Pyrotinib, Trastuzumab, Pertuzumab and Nab-paclitaxel as Neoadjuvant Therapy in HER2-positive Breast Cancer

Sponsor

Shanghai Jiao Tong University School of Medicine (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT04398914

Collaborator

Jiangsu HengRui Medicine Co., Ltd. (Industry)

216

Enrollment

Location

Arms

Anticipated Duration (Months)

2.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study aims to evaluate the efficacy and safety of pyrotinib in combination with trastuzumab, pertuzumab and nab-paclitaxel as neoadjuvant therapy in early stage or locally advanced HER2-positive breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Invasive	Drug: Pyrotinib Drug: Trastuzumab Drug: Pertuzumab Drug: Nab-paclitaxel Drug: EC chemotherapy Drug: Physician's choice Drug: T-DM1 Procedure: Surgery	Phase 2

Detailed Description

The study evaluate the pathological complete response rate, event-free survival, disease-free survival, overall survival and safety of pyrotinib in combination with trastuzumab, pertuzumab and nab-paclitaxel as neoadjuvant therapy in early stage or locally advanced HER2-positive breast cancer. Patients will receive 4 cycles of pyrotinib in combination with trastuzumab, pertuzumab and nab-paclitaxel or 4 cycles of trastuzumab, pertuzumab and nab-paclitaxel as neoadjuvant therapy, then undergo surgery, then receive adjuvant chemotherapy and targeted therapy according to pathologic response and physician's choice.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

216 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomised, Multicenter, Open-label, Phase II Study Evaluating Pyrotinib Plus Trastuzumab, Pertuzumab and Nab-paclitaxel as Neoadjuvant Therapy in Early Stage or Locally Advanced Human Epidermal Growth Factor Receptor (HER) 2 - Positive Breast Cancer

Actual Study Start Date :

May 30, 2020

Anticipated Primary Completion Date :

Dec 30, 2022

Anticipated Study Completion Date :

Dec 30, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pyrotinib, trastuzumab, pertuzmab and paclitaxel Prior to surgery: pyrotinib, trastuzumab, pertuzumab and nab-paclitaxel for 4 cycles (1 cycle = 21 days). After surgery： if non-tpCR：chemotherapy with epirubicin and cyclophosphamide (EC), followed with pertuzumab and trastuzumab up to 1 year total; or T-DM1 for 14 cycles. if tpCR: chemotherapy 0-4 cycles according to physician's choice, followed with pertuzumab and trastuzumab up to 1 year total.	Drug: Pyrotinib Pyrotinib 400 mg taken orally everyday, every 3 weeks, for 4 cycles. Drug: Trastuzumab Trastuzumab IV infusion in 3-week cycles. Neoadjuvant treatment: 8 milligrams per kilogram (mg/kg) loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2-4. Adjuvant treatment: 8 mg/kg loading dose, followed by 6 mg/kg for remaining cycles till completion of 1 year trastuzumab Drug: Pertuzumab Pertuzumab IV infusion in 3-week cycles. Neoadjuvant treatment: 840 milligrams (mg) loading dose for Cycle 1, followed by 420 mg for Cycles 2-4. Adjuvant treatment: 840 mg loading dose, followed by 420mg for remaining cycles till completion of 1 year pertuzumab Drug: Nab-paclitaxel Nab-paclitaxel 100mg/m2 by intravenous (IV) infusion on day1, day8 and day15, every 3 weeks, for 4 cycles. Drug: EC chemotherapy Epirubicin 90 mg/m2, and cyclophosphamide 600 mg/m2 by intravenous (IV) infusion every 3 weeks for 4 cycles (Cycles 5-8) Drug: Physician's choice Physician decided chemotherapy for 0-4 cycles. Drug: T-DM1 T-DM1 IV infusion in 3-week cycles. 3.6 mg/kg by intravenous (IV) infusion every 3 weeks for 14 cycles Procedure: Surgery All participants who are eligible for surgery will undergo surgery and have their pathologic response evaluated.
Active Comparator: Trastuzumab, pertuzmab and paclitaxel Prior to surgery: trastuzumab, pertuzumab and nab-paclitaxel for 4 cycles (1 cycle = 21 days). After surgery： if non-tpCR：chemotherapy with epirubicin and cyclophosphamide (EC), followed with pertuzumab and trastuzumab up to 1 year total; or T-DM1 for 14 cycles. if tpCR: chemotherapy 0-4 cycles according to physician's choice; followed with pertuzumab and trastuzumab up to 1 year total.	Drug: Trastuzumab Trastuzumab IV infusion in 3-week cycles. Neoadjuvant treatment: 8 milligrams per kilogram (mg/kg) loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2-4. Adjuvant treatment: 8 mg/kg loading dose, followed by 6 mg/kg for remaining cycles till completion of 1 year trastuzumab Drug: Pertuzumab Pertuzumab IV infusion in 3-week cycles. Neoadjuvant treatment: 840 milligrams (mg) loading dose for Cycle 1, followed by 420 mg for Cycles 2-4. Adjuvant treatment: 840 mg loading dose, followed by 420mg for remaining cycles till completion of 1 year pertuzumab Drug: Nab-paclitaxel Nab-paclitaxel 100mg/m2 by intravenous (IV) infusion on day1, day8 and day15, every 3 weeks, for 4 cycles. Drug: EC chemotherapy Epirubicin 90 mg/m2, and cyclophosphamide 600 mg/m2 by intravenous (IV) infusion every 3 weeks for 4 cycles (Cycles 5-8) Drug: Physician's choice Physician decided chemotherapy for 0-4 cycles. Drug: T-DM1 T-DM1 IV infusion in 3-week cycles. 3.6 mg/kg by intravenous (IV) infusion every 3 weeks for 14 cycles Procedure: Surgery All participants who are eligible for surgery will undergo surgery and have their pathologic response evaluated.

