A First-in-Human Escalation and Expansion Study of Patients With Advanced Solid Tumors

Inclusion criteria

• Patients who meet ALL the following inclusion criteria will be eligible to participate in the study:
• ≥18 years of age.
• Histologically confirmed, locally advanced, or metastatic solid tumor which has progressed on, or patients intolerant to, all standard therapy, or no standard therapy available, or it is documented that the therapy is refused by the patient.
• Measurable disease per RECIST v1.1.
• Life expectancy ≥3 months.
• Adequate organ and bone marrow function defined by:
• Absolute neutrophil count (ANC) ≥1.5 × 109/L (≥1500/mm3)
• Platelet count ≥100 × 109/L (≥100,000/mm3) (no platelet transfusion within 14 days prior to enrollment)
• Total bilirubin ≤1.5 × upper limit of normal (ULN), unless known Gilbert syndrome (≤3 × ULN) has been diagnosed
• AST and ALT ≤2.5 × ULN or ≤5 × ULN for patients with known liver metastases
• Estimated creatinine clearance by the Cockcroft-Gault or estimated glomerular filtration rate (eGFR) of ≥60 mL/min
• International Normalized Ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) ≤1.5 × ULN. If a patient is receiving anticoagulant therapy, PT and aPTT must be within therapeutic range of intended use of anticoagulants
• Patients with treated, stable central nervous system (CNS) metastases (including leptomeningeal carcinomatosis) are allowed if there is no evidence of progression for at least 4 weeks after CNS-directed treatment as ascertained by clinical examination and brain imaging.
• Resolution of any clinically significant toxic effects of prior therapy to Grade ≤1 according to the NCI CTCAE v5.0 (exception of alopecia and Grade 2 peripheral neuropathy).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Willingness of men and women of reproductive potential to observe conventional and effective birth control methods with failure rates of \<1% for the duration of treatment and for at least 6 months for women and at least 3 months for men following the last dose of study treatment (this must include a barrier method such as condom or diaphragm with spermicidal gel). Women of reproductive potential are defined as following menarche and who are not postmenopausal (and 2 years of nontherapy-induced amenorrhea or surgically sterile). For male patients with a nonpregnant female partner of childbearing potential and a woman of childbearing potential, 1 of the following highly effective birth control methods with a failure rate of less than 1% per year when used consistently and correctly are recommended:
• Combined estrogen and progestin containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally
• Progestin-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant
• Intrauterine device
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion/ligation
• Vasectomized partner
• Sexual abstinence Note: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the patient. Birth control methods unacceptable for this study include the following:
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• Periodic abstinence (calendar, symptothermal, or post-ovulation methods)
• Withdrawal (coitus interruptus)
• Spermicide only
• Lactational amenorrhea method Egg and sperm donation or banking is prohibited during the duration of participation on this protocol and for 90 days after the last dose of study drug. 10. A negative serum pregnancy test at screening and a negative (serum or urine) pregnancy test within 72 hours before the first dose of study drug (female patients of childbearing potential only). If the urine test is positive or cannot be confirmed negative, a serum pregnancy test will be required and must be negative for the patient to be eligible.
• \. Willing and able to provide informed consent and comply with protocol requirements for the duration of the study.
• Specific Inclusion Criteria for Expansion Cohorts:
• To be eligible during the dose expansion part of the study, patients must meet 1 of the following 2 criteria:
• Expansion Cohort 1: Documented locally advanced or metastatic gastric or
• EGJ cancer which has progressed on or after standard therapy or patient is intolerant to standard therapy or patient refuses therapy. Standard therapy options are described in (Wang,2024):
• Prior systemic standard therapy for patients with HER2-positive gastric or EGJ cancer should include trastuzumab plus chemotherapy (fluorouracil plus platinum), mono-chemotherapy (eg., paclitaxel, docetaxel, irinotecan), and other monotherapy (eg., VEGF targeted agents, anti-PD-1 or PD-L1).
• Prior system standard therapy for patients with HER2-negative gastric or EGJ cancer should include fluorouracil plus platinum or in combination with anti-PD-1, mono-chemotherapy (eg., paclitaxel, docetaxel, irinotecan) and VEGF targeted therapy.
• Expansion Cohort 2: Documented locally advanced or metastatic colorectal cancer which has progressed on or after standard therapy or patient is intolerant to standard therapy, or patient refuses therapy. Standard treatment options are described in (Association NHCOTPROCSOOCM,2023):
• Prior systemic standard therapy for patients with MMR-deficient (dMMR)/microsatellite instability-high (MSI-H): pembrolizumab for 1st line therapy, no standard therapy for 2nd and 3rd line therapy.
• Prior system standard therapy for patients with microsatellite stability (MSS) or microsatellite instability-low (MSI-L)/proficient mismatch repair (pMMR), RAS and BRAF wild-type (WT) should include cetuximab or bevacizumab monotherapy or in combination with FOLFOX/FOLFIRI/CAPEOX, and monotherapy (eg., regorafenib, fruquintinib, trifluridine tipiracil).
• Prior system standard therapy for patients with MSS or MSI-L/pMMR, RAS and BRAF mutation: should include bevacizumab monotherapy or in combination with FOLFIRI, and monotherapy (eg., regorafenib, fruquintinib, trifluridine tipiracil).

Exclusion criteria

• Patients who meet any of the following exclusion criteria will be excluded from participation in the study:
• Any condition that in the opinion of the Investigator would place the patient at an unacceptable risk or cause the patient to be unlikely to fully participate or comply with study procedures.
• Received systemic anticancer chemotherapy, targeted agents, antibody therapy for cancer, immunotherapy for cancer, hormonal therapy, or an investigational agent within 2 weeks or 5 half-lives (whichever is shorter) prior to start of study drug treatment.
• Major surgery within 3 weeks prior to start of study drug treatment.
• Radiation therapy within 4 weeks prior to start of study drug treatment (palliative radiation or stereotactic radiosurgery within 7 days prior to start of study drug treatment). Patients must have recovered from all acute radiotherapy-related toxicities.
• Severe or unstable cardiac conditions including, but not limited to, congestive heart failure (New York Heart Association Class III or IV), ischemic heart disease, uncontrolled hypertension, uncontrolled cardiac arrhythmia requiring medication (Grade ≥2, according to NCI CTCAE v5.0), myocardial infarction within 6 months prior to starting study drug treatment, congenital long QT syndrome or QT interval corrected for heart rate using Fridericia's formula (QTcF) \>470 msec at screening, and any other significant or unstable concurrent cardiac illness.
• Severe or unstable medical condition including uncontrolled diabetes or unstable psychiatric condition.
• Has a history of another active malignancy (a second cancer) within the previous 2 years except for localized cancers that are not related to the current cancer being treated, are considered cured, and, in the opinion of the Investigator, present a low risk of recurrence. These exceptions include, but are not limited to, basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• Active infection requiring systemic therapy (including asymptomatic infections with positive virus titers and the Investigator's judgment that worsening of the condition is likely with study drug or the condition will impair or prohibit a patient's participation in the study).
• Known human immunodeficiency virus, hepatitis B virus (HBV) (i.e., hepatitis B surface antigen positive), or hepatitis C virus (HCV) (i.e., detectable HCV ribonucleic acid \[RNA\]). Note: Patients with a prior history of treated HBV infection who are antigen negative, patients with a prior history of treated HCV infection who are HCV RNA undetectable, or patients with HIV who are on stable anti-retroviral therapy and have an undetectable viral load may be enrolled.
• Pregnant (or intending to become pregnant) or breastfeeding.