Neoadjuvant Dose-Dense For Early Her2Neu Positive Breast Cancer

A Phase II Randomized Trial Evaluating Neoadjuvant Dose-Dense Doxorubicin/Cyclophosphamide Followed by Paclitaxel/Trastuzumab/Pertuzumab (AC THP) and Docetaxel/Carboplatin/Trastuzumab/Pertuzumab (TCHP) For Early Her2Neu Positive Breast Cancer

Primary Objective:

• Determination of pathologic complete response (pCR) rates

Secondary Objective:

• Determination of cardiac toxicity as measured by: composite of LVEF, longitudinal strain and troponin.
• Breast conservation rates
• Overall survival

Study Design

• Approximately 34-74 patients with Her2 positive, Stage II-regional IV breast cancer will be enrolled.
• Patients will be stratified by ER/PR status.

• They will be randomized to ddACTHP vs TCHP.

  • Initially, 17 patients will be randomly assigned to each treatment arm.
  • If 3 or fewer patients have a pCR, then that arm will be terminated and no further patients will be entered on that treatment arm.
  • If 4 or more patients obtain a pCR, 20 additional patients (total of 37 patients) will be randomized to that treatment arm.
  • If 11 or more patients out of 37 have a pCR, the treatment will be of interest for further study.

Study Overview

• Status: Terminated
• Conditions: Locally Advanced Breast Cancer
• Intervention / Treatment: Drug: Trastuzumab; Drug: Pertuzumab; Drug: Trastuzumab; Drug: Paclitaxel; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Paclitaxel; Drug: Docetaxel; Drug: Carboplatin; Drug: Pegfilgrastim

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10019
      • Mount Sinai West
    • New York, New York, United States, 10011
      • Mount Sinai Beth Israel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

The patient must have signed and dated an IRB-approved consent form that conforms to federal and institutional guidelines.

• Female
• 18 years or older
• ECOG performance status of 0 or 1

• Eligible tumors must meet one of the following criteria:

  • Operable (T1c, T2-3, N0-1, M0)
  • Locally advanced (T2-3, N2-3, M0 or T4a-c, any N, M0)
  • Inflammatory breast cancer (T4d, any N, M0)

• Staging evaluation:

  • History and physical exam, cbc, chemistry profile
  • CT Chest/Abdomen/Pelvis and a bone scan or PET/CT as needed
• Diagnosis of invasive adenocarcinoma made by core needle biopsy
• Breast cancer determined to be:

• Confirmed HER2-positive : (ASCO CAP guidelines, 10/7/2013)

  • IHC 3+ based on circumferential membrane staining that is complete, intense
  • ISH positive based on:
  • Single probe average HER2 copy number ≥ 6 signals/cell
  • Dual probe HER2/CEP 17 ratio ≥ 2.0 with an average HER2 copy number ≥ 4.0 signals/cell
  • Dual probe HER2/CEP 17 ratio ≥ 2.0, with an average HER2 copy number of < 4.0 signals/cell
  • Dual probe HER2/CEP 17 ratio < 2.0 with the average HER2 copy number of ≥ 6.0 signals/cell
• any ER or PR receptor status
• LVEF assessment by echocardiogram within 30 days of initiation; EF of ≥ 55% considered normal.
• Normal troponin I level at baseline

• Blood counts must meet the following criteria:

  • ANC greater than or equal to 1500/mm3
  • Platelet count greater than or equal to 100,000/mm3
  • Hemoglobin greater than or equal to 10 g/dL
• Serum creatinine less than or equal 2.5 mg/100ml
• Adequate hepatic function by these criteria: total bilirubin must be less than or equal to 1.5 x the ULN for the lab unless the patient has a bilirubin elevation great than the ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; and alkaline phosphatase must be less than or equal to 2.5 x ULN for the lab; and AST must be less than or equal to 1.5 x ULN for the lab. Both alkaline phosphatase and AST may not both be greater than the ULN.
• Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study if liver imaging (CT, MRI, PET-CT or PET scan) performed within 90 days prior to randomization does not demonstrate metastatic disease and the requirements are met as above
• Patients with alkaline phosphatase that is > ULN but less than or equal to 2.5 x ULN or unexplained bone pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease.

