Neoadjuvant With Trastuzumab, Pyrotinib Plus Palbociclib and Fulvestrant in HER2-positive, ER-positive Breast Cancer (NeoTPPF)

This is a prospective Single-arm Study to Investigate the Efficacy and Safety of Neoadjuvant treatment with trastuzumab and pyrotinib plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer.

Study Overview

• Status: Recruiting
• Conditions: HER2-positive Breast Cancer; Estrogen Receptor-positive Breast Cancer
• Intervention / Treatment: Drug: Palbociclib; Drug: trastuzumab; Drug: pyrotinib; Drug: fulvestrant

Detailed Description

ER+HER2+ breast cancer have low response to single endocrine therapy, however the efficacy was improved when treated with endocrine therapy combined with anti-HER2 target therapy. Palbociclib, to be a CDK4/6 inhibitor, has synergistic with tamoxifen and trastuzumab in ER+/HER2+ cells. In China, there is nearly 40000 new patients with ER+/HER2+ breast cancer every year. The encouraging results in NA-PHER2 study suggested the triple targeting of ER, HER2, and RB1 could be an effective chemotherapy-free treatment strategy in neoadjuvant therapy. However, pertuzumab is very expensive. The investigators plan to replace pertuzumab with pyrotinib. Pyrotinib, a new irreversible pan-Her inhibitor in China pharmaceutical company. The objective is to evaluate the efficacy and safety of Neoadjuvant treatment with trastuzumab and pyrotinib plus palbociclib and fulvestrant (TPPF) in this target population. 37 patients will enter the single-arm treatment group. The participants will receive an association of drugs (trastuzumab, pyrotinib, palbociclib plus Fulvestrant, TPPF) as neoadjuvant therapy. Surgery will be performed not earlier than 14 days and not later than 28 days after the last dose of any of the drugs in the combination. The primary endpoint is the rate of pathological complete response (pCR) defined as ypT0-ypTis ypN0 at surgery. The secondary endpoint include the change in Ki67 expression from baseline and at C2D15 of treatment and at surgery, objective response rate and safety.

• Study Type: Interventional
• Enrollment (Anticipated): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Fudan University Shanghai Cancer Hospital
      • Contact: Yin U Liu, M.D; Phone Number: 88603 +86-021-64175590; Email: liuyinfudan@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Age: 18 or older than 18;
2. Postmenopausal; Pre-menopausal and peri-menopausal female patients must receive ovarian function inhibitors or ovariectomy concurrently.
3. Have not received chemotherapy or endocrine therapy in the past;
4. Have been confirmed as breast invasive ductal carcinoma by the imaging examination and pathological biopsy;
5. Patients with locally advanced breast cancer, stage IIa-IIIa
6. HER2 status to be centrally confirmed (HER2 3+ of neu amplified)
7. Positive estrogen receptor (ER) > 10%
8. Estimated survival > 12 months;
9. ECOG physical status score before treatment is 0-1 points;
10. The patient has a measurable lesion (according to the standard RECIST 1.1);
11. Willing to cooperate with pre-treatment needle biopsy and neoadjuvant therapy;
12. No serious metastasis, no brain metastasis, no liver metastasis;
13. Normal bone marrow function, blood neutrophils ≥ 1.5x109 / L, hemoglobin ≥ 100g / L, platelets ≥ 100x109 / L;
14. normal liver and kidney function, blood AST≤60U/L, total bilirubin ≤2.5 times of the normal upper limit, and serum creatinine ≤110µmol/L, urea nitrogen ≤7.1mmol/L;
15. No abnormal blood coagulation;
16. Normal heart function, normal ECG and LVEF ≥ 55%;
17. Women of childbearing age are willing to take reliable contraceptive measures during clinical trials, and the serum or urine pregnancy test is negative within 7 days before administration; no coagulation abnormality;

18. Sign the informed consent form (ICF) and voluntarily receive follow-up visits, treatment, laboratory tests and other study procedures as planned.

