Study to Evaluate Efficacy & Safety of Afuresertib Plus Fulvestrant in Patients With Locally Advanced or Metastatic HR+/HER2- Breast Cancer
NCT ID: NCT04851613
Last Updated: 2025-09-16
Study Results
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Basic Information
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RECRUITING
PHASE3
256 participants
INTERVENTIONAL
2022-02-18
2026-12-30
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Phase I: Afuresertib and Fulvestrant Safety Run In
Phase I: Safety run-in Cycle 1 (a cycle is 28 days) will be performed in the first 6 patients of the phase Ib. Combination regimens during the safety run-in period are: afuresertib 125 mg QD (once daily) + fulvestrant 500 mg Intra Muscular (IM) on Day 1, 15 of Cycle 1, and on Day 1 of the subsequent 28-day cycles.
Afuresertib
The starting doses of the combination therapy are afuresertib 125 mg PO, QD plus fulvestrant 500 mg IM, D1, 15 in the first cycle and afuresertib 125 mg PO, QD plus fulvestrant 500 mg IM, D1 Q4W in the subsequent cycles
Phase I: Afuresertib and Fulvestrant
Phase I: Combination regimens are: afuresertib 125 mg QD (once daily) + fulvestrant 500 mg Intra Muscular (IM) on Day 1, 15 of Cycle 1, and on Day 1 of the subsequent 28-day cycles.
Afuresertib
The starting doses of the combination therapy are afuresertib 125 mg PO, QD plus fulvestrant 500 mg IM, D1, 15 in the first cycle and afuresertib 125 mg PO, QD plus fulvestrant 500 mg IM, D1 Q4W in the subsequent cycles
Phase III: afuresertib combined with fulvestrant (experimental arm)
Phase III: afuresertib 125mg QD combined with fulvestrant 500mg Q4W (D1, 15 in cycle 1)
Afuresertib
The starting doses of the combination therapy are afuresertib 125 mg PO, QD plus fulvestrant 500 mg IM, D1, 15 in the first cycle and afuresertib 125 mg PO, QD plus fulvestrant 500 mg IM, D1 Q4W in the subsequent cycles
Phase III: placebo combined with fulvestrant (control arm)
PhaseIII：placebo combined with fulvestrant 500mg Q4W (D1, 15 in cycle 1)
Afuresertib/placebo
afuresertib/placebo 125mg QD combined with fulvestrant 500mg Q4W (D1, 15 in cycle 1)
Interventions
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Afuresertib
The starting doses of the combination therapy are afuresertib 125 mg PO, QD plus fulvestrant 500 mg IM, D1, 15 in the first cycle and afuresertib 125 mg PO, QD plus fulvestrant 500 mg IM, D1 Q4W in the subsequent cycles
Afuresertib/placebo
afuresertib/placebo 125mg QD combined with fulvestrant 500mg Q4W (D1, 15 in cycle 1)
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Patients with histologically or cytologically confirmed HR+/HER2- Breast Cancer characterized by the absence of HER2 expression and the presence of ER with/without PR expression.
3. Female patients may be post-menopausal, pre-menopausal or peri-menopausal. Male and Pre- and peri-menopausal females may be enrolled if continuously treated with ovarian suppression therapy (use LHRHa at least starting from C1D1) for the duration of study participation.
4. Before enrollment, patients who have undergone anti-cancer treatment must have a washout period of 4 weeks or 5 half-lives, whichever comes earlier.
5. HR+/HER2- BC patients must meet all the following criteria to join this study:
1. Relapsed locally advanced (LABC) or metastatic (mBC) disease; AND
2. Have received 1 to 2 prior lines of systemic treatments for LABC or mBC(at least one line was ET). If disease relapse during adjuvant therapy or relapse within 12 months from completion of adjuvant endocrine therapy, the adjuvant therapy will be counted as 1 line), including:
i. Endocrine therapies including AIs and/or SERMs (1 or 2 lines) with or without a CDK4/6 inhibitor (up to 1 therapy); OR ii. A chemotherapy (monotherapy or combination therapy, at most 1 line only), with 1 additional line of endocrine therapy .
6. For phase Ib part, patients must have at least one lesion that meets the definition of measurable disease by RECIST 1.1 criteria; for phase III, have measurable disease and/or at least 1 lytic or mixed (lytic + sclerotic) bone lesion that can be assessed by RECIST 1.1 criteria; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible (Appendix 2).
7. In the Phase Ib part, Patients must provide informed consent for the procedures and the tests for PIK3CA/AKT/PTEN alterations and ESR1 mutations. The biomarkers will be tested retrospectively by gene sequencing tests using archival tumor sample (preferably within 18 months/78 weeks) or from peripheral blood or from a tumor biopsy sample. Formalin-fixed, paraffin embedded (FFPE) tissue blocksare preferred. In phase III, blood sample is mandatory for this test.
8. In Phase III, subjects need to provide blood sample during the screening period for PIK3CA/AKT1/PTEN test, which will be conducted in the central laboratory. Only patients with PIK3CA/AKT1/PTEN alterations could include.
9. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1.
10. Patients who have adequate organ function as defined.
11. Patients without a pre-existing diagnosis of diabetes mellitus (DM) who have a fasting glucose ≤ 126 mg/dL (or ≤ 7.0 mmol/L); or patients with type 2 diabetes who have a fasting glucose ≤ 167 mg/dL (or ≤ 9.3 mmol/L) AND glycosylated hemoglobin (HbA1c) ≤ 8%. Patients with DM type 1 or patients with DM type 2 requiring insulin or ≥21 anti-abetic medications for glycemic control are excluded.
12. Patients with a life expectancy of 24 weeks or more based on investigator's assessment.
13. Patients who have recovered from adverse events associated with pre-study medical, radiation and surgical treatments to ≤ Grade 1, excluding stable symptoms (e.g., alopecia, peripheral sensory neuropathy, skin hyperpigmentation, dysgeusia, etc.).
14. Female patients of childbearing potential must have a negative pretreatment serum pregnancy test.
15. Female patients of childbearing potential must agree to use effective contraception from enrollment to 1 year after discontinuation from the last dose of this study treatment.
16. Patients who are able to swallow and retain oral medication and without gastrointestinal diseases to interfere with drug absorption.
17. Patients must have no contraindications to fulvestrant.
Exclusion Criteria
2. Patients who have additional known malignancies that are progressing or have required active treatments within 3 years of scheduled treatment starting date. (Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, that have undergone potentially curative therapy are not excluded).
3. Patients who have a history of seizure or conditions that may predispose them to seizure and require anti-epileptic medications, or patients who have brain arteriovenous malformation, or intracranial masses that are causing edema or clinical symptoms.
4. Patients who have known active CNS metastases and/or carcinomatous meningitis. (Note: Patients with previously treated brain metastases may participate provided that they are radiologically stable (i.e., without evidence of progression for at least 4 weeks by repeated imaging performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to schedule treatment starting date.
5. Patients who had prior treatment with fulvestrant or other selective estrogen receptor degraders (SERDs), or any PI3K/AKT/mTOR inhibitors, or any CDK4/6 inhibitors in phase I, II study.
6. Patients who had the following conditions within 6 months (26 weeks) of scheduled treatment starting date: New York Heart Association congestive heart failure classification III to IV, unstable angina, myocardial infarction, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or serious cardiac arrhythmia associated with significant cardiovascular impairment as determined by the investigator.
7. Patients with QT interval corrected by the Frederica's correction formula (QTcF) \> 470 msec(average value), unless the prolonged QT interval is due to (right or left) bundle branch block and/or pacemaker rhythm. If wide QRS complex is present, cardiology consultation is required to assess the risk for Torsade de Pointes. Note: QTcF = QT/(RR\^0.33) .
8. Patients who have uncontrolled hypertension (systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg under anti-hypertensive treatment). Note: Patients with a history of hypertension are allowed, provided that blood pressure is controlled to within these limits by anti-hypertensive treatment.
9. Patients with active Hepatitis B infection \[defined as HBsAg (+) and HBV-DNA ≥ 200 IU/ml (1000 copy/ml)\] or active Hepatitis C virus \[defined as HCV antibody positive and HCV RNA (qualitative) test positive\].
10. Patients with known HIV seropositivity who has 1 of the following:
1. Not receiving highly active antiretroviral therapy
2. Receiving antiretroviral therapy that may interfere with the study drug (consult the Sponsor/Medical Monitor for review of medication prior to enrollment)
3. CD4 count \< 350 based on a test within 3 months of the screening visit
4. An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months (26 weeks) of the start of study screening
11. Patients who have a history or current evidence of any condition, therapy, or laboratory abnormality that in the opinion of the investigator, might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate.
12. Patients who have a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
13. Patients who are receiving medications that are sensitive substrates of CYP3A4, OATP1B1, or BCRP with low therapeutic index. Please see related section for a list of these prohibited medications.
14. Patients who are currently pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 1 year after the last dose of study treatment.
15. Patients who have known cirrhosis with a Child-Pugh status of B and C.
16. Patients who are ineligible for endocrine therapy (e.g., visceral crisis, inflammatory breast cancer, uncontrolled pleural or abdominal fluid drainage ≥4 times within one month before planned administration).
18 Years
ALL
No
Sponsors
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Laekna Limited
INDUSTRY
Responsible Party
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Principal Investigators
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Wenyue Ma
Role: STUDY_DIRECTOR
Laekna Limited
Locations
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Providence St. Johns Health Center
Santa Monica, California, United States
Piedmont Cancer Institute
Atlanta, Georgia, United States
University of Iowa
Iowa City, Iowa, United States
University of Mississippi Medical Center
Jackson, Mississippi, United States
University of Vermont
Burlington, Vermont, United States
Virginia Cancer Specialists
Fairfax, Virginia, United States
The First Affiliated Hospital of Bengbu Medical College
Bengbu, Anhui, China
Anhui Provincial Cancer Hospital
Hefei, Anhui, China
Cancer Hospital Chinese Academy of Medical Sciences
Beijing, Beijing Municipality, China
Beijing Cancer Hospital
Beijing, Beijing Municipality, China
Peking Union Medical College Hospital (PUMCH)
Beijing, Beijing Municipality, China
The First Affiliated Hospital of Chongqing Medical University
Chongqing, Chongqing Municipality, China
Chongqing University Cancer Hospital
Chongqing, Chongqing Municipality, China
Fujian Cancer Hospital
Fuzhou, Fujian, China
The First People's Hospital of Foshan
Foshan, Guangdong, China
Sun Yat-sen Memorial Hospital，Sun Yat-sen University
Guangzhou, Guangdong, China
Sun Yat-sen University Cancer Center
Guangzhou, Guangdong, China
Zhongshan People's Hospital
Zhongshan, Guangdong, China
Guangxi Zhuang Autonomous Region People's Hospital
Nanning, Guangxi, China
The First Affiliated Hospital of Guangxi Medical University
Nanning, Guangxi, China
Affiliated Hospital of Hebei University
Baoding, Hebei, China
The Fourth Hospital of Hebei Medical University
Shijiazhuang, Hebei, China
Tangshan People's Hospital
Tangshan, Hebei, China
Harbin Medical University Cancer Hospital
Harbin, Heilongjiang, China
Anyang cancer hospital
Anyang, Henan, China
Henan Cancer Hospital
Zhengzhou, Henan, China
The First Affiliated Hospital of Zhengzhou University
Zhengzhou, Henan, China
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China
Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China
Wuhan Central Hospital
Wuhan, Hubei, China
Hubei Cancer Hospital
Wuhan, Hubei, China
Hunan Cancer Hospital
Changsha, Hunan, China
Jiangsu Cancer Hospital
Nanjing, Jiangsu, China
Jiangsu Provincial People's Hospital
Nanjing, Jiangsu, China
Affiliated Hospital of Nantong University
Nantong, Jiangsu, China
The First Affiliated Hospital of Soochow University
Suzhou, Jiangsu, China
Northern Jiangsu People's Hospital
Yangzhou, Jiangsu, China
The first hospital of Jilin University
Changchun, Jilin, China
Jilin Provincial Cancer Hospital
Changchun, Jilin, China
Liaoning Cancer Hospital
Shenyang, Liaoning, China
The First Hospital of China Medical University
Shenyang, Liaoning, China
Shengjing Hospital of China Medical University
Shenyang, Liaoning, China
Shandong Cancer Hospital
Jinan, Shandong, China
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Shanghai, Shanghai Municipality, China
Zhongshan Hospital, Fudan University
Shanghai, Shanghai Municipality, China
The First Affiliated Hospital of Xi'an Jiaotong University
Xi’an, Shanxi, China
Sichuan Cancer Hospital
Chengdu, Sichuan, China
West China Hospital, Sichuan University
Chengdu, Sichuan, China
Sichuan Provincial People's Hospital
Chengdu, Sichuan, China
Tianjin Medical University Cancer Institute & Hospital
Tianjin, Tianjin Municipality, China
The First Affiliated Hospital of Zhejiang University School of Medicine
Hangzhou, Zhejiang, China
Sir-run shaw Hospital Zhejiang University of Medicine
Hangzhou, Zhejiang, China
Zhejiang Cancer Hospital
Hangzhou, Zhejiang, China
Ningbo Li Huili Hospital
Ningbo, Zhejiang, China
Taizhou Hospital
Taizhou, Zhejiang, China
Countries
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Central Contacts
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Facility Contacts
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Alexander Spira, MD
Role: primary
Other Identifiers
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LAE205INT3101
Identifier Type: -
Identifier Source: org_study_id
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