Exclusion Criteria:

Patients with a history of decompensated congestive heart failure or an EF < 55% will be excluded

• Cardiac disease that would preclude the use of the drugs included in the above regimens. This includes but is not confined to:

• Active cardiac disease:
• angina pectoris requiring the use of anti-anginal medication;
• ventricular arrhythmias except for benign premature ventricular contractions controlled by medication;
• conduction abnormality requiring a pacemaker;
• supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; and
• clinically significant valvular disease
• symptomatic pericarditis
• pulmonary hypertension
• History of cardiac disease:
• myocardial infarction;
• congestive heart failure; or
• cardiomyopathy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ddACTHP; Doxorubicin 60 mg/m2 IV day 1 Cyclophosphamide 600 mg/m2 IV day 1 Pegfilgrastim 6mg SC, day 2 of AC Cycled every 14 days for 4 cycles, followed by, Paclitaxel 80 mg/m2 IV x 1 hour infusion on days 1, 8, and 15 Trastuzumab 8 mg/kg IV day 1, followed by 6mg/kg Pertuzumab loading dose 840 mg IV followed by 420 mg IV every 3 weeks Cycled every 21 days for 4 cycles, followed by, Trastuzumab 6mg/kg every 21 days to complete 1 year	Drug: Trastuzumab; Trastuzumab 8mg/kg IV initial dose, followed by 6mg/kg IV , day 1; Drug: Pertuzumab; Pertuzumab 840 mg IV initial dose followed by 420 mg IV, day 1; Drug: Trastuzumab; Trastuzumab 6mg/kg every 21 days to complete 1 year; Drug: Paclitaxel; Titrate the infusion rate on the initial Paclitaxel dose (40 ml/hr x 5 min, then 80 ml/hr x 5 min, then 120 ml/hr x 10 min, then 200 ml/hr). Subsequent Paclitaxel doses are given over 1 hour.; Drug: Doxorubicin; Doxorubicin 60 mg/m2 IV day 1; Drug: Cyclophosphamide; Cyclophosphamide 600 mg/m2 IV day 1; Drug: Paclitaxel; 80 mg/m2 IV x 1 hour infusion on days 1, 8, and 15
Active Comparator: TCHP; TCHP (Docetaxel, Carboplatin, Trastuzumab, Pertuzumab, Pegfilgrastim ) institutional practice is to titrate the infusion rate on the initial Paclitaxel dose (40 ml/hr x 5 min, then 80 ml/hr x 5 min, then 120 ml/hr x 10 min, then 200 ml/hr). Subsequent Paclitaxel doses are given over 1 hour.	Drug: Trastuzumab; Trastuzumab 8mg/kg IV initial dose, followed by 6mg/kg IV , day 1; Drug: Pertuzumab; Pertuzumab 840 mg IV initial dose followed by 420 mg IV, day 1; Drug: Trastuzumab; Trastuzumab 6mg/kg every 21 days to complete 1 year; Drug: Paclitaxel; Titrate the infusion rate on the initial Paclitaxel dose (40 ml/hr x 5 min, then 80 ml/hr x 5 min, then 120 ml/hr x 10 min, then 200 ml/hr). Subsequent Paclitaxel doses are given over 1 hour.; Drug: Paclitaxel; 80 mg/m2 IV x 1 hour infusion on days 1, 8, and 15; Drug: Docetaxel; Docetaxel 75mg/m2 IV, day 1; Drug: Carboplatin; Carboplatin AUC 6 IV, day 1; Drug: Pegfilgrastim; Pegfilgrastim 6mg SC, day 2 Cycled as per arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Pathologic Complete Response (pCR)	Pathologic complete response (pCR) defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of neoadjuvant systemic therapy.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Cardiac Toxicity Events	Determination of cardiac toxicity as measured by LVEF, longitudinal strain and troponin. Left ventricular ejection fraction (LVEF) measurement of amount of blood being pumped out of the left ventricle of the heart with each contraction. Peak systolic longitudinal strain is calculated by averaging the values of peak systolic strain in the basal, mid and apical segments of the LV in 4-, 3- and 2-chamber views on echocardiograms. A value of <-18% or a >15% decline in strain from patient's baseline value will be used as a cut-off value. A value of troponin I > 0.08 ng/ml will be considered elevated.	2 years
Number of Non-cardiac Toxicities	The frequency of adverse events categorized using CTCAE v4.03	2 years
Number of Participants With Breast Conservation	Number of participants with breast-conserving surgery for patients for whom mastectomy was planned before treatment. It would be based on surgical opinion at time of surgery if the tumor was appropriately "downstaged" to perform breast conserving surgery on patients previously recommended to have a mastectomy.	2 years
Number of Participants Alive at the End of the Study	Overall Survival - Number of participants alive at the end of the study.	2 years

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Investigators: Principal Investigator: Aarti Bhardwaj, MD, Icahn School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2019
• Primary Completion (Actual): March 7, 2021
• Study Completion (Actual): March 7, 2021

Study Registration Dates

• First Submitted: October 30, 2017
• First Submitted That Met QC Criteria: October 30, 2017
• First Posted (Actual): November 6, 2017

Study Record Updates

• Last Update Posted (Actual): August 22, 2023
• Last Update Submitted That Met QC Criteria: August 18, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Neoadjuvant chemotherapy; locally advanced breast cancer; Her2neu
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Docetaxel; Cyclophosphamide; Carboplatin; Paclitaxel; Trastuzumab; Albumin-Bound Paclitaxel; Doxorubicin; Pertuzumab
• Other Study ID Numbers: GCO 17-1585

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No