Fulvestrant or Capecitabine Combined With Pyrotinib in HR+/HER2+ Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT04646759
• Recruitment Status: Recruiting
• First Posted: November 30, 2020
• Last Update Posted: November 30, 2020
• Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Information provided by (Responsible Party): Ying Wang, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Study Description

Brief Summary:

Capecitabine combined with pyrotinib is the standard protocol for HR+/HER2+ advanced breast cancer after trastuzumab failure, but the incidence of grade 3 hand-foot-syndrome was 16.4%. Therefore, the search for efficient and low toxicity alternatives has become a research hotspot. Our previous basic studies have shown that ER inhibitor fulvestrant and HER2 inhibitor pyrotinib have a synergistic effect. The preliminary analysis of our prospective shows that the efficacy is close to that of capecitabine combined with pyrotinib, and the adverse events are significantly improved compared with capecitabine combined with pyrotinib. Therefore, it is necessary to further carry out a head-to-head phase III randomized controlled clinical trial to study the efficacy and safety of fulvestrant combined with pyrotinib in the treatment of HR + / HER2 + advanced breast cancer.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: Fulvestrant combined with Pyrotinib; Drug: Capecitabine combined with Pyrotinib	Phase 3

Detailed Description:

Hormone receptor (HR) positive and human epidermal growth factor receptor-2 (HER-2) positive breast cancer has the characteristics of mild biological behavior and slow progression. Currently, capecitabine combined with pyrotinib is the standard protocol for this kind of advanced breast cancer after trastuzumab failure, and the median progression free survival (PFS) is 11.0 months. The incidence of grade 3 hand-foot-syndrome was 16.4%, the incidence of grade 3 diarrhea was 30.6%, and the incidence of grade 3 myelosuppression was 6%. Therefore, the search for efficient and low toxicity alternatives has become a research hotspot.

Our previous basic studies have shown that ER inhibitor fulvestrant and HER2 inhibitor pyrotinib have synergistic effect in inhibiting the proliferation of HR + / HER2 + breast cancer cells. At the same time, the preliminary analysis of our prospective, phase II, single arm study of "Fulvestrant combined with Pyrotinib in the treatment of HR + / HER2 + advanced breast cancer" shows that the efficacy is close to that of capecitabine combined with pyrotinib (median progression free survival is more than 13 months), and the adverse events are significantly improved compared with capecitabine combined with pyrotinib (grade 3 hand-foot-syndrome). This project has been supported by the "Sun-yat sun clinical research and cultivation project" of Sun-Yat Sen Memorial Hospital, Sun-Yat Sen University. Therefore, it is necessary to further carry out a head-to-head phase III randomized controlled clinical trial to study the efficacy and safety of fulvestrant combined with pyrotinib in the treatment of HR + / HER2 + advanced breast cancer, with a non-inferiority cut-off value of HR = 1.30. Combined with the analysis of biomarkers, to find the molecular indicators to predict the benefit of pyrotinib combined with endocrine therapy, so as to provide theoretical basis for guiding precise treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 516 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Patients were randomly assigned to capecitabine plus pyrotinib or fulvestrant plus pyrotinib
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Fulvestrant or Capecitabine Combined With Pyrotinib in HR-positive and HER2-Positive Metastatic Breast Cancer: A Multicenter, Randomized, Phase III Study
• Actual Study Start Date: October 14, 2020
• Estimated Primary Completion Date: December 14, 2028
• Estimated Study Completion Date: December 14, 2030

Arms and Interventions

Arm	Intervention/treatment
Experimental: Fulvestrant Combined With Pyrotinib; Fulvestrant, 500 mg, was injected intramuscularly on D1, D15, D28, D28, once every 28 days； Pyrotinib, 400mg, orally administered daily.	Drug: Fulvestrant combined with Pyrotinib; Fulvestrant 500mg was injected intramuscularly on D1, D15, D28 and D28 Pyrotinib 400mg daily; Other Name: FASLODEX combined with Pyrotinib
Active Comparator: Capecitabine Combined With Pyrotinib; Capecitabine, 1000mg / m^2, twice daily; Pyrotinib, 400mg, orally administered daily.	Drug: Capecitabine combined with Pyrotinib; Capecitabine 1000mg/m^2 bid d1-d14，every 21 days Pyrotinib 400mg daily; Other Name: xeloda combined with Pyrotinib

