An Open-label, Multi-center, Dose-escalation and Cohort Expansion Phase I/IIa Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Profile and Efficacy of ACR246 in Patients With Advanced Solid Tumors

Inclusion Criteria:

Patients must meet all of the following inclusion criteria to be enrolled in this study:

1. Be willing to sign the ICF, be able to understand the study, and be willing tofollow and be able to complete all the study procedures;

2. Male and female, aged 18 to 75 years (inclusive);

3. For phase I dose escalation study: Patients with histologically or cytologicallyconfirmed recurrent or metastatic unresectable advanced solid tumors who experiencedisease progression after receiving systemic standard therapy, or have no standardtherapy;

4. For phase IIa cohort escalation study: Patients with histologically or cytologicallyconfirmed recurrent or metastatic unresectable advanced solid tumors who experiencedisease progression after receiving systemic standard therapy, or have no standardtherapy, including the following malignant tumors:

5. Esophageal cancer: Patients who experience disease progression after receivingprior ≥2 lines of chemotherapy;

6. Colorectal cancer: Patients who experience disease progression after receivingprior ≥2 lines of chemotherapy;

7. NSCLC: Patients with NSCLC meet the following conditions, and are unable tocontinue subsequent standard of care or have no standard of care available asjudged by the investigator: i. Positive for driver genes (such as EGFR, ALK, ROS1, MET); disease progressionafter current standard targeted therapy; ii. Negative for driver genes (such asEGFR, ALK, ROS1, MET); disease progression after prior ≥1 line(s) of therapy, anduse of platinum-based drugs in at least one regimen; d) Ovarian cancer: Patients whoexperience disease progression after receiving at least one prior line ofchemotherapy; the patient must receive prior treatment with PARP inhibitors ifharboring BRCA 1/2 mutations; e) Prostate cancer: Patients with metastaticcastration-resistant prostate cancer who receive at least one prior systemictherapy; f) Other solid tumors: Patients who experience disease progression afterreceiving prior standard of care, have no standard of care available, or arecurrently unsuitable to receive standard of care.

8. Positive for 5T4 expression as detected by the central laboratory (phase IIa only);

9. Phase I: Presence of at least one evaluable lesion by imaging as per RECIST v1.1;phase IIa: Presence of at least one measurable lesion by imaging as per RECIST v1.1.Lesions that are previously treated with radiotherapy cannot be considered targetlesions unless the lesions have unequivocal progression;

10. Toxicity from prior antitumor therapies returned to Grade ≤1 as defined by NCI-CTCAEv5.0, but with the exception for alopecia- or antitumor therapy-associated eventsthat can be tolerated by patients as judged by the investigator;

11. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1;

12. Adequate bone marrow, liver, kidney, and coagulation functions (refer to the upperlimit of normal [ULN] of each clinical study site): Bone marrow (did not receive blood transfusion or use drugs that increase whiteblood cells and platelets, e.g., cytokines or erythropoietin, within 2 weeks priorto laboratory tests): Absolute neutrophil count (ANC) count ≥1.5×109/L; Platelet (PLT) ≥100×109/L;Haemoglobin (Hb) ≥90 g/L; Liver function: Total bilirubin (TBiL) ≤1.5 × ULN; ALT, AST ≤2.5 × ULN in patients withoutmetastases to liver; ALT, AST ≤5 × ULN in patients with metastases to liver; Kidney function: Creatinine ≤1.5 × ULN or creatinine clearance (Ccr) ≥60 mL/min (according to theCockcroft-Gault formula); Coagulation function: International normalized ratio (INR) ≤1.5 × ULN; Activated partial thromboplastintime (APTT) ≤1.5 × ULN;

13. Expected survival ≥3 months;

14. At rest, left ventricular ejection fraction (LVEF) ≥50%;

15. Eligible male patients of reproductive potential and female patients of childbearingpotential, along with his/her partner, must agree to use medically acceptablecontraceptive measures (e.g., hormonal contraception, barrier method, or abstinence,etc.) during the study and for at least 6 months after the last dose.

Exclusion Criteria:

Patients meeting any of the following criteria should be excluded from the study:

1. Comorbid with other primary malignant tumors, except for:

2. Resolved non-invasive basal cell carcinoma or squamous cell carcinoma, andcervical carcinoma in situ;

3. Or other malignant tumors with a more than 5-year disease free survival;

4. Malignant tumors other than those with a more than 5-year disease freesurvival, but the patient may obtain benefits after enrollment as he/she has astable condition assessed by the investigator (for phase I dose escalationstudy only);

5. Received any systemic antitumor therapies (including chemotherapy, radiotherapy,biological therapy, immunotherapy, etc.) within 4 weeks prior to the first dose ofthe investigational drug; Received small molecule targeted drugs, Chinese herbalmedicines or Chinese patent medicines with antitumor indications or systemicimmunomodulators (including but not limited to interferon, interleukin-2, and tumornecrosis factor) within 2 weeks prior to the first dose of the investigational drug;

6. Prior treatment with any 5T4-targeted drug therapy;

7. Presence of active brain metastases or spinal cord metastases, being ineligible forinclusion in the study as assessed by the investigator; however, patients whorequire no radiotherapy, surgery or treatment with corticosteroids to control thesymptoms of metastases within 1 month prior to screening may be included in thestudy; patients with metastases to meninges will be excluded;

8. Known hypersensitivity to any of the active ingredients or excipients of ACR246, ordocumented history of allergy to protein drugs, experienced other serious allergicreactions, for which, the patient is not suitable to receive ACR246 as assessed bythe investigator;

9. History of severe heart disease as assessed by the investigator, e.g., symptomaticcardiac failure congestive (CHF) [Class ≥2 as per New York Heart Association (NYHA)functional classification], and history of myocardial infarction or unstable anginapectoris within 6 months prior to screening;

10. Serious arrhythmia requiring medication, e.g., corrected QT interval (Fredericaformula) >450 msec for male or >470 msec for female, complete left bundle branchblock, third-degree atrioventricular block;

11. Uncontrolled hypertension after medication treatment (systolic blood pressure ≥160mmHg or diastolic blood pressure ≥100 mmHg);

12. Dyspnoea at rest, severe primary pulmonary disorder currently requiring continuousoxygen therapy, history of interstitial lung disease and radiation pneumonitis,uncontrolled or potential risk of pulmonary fibrosis, or clinically active lungdiseases as indicated by any proof;

13. Serious or uncontrolled systemic diseases (e.g., unstable or uncompensatedrespiratory, heart, liver or kidney diseases), as assessed by the investigator;

14. Positive antibody tests for active hepatitis B (hepatitis B surface antigen positiveand HBV DNA≥1×103 IU/mL), active hepatitis C (hepatitis C antibody positive and HCVRNA > lower limit of detection), active syphilis (treponema pallidum antibodypositive and Rapid Plasma Reagin (RPR) titer positive), and human immunodeficiencyvirus (HIV) antibody positive, or any uncontrolled infections;

15. Had a major surgery or serious traumatic injuries (without complete recovery asassessed by the investigator) within 4 weeks prior to the first dose of theinvestigational drug, or plans to undergo a major surgery during the study;

16. Pregnant or lactating women;

17. Serious arterial/venous thrombosis (e.g., cerebrovascular accident [includingtransient ischaemic attack]), deep venous thrombosis, pulmonary embolism within 1year prior to treatment with the investigational drug, or haemorrhagic diathesiswithin 30 days prior to enrollment, or existence of risks of massivegastrointestinal hemorrhage, as assessed by the investigator;

18. Use of strong cytochrome P450 3A enzymes (CYP450 3A) inhibitors or inducers couldnot be stopped during treatment with the investigational drug;

19. Active eye disorders, such as keratitis, corneal disorder or eye infection,requiring intervention (including surgery or drug therapy, etc.);

20. Other condition that in the opinion of the investigator is not suitable for thestudy, e.g., poor compliance.