This phase 1b/2a study evaluates AL58805, an oral investigational drug that blocks PI3K and mTOR signaling, in combination with one of three anticancer treatments: AL8326 (veonetinib), eribulin, or fulvestrant. Adults with recurrent, advanced, or metastatic endometrial cancer, cervical cancer, soft tissue sarcoma, or breast cancer may be eligible after at least one prior standard treatment has failed or could not be tolerated and no effective standard treatment option remains. In phase 1b, small groups of participants will receive different doses of AL58805 with a fixed dose of the partner treatment to identify a recommended combination dose based on dose-limiting side effects. In phase 2a, disease-specific groups will receive the selected combination dose to estimate the objective response rate and further evaluate duration of response, progression-free survival, overall survival, safety, pharmacokinetics, and exploratory tumor biomarkers. Protocol treatment may continue for up to 12 months, with continued treatment beyond 12 months possible for participants who remain clinically benefiting and receive investigator and sponsor approval.
AL-GB-805 is a global, multicenter, open-label, nonrandomized phase 1b/2a study of oral AL58805, a dual PI3K/mTOR inhibitor, combined with AL8326 (veonetinib), eribulin, or fulvestrant in adults with recurrent, advanced, or metastatic endometrial cancer, cervical cancer, soft tissue sarcoma (STS), or breast cancer for whom at least one prior standard treatment has failed or was not tolerated and no standard effective option remains. Phase 1b uses a standard 3+3 dose-escalation/de-escalation design to select a regimen-specific recommended combination dose (RCD). AL58805 begins at 10 mg and may be increased to 20 mg or reduced to 5 mg based on dose-limiting toxicities (DLTs). Cohort A combines AL58805 with AL8326 40 mg in 28-day cycles; Cohort B combines AL58805 with eribulin 1.4 mg/m² intravenously on Days 1 and 8 of each 21-day cycle; and Cohort C combines AL58805 with fulvestrant 500 mg intramuscularly on Days 1, 15, and 29 and monthly thereafter in 28-day cycles. The RCD is the highest evaluated AL58805 dose at which fewer than 33% of evaluable participants experience a DLT during the first treatment cycle. Phase 2a evaluates each regimen at its RCD. Cohort D includes separate endometrial cancer, cervical cancer, and STS groups receiving AL58805 plus AL8326. Cohort E includes separate STS and breast cancer groups receiving AL58805 plus eribulin. Cohort F includes an HR-positive or other eligible breast cancer group receiving AL58805 plus fulvestrant. Each disease-specific group initially enrolls 17 participants. Under the protocol-specified Simon two-stage design, a group with no objective responses stops for futility; a group with one or more objective responses may enroll 18 additional participants for a total of 35. Tumor response is assessed by the investigator or local radiologist according to RECIST 1.1 at baseline and approximately every 8 weeks beginning on Cycle 3 Day 1. A complete response or partial response is confirmed by repeat imaging 4 to 6 weeks later. Treatment continues until disease progression, unacceptable toxicity, intercurrent illness that prevents safe treatment, withdrawal, sponsor discontinuation, or completion of 12 months of protocol treatment, whichever occurs first. Treatment beyond progression may be allowed when the investigator and sponsor determine that clinical benefit continues and urgent alternative intervention is not being delayed. Participants who remain without progression and continue to benefit may receive study treatment beyond 12 months with investigator and sponsor approval under the protocol continued-access provisions or may later transition to a separate post-trial access protocol. Safety is monitored through the final study visit 4 to 5 weeks after the last study dose, and unresolved related adverse events and serious adverse events are followed until resolution or stabilization. Long-term follow-up includes vital status and subsequent anticancer therapy every 3 to 6 months.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
138
AL58805 is a novel chemical-structure antitumor drug with independent intellectual property rights. It functions as a novel dual-target PI3K/mTOR kinase inhibitor, exhibiting effects such as inhibiting tumor cell growth and proliferation, suppressing tumor nutrient metabolism, and exerting anti-angiogenic activity. By simultaneously inhibiting both PI3K and mTOR, it completely blocks the entire PI3K/AKT/mTOR signaling pathway at relatively low safe doses, thereby enhancing antitumor efficacy.
AL8326 is a novel small molecule multi-receptor tyrosine kinase inhibitor, which shows highly selective inhibition of fibroblast growth factor receptor (FGFr1, FGFr2, FGFr3), vascular endothelial growth factor receptor (VEGFr1, VEGFr2, VEGFr3) and Aurora-B.
Eribulin Mesylate is a microtubule dynamics inhibitor used in the treatment of certain advanced solid tumors. It works by binding to tubulin, inhibiting the dynamic assembly and disassembly of microtubules, blocking mitosis in cancer cells, and inducing apoptosis.
Fulvestrant is a class of estrogen receptor antagonist, estrogen receptor downregulation agents for anti-breast cancer treatment.
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Recommended Combination Dose (RCD)
Determine the recommended combination dose (RCD) of AL58805 in combination with AL8326, Eribulin, or Fulvestrant based on the incidence of dose-limiting toxicities (DLTs) during Phase 1b. The RCD is defined as the highest evaluated dose level at which fewer than 33% of participants experience a DLT.
Time frame: 36 months
Objective Tumor Response Rate (ORR)
Percentage of participants who achieve a Complete Response (CR) or Partial Response (PR) as the best overall tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Time frame: 36 months
Pharmacokinetic endpoint: Time to Maximum Plasma Concentration (Tmax)
Time from study drug administration to the observed maximum plasma concentration (Tmax) of AL58805, and of AL8326 where applicable, determined from protocol-specified pharmacokinetic sampling.
Time frame: 36 months
Pharmacokinetic endpoint: Maximum Observed Plasma Concentration (Cmax)
Maximum observed plasma concentration (Cmax) of AL58805, and of AL8326 where applicable, determined from plasma concentration-time data collected at protocol-specified pharmacokinetic sampling time points.
Time frame: 36 months
Pharmacokinetic endpoint: Area Under the Plasma Concentration-Time Curve (AUC)
Area under the plasma concentration-time curve (AUC) of AL58805, and of AL8326 where applicable, calculated from plasma concentration-time data collected at protocol-specified pharmacokinetic sampling time points.
Time frame: 36 months
Duration of Response (DOR)
Time from the date of the first documented objective response, defined as Complete Response (CR) or Partial Response (PR), to the date of documented disease progression or death from any cause, whichever occurs first, according to RECIST version 1.1.
Time frame: 36 months
Progression-Free Survival (PFS)
Time from Cycle 1 Day 1 (C1D1) to the first documented disease progression or death from any cause, whichever occurs first.
Time frame: 36 months
Overall Survival (OS)
Time from Cycle 1 Day 1 (C1D1) to death from any cause.
Time frame: 36 months
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