Outcome Measures

Primary Outcome Measures :

1. Progression free survival [ Time Frame: 24 months ]
   The interval from the date of randomization to the first imaging confirmed progression of disease or death from any cause.
2. Incidence of grade 3 hand foot syndrome (rate) [ Time Frame: From the date of enrollment to one year ]
   From the date of enrollment to one year, the incidence of grade 3 hand-foot syndrome in the fulvestrant combined with pyrotinib group was compared with that of capecitabine combined with pyrotinib group. The incidence and severity of hand-foot syndrome were evaluated according to CTCAE 5.0 every 9 weeks (± 7 days).

Secondary Outcome Measures :

1. Overall survival (OS) [ Time Frame: 50 months ]
   The time interval from the date of randomization to death due to any cause
2. Objective response rate (ORR) [ Time Frame: 12 months ]
   According to recist1.1 standard, the proportion of patients whose best remission was CR or PR accounted for the total number of evaluable patients.
3. Clinical Benefit Rate (CBR) [ Time Frame: 12 months ]
   According to recist1.1 standard, the proportion of patients whose best remission was CR or PR or SD ≥ 24 weeks accounted for the total number of evaluable patients.
4. Biomarkers and treatment sensitivity analysis [ Time Frame: 12 months ]
   Cox univariate and multivariate analysis will be used to explore the correlation between endocrine and HER2 pathway related biomarkers and treatment sensitivity（The biomarkers to be analyzed included 324 tumor related genes included in the FoundationOne CDx, and ER/PR/HER2/ki67 in IHC）
5. Quality of life score [ Time Frame: 12 months ]
   Quality of life data will be collected using the following questionnaires: FACT-B score
6. Incidence of adverse events [ Time Frame: from the date of enrollment to one year ]
   From the date of enrollment to one year, the incidence of adverse events in the fulvestrant combined with pyrotinib group was compared with that of capecitabine combined with pyrotinib group.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adult female patients (aged 18-80 years, including 18 and 80 years) with metastatic breast cancer confirmed by pathology or imaging are not suitable for surgical resection or radiotherapy for the purpose of cure;
2. Pathological examination confirmed that ER and / or PR were positive, and HER-2 was positive (ER expression: immunohistochemical staining of tumor cells ≥ 10%; PR expression: immunohistochemical staining of tumor cells ≥ 10%; HER-2 positive: immunohistochemical staining of 3 + or fish positive);
3. Postmenopausal patients (for premenopausal patients, ofs includes bilateral ovariectomy and GnRHa drugs);
4. The disease-free interval between the end of the last trastuzumab and tumor progression was more than 12 months;
5. Trastuzumab has not been treated or only received first-line treatment based on trastuzumab for metastatic diseases, and trastuzumab should be evaluated as effective in the rescue treatment of metastatic breast cancer for the first time.
6. Patients who have received chemotherapy and endocrine therapy in the past (New) adjuvant or for metastatic diseases, and have disease progression during or after treatment;
7. The WHO physical status was 0-2 points, and the expected survival time was not less than 3 months;
8. At least one measurable lesion (short diameter of lymph node ≥ 15mm) was detected in the imaging examination within 2 weeks before enrollment, including normal CT scan ≥ 20 mm, spiral CT scan diameter ≥ 10 mm, or simple bone metastasis.
9. Previous treatment related toxicity should be reduced to NCI CTCAE (version 5.0) ≤ 1 degree (except for hair loss or other toxicity which is judged by the researcher to be safe for the patient)
10. Within one week before admission, blood routine examination was basically normal: A. white blood cell count (WBC) ≥ 3.0 × 10 ^ 9 / L; B. neutrophil count (ANC) ≥ 1.5 × 10 ^ 9 / L; C. platelet count (PLT) ≥ 100 × 10 ^ 9 / L;
11. Liver, kidney and heart function tests were basically normal within one week before enrollment (based on the normal values of laboratories in each research center): A. total bilirubin (TBIL) ≤ 1.5 × upper limit of normal value (ULN), B. alanine aminotransferase (ALT / AST) ≤ 2.5 × ULN (liver metastasis patients ≤ 5xuln), C. serum creatinine ≤ 1.5 × ULN or creatinine clearance rate (CCR) ≥ 60 ml / min; D. left ventricular ejection fraction (LVEF) ≥ 55%, e. QTcF(Fridericia correction) ≤ 470 ms.

Exclusion Criteria:

You cannot be grouped if you meet any of the following:

1. Patients who had not received trastuzumab, chemotherapy and endocrine therapy before;
2. Patients with central nervous system metastasis and clinical symptoms;
3. Patients with visceral crisis;
4. Patients who were considered suitable for chemotherapy by the researchers;
5. There are many factors that affect drug administration and absorption, such as dysphagia, chronic diarrhea and intestinal obstruction.
6. Patients who received radiotherapy, chemotherapy, endocrine therapy, surgery (excluding local puncture) or molecular targeted therapy within 4 weeks before enrollment.
7. He participated in other clinical trials within 4 weeks before enrollment.
8. Patients with metastatic disease received more than first-line endocrine therapy, chemotherapy or targeted therapy.
9. Other malignant tumors in the past 5 years, excluding cured cervical carcinoma in situ, skin basal cell carcinoma or skin squamous cell carcinoma.
10. At the same time, they received any other anti-tumor treatment.
11. Those who have been known to have allergic history to the drug components of this regimen; have a history of immunodeficiency, including HIV positive, HCV, active hepatitis B, or other acquired and congenital immunodeficiency diseases, or have a history of organ transplantation.
12. Severe heart disease or discomfort, including, but not limited to, the following: a history of heart failure or systolic dysfunction (LVEF < 50%); high risk uncontrolled arrhythmias such as atrial tachycardia, resting heart rate > 100bpm, significant ventricular arrhythmias (such as ventricular tachycardia), or higher-level atrioventricular block (i.e., mobitz) The results showed that there was no significant difference between the two groups (systolic blood pressure > 180 mmHg and diastolic blood pressure > 100 mmHg);
13. Pregnant and lactating women, fertile women with positive baseline pregnancy test.
14. According to the judgment of the researchers, there are some accompanying diseases that seriously endanger the safety of patients or affect patients to complete the study.
15. Have a clear history of neurological or mental disorders, including epilepsy or dementia.
16. Any other situation in which the researcher believes that the patient is not suitable for the study, which may interfere with the accompanying diseases or conditions of the study, or have any serious medical obstacles that may affect the safety of the subjects (such as uncontrollable heart disease, hypertension, active or uncontrollable infection, active hepatitis B virus infection)

Contacts and Locations

Contacts

Contact: Ying Wang; 86-20-34070870; wangy556@mail.sysu.edu.cn

Contact: Jianli Zhao; 86-20-34070499; zhaojli5@mail.sysu.edu.cn

Locations

China, Guangdong

Sun Yat-sen Memorial Hospital, Sun Yat-sen University; Recruiting

Guangzhou, Guangdong, China, 510000

Contact: Ying Wang 020-34070870 wangy556@mail.sysu.edu.cn

Contact: Jianli Zhao 020-34070499 zhaojli5@mail.sysu.edu.cn

Sponsors and Collaborators

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Investigators

• Principal Investigator: Ying Wang; Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

More Information

Publications:

Ma F, Ouyang Q, Li W, Jiang Z, Tong Z, Liu Y, Li H, Yu S, Feng J, Wang S, Hu X, Zou J, Zhu X, Xu B. Pyrotinib or Lapatinib Combined With Capecitabine in HER2-Positive Metastatic Breast Cancer With Prior Taxanes, Anthracyclines, and/or Trastuzumab: A Randomized, Phase II Study. J Clin Oncol. 2019 Oct 10;37(29):2610-2619. doi: 10.1200/JCO.19.00108. Epub 2019 Aug 20.

