Neoadjuvant Dalpiciclib Plus Letrozole for HR+/HER2- Breast Cancer

Study Overview
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Brief Summary
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In this single arm, open label, phase 2 trial, operable patients with stage IIB-III HR+/HER2- breast cancer will be enrolled and receive six cycles of adjuvant dalpiciclib plus letrozole. This study aims to assessed the biological effects and safety of dalpiciclib in combination with letrozole for HR+/HER2- breast cancer in the neoadjuvant setting.

Detailed Description
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This is a single arm, open label, phase 2 trial aimed to investigate the biological effects and safety of neoadjuvant dalpiciclib in combination with letrozole for HR+/HER2- breast cancer. A total of 35 patients with stage IIB-III HR+/HER2- breast cancer will be enrolled. Six 4-week cycles of adjuvant therapy will be administrated. In each cycle, patients use dalpiciclib orally, 150mg, day 1-21, and letrozole orally, 2.5 mg, day 1-28. Premenopausal or perimenopausal patients should combine ovarian function suppression, including bilateral oophorectomy or treatment with gonadotropin-releasing hormone agonists. The primary endpoint is complete cell-cycle arrest at C1D15, defined as ki67≤2.7%. The secondary endpoints include residual cancer burden, overall response rate, change in Ki67 from baseline to 2 weeks of treatment, preoperative endocrine prognostic index, pathologic complete response, breast-conserving surgery rate and safety profile.

Official Title
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Neoadjuvant Dalpiciclib Plus Letrozole for HR+/HER2- Breast Cancer: A Single Arm, Open Label, Phase II Trial

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: dalpiciclib plus letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria： Postmenopausal, premenopausal or perimenopausal women aged ≥18. Postmenopausal was defined as: 1) received bilateral oophorectomy, or aged ≥60; 2) aged <60, reached natural menopause (defined as no menses for 12 or more consecutive months with no other reason for the amenorrhea), and with postmenopausal E2 and FSH level; 3) premenopausal or perimenopausal women may also be enrolled as long as they are willing to receive LHRH agonist therapy during the study； Operable patients with ER+ (>10%), HER2- invasive breast carcinomas, regardless of PR level. HER2- was defined as IHC score of 0+, or IHC score of 2+ with negative ISH (amplification ratio <2.0) according to 2018 ASCO-CAP guideline； Untreated patients with stage IIB-III according to AJCC criteria (8th edition)； Without known hypersensitivity to the study drug or its excipients； A ECOG PS score of 0-1； With the ability to swallow the study drug； With sufficient organ function, including 1) bone marrow function: ANC ≥ 1.5 x 109/L (without growth factors within 14 days); PLT ≥ 100 x 109/L (without corrective therapy within 7 days); Hb ≥ 100 g/L (without corrective therapy within 7 days); 2）liver and kidney function: TBIL ≤ ULN; ALT and AST ≤ 3 × ULN (ALT and AST ≤ 5 × ULN for those with liver metastases); BUN and Cr ≤ 1.5×ULN, and creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula); 3) QT interval ≤ 480 ms from the 12-lead electrocardiogram； Able to undergo all puncture biopsies required by the protocol； Volunteered to participate in this study; signed informed consent; with good compliance and willingness to follow-up； Exclusion Criteria： Previously treated patients, including chemotherapy, radiotherapy, targeted therapy or endocrine therapy, etc.； Concurrently receiving any anti-tumor treatments other than that prescribed by the protocol； Patients with bilateral breast cancer, inflammatory breast cancer or occult breast cancer； Patients with stage IV breast cancer； Patients with severe liver, kidney, or heart dysfunction； Inability to swallow, with chronic diarrhea, with intestinal obstruction, or with other factors affecting drug administration and absorption； Participated in other clinical trials within 4 weeks before enrollment； Known hypersensitivity to the study drug or its excipients; history of ；immunodeficiency, including HIV positive, HCV positive, active viral hepatitis B, other acquired or congenital immunodeficiency diseases, or a history of organ transplantation； History of any cardiac disease, including: 1) arrhythmias requiring drug treatment or of clinical significance; 2) myocardial infarction; 3) heart failure; 4) any other cardiac disease to be inappropriate for this trial judged by the investigator； Women who are pregnant or breastfeeding, women of childbearing potential who test positive for pregnancy test at baseline, or women of childbearing potential who are unwilling to use effective contraception during the study； With serious concomitant disease that endanger safety, or interferes with the ability to complete the study judged by the investigator (including, but not limited to, uncontrolled hypertension, severe diabetes, active infection, etc.)； History of neurological or psychiatric disorders, including epilepsy or dementia; or any other condition inappropriate for this study deemed by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cohort 1<br>patients with stage IIB-III HR+/HER2- breast cancer | Drug: dalpiciclib plus letrozole<br>* Six 4-week cycles of dalpiciclib orally, 150mg, day 1-21, and letrozole orally, 2.5 mg, day 1-28<br>* Other names: D+L;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete cell-cycle arrest at C1D15, defined as ki67≤2.7% | From the date into this study(signed ICF) to C1D15,defined as ki67≤2.7% | up 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| residual cancer burden | The percentage of residual tumors after neoadjuvant therapy is assessed according to breast tumor bed tumors and regional lymph nodes | up 2 years | 
| objective response rate | The rate of CR and PR,determined using RECIST v1.1 criteria | up 2 years | 
| change in Ki67 from baseline to 2 weeks of treatment | change in Ki67 from baseline（From the date into this study(signed ICF) ） to 2 weeks of treatment | up 2 years | 
| preoperative endocrine prognostic index | Prognostic indicators of preoperative endocrine therapy, including mass size after neoadjuvant endocrine therapy, lymph node status, ki67 levels, and estrogen receptor (ER) status | up 2 years | 
| pathologic complete response | After neoadjuvant therapy, there are no residual invasive tumors in the primary focus and regional lymph nodes of breast cancer, but ductal carcinoma in situ may be present(ypT0/is ypN0) | up 2 years | 
| breast-conserving surgery rate | The number of cases that actually underwent breast-conserving surgery after surgery accounted for the percentage of all breast cancer patients who underwent surgery | up 2 years | 
| safety profile | Adverse events (AE) and severe adverse events (SAEs) are recorded. Refer to NCI-CTC AE 5.0 standard | up 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, CDK4/6 inhibitor, endocrine therapy, hormone receptor-positive, dalpiciclib, letrozole