Arm

Intervention/Treatment

Experimental: Pyrotinib, trastuzumab, pertuzmab and paclitaxel

Prior to surgery: pyrotinib, trastuzumab, pertuzumab and nab-paclitaxel for 4 cycles (1 cycle = 21 days). After surgery： if non-tpCR：chemotherapy with epirubicin and cyclophosphamide (EC), followed with pertuzumab and trastuzumab up to 1 year total; or T-DM1 for 14 cycles. if tpCR: chemotherapy 0-4 cycles according to physician's choice, followed with pertuzumab and trastuzumab up to 1 year total.

Drug: Pyrotinib

Pyrotinib 400 mg taken orally everyday, every 3 weeks, for 4 cycles.

Drug: Trastuzumab

Trastuzumab IV infusion in 3-week cycles. Neoadjuvant treatment: 8 milligrams per kilogram (mg/kg) loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2-4. Adjuvant treatment: 8 mg/kg loading dose, followed by 6 mg/kg for remaining cycles till completion of 1 year trastuzumab

Drug: Pertuzumab

Pertuzumab IV infusion in 3-week cycles. Neoadjuvant treatment: 840 milligrams (mg) loading dose for Cycle 1, followed by 420 mg for Cycles 2-4. Adjuvant treatment: 840 mg loading dose, followed by 420mg for remaining cycles till completion of 1 year pertuzumab

Drug: Nab-paclitaxel

Nab-paclitaxel 100mg/m2 by intravenous (IV) infusion on day1, day8 and day15, every 3 weeks, for 4 cycles.

Drug: EC chemotherapy

Epirubicin 90 mg/m2, and cyclophosphamide 600 mg/m2 by intravenous (IV) infusion every 3 weeks for 4 cycles (Cycles 5-8)

Drug: Physician's choice

Physician decided chemotherapy for 0-4 cycles.

Drug: T-DM1

T-DM1 IV infusion in 3-week cycles. 3.6 mg/kg by intravenous (IV) infusion every 3 weeks for 14 cycles

Procedure: Surgery

All participants who are eligible for surgery will undergo surgery and have their pathologic response evaluated.

Active Comparator: Trastuzumab, pertuzmab and paclitaxel

Prior to surgery: trastuzumab, pertuzumab and nab-paclitaxel for 4 cycles (1 cycle = 21 days). After surgery： if non-tpCR：chemotherapy with epirubicin and cyclophosphamide (EC), followed with pertuzumab and trastuzumab up to 1 year total; or T-DM1 for 14 cycles. if tpCR: chemotherapy 0-4 cycles according to physician's choice; followed with pertuzumab and trastuzumab up to 1 year total.

Drug: Trastuzumab

Drug: Pertuzumab

Drug: Nab-paclitaxel

Nab-paclitaxel 100mg/m2 by intravenous (IV) infusion on day1, day8 and day15, every 3 weeks, for 4 cycles.

