Safety of AM-928 Infusion in Advanced Solid Tumors

This is a first-in-human Phase I, open-label, dose-escalation study to investigate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of AM-928 infusion in subjects with advanced solid tumors in multiple sites in Taiwan.

Eligible subjects will be dosed with different dosages of AM-928 in 1 of the 7 dose levels (0.1, 0.3, 1, 3, 6, 10, 15 mg/kg). Dose levels will be escalated from dose Level 1 at 0.3 mg/kg to Level 6 at 15 mg/kg of AM-928 (or may be de-escalated to Level -1 at 0.1 mg/kg), which will be administered (intravenous infusion) once weekly (QW) for 4 weeks (D1, D8, D15, D22) as a treatment cycle until any treatment discontinuation criterion is met. Basically, there will be no breaks between dosing cycles. From Cycle 4, intra-subject dose escalation may be applied if supported by preliminary safety and PK data.

The dose escalation strategy will adopt accelerated titration combined with a Bayesian optimal interval (BOIN) design. The accelerated titration will be adopted for 0.3 mg/kg, while the BOIN design will be adopted for other dose levels, including 1 mg/kg, 3 mg/kg, 6 mg/kg, 10 mg/kg, and 15 mg/kg. In the "accelerated titration" stage, if any ≥ Grade 2 adverse event occurs, the current and subsequent dose groups will be changed to the BOIN dose escalation method. The target toxicity rate for the maximum tolerated dose (MTD) is ϕ= 0.3, and the maximum sample size is determined to be 30, maximum of 9 subjects per dose level. A cohort size of 3 and a maximum cohort number of 3 for each dose level will be adopted for subject recruitment. The dose escalation may end when one of the following criteria is met: (1) The planned sample size of 30 has been reached; (2) 9 subjects have been treated and evaluable for DLT at the next intended dose level (should not exceed 9 subjects at one dose level); (3) all doses explored appear to be overly toxic, and the MTD cannot be determined.

The Scientific Review Committee (SRC) will review the safety and/or efficacy data at the end of each dose level cohort for escalation or de-escalation decision (when the DLT rate indicates staying at the current dose, the review process may be waived). Besides, an emergency meeting will be held if the SRC has any safety concerns. A final review process is scheduled at the end of dose escalation for MTD determination. The dose with the toxicity rate closest to the target toxicity rate (ϕ= 0.3) will be selected as MTD.

If the SRC determines that the safety profile of a specific dose level is unfavorable for subjects, the SRC may eliminate that dose level even if the toxicity rate is below 0.3. In this case, the subsequent subjects will be enrolled into the lower dose level(s) following the BOIN design and the lower dose level with the toxicity rate closest to the target toxicity rate (ϕ= 0.3) will be selected as MTD.

Inclusion criteria

• Male or female, age ≥ 18 years
• Histologically/cytologically confirmed, locally advanced unresectable or metastatic solid tumors that are refractory to or intolerant of existing standard therapy, for which no effective standard therapy that confers clinical benefit is available
• Availability of archival tissue specimens for EpCAM immunohistochemistry (IHC) staining. Tumor tissues acceptable include:

• Tumor tissue sample collected at the time of initial diagnosis

• The most recent available recurrent/metastatic tumor biopsy tissue if available (a pre-treatment biopsy is encouraged if the biopsy site is safely accessible) Note: this criterion is fulfilled if there is a qualified tumor sample (tumor cells were presented in the tumor biopsy tissue), and the tumor tissue slides can be obtained for IHC staining. It is not violated even if the staining result from biopsy obtained after the screening visit reveals that the slides contain no identifiable tumor cells.
• Has at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2
• Subject's life expectancy of at least 12 weeks
• Has adequate hematopoietic, coagulation, hepatic function and renal function:

• Hemoglobin ≥ 8.0 g/dL without transfusion or erythropoiesis stimulating agent support within 1 week
• Absolute neutrophil count (ANC) ≥ 1,500 cells/μL without WBC growth factor support within 1 week
• Total white blood cell (WBC) ≥ 2,500 cells/μL
• Platelet ≥ 80,000 counts/μL without transfusion support within 1 week
• International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 upper limit of normal (ULN)
• Total bilirubin ≤ 1.5× ULN and no sign of jaundice (≤ 3× ULN for subjects with known Gilbert disease)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3× ULN (≤ 5× ULN for subjects with tumor involvement in liver)
• Serum albumin ≥ 3.0 g/dL
• eGFR (CKD-EPI) ≥ 60 mL/min/1.73 m^2
• A female subject with childbearing potential should be confirmed of not being pregnant or not lactating at the screening and during the study
• Willingness and ability to comply with protocol-stated requirements, instructions, and restrictions in the investigator's judgement
• Is able to understand the nature of this study and accepts to enter the study by signing written informed consent