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Exclusion Criteria:

1. Have performed any local or systemic treatment (including chemotherapy, radiotherapy, targeted drug therapy, experimental treatment, etc.) for the breast cancer;
2. Inflammatory breast cancer, bilateral breast cancer or breast cancer with distant metastasis found;
3. Subjects with uncontrolled lung disease, severe infection, active gastrointestinal ulcer, coagulopathy, severe uncontrolled diabetes, connective tissue disease or inhibition of bone marrow function who cannot tolerate neoadjuvant therapy and related therapy;
4. Peripheral neuropathy caused by any factor > 1 degree;
5. Subjects who previously have a history of congestive heart failure, uncontrolled or symptomatic angina, arrhythmia or myocardial infarction, and uncontrollable hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg);
6. Previous extensive radiotherapy

7. Current use or anticipated need for food or drugs that are known strong CYP3A4 (cytochrome P450 3A4) inhibitors or inducers.

   1. Strong CYP3A inhibitors, including, boceprevir, clarithromycin, conivaptan, delavirdine, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, suboxone, telaprevir, telithromycin, voriconazole, and grapefruit, grapefruit juice or any product containing grapefruit.
   2. Strong CYP3A inducers, including carbamazepine, phenytoin, primidone, rifampin, rifapentin, and St. John's wort.
8. Breast cancer during the lactation period and gestation period;
9. Reluctance to receive pre-treatment biopsy and neoadjuvant therapy;
10. Psychiatric patients or other factors that cause non-compliance with the treatment;
11. Subjects who are known to have a history of severe allergies to any drug in the treatment regimen; patients who have undergone major surgery or severe trauma within 2 months prior to the first administration; subjects who currently or recently (within 30 days prior to enrolment) have used another investigational drug or participated in another study;
12. Subjects who are known to have infected with human immunodeficiency virus (HIV);
13. Subjects who have other conditions unsuitable for inclusion as considered by investigators, combined with CYP3A4 inhibitors or inducers;
14. Subjects with long QT syndrome or QTc > 470 ms.
15. According to the judgement of the researchers, there are concomitant diseases that seriously endanger the safety of patients or affect the completion of research (including, but not limited to, severe hypertension, severe diabetes, active infections, etc.).

16. Moderate infection occurs within 4 weeks before the first administration (e.g. intravenous drip of antibiotics, antifungal or antiviral drugs according to clinical criteria), fever of unknown origin occurs during the screening period/before the first administration.

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: TPPF group; Patients will be treated with Trastuzumab, Pyrotinib, Palbociclib plus Fulvestrant(TPPF).

Drug: Palbociclib; Palbociclib will be given at the dose of 125 mg po q.d. x 21 every 4 weeks (i.e. 1 week rest period for a total of 5 cycles); Drug: trastuzumab; 8 mg/kg loading dose IV, then 6 mg/kg IV, every 3 weeks for a total of 6 administrations.; Drug: pyrotinib; Pyrotinib 400mg, PO daily, continuously; Drug: fulvestrant; Fulvestrant will be administered according to local prescription guidelines and will be given intramuscle at the dose of 500 mg every 4 weeks (repeat for 5 times) with an additional 500 mg dose given two weeks after the initial dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pathological complete response (pCR)	Defined as the absence of any invasive cancer cells in the resected breast specimen and all resected lymph nodes following the completion of neoadjuvant therapy. If there is only carcinoma in situ remains, it can be regarded as pCR.	Immediately after the surgery,through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
changes of Ki67	changes of Ki67 from baseline and at cycle2/day 15 and at surgery (approximately 22 weeks after start of neoadjuvant therapy.	through study completion, an average of 1 year
objective response rate (ORR)	The proportion of participants whose best outcome is complete remission or partial remission (according to RECIST1.1)	at the end of the combination treatment, up to 1 year

Collaborators and Investigators

• Sponsor: Fudan University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): October 15, 2021
• Primary Completion (ANTICIPATED): October 15, 2023
• Study Completion (ANTICIPATED): October 15, 2024

Study Registration Dates

• First Submitted: September 18, 2021
• First Submitted That Met QC Criteria: September 29, 2021
• First Posted (ACTUAL): October 13, 2021

Study Record Updates

• Last Update Posted (ACTUAL): October 13, 2021
• Last Update Submitted That Met QC Criteria: September 29, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• 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; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Trastuzumab; Fulvestrant; Palbociclib
• Other Study ID Numbers: SCHBCC-N032

Drug and device information, study documents

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