Pyrotinib, Dalpiciclib(SHR6390) and Endocrine Therapy in Subjects With Dual-receptor Positive(ER+/HER2+) Advanced Breast Cancer

NCT03772353 | Unknown Phase 1

• 1 other identifier: PLEASURABLE
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single-center Ib / II study of triple targeted drug combination (endocrine therapy，novel HER2-targeted small molecule inhibitor pyrotinib and CDK4/6 inhibitor dalpiciclib(SHR6390) ) as a first or second line of therapy in patients with relapsed/metastatic hormone receptor positive and HER2-positive breast cancer.

Conditions

Breast Cancer

Keywords

hormone receptor; HER2; pyrotinib; CDK4/6 inhibitor

Outcome Measures

Primary Outcomes (2)

• The number of patients in the Phase 1b part of the study with any adverse events (AE).

  To measure safety and tolerability of SHR6390 used in combination with and letrozole and pyrotinib (phase Ib part) we will assess the incidence, nature and severity of all adverse events (AE) that occur on or after C1D1 of therapy, AE severities will be classified using the CTCAE criteria.

  2 years

• Objective response rate (ORR)

  According to recist1.1 standard, the proportion of patients whose best remission was CR or PR accounted for the total number of evaluable patients.

  12 months

Study Arms (1)

Dalpiciclib combined with Pyrotinib and Endocrine therapy

EXPERIMENTAL

Data from phase Ib showed the triplet of pyrotinib, SHR6390, and letrozole had an acceptable safety profile and encouraging efficacy, potentially offering a chemotherapy-sparing treatment option for patients with HER2-positive/HR-positive MBC. Based on DLTs and clinical efficacy, pyrotinib 320mg/d, SHR6390 125mg/d, and letrozole 2.5mg/d was declared as RP2D. The pharmacokinetic analysis had not yielded conclusive results and would involve more samples in phase II trial. Dalpiciclib combined with Pyrotinib and Endocrine therapy (treatment of physician's choice: letrozole or fulvestrant) ER+/HER2+ metastatic breast cancer patients eligible for first- or second-line treatment were enrolled to receive dalpiciclib combined with pyrotinib and endocrine therapy (treatment of physician's choice: letrozole or fulvestrant)

Drug: Dalpiciclib; Drug: Pyrotinib; Drug: Letrozole; Drug: Fulvestrant

Interventions

Dalpiciclib DRUG

Dalpiciclib (SHR6390) is a novel small molecule inhibitor specifically targeting the CDK4/6 pathway.

Also known as: SHR6390

Dalpiciclib combined with Pyrotinib and Endocrine therapy

Pyrotinib DRUG

Pyrotinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising anti-tumour activity and acceptable tolerability in patients with HER2+ metastatic breast cancer (MBC)

Dalpiciclib combined with Pyrotinib and Endocrine therapy

Letrozole DRUG

Letrozole, a third-generation aromatase inhibitor, is the principal drug used in the treatment of postmenopausal patients with both early- and advanced-stage endocrine-responsive breast cancer (BC).

Dalpiciclib combined with Pyrotinib and Endocrine therapy

Fulvestrant DRUG

Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer

Dalpiciclib combined with Pyrotinib and Endocrine therapy

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects voluntarily joined the study, signed informed consent, and had good compliance.
• Postmenopausal or premenopausal perimenopausal female patients aged ≥ 18 years and ≤ 75 years old,Meet one of the following:
• Previous bilateral oophorectomy, or age ≥ 60 years; or Age \<60, natural postmenopausal state (defined as regular months for at least 12 consecutive months After spontaneous cessation and no other pathological or physiological reasons),E2 and FSH in menopause Post-level; or
• Pre-menopausal or perimenopausal female patients can also be included, but must be willing to receive treatment with LHRH agonists;
• Patients with HR+/HER2+ recurrent or metastatic breast cancer confirmed by histopathology
• HER2 positivity is defined by standard of 3+ staining by immunohistochemical staining (IHC) or positive for in situ hybridization (ISH)
• Estrogen receptor(ER) or Progesterone receptor(PR) positive is defined as the percentage of cells positive for ER or PR expression ≥ 1%
• Local recurrence needs to be confirmed by the physician that is unresectable
• At least one extracranial measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1.
• Prior treatment:
• Previously received no more than 1 prior lines of systemic treatment with trastuzumab regimen for repetitive metastatic diabetes \[including anti-HER2 ADC, subsequent meaning is the same\]
• The early stage includes trastuzumab-containing regimen treatment， or trastuzumab-containing regimen that relapses more than 1 year after the end of adjuvant treatment, and subsequent treatment is included as the first-line anti-HER2 treatment;
• The first-line treatment fails with the trastuzumab-containing regimen, or the trastuzumab-containing regimen recurs during the adjuvant treatment or relapses within 1 year after the adjuvant treatment ends, the follow-up treatment will be included as the second-line anti-HER2 treatment;
• Have not received anti-HER2 TKI treatment before or received but did not prove that the treatment failed;
• Past endocrine therapy has not proven resistance to aromatase inhibitors (definition of resistance: recurrence during or within 1 year after treatment with adjuvant aromatase inhibitors, received aromatase inhibitors in the recurrence and metastasis stage and disease progression), follow-up Letrozole is selected for endocrine therapy. Past endocrine therapy has aromatase inhibitor resistance, and follow-up endocrine therapy is fulvestrant.