Drug: EC chemotherapy

Epirubicin 90 mg/m2, and cyclophosphamide 600 mg/m2 by intravenous (IV) infusion every 3 weeks for 4 cycles (Cycles 5-8)

Drug: Physician's choice

Physician decided chemotherapy for 0-4 cycles.

Drug: T-DM1

T-DM1 IV infusion in 3-week cycles. 3.6 mg/kg by intravenous (IV) infusion every 3 weeks for 14 cycles

Procedure: Surgery

All participants who are eligible for surgery will undergo surgery and have their pathologic response evaluated.

Outcome Measures

Primary Outcome Measures

Percentage of Participants With Total Pathologic Complete Response (tpCR) [After completion of 4 cycles of neoadjuvant therapy. The duration of one treatment cycle is 21 days]
tpCR is 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 after completion of neoadjuvant therapy and surgery (that is, ypT0/is, ypN0, in accordance with the current American Joint Committee on Cancer [AJCC] staging system).The duration of one treatment cycle is 21 days.

Secondary Outcome Measures

Percentage of Participants With Breast Pathologic Complete Response (bpCR) [After completion of 4 cycles of neoadjuvant therapy The duration of one treatment cycle is 21 days. at the time of surgery]
bpCR is defined as the absence of any residual invasive cancer on the hematoxylin and eosin evaluation of the resected breast specimen after completion of neoadjuvant therapy and surgery (that is, ypT0/is, in accordance with current AJCC staging system).The duration of one treatment cycle is 21 days.
Clinical response [Cycle 1-4. The duration of one treatment cycle is 21 days.]
Percentage of Participants With Complete Response, Partial Response, Stable Disease, or Progressive Disease During Cycles 1-4, According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. The duration of one treatment cycle is 21 days.
Event-free survival (EFS) [From Baseline to EFS event or date last known to be alive and event-free (up to 5 years)]
EFS is defined as the time from randomization to the first documentation of one of the following events: Disease progression (before surgery) as determined by the investigator with use of RECIST v1.1 Any evidence of contralateral disease in situ was not identified as progressive disease; Disease recurrence (local, regional, distant, or contralateral) after surgery; Death from any cause.
Disease-free survival (DFS) [From surgery to DFS event or date last known to be alive and event-free (up to 5 years)]
DFS was defined as the time from first date of no disease (i.e., date of surgery) to first documentation of one of the following events: Disease recurrence (local, regional, distant, or contralateral) after surgery. Any evidence of contralateral disease in situ was not identified as disease recurrence; Death from any cause.
Overall survival (OS) [From Baseline to OS event or date last known to be alive (up to 5 years)]
OS was defined as the time from randomization to death from any cause.

Other Outcome Measures

Percentage of Participants With At Least One Adverse Event During Treatment Period [From randomization to 30 days after completion of study treatment]
The percentage of participants who experienced at least one adverse event during the neoadjuvant period, surgery, adjuvant treatment period.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

With signed consent
Histologically confirmed invasive breast carcinoma with a primary tumor size of no less than (≥) 2 centimeters (cm) by standard local assessment technique
Breast cancer stage at presentation: stage II-III
HER2-positive breast cancer defined as 3+ score by immunohistochemistry in > 10 percent (%) of immunoreactive cells or HER2 gene amplification by in situ hybridization
Known hormone receptor status (estrogen receptor and/or progesterone receptor)
Eastern Cooperative Oncology Group Performance Status equal to or less than (<=) 1
Baseline left ventricular ejection fracture >= 50% measured by echocardiography
Willing to use highly effective form of nonhormonal contraception while on study and for 7 months after end of study treatment for female with fertility or male
Willing to obey the study protocol

Exclusion Criteria:

Stage IV disease
Previous anti-cancer therapy or radiotherapy for any malignancy
History of other malignancy within 5 years prior to screening, except for appropriately-treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, ,Stage I uterine cancer or thyroid papillary microcarcinoma
Concurrent anti-cancer treatment in another investigational trial, including hormone therapy, bisphosphonate therapy, or immunotherapy
Major surgical procedure unrelated to breast cancer within 4 weeks prior to randomization or from which the participant has not fully recovered
Serious cardiac illness or medical condition
Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness
Any abnormalities in liver, kidney or hematologic function laboratory tests immediately prior to randomization
Sensitivity to any of the study medications, any of the ingredients or excipients of these medications, or benzyl alcohol
Not able to swallow the drug
Pregnant or lactating
Positive serum or urine pregnancy test or above mentioned tests cannot be achieved for women with fertility