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

Breast Cancer Clinical Trial

Official title:

A Phase Ib/III Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients With Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04851613
• Other study ID #: LAE205INT3101
• Status: Recruiting
• Phase: Phase 3
• Start date: February 18, 2022
• Est. completion date: December 30, 2026

Study information

• Verified date: June 2024
• Source: Laekna Limited
• Contact: Shimei Liu
• Phone: 7037281500
• Email: shimei.liu[@]laekna.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Eligible patients for this study must have either (1) progressive disease whilst receiving an endocrine therapy (AI or a SERM), and/or a CDK4/6 inhibitor for locally advanced or metastatic disease; or (2) relapsed with metastatic disease whilst receiving an ET (AI or SERM), and/or a CDK4/6 inhibitor, and/or chemotherapy in adjuvant setting. No more than 2 prior lines of systemic treatments for locally advanced or metastatic disease are allowed for this study, including 1-2 prior lines of endocrine therapy, with/without CDK4/6 inhibitor (up to 1 therapy), and/or chemotherapy (up to 1 therapy).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 256
• Est. completion date: December 30, 2026
• Est. primary completion date: October 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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.

2. Patients with histologically or cytologically confirmed HR+/HER2- BC characterized by the absence of HER2 expression and the presence of ER and/or PR expression.

3. 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).

4. 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 CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible.

5. 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.

6. 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.

7. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1.

8. Patients who have adequate organ function

9. Female patients of childbearing potential must have a negative pretreatment serum pregnancy test.

10. 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,

11. Patients who are able to swallow and retain oral medication and without gastrointestinal diseases to interfere with drug absorption.

12. Patients must have no contraindications to fulvestrant.

Exclusion Criteria:

1. 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).

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.

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 with QT interval corrected by the Frederica's correction formula (QTcF) > 470 msec

7. Patients who have uncontrolled hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg under anti-hypertensive treatment).

8. 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].

9. Patients with known HIV seropositivity

10. Patients who are receiving medications that are sensitive substrates of CYP3A4, OATP1B1, or BCRP with low therapeutic index.

11. Patients who are ineligible for endocrine therapy (e.g., visceral crisis, inflammatory breast cancer).

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• 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)

Locations

Country	Name	City	State
China	Cancer Hospital Chinese Academy of Medical Sciences	Beijing	Beijing
United States	Piedmont Cancer Institute	Atlanta	Georgia
United States	University of Vermont	Burlington	Vermont
United States	Virginia Cancer Specialists	Fairfax	Virginia
United States	University of Iowa	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Providence St. Johns Health Center	Santa Monica	California

Sponsors (1)

Lead Sponsor	Collaborator
Laekna Limited

Countries where clinical trial is conducted

United States,  China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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 × 40 weeks then every 3 months through study completion, an average of 1 year (each cycle is 28 days)
Secondary	Phase I: Duration of Response (DOR) 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 x 40 weeks then every 3 months through study completion, an average of 1 year (each cycle is 28 days)
Secondary	Phase I: Disease Control Rate (DCR) 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 x 40 weeks then every 3 months through study completion, an average of 1 year (each cycle is 28 days)
Secondary	Phase I: Best Overall Response (BOR) 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 x 40 weeks then every 3 months through study completion, an average of 1 year (each cycle is 28 days)
Secondary	Phase I: Progression Free Survival (PFS) 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: 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)
Secondary	Phase I: Pharmacokinetics- Time to Maximum Concentration (T-Max)	Phase I: Time to peak level of afuresertib	Phase I: Assessed on Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)
Secondary	Phase I: Pharmacokinetics- Area Under the Curve (AUC)	Area under the curve of afuresertib	Assessed on Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)
Secondary	Phase I: Frequency and severity of Adverse Events (AEs)	Phase I: findings on physical examination, ECG, vital signs, and reports of the laboratory results based on the CTCAE v5.0	Phase I: Through study completion for an average of 12 months
Secondary	Phase III: Progression Free Survival (PFS) based on RECIST 1.1, as assessed by BICR	Phase III: Anti-tumor activity of the combination therapy with afuresertib plus fulvestrant in patients with HR+/HER2- BC	Phase III: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)
Secondary	Phase III:Frequency and severity of Adverse Events (AEs)	Phase III:findings on physical examination, ECG, vital signs, and reports of the laboratory results based on the CTCAE v5.0	Phase III:Through study completion
Secondary	Phase III:Pharmacokinetics- Time to Maximum Concentration (T-Max)	Time to peak level of afuresertib	Assessed on Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)
Secondary	Phase III:Pharmacokinetics- Area Under the Curve (AUC)	Area under the curve of afuresertib	Assessed on Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)