Neoadjuvant Dose-Dense For Early Her2Neu Positive Breast Cancer

• Sponsor: Icahn School of Medicine at Mount Sinai
• Information provided by (Responsible Party): Aarti S. Bhardwaj, Icahn School of Medicine at Mount Sinai

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Locally Advanced Breast Cancer	Drug: Docetaxel; Drug: Carboplatin; Drug: Trastuzumab; Drug: Pertuzumab; Drug: Pegfilgrastim; Drug: Paclitaxel; Drug: Doxorubicin; Drug: Cyclophosphamide	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	75 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Estimated Study Start Date :	February 1, 2019
Estimated Primary Completion Date :	October 16, 2019
Estimated Study Completion Date :	October 16, 2019

Arms and Interventions

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: 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: Docetaxel; Docetaxel 75mg/m2 IV, day 1; Drug: Carboplatin; Carboplatin AUC 6 IV, day 1; 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: Pegfilgrastim; Pegfilgrastim 6mg SC, day 2 Cycled as per arm; 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.

Outcome Measures

Primary Outcome Measures :

1. pCR rates [ Time Frame: up to 2 years ]
   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.

Secondary Outcome Measures :

1. Cardiac Toxicity [ Time Frame: up to 2 years ]

   Determination of cardiac toxicity as measured by: composite of 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 21, 30,31 will be considered elevated.

2. Number of non-cardiac toxicities [ Time Frame: up to 2 years ]
   The frequency of adverse events categorized using CTCAE v4.03
3. Breast Conservation Rates [ Time Frame: up to 2 years ]
   rate of 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.
4. Overall Survival [ Time Frame: up to 2 years ]
   Overall Survival Rate

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	Female
Gender Based Eligibility:	Yes
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Contacts

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Contact: Neha Kumarley	212-824-7659	neha.kumarley@mssm.edu
Contact: Jalwa Afroz	212-824-7320	jalwa.afroz@mssm.edu

Locations

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United States, New York
Mount Sinai Beth Israel	Recruiting
New York, New York, United States, 10011
Contact: Damien Francois 212-604-6021 damien.francois@mssm.edu
Contact: Tiffany Xing 212-604-6021 tiffany.xing@mountsinai.org
Principal Investigator: Paula Klein, MD
Mount Sinai West	Recruiting
New York, New York, United States, 10019
Contact: Tahkir Mirzoyev, MD 212-523-7289 takhir.mirzoyev@mountsinai.org
Principal Investigator: Anupama Goel, MD
Icahn School of Medicine at Mount Sinai	Recruiting
New York, New York, United States, 10029
Contact: Neha Kumarley 212-824-7659 neha.kumarley@mssm.edu
Contact: Jalwa Afroz 212-824-7320 jalwa.afroz@mssm.edu
Principal Investigator: Aarti Bhardwaj, MD

Sponsors and Collaborators

Icahn School of Medicine at Mount Sinai

Investigators

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

More Information

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Responsible Party:	Aarti S. Bhardwaj, Assistant Professor, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier:	NCT03329378 History of Changes
Other Study ID Numbers:	GCO 17-1585
First Posted:	November 6, 2017
Last Update Posted:	February 12, 2019
Last Verified:	February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Aarti S. Bhardwaj, Icahn School of Medicine at Mount Sinai:

Neoadjuvant chemotherapy; locally advanced breast cancer; Her2neu

Additional relevant MeSH terms:

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Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Paclitaxel; Docetaxel; Albumin-Bound Paclitaxel; Cyclophosphamide; Carboplatin; Doxorubicin; Liposomal doxorubicin; Trastuzumab; Pertuzumab; Antineoplastic Agents, Phytogenic	Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors