organisation for Research and Treatment of Cancer QLQ-BR23 [with 4 functional and 4 symptom scales], at baseline, Day 1 of cycles 2-4, then on Day 1 of each subsequent cycle starting with cycle 6, and at the end-of-treatment. Responses to all items are converted to a 0-100 scale using a standard scoring algorithm. For functional scales, higher score represents a better level of functioning; for symptom scales, a higher score represents a higher severity of symptoms. | Baseline up to 5 years |