Ma F, Li Q, Chen S, Zhu W, Fan Y, Wang J, Luo Y, Xing P, Lan B, Li M, Yi Z, Cai R, Yuan P, Zhang P, Li Q, Xu B. Phase I Study and Biomarker Analysis of Pyrotinib, a Novel Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. J Clin Oncol. 2017 Sep 20;35(27):3105-3112. doi: 10.1200/JCO.2016.69.6179. Epub 2017 May 12.

Chen Q, Ouyang D, Anwar M, Xie N, Wang S, Fan P, Qian L, Chen G, Zhou E, Guo L, Gu X, Ding B, Yang X, Liu L, Deng C, Xiao Z, Li J, Wang Y, Zeng S, Hu J, Zhou W, Qiu B, Wang Z, Weng J, Liu M, Li Y, Tang T, Wang J, Zhang H, Dai B, Tang W, Wu T, Xiao M, Li X, Liu H, Li L, Yi W, Ouyang Q. Effectiveness and Safety of Pyrotinib, and Association of Biomarker With Progression-Free Survival in Patients With HER2-Positive Metastatic Breast Cancer: A Real-World, Multicentre Analysis. Front Oncol. 2020 May 25;10:811. doi: 10.3389/fonc.2020.00811. eCollection 2020. Erratum in: Front Oncol. 2021 Mar 05;11:661128.

Lin Y, Lin M, Zhang J, Wang B, Tao Z, Du Y, Zhang S, Cao J, Wang L, Hu X. Real-World Data of Pyrotinib-Based Therapy in Metastatic HER2-Positive Breast Cancer: Promising Efficacy in Lapatinib-Treated Patients and in Brain Metastasis. Cancer Res Treat. 2020 Oct;52(4):1059-1066. doi: 10.4143/crt.2019.633. Epub 2020 Apr 24.

Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol. 2018 Mar 10;36(8):741-748. doi: 10.1200/JCO.2017.74.7824. Epub 2017 Dec 15. Retraction in: J Clin Oncol. 2021 Jan 1;39(1):95.

Retraction in: J Clin Oncol. 2021 Jan 1;39(1):95

Robertson JFR, Steger GG, Neven P, Barni S, Gieseking F, Nolè F, Pritchard KI, O'Malley FP, Simon SD, Kaufman B, Petruzelka L. Activity of fulvestrant in HER2-overexpressing advanced breast cancer. Ann Oncol. 2010 Jun;21(6):1246-1253. doi: 10.1093/annonc/mdp447. Epub 2009 Oct 29.

Tolaney SM, Wardley AM, Zambelli S, Hilton JF, Troso-Sandoval TA, Ricci F, Im SA, Kim SB, Johnston SR, Chan A, Goel S, Catron K, Chapman SC, Price GL, Yang Z, Gainford MC, André F. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial. Lancet Oncol. 2020 Jun;21(6):763-775. doi: 10.1016/S1470-2045(20)30112-1. Epub 2020 Apr 27. Erratum in: Lancet Oncol. 2021 Mar;22(3):e92. Lancet Oncol. 2021 Nov;22(11):e472.

• Responsible Party: Ying Wang, Associate Professor, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• ClinicalTrials.gov Identifier: NCT04646759
• Other Study ID Numbers: 2020-KY-140
• First Posted: November 30, 2020
• Last Update Posted: November 30, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Because the data involves the patient's personal information, it is temporarily decided that we will not disclose the individual participant data.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Ying Wang, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University:

HR-postitive/HER2-positive metastatic breast cancer; fulvestrant; Pyrotinib; capecitabine

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Capecitabine; Fulvestrant; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Estrogen Receptor Antagonists; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs