First-in-Human, Multicenter, Phase I Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of YL-18319 Monotherapy in Patients With Locally Advanced/Metastatic Solid Tumors

Prior treatment

• Known symptomatic brain metastases requiring dexamethasone \>4mg (or equivalent) or requiring steroid dose increase within 14 days prior to the first dose of YL-18319.
• Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment.
• Unresolved toxicities from prior therapy, defined as having not resolved to NCI CTCAE v.5.0 Grade ≤1 or baseline, with exception of endocrinopathies from prior therapy and successfully treated (such as hypothyroidism), alopecia, vitiligo, and ≤ grade 2 peripheral neuropathy.
• Patients with active viral (any etiology) hepatitis are excluded. However, patients with serologic evidence of chronic hepatitis B virus (HBV) infection (defined by a positive hepatitis B surface antigen test and a positive anti-hepatitis core antigen antibody test) who have a viral load below the limit quantification (HBV DNA titer \<1000 cps/mL or 200 IU/mL), and are not currently on viral suppressive therapy may be eligible and should be discussed with the Medical Monitor. Patients with a history of hepatitis C virus (HCV) infection who have completed curative antiviral treatment and have a viral load below the limit of quantitation may be eligible and should be discussed with the Medical Monitor.
• Patients receiving proton pump inhibitors (PPIs), strong cytochrome P450 (CYP)3A inhibitors and inducers, or P-glycoprotein (P-gp) inhibitors. Patients should not receive PPIs within 7 days prior to first dose of study drug. Strong CYP3A inducers or inhibitors or strong P-gp inhibitors should not be given within 6 half-lives prior to first dose of study drug

Other illness

• Any of the following cardiac criteria experienced currently or within the last 6 months:
  • Congestive heart failure (New York Heart Association ≥ Class 2).
  • Any clinically significant abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block or third-degree heart block.
  • Acute coronary syndrome within 6 months.
  • Clinically significant cardiac arrhythmia.
• Evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding diatheses, or active infection, as determined by the investigator.
• Any condition that impairs a patient's ability to swallow whole pills. Presence of an active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of YL-18319, as determined by the investigator.
• Known pulmonary interstitial disease or pulmonary interstitial fibrosis
• An active additional malignancy that is progressing or requires active treatment within the past 2 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Known allergy to any component of YL-18319.
• History or evidence of any other clinically significant condition or disease (with the exception of those outlined above) that, in the opinion of the investigator, would be a risk to patient safety or interfere with the study evaluation, procedures or completion.

Lab values

• Human immunodeficiency virus (HIV) infection with a current or a known history of AIDS-defining illness or HIV infection with a CD4+ T cell count \<350 cells/µL and an HIV viral load more than 400 copies/µL.
• Mean QTC interval corrected (Frederica) for heart rate \>470 ms.
• Left ventricular ejection fraction (LVEF) \<50% or the lower limit of normal (per institutional standard).

Other

• Patients who are pregnant or breastfeeding or expecting to conceive within the projected duration of the trial, starting with the screening visit through 3 months after the last dose of trial treatment.

• Patients with advanced solid tumors that is unresectable or metastatic who have no standard therapies, or have progressed on or intolerable to standard therapies. Preferential enrollment consideration will be made for patients (at least 2 patients per cohort) with known genetic alterations causing deficiencies of BRCA1, BRCA2, and/or Homologous Recombination Defective (HRD), or selected gene mutations of genome instability or cell cycle control, based on the mechanism of YL-18319.
• Patient has at least 1 measurable target lesion or evaluable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Demonstrate adequate organ function as defined below. The following screening laboratories should be performed within 7 days of study treatment initiation.
  • Absolute neutrophil count (ANC) ≥1.5 × 109/L Platelets ≥100 × 109/L Hemoglobin ≥9 g/dL Measured and/or Calculated creatinine clearance (CrCl) (Cockroft-Gault) ≥ 60 mL/min Total bilirubin ≤1.5 × ULN (patients with Gilbert's syndrome, total bilirubin ≤3.0 × ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN for patients with liver metastases
• Has an ECOG performance status of 0-1.
• Life expectancy at least 3 months.
• Women of childbearing potential must have negative serum or urine pregnancy test within 72 hours prior to receiving the first study drug administration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• For women of childbearing potential, must be willing to use an adequate method of contraception from 30 days prior to the first study drug administration and at least 3 months following last day study drug administration.
• Male patients of childbearing potential must be surgically sterile or must agree to use adequate method of contraception during the study and at least 3 months following the last day of study drug administration.
• Age ≥18 years at screening.
• Able and willing to provide written informed consent and to comply with all protocol-required visits, assessments, and procedures.
• Washout from prior anti-tumor therapy:
  • Cytotoxic therapies ≥ 3 weeks Mitomycin C or nitrosoureas ≥ 6 weeks Small molecule agents ≥2 weeks or 5x T1/2, whichever is longer Biologic agents (e.g., antibodies) ≥ 4weeks Immunotherapy (e.g., CTLA4, PD-1, PD-L1 inhibitors) ≥ 4 weeks Radiotherapy ≥ 2 weeks Limited field radiotherapy or palliative radiotherapy ≥ 2 weeks Major surgery, excluding biopsy ≥ 4 weeks (exception: patients may enroll if fully recovered without intolerable or clinically significant adverse effects, but at least 14 days must have elapsed between major surgery and first study drug administration) Study drug with an investigational product, or non-approved use of a drug or device ≥ 4 weeks (≥2 weeks or 5x T1/2, whichever is longer for small molecule agents)