A Phase 1 Open-label, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of HBM4003 in Subjects with Advanced Solid Tumors

1. Subject with HBV negative will be allowed.
a. If the subject has positive HBsAg, he/she should receive appropriate
antiviral therapy for hepatitis B virus (HBV) according to institutional
standard of care and HBV DNA level must be < 2000 UI/ml.
b. Negative HBsAg and positive HBcAb (past HBV), HBV DNA level must be <2000
UI/ml and the patient should be monitored for viral re-activation during the
study.
2. Subject with positive HCV-Ab should be tested HCV-RNA and could be enrolled
if HCVRNA titer is negative and should be monitored during the study.
3. Must have at least one measurable lesion at baseline based on Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1.
4. Must undergo tumor biopsy or provide archived tumor samples at screening.
5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
6. Adequate organ and bone marrow function, defined as:
a. Absolute neutrophil count *1×109/L, hemoglobin *9 g/dL, and platelet count
*50×109/L.
b. Adequate liver function defined as
* AST and ALT *2.5×upper limit of normal (ULN) and total bilirubin (TBIL)
*1.5×ULN;
* For subjects with liver metastases, ALT and AST * 5×ULN and TBIL * 2×ULN;
* For subjects with Gilbert syndrome, TBIL * 2×ULN.
c. Adequate renal function defined as creatinine clearance rate * 45mL/min
according to Cockcroft-Gault.
7. Subjects of reproductive potential must be willing to use adequate
contraception during the course of the study and through 3 months after the
last dose of HBM4003.
a. Females of childbearing potential may participate, providing they meet the
following conditions:
* Agree to practice abstinence; and If heterosexually active, agree to use at
least 2 highly effective contraceptive methods (oral, injectable, or
implantable hormonal contraceptive; tubal ligation; intra-uterine device;
barrier contraceptive with spermicide; or vasectomized partner) throughout the
study, and for 3 months following the last dose of IP; and
* Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL)
within 7 days prior to starting study therapy (note that the screening serum
pregnancy test can be used as the test prior to starting study therapy if it is
performed within the 7-day timeframe).
b. Or must be a female of non-childbearing potential, defined as:
* Postmenopausal (i.e., *1 year without any menses) prior to Screening Visit, or
* Documented surgically sterile (*1 month prior to Screening Visit).
c. Male subjects with a female partner of childbearing potential must agree to
practice
* Abstinence or to the use of a physician-approved contraceptive method
throughout the course of the study and avoid fathering a child during the
course of the study and for 3 months following the last dose of IP.
8. Life expectancy of*12 weeks (as determined by the investigator which could
be estimated according to the tumor burden, general conditions and function of
the organs of the patient)

Part 2 (Dose-Expansion Stage):
Male or female subject aged *18 years at the time of screening who has signed
the ICF prior to the initiation of any study-specific procedures and are
willing and able to comply with scheduled visits and other requirements of the
study.
Melanoma Cohort:
a. Histologically confirmed metastatic or unresectable melanoma that progressed
during or after treatment with a PD-1 inhibitor
b. Must have received BRAF inhibitor with/without a MEK inhibitor if positive
with BRAF V600-activating mutation and in addition to anti-PD-1 inhibitor
HCC Cohort:
a. Histologically confirmed metastatic or unresectable HCC;
b. Child-Pugh Score of 6 points or less (A5-A6);
c. Progressed on or after previous anti-PD-1 treatment, with or without other
synchronous or sequential systemic treatments (including anti-VEGFR TKI,
anti-VEGF/VEGFR monoclonal antibody or chemotherapy, etc).
RCC Cohort:
a. Histologically confirmed metastatic or unresectable renal cell cancer
(including both clear cell and non-clear histology);
b. Subjects with clear cell RCC must have failed at least 1 anti-VEGFR TKI
treatment and/or anti-PD(L)1 treatment;
c. For subjects with non-clear cell RCC (e.g. PRCC), treatment naive is
permitted.

