Study Title:
A Phase I, Open-Label, Dose-Escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of LAE118 as Monotherapy and in Combination With Other Antitumor Agents in Patients With Advanced Solid Tumors
Study Design Overview:
This is an open-label, multicenter Phase I clinical trial comprising three cohorts: Cohort A (LAE118 monotherapy), Cohort B (LAE118 plus fulvestrant), and Cohort C (LAE118 plus fulvestrant and palbociclib). Each cohort consists of two stages. Stage I evaluates safety and determines the maximum tolerated dose (MTD) and recommended dose (RD) of LAE118; Stage II assesses the preliminary efficacy of LAE118 at the RD.
Age ≥18 years at the time of signing the informed consent form.
Ability to provide written informed consent to participate in this study.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
During the screening period, a blood sample must be provided for PIK3CA testing at the central laboratory. Only participants with confirmed positive PIK3CA mutation results are eligible for enrollment. Participants with previously documented positive PIK3CA mutation results from local laboratory testing may be enrolled; however, a blood sample must still be collected during the screening period for central laboratory confirmation.
Prior treatment with a PI3K, AKT, or mTOR inhibitor without clinical benefit ("benefit" defined as achieving a best overall response [BOR] of CR/PR/SD during PI3K, AKT, or mTOR inhibitor therapy), except for participants who discontinued treatment due to documented intolerance.
Cohort C only: Participants with prior palbociclib exposure are not eligible for enrollment.
Participants with type 1 diabetes mellitus or type 2 diabetes mellitus requiring antidiabetic medication are not eligible for enrollment.
Participants with metaplastic breast cancer or inflammatory breast cancer.
Sequential
LAE118
DrugLAЕ118 is a novel, allosteric and highly potent selective inhibitor of PIK3CA. Its activity against PIK3CA mutant cells is superior to that of other broad-spectrum selective inhibitors.
Fulvestrant
DrugFulvestrant is approved for the treatment of post-menopausal metastatic breast cancer following disease progression on therapy with an anti-estrogen therapy.
Palbociclib
DrugPalbociclib is a CDK4/6 inhibitor. Multiple clinical studies have shown that palbociclib combined with endocrine therapy has demonstrated significant clinical benefits in study participants with HR+/HER2- advanced breast cancer.
Number of participants with adverse events (AEs)
Frequency and severity of AEs, including treatment-related AEs, serious AEs (SAEs), and AEs leading to treatment discontinuation, as assessed by CTCAE v5.0.
Number of participants with dose-limiting toxicities (DLTs)
Per protocol definition. DLT observation period: C0D1-C1D28 for Cohort A; C1D1-C1D28 for Cohorts B and C.
Change from baseline in QTcF interval as assessed by 12-lead ECG
Triplicate recordings within 10 min, ≥1 min apart. Fridericia's correction。 Unit: msec
Change from baseline in PR interval as assessed by 12-lead ECG
Unit: bpm
Objective response rate (ORR)
Proportion of participants with CR or PR per RECIST v1.1 by investigator assessment.
Clinical benefit rate (CBR)
Proportion of participants with CR, PR, or SD ≥24 weeks per RECIST v1.1.
Duration of response (DOR)
Time from first CR/PR to disease progression or death per RECIST v1.1.
Progression-free survival (PFS)
Time from first dose to disease progression per RECIST v1.1
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