Pyrotinib in Combination With Fulvestrant in Patients With HER2 Positive，HR-Positive Metastatic Breast Cancer

Phase II Study of Pyrotinib in Combination With Fulvestrant in Patients With Human Epidermal Growth Factor Receptor 2 (HER2) Positive，Hormone Receptor（HR）-Positive Metastatic Breast Cancer

HR+/HER2+（Human epidermal growth factor receptor 2 positive and hormone receptor positive）metastatic breast cancer is a special subtype of HER2+breast cancer. Conventional guidelines recommend chemotherapy combined with trastuzumab targeted therapy for this subtype of patients. However, the choice of treatment for these patients after treatment progress is a research hotspot in this field. Pyrotinib is a new class I small molecule Tyrosine kinase inhibitors（TKI） drug with high efficacy and low toxicity after the progress of trastuzumab therapy. Fulvestrant is the most preferred single-drug therapy for HR + metastatic breast cancer recommended unanimously by the guidelines, and fulvestrant and small molecule TKI have synergistic effects. Therefore, we envisage that fulvestrant combined with Pyrotinib in the treatment of HR+/HER2+ metastatic breast cancer in clinical practice has the advantages of improving efficacy and survival. To this end, we intend to conduct a prospective, multi-center, phase II clinical trial to evaluate the efficacy and safety of erlotinib in combination with fulvestrant in patients with human epidermal growth factor receptor 2 (HER2) positive，hormone receptor-positive metastatic breast cancer.

Study Overview

• Status: Unknown
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Pyrotinib combined with fulvestrant

• Study Type: Interventional
• Enrollment (Anticipated): 46
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ying Wang, M.D., Ph. D.; Phone Number: 86-20-34070870; Email: wangy556@mail.sysu.edu.cn
• Study Contact Backup: Name: Herui Yao, M.D., Ph. D.; Phone Number: 86-20-34070091; Email: yaoherui@mail.sysu.edu.cn

Study Locations

• China
  • Guangyuan, China
    • Not yet recruiting
    • Sun Yat-Sen University Cancer Center
    • Contact: Zhongyu Yuan, M.D.
    • Principal Investigator: Zhongyu Yuan, M.D.
  • Guangzhou, China
    • Recruiting
    • Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
    • Contact: Ying Wang, M.D.,Ph.D.
    • Contact: Herui Yao, M.D.,Ph.D.
    • Principal Investigator: Ying Wang, M.D.,Ph.D.
    • Principal Investigator: Herui Yao, M.D.,Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Pathologically confirmed HER2 positive, hormone receptor-positive patients with locally advanced or metastatic breast cancer: HER2 IHC 3+, or HER2 IHC 2+ and FISH detection gene amplification, ER（estrogen receptor） and/or PR（progesterone receptor） Immunohistochemical staining of more than 10% tumor cells)
2. Aged ≥18 and ≤70 years.
3. ECOG（Eastern Cooperative Oncology Group） performance status of 0 to 1.
4. The life expectancy of more than 12 weeks;
5. At least one measurable lesion exists(RECIST 1.1，Response Evaluation Criteria in Solid Tumors ), or only bone metastasis.
6. Previous neoadjuvant or adjuvant use of trastuzumab, but the disease-free interval between the end of the last trastuzumab and the progression of tumors was more than 12 months
7. Trastuzumab has not been treated in the past or only received first-line treatment for metastatic diseases.
8. It is required that previous (neo) adjuvant or endocrine therapy be given to patients, and that progress of the disease occur during or after treatment.
9. Patients with adequate organ function before enrollment:

Neutrophil granulocyte≥1.5×10^9/L Platelet≥100×10^9/L Hemoglobin≥90 g/L Signed informed consent.