1. History of severe or not under well controlled allergic diseases, history of
severe drug allergy, or are known to be allergic to macromolecular protein
preparations or any component of HBM4003
2. Subject receiving the following anti-cancer medications or investigational
drugs will be excluded:
a. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody or any CTLA-4
bispecific antibody before the first dose of HBM4003;
b. Programmed cell death protein 1 (PD-1)/Programmed cell death protein ligand
1 (PD-L1)/Programmed cell death protein ligand 2 (PD-L2)-directed antibody
within 8 weeks of first dose of HBM4003
c. Cancer vaccines within 3 months prior to first dose of HBM4003
d. Live vaccine within 4 weeks prior to first dose of HBM4003
e. Any other anti-cancer therapy within 2 weeks prior to first dose of HBM4003
3. Not yet recovered from surgery or (immune-related) toxicity related with
previous treatment
* Subject who has had major surgical procedure(s) within 28 days prior to the
first dose of HBM4003, or not yet recovered from a previous surgical procedure
4. Failed to recover from any immune-related toxicity from prior cancer therapy
to * Grade 1 prior to screening for this study
5. Concomitant medication or treatment
a. Any concurrent chemotherapy, radiotherapy, immunotherapy, or biological
therapy for cancer treatment. Concurrent use of hormones on a stable dose for
non-cancer related conditions is acceptable. Androgen deprivation therapy for
advanced prostate cancers is acceptable. Local treatment of isolated non-target
lesions for palliative intent is acceptable
b. Any traditional anti-tumor herbal medications (for example, semen coicis and
glaucescent fissistigma root are considered to have anti-tumor effect according
to the Traditional Chinese Medicine Pharmacopoeia of Chinese Pharmacopoeia);
c. Receipt of red blood cells or platelets infusion, granulocyte colony
stimulating factor (G-CSF) or granulocyte monocyte colony stimulating factor
(GM-CSF) within 1 week of the first dose of IP
d. Received treatment with corticosteroids or other immunosuppressive
medications within 2 weeks before the first dose of HBM4003
6. Have concomitant diseases that may affect the treatment efficacy and safety
evaluation
a. Known brain metastases or other central nervous system metastases that are
either symptomatic or untreated that require concurrent treatment, inclusive of
but not limited to surgery, radiation, and/or corticosteroids. Subjects with
previously treated brain metastases may participate provided they are
clinically stable for at least 4 weeks prior to study entry, have no evidence
of new or enlarging metastases, and are on a stable dose of steroids of total
daily dose of <1.5 mg/kg of dexamethasone
b. Active infection that requires treatment with antibiotics within 14 days
prior to first dose of HBM4003
c. Known history of infection with human immunodeficiency virus or known AIDS
d. autoimmune disease, including but not limited to inflammatory bowel disease,
autoimmune hepatitis, Guillain-Barré syndrome, demyelinating lesions, extensive
dermatitis, immune-related interstitial pneumonia or Grave*s disease requiring
antithyroid drugs
e. Known primary immunodeficiency
f. Clinically significant gastrointestinal disorders
g. Have received allogeneic organ transplantation or allogeneic hematopoietic
stem cell transplantation or have received autologous hematopoietic stem cell
transplantation within 3 months prior to the first dose
h. Subjects with medically confirmed autoimmune coeliac disease are to be
excluded
7. Subjects with clinically significant congenital or acquired cardiovascular
disease cardiovascular diseases
a. Electrocardiogram abnormalities that the Investigator believes the study
will pose an additional risk to the subject
b. Symptomatic congestive heart failure
c. Myocardial infarction within 3 months prior to the first dose of HBM4003
d. Uncontrolled hypertension, defined as an average systolic blood pressure *
160 mmHg or an average DBP * 100 mmHg
e. Unstable angina pectoris
f. Severe uncontrolled ventricular arrhythmia
8. History of other uncured or history of other malignancies
9. Pregnant or breastfeeding women
10. Any condition in the opinion of the Investigator would interfere with
evaluation of HBM4003
11. Have experienced immune-related GI adverse events on any prior
immunotherapy or toxicity that led to permanent discontinuation of prior
immunotherapy
12. Severe cirrhosis, hepatic atrophy or portal hypertension
13. Imaging studies indicated that the main portal vein tumor embolus is more
than 1/2 of the lumen, or inferior vena cava tumor embolus or heart involvement.
14. Any clinically significant pleural effusion, pericardial effusion or
ascites that cannot be controlled with continuous draining or other methods at
screening
15. Any history of hepatic encephalopathy (greater than or equal to Grade 2)
within 12 months prior to enrolment or require medications to prevent or
control encephalopathy.
16. Subjects weighing < 30 kg
17. Active or prior documented GI bleeding within 12 months