Exclusion criteria

• Received any localized cancer therapeutic modalities (e.g., surgery on target lesions, radiotherapy) within 4 weeks prior to initial dosing (except the palliative radiotherapy performed on non-target local lesions), or have any unrecovered surgical wound (except the wound from the biopsy at screening)
• Received anti-tumor therapies such as chemotherapy, small molecular targeted therapy, hormone therapy, biological product therapy (mAbs, bispecific antibody, and ADC), or other anti-cancer agents within 2 weeks or 5 half-lives (whichever is shorter) before the first AM-928 dosing; received immunotherapy within 4 weeks or 5 half-lives (whichever is shorter) before the first AM-928 dosing.
• Carries history of primary malignancy other than the entry diagnosis that could affect compliance with the protocol or interpretation of results within 3 years prior to the Screening Visit, except curatively treated non-melanoma skin cancer, cervical carcinoma in situ, or superficial bladder tumors
• Received immunosuppressive medication(s) (including, but not limited to, steroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, tumor necrosis factor-ɑ antagonists, and calcineurin inhibitors) within 2 weeks (for those half-life ≤ 72 hours) or 4 weeks (for those half-life > 72 hours) prior to study dosing and during the study period, with the following caveats:

• For steroids, ≤10 mg of prednisone per day or equivalent is allowed
• Topical, ocular, intra-articular, intranasal, and inhaled corticosteroids is allowed. For a subject under long-term treatment of a concurrent disease/status, the dose should be stable (i.e., no change or decreasing dose) within 3 months prior to C1D1
• The use of inhaled corticosteroids is allowed if they are on a stable dose (i.e., no change or decreasing dose within 3 months prior to C1D1)
• The use of oral mineralocorticoids is allowed
• Physiologic doses of corticosteroids for adrenal insufficiency or supportive care for a subject's advanced tumor may be allowed at the investigator's discretion
• Subject with significant cardiopulmonary abnormalities as defined by:

• Poorly controlled hypertension (systolic blood pressure > 150 mm-Hg and/or diastolic blood pressure > 100 mm-Hg on anti-hypersensitive medications)
• Left ventricular ejection fraction (LVEF) < 50% at screening
• History of symptomatic congestive heart failure > class 2 per New York Heart Association (NYHA) classification
• History of myocarditis
• Myocardial ischemia/infarction or unstable angina within 6 months of study enrollment
• Uncontrolled serious cardiac arrhythmias
• Corrected QT interval > 470 ms demonstrated by at least 2 ECGs > 30 minutes apart
• Evidence of active pneumonitis (including drug-induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or history of idiopathic pulmonary fibrosis. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• History of 2nd or 3rd-degree atrioventricular conduction defects
• History of thromboembolic or cerebrovascular events within the last 6 months at screening, including transient ischemic attack, cerebrovascular accident, or deep vein thrombosis
• Prior treatment with any EpCAM-targeted anti-cancer therapies
• Subjects with the following infections:

• History of active pulmonary tuberculosis infection ≤ 48 weeks prior to C1D1, regardless of treatment
• Any major episode of infection requiring treatment with systemic antibiotics or hospitalization within 2 weeks prior to C1D1
• Known human immunodeficiency virus (HIV) history
• Presence of hepatitis B surface antigen (HBsAg) with HBV viral load > 2000 IU/mL (HBsAg-positive subjects with HBV viral load ≤ 2000 IU/mL are eligible. These subjects should continue to receive antiviral treatment during the study treatment and follow local HBV antiviral treatment standards after the study treatment during the study)
• HCV RNA positive (subjects with a history of HCV infection are eligible if their HCV viral load cannot be detected at screening; curative antiviral therapy should have been completed at least 4 weeks before C1D1)
• Administration of a live, attenuated vaccine within 4 weeks before C1D1 or anticipation that such a live, attenuated vaccine will be required during the study
• Received any investigational product within 4 weeks before C1D1
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to humanized antibodies
• Known hypersensitivity to any of the components of AM-928
• Has unstable/uncontrolled central nervous system (CNS) malignancy, leptomeningeal, or brain metastasis (progressing or those who continue to require glucocorticoids or intrathecal chemotherapy)
• Has symptomatic pleural effusion, pericardial effusion, or poorly controlled ascites
• Suffering from side/toxic effects of previous or current therapy [i.e., National Cancer Institute - Common Terminology Criteria for Adverse Event (NCI-CTCAE) ≥ Grade 2] that, judged by the investigator, may interfere with the trial results or the subject's safety
• Prior allogeneic stem cell, solid organ, or bone marrow transplantation
• Subject with any underlying medical, mental, or psychological conditions that would impair the treatment compliance, contraindicate the use of the investigational product, or that may render the subject at high risk from treatment complications, in the opinion of the investigator, would not permit to participate in the study
• All male subjects and female subjects with childbearing potential (between puberty and 1 year after menopause) should use at least one of the appropriate contraception methods shown below from signing ICF to at least 4 months or 5 half-lives (if data available), whichever is longer, after stopping study treatment.

• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject.
• Combination of any two of the following listed methods: (d.1+d.2 or d.1+d.3, or d.2+d.3):

d.1. Use oral, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example, hormone vaginal ring or transdermal hormone contraception.

d.2. Placement of an intrauterine device (IUD) or intrauterine system (IUS). d.3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.