Study of CHO-A04 in Advanced Solid Tumors

This Phase I/IIa, open-label, dose-escalation and cohort-expansion study aims to evaluate the safety, pharmacokinetics, and preliminary efficacy of CHO-A04 in subjects aged ≥ 18 years with advanced solid tumors.

Both Phases I and Phase IIa include a screening period of up to 4 weeks and study treatment once every week starting from Cycle 1 Day 1 (C1D1) until any treatment discontinuation criterion is met. Each treatment cycle of the study treatment is 28 days.

Subjects will receive intravenous (IV) infusion of CHO-A04 once a week for 4 weeks (D1, D8, D15, D22) as a treatment cycle. After the completion of last dose of the study treatment, subjects should complete the end-of-treatment (EOT) visit, safety follow-up (EOS) visit, and survival follow-up visits, unless withdrawn from this study.

• Phase I (accelerated titration and traditional 3+3 dose-escalation): Phase I consists of the accelerated titration and the traditional 3+3 dose-escalation design. Eligible subjects will be sequentially assigned into one of the dose levels. Dose level will be escalated from dose level 1 (starting dose) at 1 mg/kg/week to dose level 5 at 12 mg/kg/week of CHO-A04 (or may be de-escalated to dose level -1 at 0.5 mg/kg/week). If any ≥ Grade 2 CHO-A04 related adverse events (AEs) occurs in dose level 1 or dose level 2 subjects, the dose escalation/de-escalation rule will follow the 3+3 design. Intra-subject dose-escalation is not allowed in this study.

• Phase IIa (cohort-expansion): Two cohorts of up to 10 subjects per cohort will receive the Recommend Phase 2 Dose (R2PD), which is a dose equal to or lower than MTD based on the SRC's decision. The Sponsor will determine the cancer type for each cohort before initiation of Phase IIa.

Inclusion criteria

• With either gender aged ≥ 18 years
• Histologically/cytologically confirmed, locally advanced unresectable or metastatic solid tumors
• Must have been treated with established standard-of-care therapy, or physicians have determined that such established therapy is not sufficiently efficacious, or patients have declined to receive standard-of-care therapy
• Availability of archival tissue specimens for SSEA-4 immunohistochemistry (IHC) staining (optional for Phase I). Acceptable tumor tissues include:

• Tumor tissue sample collected at the time of initial diagnosis
• The most recent available recurrent/metastatic tumor biopsy tissue is preferred 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 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
• Has a life expectancy of at least 12 weeks in the opinion of the Investigator
• Has adequate hematopoietic function:

• Absolute neutrophil count (ANC) ≥ 1500 cells/μL without the need of myeloid growth factor support within 1 week
• Platelet ≥ 90×103 counts/μL without the need of platelet transfusion support within 1 week
• Hemoglobin ≥ 9.0 g/dL without the need of red blood cell (RBC) transfusion within 1 week
• Has adequate coagulation function: International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5× upper limit of the normal range (ULN)
• Has adequate liver function:

• Total bilirubin ≤ 1.5× ULN and no signs of jaundice (≤ 3× ULN for subjects with known Gilbert disease)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5× ULN or ≤ 5.0× ULN in case of documented hepatic metastasis or hepatocellular carcinoma (HCC). For subjects with HCC, the Child-Pugh score must be ≤ 6
• Has adequate renal function: estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2) Note: eGFR (mL/min/1.73 m2) = 186.3 × (serum creatinine in mg/dL)-1.154 × (age)-0.203× (0.742 if female) × (1.212 if African American/black)
• Willingness and ability to comply with protocol-stated requirements, instructions, and restrictions per Investigator's judgment
• Is able to understand the nature of this clinical study and accepts to enter the study by signing the informed consent form (ICF)

Exclusion criteria

• Has unresolved toxicities from prior anticancer therapy, defined as having not resolved to ≤ Grade 1 (NCI-CTCAE v5.0), except for alopecia and laboratory values listed in the inclusion criteria
• Has signs or symptoms of end-stage organ failure, major chronic illnesses other than cancer(s), or any severe concomitant conditions which, in the Investigator's opinion, make it undesirable for the subject to participate in the study, or could jeopardize compliance with the protocol
• History of another primary malignancy within the last 3 years (except for treated basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, or in situ cancer of the cervix) prior to the planned first infusion
• Has any significant cardiovascular or pulmonary diseases, including:

• Poorly controlled hypertension (systolic blood pressure ≥ 160 mm Hg and diastolic blood pressure ≥ 100 mm Hg)
• Left ventricular ejection fraction (LVEF) < 50% at the screening visit
• Congestive heart failure (defined as New York Heart Association Class III or IV), myocarditis, myocardial infarction, unstable angina, coronary angioplasty, coronary stenting, or coronary artery bypass graft within 24 weeks prior to the planned first infusion
• Uncontrolled serious cardiac arrhythmias, such as ongoing clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes) Note: Sustained ventricular tachycardia is defined as tachycardia that continues for more than 30 seconds or leads to hemodynamic compromise within 30 seconds and requires intervention
• Corrected QT interval (QTcF) > 480 ms demonstrated by at least two 12-lead 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 24 weeks before the screening visit, including transient ischemic attack, cerebrovascular accident, or deep vein thrombosis
• Has other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that would make the subject inappropriate for enrollment in this study in the opinion of the Investigator
• Has received anti-cancer therapies such as surgery on target lesions, chemotherapy, small molecule agent(s), hormone therapy, radiation therapy (except for palliative radiotherapy for bone metastasis of non-skeletal tumors), or any other anti-cancer agent(s) within 4 weeks or 5 half-lives of the treated agents, whichever is longer, prior to the first dosing. Has received prior anti-cancer monoclonal antibody therapy within 8 weeks prior to the first infusion.
• Has received systemic 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 with a half-life ≤ 72 hours) or 4 weeks (for those half-life > 72 hours) prior to study dosing.

Note: For regular steroid use, ≤ 10 mg of prednisolone per day or equivalent is allowed. Inhaled or topical corticosteroids are allowed.

• Has participated in other clinical studies for investigational product(s) or medical device within 4 weeks or 5 half-lives (if known) prior to the planned first infusion, whichever is longer
• Has received cell therapy within 12 weeks prior to the planned first infusion
• Prior allogeneic hematopoietic stem cell, solid organ, or bone marrow transplantation(s)
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the planned first infusion and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases. This exception does not include carcinomatous meningitis which is excluded regardless of its clinical stability

• Has symptomatic or poorly controlled pleural effusion, pericardial effusion, or ascites
• With the following infections:

• History of active pulmonary tuberculosis infection ≤ 48 weeks prior to the planned first infusion, regardless of tuberculosis treatment
• Any major episode of infection requiring treatment with systemic antibiotics or hospitalization within 4 weeks prior to the planned first infusion
• Positive HBsAg; subjects with positive HBsAg test results can be considered as eligible if subjects can receive anti-HBV viral treatment(s), e.g., entecavir or tenofovir
• Positive anti-HCV; subjects with positive for anti-HCV but with negative results for HCV viremia as shown by PCR are considered as eligible.
• Medical history showing confirmed HIV-1 positivity
• Administration of a live, attenuated vaccine within 4 weeks prior to the planned first infusion or anticipation that such a live, attenuated vaccine will be required during the treatment period.
• With known or suspected hypersensitivity to any ingredients of investigational product
• History of severe allergic, anaphylactic, or other severe hypersensitivity reactions to therapeutic humanized antibodies
• Female subject who is breastfeeding, has a positive pregnancy test result at eligibility checking, or expecting to conceive or have children within the projected duration of the trial, starting from the screening visit through 90 days after the last dose of study treatment.
• All male subjects and female subjects with childbearing potential* (between puberty and 2 years after menopause) refuse to use at least two of appropriate contraception methods shown below from signing the ICF to at least 3 months after taking the last dose of study treatment.

• 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.
• Placement of an intrauterine device (IUD) or intrauterine system (IUS).
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

• Male or female subjects who have undergone the following procedures are considered without childbearing potential.

• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 12 weeks before the screening visit. 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 (24 weeks prior to the first infusion).