You may not qualify if:

• Meningeal metastasis or active brain parenchymal metastasis. Patients with clinically stable brain parenchymal metastases can be included, including asymptomatic brain metastases that have not received local treatment; or patients who have previously received central nervous system metastasis therapy (radiotherapy or surgery), if imaging confirms that stability has been maintained for at least 4 weeks , and have stopped symptomatic treatment (including hormones and mannitol, etc.) for more than 2 weeks
• Previously received any CDK4/6 inhibitor treatment.
• There are ascites, pleural effusion, pericardial effusion with clinical symptoms at baseline, those who need drainage, or those who have undergone drainage of serous effusion within 4 weeks before the first dose.
• Inability to swallow, intestinal obstruction or other factors affecting the administration and absorption of the drug.
• Received systemic therapy such as chemotherapy, molecular targeted therapy or other clinical trial drugs within 4 weeks before enrollment; received endocrine therapy within 2 weeks before enrollment.
• Patients with other malignant tumors within 5 years or at the same time( except for cured skin basal cell carcinoma and cervical carcinoma in situ).
• Have undergone major surgical procedures or significant trauma within 4 weeks prior to randomization, or are expected to undergo major surgery.
• Pregnant women, lactating female, or women of childbearing age who are unwilling to take effective contraceptive measures.
• Have a history of allergies to the drug components of this regimen.
• Patients with active HBV and HCV infection; stable hepatitis B after drug treatment (HBV virus copy number is higher than the upper limit of reference value) and cured hepatitis C patients (HCV virus copy number exceeds the lower limit of detection method).
• History of immunodeficiency, including HIV positive, or other acquired or congenital immunodeficiency disease, history of organ transplantation.
• History of cardiac dysfunction, include(1)angina (2)clinical significant arrythmia or require drug intervention (3)myocardial infarction (4)heart failure (5) other cardiac dysfunction (judged by the physician); any cardiac or nephric abnormal ≥ grade 2 found in screening.
• Female patients who are pregnancy, lactation or women who are of childbearing potential tested positive in baseline pregnancy test.
• Childbearing female who refuse to accept any contraception practice.
• Determined by the physician, any serious coexisting disease might be harmful to the patient's safety or avoid the patients from accomplishing the treatment(e.g serious hypertension, diabetes, thyroid dysfunction,active infection etc.).

Sponsors & Collaborators

• Fudan University: lead
• Jiangsu HengRui Medicine Co., Ltd.: collaborator

Study Sites (1)

Fudan University Shanghai Cancer Center

Shanghai, 200032, China

Location

Related Publications (2)

• Zhang J, Meng Y, Wang B, Wu X, Zheng H, Hu J, Liu W, Chen W, Wang L, Cao J, Tao Z, Li T, Ni S, Yu Z, Sun L, Wang Y, Peng Q, Wang S, Hu X, Wang J, Wu Y, Hu X. Dalpiciclib combined with pyrotinib and endocrine therapy in women with ER-positive, HER2-positive advanced breast cancer: A prospective, multicenter, single-arm, phase 2 trial. PLoS Med. 2025 Jul 31;22(7):e1004669. doi: 10.1371/journal.pmed.1004669. eCollection 2025 Jul.

  PMID: 40743286 DERIVED

• Zhang J, Meng Y, Wang B, Wang L, Cao J, Tao Z, Li T, Yao W, Hu X. Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study. Front Oncol. 2022 Mar 7;12:775081. doi: 10.3389/fonc.2022.775081. eCollection 2022.

  PMID: 35321427 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

dalpiciclib; pyrotinib; Letrozole; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 10, 2018
• First Posted: December 11, 2018
• Study Start: May 12, 2019
• Primary Completion: June 10, 2023
• Study Completion: December 10, 2025
• Last Updated: March 7, 2023

Record last verified: 2023-03

Locations

CN (1)