Exclusion Criteria:

1. Patients who have not received trastuzumab, chemotherapy or endocrine therapy before;
2. Patients with visceral crisis;
3. Patients unable to swallow, with chronic diarrhea, intestinal obstruction, or multiple factors that affect drug use and absorption;
4. Patients with malignant serous effusion which cannot be controlled by drainage or other methods;
5. Less than 4 weeks from the last treatment in the last clinical trial;
6. Receiving any other antitumor therapy;
7. History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent;
8. Patients with serious heart disease;
9. Allergy to Pyrotinib; the history of immunodeficiency；
10. Known history of neurological or psychiatric disease, including epilepsy or dementia;
11. Patients during pregnancy or lactation, patients with childbearing potential tested positive in a baseline pregnancy test, or patients unwilling to take effective contraceptive measures throughout the trial;
12. Evidence of significant medical illness that will substantially increase the risk of the participation or completion of the study in the investigator's judgment. Examples included, but not limited to, hypertension, severe diabetes, etc;
13. Patients not eligible for this study judged by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pyrotinib plus fulvestrant; Pyrotinib(400 mg once daily) + fulvestrant (500 mg, administered on days 0, 14 (plus or minus 3 days), 28 (plus or minus 3 days), and every 28 (plus or minus 3 days) days)	Drug: Pyrotinib combined with fulvestrant; Pyrotinib 400 mg once daily; Fulvestrant 500 mg administered on days 0, 14 (plus or minus 3 days), 28 (plus or minus 3 days), and every 28 (plus or minus 3 days) days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	From enrollment to progression or death (for any reason)	Estimated 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Ratio of CR and PR in all subjects	Estimated 12 months
Clinical Benefit rate (CBR)	Ratio of CR,PR and SD greater than or equal to 24 weeks in all subjects	Estimated 12 months
Overall Survival (OS)	From enrollment to death (for any reason)	Estimated 24 months
Adverse Events and Serious Adverse Events	Safety	From informed consent through 28 days following treatment completion
Efficacy correlation biomarkers	Next Generation Gene Sequencing（NGS） detection of tissue specimens to obtain information on drug sensitivity-related biomarkers , eg, PIK3CA, PTEN, TMB，ESR1，ESR2	Estimated 12 months
the quality of life	All patients need to fill in the Functional Assessment of Cancer Therapy-Breast (FACT-B), a 44-item self-report instrument designed to measure multidimensional quality of life (QL) in patients with breast cancer.	Estimated 24 months

Collaborators and Investigators

• Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Publications and helpful links

General Publications

• Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009 Nov 20;27(33):5538-46. doi: 10.1200/JCO.2009.23.3734. Epub 2009 Sep 28.
• Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Revil C, Jones A. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009 Nov 20;27(33):5529-37. doi: 10.1200/JCO.2008.20.6847. Epub 2009 Sep 28.
• Xia W, Bacus S, Hegde P, Husain I, Strum J, Liu L, Paulazzo G, Lyass L, Trusk P, Hill J, Harris J, Spector NL. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7795-800. doi: 10.1073/pnas.0602468103. Epub 2006 May 8.
• 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.
• Robertson JFR, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A, Shparyk Y, Cardona-Huerta S, Cheung KL, Philco-Salas MJ, Ruiz-Borrego M, Shao Z, Noguchi S, Rowbottom J, Stuart M, Grinsted LM, Fazal M, Ellis MJ. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005. doi: 10.1016/S0140-6736(16)32389-3. Epub 2016 Nov 29.
• Robertson JFR, Steger GG, Neven P, Barni S, Gieseking F, Nole 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.
• Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, Botero MF, Healy NA, Hilsenbeck SG, Phillips GL, Chamness GC, Rimawi MF, Osborne CK, Schiff R. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers--role of estrogen receptor and HER2 reactivation. Breast Cancer Res. 2011;13(6):R121. doi: 10.1186/bcr3067. Epub 2011 Nov 28.

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2019
• Primary Completion (Anticipated): July 6, 2021
• Study Completion (Anticipated): July 6, 2022

Study Registration Dates

• First Submitted: July 21, 2019
• First Submitted That Met QC Criteria: July 24, 2019
• First Posted (Actual): July 26, 2019

Study Record Updates

• Last Update Posted (Actual): December 22, 2020
• Last Update Submitted That Met QC Criteria: December 19, 2020
• Last Verified: December 1, 2020

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; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Fulvestrant
• Other Study ID Numbers: 2019-KY-049

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data can be obtained by writing to researchers.

Drug and device information, study documents

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