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

Plain English Summary

Study to Evaluate Efficacy & Safety of Afuresertib Plus Fulvestrant in Patients With Locally Advanced or Metastatic HR+/HER2- Breast Cancer is a Phase 3 clinical trial sponsored by Laekna Limited studying Breast Cancer. This trial tests a combination of afuresertib and fulvestrant, a standard treatment, to see if it's more effective than standard treatment alone for certain types of breast cancer. It is for patients with locally advanced or metastatic hormone receptor-positive, HER2-negative breast cancer that has not responded to previous treatments. Participants will receive either the combination therapy or a placebo with fulvestrant, and will have regular check-ups and tests. Alternative treatments may include other hormone therapies, targeted drugs, or chemotherapy, depending on the patient's specific situation and prior treatments. The trial aims to enroll 256 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 and older with confirmed HR+/HER2- breast cancer. Patients whose cancer has spread or cannot be removed by surgery and has progressed after 1-2 prior treatments, including hormone therapy and/or CDK4/6 inhibitors or chemotherapy. Individuals with measurable disease or specific types of bone lesions. Patients must have good organ function and a life expectancy of at least 24 weeks. This trial is studying Breast Cancer, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome, Progression-Free Survival (PFS), measures how long patients live without their cancer getting worse, indicating how well the new treatment combination works. The specific primary outcome measures are: Phase I: Overall Response Rate (ORR) based on RECIST 1.1 (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: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). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial addresses a critical need for new treatments for patients with advanced HR+/HER2- breast cancer who have exhausted standard options, potentially offering a new way to control the disease. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Breast Cancer, where improved treatment options are needed.

Investor Insight

This trial targets a significant market of advanced breast cancer patients, aiming to improve upon existing therapies and potentially gain market share if successful. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor about the specific treatments being tested, potential benefits, and risks. Understand what tests and appointments will be required throughout the study. Discuss how this trial fits with your current health and lifestyle. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: QUADRUPLE
• Enrollment: 256 participants

Interventions

• 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
• DRUG: Afuresertib/placebo — afuresertib/placebo 125mg QD combined with fulvestrant 500mg Q4W (D1, 15 in cycle 1)

Primary Outcomes

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

• 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))

Full Eligibility Criteria

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- 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:

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. (Note: Patients with previously treated brain metastases may participate provided that they are radiologically

Trial Locations

• 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
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Breast Cancer
• Hormone Receptor-Positive Breast Cancer
• HER2-Negative Breast Cancer
• Metastatic Breast Cancer
• Locally Advanced Breast Cancer
• Endocrine Therapy Resistance
• CDK4/6 Inhibitor Resistance
• ER-Positive Breast Cancer
• PR-Positive Breast Cancer
• Advanced Solid Tumors

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