Study to Evaluate Efficacy & Safety of Afuresertib Plus Fulvestrant in Patients With Locally Advanced or Metastatic HR+/HER2- Breast Cancer

NCT04851613 | Active Not Recruiting Phase 3 FDA Drug

• 1 other identifier: LAE205INT3101
• Study Type: interventional
• Target: 256
• Locations: 2 countries
• Sites: 55

Brief Summary

Study LAE205INT3101 is a Phase Ib/III study to evaluate the efficacy and safety of the combination therapy with afuresertib plus fulvestrant (afuresertib/placebo plus fulvestrant in Phase III) in patients with HR+/HER2- breast cancer who have failed 1 to 2 prior lines of endocrine therapy, and/or CDK4/6 inhibitor (up to 1 therapy), and/or chemotherapy (up to 1 chemotherapy) as described in the inclusion criteria.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Phase I: Overall Response Rate (ORR) based on RECIST 1.1

  Phase I: Anti-tumor activity of the combination therapy with afuresertib plus fulvestrant in patients with HR+/HER2- BC

  Phase I: Change from Baseline beginning at Cycle 3 Day 1 and then every 8 weeks × 40 weeks then every 3 months through study completion, an average of 1 year (each cycle is 28 days)

• Phase III: Progression Free Survival (PFS) based on RECIST 1.1, as assessed by investigators

  Phase III:To assess the anti-tumor activity of the combination therapy with afuresertib plus fulvestrant versus placebo plus fulvestrant in patients with PIK3CA/AKT1/PTEN alterations HR+/HER2- BC who have failed 1 to 2 prior lines of ET with/without a Phase III: CDK4/6 inhibitor (up to 1 therapy), or chemotherapy (up to 1 chemotherapy)

  Phase III:Change from Baseline beginning at Cycle 3 Day 1 and then every 8 weeks for the first 12 months, then every 3 months through study completion

Secondary Outcomes (11)

• Phase I: Duration of Response (DOR) based on RECIST 1.1

  Phase I: Change from Baseline beginning at Cycle 3 Day 1 and then every 8 weeks x 40 weeks then every 3 months through study completion, an average of 1 year (each cycle is 28 days)

• Phase I: Clinical rate of benefit (CBR) based on RECIST 1.1

  Phase I: Change from Baseline beginning at Cycle 3 Day 1 and then every 8 weeks x 40 weeks then every 3 months through study completion, an average of 1 year (each cycle is 28 days)

• Phase I: Best Overall Response (BOR) based on RECIST 1.1

  Phase I: Change from Baseline beginning at Cycle 3 Day 1 and then every 8 weeks x 40 weeks then every 3 months through study completion, an average of 1 year (each cycle is 28 days)

• Phase I: Progression Free Survival (PFS) based on RECIST 1.1

  Phase I: After Cycle 3 Day 1 and then every 8 weeks x 40 weeks then every 3 months through study completion, an average of 1 year (each cycle is 28 days)

• Phase I: Pharmacokinetics- Time to Maximum Concentration (T-Max)

  Phase I: Assessed on Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)

Study Arms (4)

Phase I: Afuresertib and Fulvestrant Safety Run In

EXPERIMENTAL

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.

Drug: Afuresertib

Phase I: Afuresertib and Fulvestrant

EXPERIMENTAL

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.

Drug: Afuresertib

Phase III: afuresertib combined with fulvestrant (experimental arm)

EXPERIMENTAL

Phase III: afuresertib 125mg QD combined with fulvestrant 500mg Q4W (D1, 15 in cycle 1)

Drug: Afuresertib

Phase III: placebo combined with fulvestrant (control arm)

PLACEBO COMPARATOR

PhaseIII：placebo combined with fulvestrant 500mg Q4W (D1, 15 in cycle 1)

Drug: Afuresertib/placebo

Interventions

Afuresertib DRUG

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

Also known as: Fulvestrant

Phase I: Afuresertib and Fulvestrant; Phase I: Afuresertib and Fulvestrant Safety Run In; Phase III: afuresertib combined with fulvestrant (experimental arm)

Afuresertib/placebo DRUG

afuresertib/placebo 125mg QD combined with fulvestrant 500mg Q4W (D1, 15 in cycle 1)

Also known as: Fulvestrant

Phase III: placebo combined with fulvestrant (control arm)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female or male patients must be ≥ 18 years of age on the day of signing the informed consent and be able to provide written informed consent for the study.
• 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.
• 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.
• Before enrollment, patients who have undergone anti-cancer treatment must have a washout period of 4 weeks or 5 half-lives, whichever comes earlier.
• HR+/HER2- BC patients must meet all the following criteria to join this study:
• Relapsed locally advanced (LABC) or metastatic (mBC) disease; AND
• 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 .
• 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).
• 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.
• 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.
• Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1.
• Patients who have adequate organ function as defined.
• 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.
• Patients with a life expectancy of 24 weeks or more based on investigator's assessment.

You may not qualify if:

• Patients who had a recent major surgery that required hospitalization for longer than 48 hours (\< 8 weeks from scheduled treatment starting date) or have used IV antibiotics for the treatment of systemic infection (\< 2 weeks from scheduled treatment starting date).
• 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).
• 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.
• 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.
• 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.
• 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.
• 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) .
• 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.
• Patients with active Hepatitis B infection \[defined as HBsAg (+) and HBV-DNA ≥ 200 IU/ml (1000 copy/ml)\] or active Hepatitis C virus \[defined as HCV antibody positive and HCV RNA (qualitative) test positive\].
• Patients with known HIV seropositivity who has 1 of the following:
• Not receiving highly active antiretroviral therapy
• Receiving antiretroviral therapy that may interfere with the study drug (consult the Sponsor/Medical Monitor for review of medication prior to enrollment)
• CD4 count \< 350 based on a test within 3 months of the screening visit
• An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months (26 weeks) of the start of study screening
• 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.

Sponsors & Collaborators

• Laekna Limited: lead

Study Sites (55)

Providence St. Johns Health Center

Santa Monica, California, 90404, United States

Location

Piedmont Cancer Institute

Atlanta, Georgia, 30318, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

University of Vermont

Burlington, Vermont, 05401, United States

Location

Virginia Cancer Specialists

Fairfax, Virginia, 22031, United States

Location

The First Affiliated Hospital of Bengbu Medical College

Bengbu, Anhui, 233004, China

Location

Anhui Provincial Cancer Hospital

Hefei, Anhui, 230031, China

Location

Cancer Hospital Chinese Academy of Medical Sciences

Beijing, Beijing Municipality, 100021, China

Location

Beijing Cancer Hospital

Beijing, Beijing Municipality, 100142, China

Location

Peking Union Medical College Hospital (PUMCH)

Beijing, Beijing Municipality, 100730, China

Location

The First Affiliated Hospital of Chongqing Medical University

Chongqing, Chongqing Municipality, 400016, China

Location

Chongqing University Cancer Hospital

Chongqing, Chongqing Municipality, 400030, China

Location

Fujian Cancer Hospital

Fuzhou, Fujian, 350014, China

Location

The First People's Hospital of Foshan

Foshan, Guangdong, 528000, China

Location

Sun Yat-sen Memorial Hospital，Sun Yat-sen University

Guangzhou, Guangdong, 510000, China

Location

Sun Yat-sen University Cancer Center

Guangzhou, Guangdong, 510050, China

Location

Zhongshan People's Hospital

Zhongshan, Guangdong, 528403, China

Location

Guangxi Zhuang Autonomous Region People's Hospital

Nanning, Guangxi, 530021, China

Location

The First Affiliated Hospital of Guangxi Medical University

Nanning, Guangxi, 530021, China

Location

Affiliated Hospital of Hebei University

Baoding, Hebei, 071000, China

Location

The Fourth Hospital of Hebei Medical University

Shijiazhuang, Hebei, 050011, China

Location

Tangshan People's Hospital

Tangshan, Hebei, 063000, China

Location

Harbin Medical University Cancer Hospital

Harbin, Heilongjiang, 150081, China

Location

Anyang cancer hospital

Anyang, Henan, 455000, China

Location

Henan Cancer Hospital

Zhengzhou, Henan, 450008, China

Location

The First Affiliated Hospital of Zhengzhou University

Zhengzhou, Henan, 450052, China

Location

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Wuhan, Hubei, 430022, China

Location

Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology

Wuhan, Hubei, 430022, China

Location

Wuhan Central Hospital

Wuhan, Hubei, 430022, China

Location

Hubei Cancer Hospital

Wuhan, Hubei, 430079, China

Location

Hunan Cancer Hospital

Changsha, Hunan, 410013, China

Location

Jiangsu Cancer Hospital

Nanjing, Jiangsu, 210009, China

Location

Jiangsu Provincial People's Hospital

Nanjing, Jiangsu, 210029, China

Location

Affiliated Hospital of Nantong University

Nantong, Jiangsu, China

Location

The First Affiliated Hospital of Soochow University

Suzhou, Jiangsu, 215006, China

Location

Northern Jiangsu People's Hospital

Yangzhou, Jiangsu, 225001, China

Location

The first hospital of Jilin University

Changchun, Jilin, 130000, China

Location

Jilin Provincial Cancer Hospital

Changchun, Jilin, 130012, China

Location

Liaoning Cancer Hospital

Shenyang, Liaoning, 110000, China

Location

The First Hospital of China Medical University

Shenyang, Liaoning, 110001, China

Location

Shengjing Hospital of China Medical University

Shenyang, Liaoning, 110004, China

Location

Shandong Cancer Hospital

Jinan, Shandong, 250117, China

Location

Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Shanghai, Shanghai Municipality, 200020, China

Location

Zhongshan Hospital, Fudan University

Shanghai, Shanghai Municipality, 200032, China

Location

The First Affiliated Hospital of Xi'an Jiaotong University

Xi’an, Shanxi, 710061, China

Location

Sichuan Cancer Hospital

Chengdu, Sichuan, 610041, China

Location

West China Hospital, Sichuan University

Chengdu, Sichuan, 610041, China

Location

Sichuan Provincial People's Hospital

Chengdu, Sichuan, 610072, China

Location

Tianjin Medical University Cancer Institute & Hospital

Tianjin, Tianjin Municipality, 300060, China

Location

The First Affiliated Hospital of Zhejiang University School of Medicine

Hangzhou, Zhejiang, 310003, China

Location

Sir-run shaw Hospital Zhejiang University of Medicine

Hangzhou, Zhejiang, 310016, China

Location

Zhejiang Cancer Hospital

Hangzhou, Zhejiang, 310022, China

Location

Ningbo Li Huili Hospital

Ningbo, Zhejiang, 315040, China

Location

Taizhou Hospital

Taizhou, Zhejiang, 317000, China

Location

Related Publications (1)

• Zhang P, Sun T, Wang Y, Li W, Tong Z, Phadke S, Feinstein T, Ma W, Guo P, Zhang M, Yue Y, Xu B. Afuresertib plus fulvestrant for pretreated HR-positive, HER2-negative, advanced breast cancer: a phase Ib trial. Nat Commun. 2026 Feb 6. doi: 10.1038/s41467-026-69225-2. Online ahead of print.

  PMID: 41651834 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

afuresertib; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Wenyue Ma

  Laekna Limited

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Phase I: Single-arm, open-label study to evaluate efficacy, safety, tolerability, PK of the therapy with afuresertib plus fulvestrant. Phase III: A multi-center, randomized, double-blind, placebo-controlled study to assess efficacy and safety of afuresertib/placebo plus fulvestrant in patients with HR+/HER2- locally advanced or metastatic BC who have failed 1 to 2 prior lines of ET with/without a CDK4/6 inhibitor (up to 1 therapy), or chemotherapy (up to 1 chemotherapy).

Study Record Dates

• First Submitted: April 13, 2021
• First Posted: April 20, 2021
• Study Start: February 18, 2022
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): December 30, 2026
• Last Updated: April 2, 2026

Record last verified: 2026-03

Locations

CN (49); US (6)