A Study of AL58805 in Advanced, Metastatic GYN, STS or Breast Cancers

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.

Inclusion criteria

• Subjects must meet all of the following inclusion criteria to be eligible for this study:

• Age ≥ 18 years.
• Histologically proven diagnosis of:

• Pathologically confirmed recurrent or metastatic solid tumors such as Endometrial cancer, Cervical cancer, STS and Breast cancer;
• Failure of at least 1 prior line of standard therapy (disease progression after treatment or intolerable treatment toxicities);

• Patients with mismatch repair deficient/microsatellite-instability high tumors must have received a prior anti-PD-1/PD-L1 therapeutic agent.
• No standard and effective treatment available.
• Have measurable disease defined by RECIST 1.1 confirmed by CT or MRI scan within 28 days of enrollment.
• Life expectancy of ≥ 3 months at the time of enrollment.
• Able to take orally administered study medication.
• Have adequate baseline function and performance status within 28 days of enrollment:

• Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3, platelets ≥75,000/mm3 and Hemoglobin ≥ 9g/dl.
• Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN) or if creatinine is > 1.5 x ULN, creatinine clearance must be > 50 mL/min.
• Hepatic function: bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN for subjects with Gilbert Syndrome; No liver metastasis, AST and ALT ≤ 2.5 × ULN; When liver metastasis occurs, AST and ALT ≤ 5.0 × ULN.
• Coagulation profile: international normalized ratio (INR) is ≤ 1.5 and an aPTT or PTT < 1.2 x ULN.
• ECOG performance ≤ 2
• Left ventricular ejection fraction (LVEF) ≥ 50%
• No gastrointestinal diseases that affect drug absorption, such as malabsorption.
• Women of child-bearing potential must agree to use contraceptive measures starting 1 week before C1D1 until 4 weeks after the last dose of study treatment and have a negative serum pregnancy test within 28 days of enrollment. The patient must be non-lactating; if a female patient has not yet reached menopause (menopause is defined as the cessation of menstruation for at least 12 consecutive months, with no other causes), and has not undergone sterilization (removal of the ovaries and/or uterus), she is considered to be fertile. Her sexual partner should use medically approved contraception during the treatment period and for 4 weeks after the treatment ends;
• Provide written informed consent and authorization permitting release of Protected Health Information.
• Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures.

Exclusion criteria

• Subjects presenting with any of the following will not be included in the study:

• Treatment with an investigational agent within 28 days of enrollment.
• Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 28 days (42 days in cases of mitomycin C, nitrosourea, lomustine) prior to enrollment.
• Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 within 14 days prior to enrollment and during the study unless there is an emergent or life- threatening medical condition that required it.
• Known allergy or intolerance to investigational drugs (e.g.AL58805, AL8326, eriblin, fulvestrant, etc.) and excipients. (For example, who have had intolerable adverse reactions such as local injection site pain or systemic discomfort after application of fulvestrant should be excluded.)
• Other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of other cancer presents within the last 5 years prior to enrollment or whose previous cancer treatment contraindicates this protocol therapy.
• Myocardial infarction or unstable angina within 6 months prior to enrollment; New York Heart Association (NYHA) Grade II or greater congestive heart failure; serious cardiac arrhythmia requiring medication; and Grade II or greater peripheral vascular disease.
• Pre-existing uncontrolled hypertension as documented by two baseline blood pressure readings taken at least five minutes apart, defined as systolic BP >150 mm Hg or diastolic BP>90 mm Hg pressure.
• QTc≥ 480 msec on screening ECG per Fridericia's formula.
• History of or existing risk factors for Torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
• Concurrent use of concomitant medications that prolong the QT/QTc interval.
• History of significant vascular disease (e.g. aortic aneurysm, aortic dissection, peripheral vascular disease).
• Patients with severe chronic obstructive pulmonary disease (COPD) in acute exacerbation, severe pulmonary fibrosis (such as idiopathic pulmonary fibrosis with rapid disease progression), etc.
• History or evidence upon physical examination of central nervous system (CNS) disease including primary brain tumor; seizures not controlled with standard medical therapy; and history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA), or subarachnoid hemorrhage within 6 months of enrollment.

a. Subjects with metastatic CNS tumors may participate in this study if the subject is > 28 days from therapy completion (including radiation and/or surgery), is clinically stable at the time of study enrollment, and is not receiving corticosteroid therapy.

• History of neurological or psychiatric disorder, such as dementia, which in the investigator's assessment may prevent protocol compliance.
• Serious, non-healing wound, ulcer or bone fracture.
• Major surgical procedure within 28 days or minor surgical procedure performed within 7 days prior to C1D1 (a major surgical procedure is defined as requiring general anesthesia).
• Diabetes with poor blood sugar control. (If a patient with diabetes requires long-term use of insulin or hypoglycemic drugs, with no history of hypoglycemic drug dose adjustment in the past 1 month, they may be considered for inclusion after investigator assessment, even if their HbA1c is between 7.5% and 8.0%.)
• History of pancreatitis; history of renal disease that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy or other renal insufficiencies.
• Proteinuria on urinalysis within 28 days of enrollment. Subjects discovered to have a urine protein of 1+ on dipstick or ≥ 30 mg/dl at baseline should undergo a 24-hour urine collection and demonstrate < 1000 mg protein per 24 hours or spot urine protein (mg/dL) to creatinine (mg/dL) ratio must be <1.0 to allow participation in the study.
• Clinically significant, uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
• Hemoptysis within 3 months prior to enrollment.
• Acute or chronic liver disease, active hepatitis A, B, or C with known cirrhosis or liver dysfunction.
• Active bacterial infections requiring IV antibiotics (excluding uncomplicated urinary tract infection).
• Active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
• History of non-malignant gastrointestinal bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3-months prior to enrollment that in the opinion of the investigator may place the subject at risk of side effects on an anti-angiogenesis product.
• Intra-abdominal abscess within the last 3 months of enrollment.
• Ascites or pleural effusion (CTCAE5.0 ≥2)
• History of difficulty swallowing, malabsorption, active partial or complete bowel obstruction, or other chronic gastrointestinal disease or condition that may hamper compliance and/or absorption.
• Anticoagulation therapy with warfarin. Subjects treated with heparin, low molecular weight heparin, or any other anticoagulant may be included provided the subject has been on a stable therapeutic dose of the anticoagulant for at least 14 days prior to enrollment.
• Known history of human immunodeficiency virus infection (HIV) with viral load is detectable.
• HBsAg-positive patients with HBV DNA ≥ 104 copies or ≥ 2000IU/mL, antiviral and liver protection treatment should be performed first, and they can be enrolled only when HBV-DNA ≤ 104 copies/mL (2000IU/mL), and continue to take antiviral drugs, monitor liver function and hepatitis B virus load; HCV antibody positive and HCV-RNA positive.
• The investigator deems that the subject is not suitable to participate in this study.