Neoadjuvant Dose-Dense For Early Her2Neu Positive Breast Cancer

Sponsor

Icahn School of Medicine at Mount Sinai (Other)

Overall Status

Terminated

CT.gov ID

NCT03329378

Collaborator

(none)

Enrollment

Locations

Arms

15.9

Actual Duration (Months)

2.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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: Trastuzumab Drug: Paclitaxel Drug: Doxorubicin Drug: Cyclophosphamide Drug: Paclitaxel	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

7 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

Actual Study Start Date :

Jan 30, 2019

Actual Primary Completion Date :

May 29, 2020

Actual Study Completion Date :

May 29, 2020

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.

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

pCR rates [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

Cardiac Toxicity [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.
Number of non-cardiac toxicities [up to 2 years]
The frequency of adverse events categorized using CTCAE v4.03
Breast Conservation Rates [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.
Overall Survival [up to 2 years]
Overall Survival Rate

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Mount Sinai Beth Israel	New York	New York	United States	10011
2	Mount Sinai West	New York	New York	United States	10019
3	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029