Safety of AM-928 Infusion in Advanced Solid Tumors

This is a Phase I, open-label, dose-escalation study for a novel cancer treatment, AM-928, intravenous infusion antibody for advanced solid tumor. The study is aimed to learn the safety, tolerability, pharmacokinetics, and preliminary efficacy profile of AM-928.The dose escalation strategy will adopt accelerated titration combined with a Bayesian optimal interval (BOIN) design. Seven dose levels are designed and each participant will be assigned to a specific dose regimen depending on the time of enrollment. In the study, each participant will receive AM-928 treatment cycles till meeting any treatment discontinuation criterion and be followed for safety and long-term survival.The whole study is expected to take approximately three years to complete.

Inclusion Criteria:Male or female, age ≥ 18 yearsHistologically/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 availableAvailability 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 metastatic tumor biopsy tissue if available (a pre-treatment biopsy may be obtained if the biopsy site is safely accessible)Has at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2Subject's life expectancy of at least 12 weeksHas adequate hematopoietic, hepatic function and renal function:Hemoglobin ≥ 8.0 g/dL without transfusion or erythropoiesis stimulating agent support within 1 weekAbsolute neutrophil count (ANC) ≥ 1,500 cells/μL without WBC growth factor support within 1 weekTotal white blood cell (WBC) ≥ 2,500 cells/μLPlatelet ≥ 80,000 counts/μL without transfusion support within 1 weekTotal bilirubin ≤ 1.5× upper limit of normal (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/dLeGFR (CKD-EPI) ≥ 60 mL/min/1.73 m^2A female subject with childbearing potential should be confirmed of not being pregnant or not lactating at the screening and during the studyWillingness and ability to comply with protocol-stated requirements, instructions, and restrictions in the investigator's judgementIs able to understand the nature of this study and accepts to enter the study by signing written informed consentExclusion Criteria:Received any 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.Treatment with any chemotherapeutic agent, hormonal therapy (except hormone replacement therapy or oral contraceptives), or any other anti-cancer agent within 4 weeks or 5 half-lives of the treated agents, whichever is shorter, prior to initiation of AM-928 infusionCarries history of primary malignancy other than the entry diagnosis that could affect compliance with the protocol or interpretation of results within 5 years prior to the Screening Visit, except curatively treated non-melanoma skin cancer, cervical carcinoma in situ, or superficial bladder tumorsReceived systemic immunosuppressive medication(s) (including, but not limited to, steroids [excluding ≤10 mg of prednisone per day or equivalent], 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:Well-controlled eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., no psoriatic arthritis) at baseline that only requires low potency topical steroids is allowedThe use of inhaled corticosteroids is allowed if they are on a stable dose (i.e., no change in dose within 3 months prior to C1D1)The use of oral mineralocorticoids is allowedPhysiologic doses of corticosteroids for adrenal insufficiency or supportive care for a subject's advanced tumor may be allowed at the investigator's discretionSubject 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 screeningHistory of symptomatic congestive heart failure > class 2 per New York Heart Association (NYHA) classificationHistory of myocarditisMyocardial ischemia/infarction or unstable angina within 6 months of study enrollmentUncontrolled serious cardiac arrhythmiasCorrected QT interval > 470 ms demonstrated by at least 2 ECGs > 30 minutes apartEvidence 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 defectsHistory of thromboembolic or cerebrovascular events within the last 6 months at screening, including transient ischemic attack, cerebrovascular accident, or deep vein thrombosisPrior treatment with any EpCAM-targeted anti-cancer therapiesSubjects with the following infections:- History of active pulmonary tuberculosis infection ≤ 48 weeks prior to C1D1, regardless of treatmentAny major episode of infection requiring treatment with systemic antibiotics or hospitalization within 4 weeks prior to C1D1Known human immunodeficiency virus (HIV) historyPresence of hepatitis B surface antigen (HBsAg) or HCV RNA positiveAdministration of a live, attenuated vaccine within 4 weeks before C1D1 or anticipation that such a live, attenuated vaccine will be required during the studyReceived any investigational product within 4 weeks before C1D1History of severe allergic, anaphylactic, or other hypersensitivity reactions to humanized antibodiesKnown hypersensitivity to any of the components of AM-928Has 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 ascitesSuffering 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 safetyPrior allogeneic stem cell, solid organ, or bone marrow transplantationSubject 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 studyAll male subjects and female subjects with childbearing potential (between puberty and 2 years after menopause) should use at least one of the appropriate contraception methods shown below from signing ICF to at least 4 weeks 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.