Image-guided De-escalation of Neo-adjuvant Chemotherapy in HER2-positive Breast Cancer: the TRAIN-3 Study

Study Overview
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Brief Summary
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This is a multicenter, single arm, phase II study evaluating the efficacy of image-guided de-escalating neoadjuvant treatment with paclitaxel, Herceptin® (trastuzumab), carboplatin, and pertuzumab (PTC-Ptz) in stage II-Ill HER2-positive breast cancer.

Detailed Description
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High pathological complete response (pCR)-rates are seen using different neoadjuvant chemotherapy schedules with trastuzumab and pertuzumab in HER2-positive stage II - III breast cancer patients. Total pCR rates in breast and axilla have been described as high as 64%, and with an even higher rate of >80% in patients with HER2-positive and hormone receptor (HR) negative tumors. PCR is associated with better long-term outcomes in patients with HER2-positive breast cancer. Three year progression-free survival ranges between 85-90%. Neoadjuvant treatment of HER2-positive breast cancer typically consists of six to nine cycles of treatment. Longer duration of treatment is associated with higher pCR-rates but gives more toxicity. Pathological complete responses are sometimes seen after only 10-12 days of neoadjuvant treatment. It is therefore important to investigate which patients can safely be treated with less than six cycles of chemotherapy and who requires more than six cycles for maximum activity. The radiologic response of a breast tumor after neoadjuvant therapy is predictive of the pathologic response, although the accuracy differs between breast cancer subtypes. It is hypothesized that patients with an early complete radiologic response may not benefit from additional chemotherapy and can be referred for early surgery. Patients who have not achieved pCR after early surgery despite radiologic complete response (rCR) are candidates for further adjuvant chemotherapy to complete the initially planned number of treatment cycles and maintain maximum treatment activity. Imaged guided de-escalation in which the number of treatment cycles is determined by the radiologic response could thus reduce toxicity in neoadjuvant treatment while maintaining activity. This study will evaluate the efficacy of image-guided de-escalation of neoadjuvant chemotherapy in patients with HER2-positive breast cancer. To maintain efficacy, patients who do not achieve pCR will complete a total of nine cycles taxane-containing chemotherapy followed by 14 cycles of treatment with adjuvant T-DM1. Patients who achieve early pCR will continue treatment with Herceptin® and pertuzumab to complete one full year of treatment.

Official Title
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Image-guided De-escalation of Neo-adjuvant Chemotherapy in HER2-positive Breast Cancer: the TRAIN-3 Study

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: PTC-Pz


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed primairy infiltrating breast cancer. Stage II or Ill disease. Overexpression and/or amplification of HER2 in an invasive component of the core biopsy. Age <:18 ECOG Group performance status LVEF >50% measured by echocardiography, MRI or MUGA Known HR-status ( in percentages) Exclusion Criteria: Previous radiation therapy of chemotherapy Pregnancy or breastfeeding Evidence of distant metastases Evidence of bilateral infiltrating breast cancer Concurrent anti-cancer treatment or another investigational drug

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
Interventional Model Description: neoadjuvant courses PTC-Ptz; adjuvant courses Ptz (pCR) or T-DM1 (non-pCR)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTC-Pz<br>Paclitaxel 80mg/m2 administered intravenously on day 1 and day 8 Herceptin® 6mg/kg administered intravenously on day 1 (loading dose 8mg/kg) or Herceptin® administered subcutaneously 600mg on day 1 Carboplatin AUC 6mg•ml/min administered intravenously on day 1 Pertuzumab 420mg administered intravenously on day 1 (loading dose 840mg) Treatment cycles are repeated on day 22 Patients who do not achieve pCR will complete a total of nine cycles taxane-containing chemotherapy followed by 14 cycles of treatment with adjuvant T-DM1. | Drug: PTC-Pz<br>* Paclitaxel 80mg/m2 administered intravenously on day 1 and day 8 Herceptin® 6mg/kg administered intravenously on day 1 (loading dose 8mg/kg) or Herceptin® administered subcutaneously 600mg on day 1 Carboplatin AUC 6mg•ml/min administered intravenously on day 1 Pertuzumab 420mg administered intravenously on day 1 (loading dose 840mg) Treatment cycles are repeated on day 22 In case of non pCR; Adjuvant T-DM1, 3.6mg/kg Q 22 days, for 14 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival at three years | Number of patients without progression of disease recurrence, second primary or death | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival at three years | Number of patients alive at three years | 3 years | 
| Pathologic complete response in breast and axilla | Number of patients with absence of invasive tumor cells in breast and axilla at surgery | an average of 6 months | 
| Radiologic complete response | Number of patients with absence of pathologic enhancement on MRI | an average of 6 months | 
| Number of neoadjuvant chemotherapy cycles administered | Number of neoadjuvant chemotherapy cycles administered per patient | an average of 1 year | 
| Number of radical and non-radical resections | Number of patients with radical and non-radical resections | an average of 6 months | 
| Incidence and severity of adverse events | Number of patients with toxicity grade >= 3 (CTCAE v5.0) until 30 days after last adjuvant administration | an average of 1 year | 
| Incidence and severity of cardiotoxicity and neuropathy | Number of patients with cardiotoxicity and neuropathy grade >= 2 (CTCAE v5.0) until 30 days after last adjuvant administration | an average of 1 year | 
| Incidence of symptomatic LVSD (heart failure), | Number of patients with an asymptomatic decline in LVEF requiring treatment or leading to discontinuation of pertuzumab and Herceptin, or a decrease ≥10 percentage points from baseline to a LVEF <50% | an average of 1 year | 
| Grade ≥3 laboratory test abnormalities | Number of patients with Grade ≥3 laboratory test abnormalities | an average of 1 year | 
| Incidence of number of tumor positive Vacuum Assisted Core Biopsy | Number of patients with tumor present at Vacuum Assisted Core Biopsy at the moment of radiological complete response on MRI | an average 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neo adjuvant, HER2 positive, de-escalation