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Letrozole, Pyrotinib Combined With SHR6390 in Patients With HR+/HER2+ Relapsed/Metastatic Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03772353
Recruitment Status : Recruiting
First Posted : December 11, 2018
Last Update Posted : December 10, 2019
Jiangsu HengRui Medicine Co., Ltd.
Information provided by (Responsible Party):
Xichun Hu, Fudan University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Letrozole Drug: Pyrotinib Drug: SHR6390 Phase 1 Phase 2

Detailed Description:
This is a single-center, single arm, open-label, run-in phase Ib / roll-over phase II study of letrozole 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 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 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 combination treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib/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/Metastatic Breast Cancer
Actual Study Start Date : May 12, 2019
Estimated Primary Completion Date : June 12, 2020
Estimated Study Completion Date : November 12, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Letrozole

Arm Intervention/treatment
Experimental: Letrozole Combined with Pyrotinib and SHR6390
During phase 1b part of this trial, treatment will be administered in cycles of 28 days and consist of letrozole 2.5 mg and pyrotinib 400 mg orally once daily in combination with SHR6390 (at protocol defined dose levels) po daily for 21 days followed by 7 days off. Once the recommended phase II dose (RP2D) has been determined, testing of this drug combination will be expanded in the phase II part to determine the progression-free survival (PFS) rate.
Drug: Letrozole
Letrozole, 2.5mg, PO daily (continuously)

Drug: Pyrotinib
Pyrotinib, 400mg, PO daily (continuously)

Drug: SHR6390
SHR6390 either 100mg,125mg, 150 mg PO daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment

Primary Outcome Measures :
  1. The number of patients in the Phase 1b part of the study with any adverse events (AE). [ Time Frame: 2 years ]
    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. The number of patients with progression-free survival (PFS) [ Time Frame: 2 years ]
    To measure efficacy of SHR6390 used in combination with letrozole and pyrotinib PFS (phase II part) will be assessed. PFS is defined as the time from allocation to the first documented disease progression according to RECIST 1.1, or death due to any cause, whichever occurs first.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Subjects voluntarily joined the study, signed informed consent, and had good compliance.
  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

    • 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
  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:

    • Previously received no more than 1prior lines of systemic chemotherapy for metastatic breast cancer
    • No more than 1prior lines of anti-HER2 treatment (alone or in combination with chemotherapy or endocrine therapy) in the advanced stage
    • 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 randomization):

    • 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:

  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 method).
  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 in screening.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03772353

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Contact: Xichun Hu, MD, PhD 64175590 ext 5006

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Fudan University Shanghai Cancer Center Recruiting
Shanghai, China, 200032
Contact: Xichun Hu, M.D., Ph.D.    64175590 ext 5006   
Sponsors and Collaborators
Fudan University
Jiangsu HengRui Medicine Co., Ltd.
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Responsible Party: Xichun Hu, Professor, Fudan University Identifier: NCT03772353    
Other Study ID Numbers: LORDSHIPS
First Posted: December 11, 2018    Key Record Dates
Last Update Posted: December 10, 2019
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs