Feasibility of Chemotherapy De-escalation in Early-Stage HER2 Positive Breast Cancer

Study Overview
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Brief Summary
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The main purpose of this research study is to find out if de-escalation of chemotherapy before surgery followed by a selective escalation of adjuvant targeted therapies are efficacious and tolerable in early-stage HER2 positive breast cancer.

Detailed Description
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Assess the feasibility of four cycles of neoadjuvant Docetaxel Carboplatin Trastuzumab and Pertuzumab (TCHP) in women with early-stage (local/locally advanced) HER2+ breast cancer with a selective escalation of targeted HER2 directed therapy in the high risk group in the adjuvant setting. Participants with any residual disease after four cycles of TCHP will receive Trastuzumab Emtansine (TDM1) plus Pertuzumab while those with complete pathological response will receive Trastuzumab in the adjuvant settings.

Official Title
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A Feasibility Study of De-escalation of Chemotherapy in Patients With Early-Stage HER2 Positive Breast Cancer

Conditions
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HER2-positive Breast Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Carboplatin
* Drug: Trastuzumab
* Drug: Pertuzumab
* Drug: Trastuzumab emtansine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women ≥18 years of age Biopsy proven HER2+ early breast cancer ECOG performance status 0-1 Should be a candidate for neoadjuvant chemotherapy using standard guidelines of tumor size of 2cm or more and /or axillary lymph node-positive disease. Adequate cardiac, bone marrow, kidney, and liver functions per treating physician's discretion. Women of childbearing potential who are sexually active must agree to use highly effective methods of contraception during treatment and for three weeks after the last dose of chemotherapy or anti-HER2 therapy. The women currently using hormonal contraceptives must agree to change to an alternative highly effective method of contraception Willingness and ability to comply with study and follow-up procedures and give written informed consent. Exclusion Criteria: Any evidence of stage IV breast cancer Participant deemed unsuitable for clinical trial enrolment by treating physician based on the participants' compliance, location and commute requirements, or tolerance of therapies involved Any invasive malignancy within the last two years of study enrollment except for adequately treated basal cell carcinoma, squamous cell carcinoma, or non-melanoma skin cancer. Women who are pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be assigned to an arm of the trial based on their outcomes after surgery.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pathologic complete response (pCR)<br>Participants will receive four cycles of TCHP [docetaxel (Taxotere®), carboplatin, trastuzumab (Herceptin®), pertuzumab], followed by surgery. Participants who achieve pathologic complete response will receive infusions of trastuzumab every 3 weeks for a total of 12 cycles/infusions. | Drug: Docetaxel<br>* Dose: 75 mg/m2 q3w<br>* Other names: Taxotere;Drug: Carboplatin<br>* Dose: area under the concentration-time curve [AUC] 6 q3w<br>* Other names: Paraplatin;Drug: Trastuzumab<br>* Dose: 8-mg/kg loading dose, 6-mg/kg maintenance dose q3w<br>* Other names: Herceptin;Drug: Pertuzumab<br>* Dose: 840-mg loading dose, 420-mg maintenance dose q3w<br>* Other names: Perjeta;|
| Experimental: Residual Disease<br>Participants will receive four cycles of TCHP [docetaxel (Taxotere®, carboplatin, trastuzumab (Herceptin®), pertuzumab], followed by surgery. Participants who have residual disease may be offered two more cycles of TCHP in the adjuvant settings (optional) per treating oncologist's discretion and then will receive infusion of Trastuzumab Emtansine (TDM1) plus pertuzumab every three weeks for a total of 12 cycles/infusions. | Drug: Docetaxel<br>* Dose: 75 mg/m2 q3w<br>* Other names: Taxotere;Drug: Carboplatin<br>* Dose: area under the concentration-time curve [AUC] 6 q3w<br>* Other names: Paraplatin;Drug: Trastuzumab<br>* Dose: 8-mg/kg loading dose, 6-mg/kg maintenance dose q3w<br>* Other names: Herceptin;Drug: Pertuzumab<br>* Dose: 840-mg loading dose, 420-mg maintenance dose q3w<br>* Other names: Perjeta;Drug: Trastuzumab emtansine<br>* Dose: 3.6mg/kg q3w<br>* Other names: TDM1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One Year Invasive Disease-Free Survival | The study will be considered feasible if the researchers observe the invasive disease free survival (IDFS) estimate at one year to be 90% or more among those who achieved a pCR, or if the researchers observe the IDFS estimate at one year to be 85% or more among those who had residual disease. | One year from the breast cancer surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response rate | Assess the pCR rate after four cycles (12 weeks) of TCHP. | 12 weeks from start of treatment | 
| Toxicity of chemo and HER2 therapies | Evaluate toxicity associated with neoadjuvant and adjuvant chemo and/or HER2 directed therapies. Percentage of grade 1 to grade 5 toxicities will be assessed during the neo-adjuvant TCHP therapy for all participants. Percentage of grade 1 to grade 5 toxicities will be assessed with adjuvant trastuzumab therapy for the cohort with pathological complete response, and with optional adjuvant TCHP therapy and adjuvant TDM1 + pertuzumab therapy for the residual disease cohort. Toxicity data will be obtained based on the clinical assessment of the participants by the investigators and based on laboratory data. | One year from the start of treatment | 
| Two Year Invasive Disease-Free Survival | Two year invasive disease-free survival (IDFS) of participants with pCR and participants with residual disease | Two years from the breast cancer surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-positive Breast Cancer, De-escalation