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

STATUS

Recruiting
End date

Dec 12, 2022
participants needed

79
sponsor

Fudan University

Send

Updated on 25 March 2022

See if I qualify

estrogen

measurable disease

growth factor

endocrine therapy

progesterone

metastasis

hormone therapy

advanced breast cancer

HER2

trastuzumab

progesterone receptor

fulvestrant

stage iv breast cancer

erbb2

aromatase inhibitor

estrogen receptor

anastrozole

her2/neu-positive breast cancer

letrozole

mammogram

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.

Description

This is a single-center, single arm, open-label, run-in phase Ib / roll-over phase II study of endocrine therapy in combination with novel human epidermal growth factor receptor-2(HER2)-targeted tyrosine kinase Inhibitor pyrotinib and cyclin-dependent kinase 4/6(CDK4/6) Inhibitor dalpiciclib(SHR6390) in subjects with hormone receptor(HR)+/HER2+ relapsed or metastatic breast cancer. The study will enroll natural postmenopausal women, or women who have undergone bilateral oophorectomy.The phase Ib part of the study will determine safety and tolerability of the combination of endocrine therapy, pyrotinib and dalpiciclib to define that appropriate dose of dalpiciclib for phase II.Data from phase Ib showed the triplet of pyrotinib, dalpiciclib, andendocrine therapy had an acceptable safety profile and encouraging efficacy, potentially offering a chemotherapy-sparing treatment option for patients with HER2-positive/HR-positive MBC.Once the recommended regimen has been identified, subjects with the selected tumor type will be enrolled into expansion cohorts for the purpose of assessing efficacy and safety of the combination treatment.

Details

Condition	Breast Cancer
Treatment	Letrozole, fulvestrant, Pyrotinib, SHR6390, Dalpiciclib(SHR6390)
Clinical Study Identifier	NCT03772353
Sponsor	Fudan University
Last Modified on	25 March 2022

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	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
	HER2 positivity is defined by standard of 3+ staining by immunohistochemical staining (IHC) or positive for in situ hybridization (ISH)
	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
	Local recurrence needs to be confirmed by the physician that is unresectable
	Estrogen receptor(ER) or Progesterone receptor(PR) positive is defined as the percentage of cells positive for ER or PR expression ≥ 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]
	At least one extracranial measurable lesion according to Response Evaluation Criteria
	in Solid Tumors (RECIST) criteria version 1.1
	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
	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
	Adequate function of major organs meets the following requirements (no blood components and cell growth factors have been used within 14 days before randomization)
	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
	Eastern Cooperative Oncology Group Performance Status of 0-1
	Life expectancy ≥ 12 weeks
	Neutrophils ≥ 1.5×10^9/L
	Platelets ≥ 90×10^9/L
	Hemoglobin ≥ 90g/L
	Total bilirubin≤ 1.5 × the upper limit of normal (ULN)
	ALT and AST ≤ 2.5 × ULN
	BUN and Cr ≤ 1.5 × ULN
	Left ventricular ejection fraction (LVEF) ≥ 50%
	QTcF(Fridericia correction) ≤ 470 ms
	International normalized ratio(INR)≤1.5 × ULN，activated partial thromboplastin time(APTT) ≤ 1.5 × ULN
Exclusion Criteria
	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
	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
	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
	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.)
	History of neurological or psychiatric disorders, including epilepsy or dementia
	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
	Severe infections within 4 weeks prior to first dose (eg, intravenous infusion of antibiotics, antifungal or antiviral drugs according to clinical protocols), or unexplained fever (T > 38.3 °C ) during screening or prior to first administration

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