This is a single-center Ib / II study of triple targeted drug combination (aromatase
inhibitor letrozole，novel HER2-targeted small molecule inhibitor pyrotinib and CDK4/6
inhibitor SHR6390) as a first or second line of therapy in patients with relapsed/metastatic
hormone receptor positive and HER2-positive breast cancer.
This is a single-center, single arm, open-label, run-in phase Ib / roll-over phase II study
of letrozole in combination with novel HER2-targeted tyrosine kinase Inhibitor pyrotinib and
CDK4/6 Inhibitor SHR6390 in subjects with 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 letrozole, pyrotinib and SHR6390 to define that appropriate dose of SHR6390
for phase II.The dose of letrozole and pyrotinib will be constant through the study period.
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
1. Subjects voluntarily joined the study, signed informed consent, and had good
2. Female patients aged 18-75 years (including cutoff value).
3. Patients with HR+/HER2+ recurrent or metastatic breast cancer confirmed by
histopathology in Department of Pathology, Fudan University Cancer Center
1. HER2 positivity is defined by standard of 3+ staining by immunohistochemical
staining (IHC) or positive for in situ hybridization (ISH)
2. ER or PR positive is defined as the percentage of cells positive for ER or PR
expression ≥ 1%
3. Local recurrence needs to be confirmed by the physician that is unresectable
4. At least one extracranial measurable lesion according to Response Evaluation Criteria
in Solid Tumors (RECIST) criteria version 1.1.
5. Natural postmenopausal women, or women who have undergone bilateral oophorectomy.
6. Prior treatment:
1. Previously received no more than 1prior lines of systemic chemotherapy for
metastatic breast cancer
2. No more than 1prior lines of anti-HER2 treatment (alone or in combination with
chemotherapy or endocrine therapy) in the advanced stage
3. No more than 1prior lines of endocrine therapy in the late stage, except for
those with primary or acquired resistance to letrozole or anastrozole
7. Eastern Cooperative Oncology Group Performance Status of 0-2.
8. Life expectancy ≥ 12 weeks.
9. Adequate function of major organs meets the following requirements (no blood
components and cell growth factors have been used within 14 days before
1. Neutrophils ≥ 1.5×10^9/L
2. Platelets ≥ 90×10^9/L
3. Hemoglobin ≥ 90g/L
4. Total bilirubin≤ 1.5 × the upper limit of normal (ULN)
5. ALT and AST ≤ 2.5 × ULN
6. BUN and Cr ≤ 1.5 × ULN
7. Left ventricular ejection fraction (LVEF) ≥ 50%
8. QTcF(Fridericia correction) ≤ 470 ms
9. INR ≤ 1.5 × ULN，APTT≤ 1.5 × ULN
1. The subject has untreated central nervous system (CNS) metastases.
2. Patients who have undergone systemic, radical brain or meningeal metastasis
(radiotherapy or surgery), but have been confirmed to have been stable for at least 4
weeks, and who have stopped systemic hormonal therapy for more than 2 weeks without
clinical symptoms can be included.
3. Previously received any CDK4/6 inhibitor treatment.
4. 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.
5. Inability to swallow, intestinal obstruction or other factors affecting the
administration and absorption of the drug.
6. 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.
7. 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).
8. Have undergone major surgical procedures or significant trauma within 4 weeks prior to
randomization, or are expected to undergo major surgery.
9. Pregnant women, lactating female, or women of childbearing age who are unwilling to
take effective contraceptive measures.
10. Have a history of allergies to the drug components of this regimen.
11. 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
12. History of immunodeficiency, including HIV positive, or other acquired or congenital
immunodeficiency disease, history of organ transplantation.
13. 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
14. Female patients who are pregnancy, lactation or women who are of childbearing
potential tested positive in baseline pregnancy test.
15. Childbearing female who refuse to accept any contraception practice.
16. 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.).
17. History of neurological or psychiatric disorders, including epilepsy or dementia.
18. 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.