A Study of LAE118 as Monotherapy and in Combination With Antitumor Agents in Advanced Solid Tumors

1. Age ≥18 years at the time of signing the informed consent form.
2. Ability to provide written informed consent to participate in this study.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4. 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.
5. At least one measurable lesion as defined by RECIST version 1.1 criteria.

6. Histologically or cytologically confirmed locally advanced (unresectable) or metastatic solid tumor, meeting the specific criteria for each cohort:

   Cohort A (Stage I, Dose Escalation): Histologically or cytologically confirmed locally advanced (unresectable) or metastatic solid tumor. Lymphoma is excluded.

   Cohort A (Stage II): Histologically or cytologically confirmed locally advanced (unresectable) or metastatic head and neck squamous cell carcinoma (HNSCC) or gynecologic cancers (ovarian, cervical, or endometrial cancer).

   Cohort A (Stage I, Backfill Enrollment) and Cohorts B/C: Histologically or cytologically confirmed locally advanced (unresectable) or metastatic HR+/HER2- breast cancer, based on the most recent tumor specimen.

   HR+/HER2- breast cancer is defined as HER2-negative and ER-positive, regardless of PR expression status.

   Estrogen receptor (ER) positive: Defined as ≥1% of tumor cells demonstrating ER positivity by immunohistochemistry (IHC).

   Progesterone receptor (PR) positive: Defined as ≥1% of tumor cells demonstrating PR positivity by IHC.

   HER2-negative: Defined as IHC intensity of 0 or 1+, or IHC intensity of 2+ without evidence of amplification by in situ hybridization (ISH), or absence of IHC testing and no evidence of amplification by ISH (based on the 2023 updated ASCO-CAP guidelines).

7. Prior antitumor therapy:

   Cohort A: Disease progression after adequate standard therapy, or no effective standard therapy available.

   Cohorts B/C:

   Receipt of no more than 3 lines of systemic antitumor therapy in the advanced setting (including at least 1 line of endocrine therapy, no more than 1 line of CDK4/6 inhibitor therapy, and no more than 1 line of chemotherapy).

   If disease recurrence occurs during adjuvant endocrine therapy or within 12 months of completion of adjuvant endocrine therapy, such adjuvant therapy will be counted as one line of prior therapy.

   Prior fulvestrant therapy is permitted; however, the proportion of participants with prior fulvestrant exposure must not exceed 50% of the total enrolled participants in Cohort B and Cohort C, respectively.

8. Female participants with HR+/HER2- advanced breast cancer who are postmenopausal, premenopausal, or perimenopausal are eligible for enrollment. In Cohorts B/C, male participants and female participants with HR+/HER2- advanced breast cancer who are premenopausal or perimenopausal must receive continuous ovarian function suppression throughout the study period (initiation of luteinizing hormone-releasing hormone agonist [LHRHa] no later than Day 1 of Cycle 1).

   Menopause is defined as follows [34]:

   Prior bilateral oophorectomy. Age ≥60 years. Age \<60 years with amenorrhea for ≥12 months in the absence of prior chemotherapy, tamoxifen, toremifene, or ovarian suppression, and with estradiol and follicle-stimulating hormone (FSH) levels in the postmenopausal range.

   Age \<60 years with chemotherapy-induced amenorrhea for ≥12 months and FSH and estradiol levels consistently in the postmenopausal range upon serial assessment.

   Age \<60 years currently receiving tamoxifen with FSH and estradiol levels in the postmenopausal range.

9. Participants in Cohorts B/C must have no contraindications to fulvestrant, including hypersensitivity to fulvestrant or any of its components, or hepatic impairment classified as Child-Pugh Class B or C. Participants in Cohort C must have no contraindications to palbociclib, including hypersensitivity to palbociclib or any of its components.
10. Fasting plasma glucose \<7.7 mmol/L and hemoglobin A1c (HbA1c) \<7.0%.
11. A minimum washout period of 4 weeks or 5 half-lives (whichever is shorter) between the end of the last antitumor therapy and the planned start date of study treatment.
12. Completion of radiotherapy at least 4 weeks prior to the planned start date of study treatment; completion of palliative radiotherapy for bone or other metastatic lesions at least 2 weeks prior to the planned start date of study treatment.
13. Ability to swallow and absorb oral medications, with no gastrointestinal disorders that would interfere with drug absorption.
14. Resolution of toxicities related to prior antitumor therapy to Grade ≤1, except for stable residual symptoms (alopecia, peripheral sensory neuropathy, skin hyperpigmentation, dysgeusia).

15. Female participants of childbearing potential must agree to use highly effective contraception from the time of enrollment until at least 1 year after the last dose of study treatment. Acceptable methods include:

    Complete abstinence (if this is their preferred and usual lifestyle). Intrauterine device (IUD) or hormonal intrauterine system. Contraceptive implant. Oral contraceptives (combined with barrier contraception). Partner has undergone vasectomy with confirmed azoospermia. Male participants with female partners of childbearing potential must agree to use effective contraception (e.g., condom use) from the time of enrollment until at least 1 year after the last dose of study treatment.

16. Female participants of childbearing potential must have a negative serum pregnancy test during the screening period.

17. Adequate organ function, defined as follows:

    Hematologic: The following criteria must be met without the use of erythropoietin, growth factors, or packed red blood cell transfusion within 14 days prior to screening laboratory assessments:

    Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L. Platelet count ≥100 × 10⁹/L. Hemoglobin ≥10.0 g/dL.

    Hepatic:

    Total bilirubin ≤1.5 × upper limit of normal (ULN). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (or ≤3 × ULN for participants with liver metastases).

    Serum albumin ≥30 g/L.

    Renal:

    Creatinine clearance ≥60 mL/min (calculated using the Cockcroft-Gault formula).

    Coagulation:

    International normalized ratio (INR) ≤1.5 × ULN. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN. For participants requiring anticoagulation with warfarin, INR must be stably maintained within the range of 2 to 3. For participants with mechanical heart valves requiring anticoagulation, INR may be maintained within the range of 2.5 to 3.5.

    Adrenal function tests during screening show no clinically significant abnormalities.

18. Bone mineral density testing (dual-energy X-ray absorptiometry [DEXA]) must be performed during the screening period, with a T-score >-2.5 (based on the lowest value across multiple sites assessed).

Exclusion Criteria:

1. 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.
2. Cohort C only: Participants with prior palbociclib exposure are not eligible for enrollment.
3. Participants with type 1 diabetes mellitus or type 2 diabetes mellitus requiring antidiabetic medication are not eligible for enrollment.
4. Participants with metaplastic breast cancer or inflammatory breast cancer.

5. Known active, uncontrolled, or symptomatic central nervous system (CNS) metastases or leptomeningeal carcinomatosis. Participants with previously treated CNS metastases may be enrolled if all of the following criteria are met:

   At least one measurable non-CNS lesion per RECIST version 1.1 criteria. No history of intracranial or spinal cord hemorrhage. Radiographic stability: No evidence of progression on imaging following completion of CNS-directed therapy. The interval between post-treatment imaging and screening imaging must be at least 4 weeks, with no evidence of progression.

   Clinical stability: No requirement for corticosteroids, diuretics, mannitol, or other agents to reduce intracranial pressure, and no requirement for antiepileptic drugs for at least 14 days prior to the planned start date of study treatment.

6. Uncontrolled pleural effusion or ascites (requiring drainage every 2 weeks or more frequently, or requiring an indwelling pleural or peritoneal catheter).
7. Concurrent malignancy or history of another malignancy within 3 years prior to the planned start date of study treatment, except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, non-melanoma skin cancer, or cervical carcinoma in situ treated with curative intent.
8. Major surgery or significant trauma within 28 days prior to initiation of study treatment, or anticipated need for major surgery during the study treatment period. Participants must have fully recovered from prior surgery, including adequate wound healing.
9. Receipt of intravenous antibiotics for infection within 2 weeks prior to the planned start date of study treatment.
10. History of seizures or predisposing factors for seizures; cerebral arteriovenous malformation; or intracranial space-occupying lesions causing edema or clinical symptoms.

11. Meeting any of the following criteria within 26 weeks prior to the planned start date of study treatment:

    History of angina pectoris, coronary artery bypass grafting, symptomatic pericarditis, or myocardial infarction within 12 months prior to initiation of study treatment.

    Documented history of congestive heart failure (New York Heart Association [NYHA] Class III-IV).

    Documented cardiomyopathy. Left ventricular ejection fraction (LVEF) \<50% (if applicable). History of clinically significant arrhythmias (including but not limited to ventricular tachycardia, complete left bundle branch block, high-grade atrioventricular block, supraventricular tachycardia, or atrial fibrillation).

12. Corrected QTcF interval >450 ms (corrected using Fridericia's formula), based on the mean of 3 consecutive electrocardiograms obtained within 10 minutes at intervals of at least 1 minute apart. Participants with a history of additional risk factors for torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of long QT syndrome) are not eligible for enrollment.
13. Suspected pneumonitis or interstitial lung disease (confirmed by imaging or CT scan), or history of pneumonitis or interstitial lung disease within the past 6 months.
14. Electrolyte abnormalities requiring treatment.
15. History of and/or current adrenal disorders (e.g., Cushing's disease, Addison's disease, adrenal insufficiency).
16. Systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg; however, participants with hypertension controlled with oral antihypertensive medication (systolic BP \<140 mmHg and diastolic BP \<90 mmHg) are eligible for enrollment.

17. Active HBV infection (defined as HBsAg positive with HBV DNA ≥200 IU/mL or ≥1000 copies/mL), active HCV infection (defined as anti-HCV antibody positive with detectable HCV RNA), or HIV infection (defined as anti-HIV antibody positive).

    Note: As outlined in the U.S. FDA guidance "Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, or Hepatitis C Virus Infections," participants with well-controlled HIV, HBV, or HCV are eligible. Participants receiving effective antiviral therapy with controlled viral loads should continue the same regimen throughout the study treatment period.

18. Known psychiatric illness or substance use disorder that would impair the ability to comply with study requirements.
19. Known history of solid organ transplantation or hematopoietic stem cell transplantation.
20. Receipt of a live vaccine or live attenuated vaccine within 30 days prior to the first dose of study treatment.
21. Any known medical condition, concurrent therapy, or laboratory abnormality that, in the investigator's judgment, could confound study results, interfere with participant adherence to study procedures, or render participation inconsistent with the participant's best interest.
22. Any concurrent ocular or intraocular disease (e.g., uveitis, vitritis) that, in the opinion of the investigator or ophthalmologist, requires medical or surgical intervention during the study to prevent or treat conditions that could lead to vision loss.
23. Cataract of Grade ≥2 severity per CTCAE version 5.0.
24. Use of moderate or strong CYP3A4 and/or CYP2C8 inhibitors and/or P-gp inhibitors within less than 5 elimination half-lives or 1 week (whichever is longer) prior to the first dose of study treatment; or use of moderate or strong CYP3A4 and/or CYP2C8 inducers within less than 5 elimination half-lives or 2 weeks (whichever is longer) prior to the first dose of study treatment; or anticipated need for continuous use of these medications during the study period (see Appendix 1 for examples of known strong or moderate CYP3A4 and CYP2C8 inhibitors/inducers and/or P-gp inhibitors).
25. Cohorts B/C only: Disease progression within 3 months of the most recent endocrine therapy in the advanced/metastatic setting.
26. History of or active inflammatory bowel disease requiring treatment, including ulcerative colitis, Crohn's disease, etc.
27. Any other condition that, in the investigator's opinion, renders the participant unsuitable for participation in this trial.