| Eligibility |
Inclusion Criteria:
1. Male or female subjects aged =18 years old (inclusive);
2. ECOG score: 0-1 points;
3. Patients with histologically or cytologically confirmed locally advanced or metastatic
solid tumors, and those who failed or were intolerant to standard therapy, or have no
effective treatment options:
- Enrollment of patients with advanced solid tumors in the dose escalation phase;
- Subjects with melanoma, gastric cancer, head and neck squamous cell carcinoma
will be enrolled in the dose expansion phase;
4. Collect FFPE tumor tissue slides: Collect 12 to 13 archival pre-treatment (mandatory)
and 10 on-treatment (optional) paraffin sections from fresh tumor biopsies.
5. Subjects with at least 1 measurable lesion as per RECIST V1.1;
6. Expected survival = 3 months;
7. Main organ function is normal (within 7 days prior to the first dose), i.e., relevant
laboratory test criteria are met, and some laboratory indicators meet the following
criteria:
a) Hematology: i. Hemoglobin = 11.0 g/dL or 6.8 mmol/L, received no blood transfusion
within 7 days of evaluation, and without dependence on erythropoietin (EPO), ii.
Absolute neutrophil count (ANC) =1.5×109/L, iii. Platelets = 75×109/L; b) Renal
function: i. Creatinine clearance = 45 mL/min (calculated by Cockcroft-Gault formula),
ii. Qualitative urine protein = 1+; or qualitative urine protein = 2+, 24-hour urine
protein < 1 g; c) Liver function i. Serum total bilirubin = 1.5 × ULN, ii. Both
aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) = 2.5
× ULN, iii. Serum albumin = 2.8 g/dL (received no albumin infusion within 2 weeks
prior to blood collection); d) Coagulation function: i. International normalized ratio
(INR), or prothrombin time (PT) = 1.5 x ULN, or PT parameters can be maintained = 1.5
x ULN with an anticoagulant at a stable dose, ii. Activated partial thrombin time
(aPTT) = 1.5 × ULN, or aPTT parameters can be maintained = 1.5 × ULN with the use of
anticoagulants;
8. Male subjects with reproductive potential and female subjects with pregnancy potential
(which refer to men or women who have not been surgically sterilized, and women who
are not post-menopausal) must use highly effective contraceptive methods such as oral
contraceptives, intrauterine devices, sexual abstinence or barrier contraception in
conjunction with spermicides during the course of the study and until 6 months after
the last dose;
9. Subjects who are willing to participate in this study and sign the ICF, have good
compliance and cooperate with the follow-up.
Subjects must be excluded if they meet any of the following criteria:
1. Pregnant or breast-feeding women;
2. Have received prior treatment with CD47 or SIRPa inhibitors;
3. Have received prior treatment with CAR-T cell therapy;
4. Have received systemic anti-tumor therapy within 4 weeks prior to the start of the
study treatment, except for the following;
- Have received nitrosoureas or mitomycin C within 6 weeks prior to the first dose
of the investigational product;
- Have received oral fluorouracils and small-molecule targeted agents within 2
weeks prior to the first dose of the investigational product or within 5
half-lives of the drug, whichever is longer;
- Have received traditional Chinese medicine with anti-tumor indications within 2
weeks prior to the first dose of the investigational product.
5. With present or previous history of two or more primary tumors, except for cured
carcinoma in situ and basal cell carcinoma. Subjects with concurrent tumors that have
remained stable for more than 5 years prior to study enrollment are eligible;
6. Subjects who have active auto-immune diseases requiring systemic treatment with
immunomodulatory drugs within 12 months prior to treatment initiation, but relevant
alternative therapies are allowed;
7. Subjects who have received systemic treatment with corticosteroids (at doses higher
than 10 mg/day prednisone or the equivalent) or other immunosuppressants for more than
7 days within 2 weeks prior to the start of the study treatment (use of inhaled or
topical steroids or an adrenal replacement therapy at a dose exceeding 10 mg
prednisone equivalents is acceptable in the absence of active auto-immune diseases);
8. Subjects who have received other unmarketed investigational drugs or treatment within
4 weeks prior to the start of the study treatment;
9. Subjects who have undergone major surgeries or were severely traumatized within 4
weeks prior to the start of the study treatment, or those who are recovering from such
surgeries or traumas and the study results will be affected in the opinion of the
investigator, or those have been scheduled to undergo surgeries during their
participation in the study;
10. Have received chest radiotherapy or extended field radiotherapy (defined as more than
50% pelvic bone mass or equivalent) within 4 weeks prior to the initiation of study
treatment, or palliative radiotherapy within 2 weeks prior to the initiation of
treatment;
11. With the presence of symptomatic central nervous system (CNS) metastases and
neurological instability or a need to increase the dose of corticosteroids to control
CNS symptoms within 2 weeks prior to the start of the study treatment;
12. Have positive HBsAg and HBV-DNA > 500 IU/mL or the lower limit of detection of the
study site [only if the lower limit of detection at the site is higher than 500
IU/mL]); HCV antibody positive and HCV-RNA quantitative detection is above the upper
limit of normal;
13. With known positive human immunodeficiency virus (HIV) serum reaction;
14. With uncontrolled hydrothorax, ascites, or pericardial effusion;
15. Subjects who have or had prior active interstitial lung disease;
16. Subjects with hypertension that cannot be well controlled with drug therapies.
Clinical uncontrollable hypertension is defined as a systolic blood pressure > 150 mm
Hg or a diastolic blood pressure > 90 mm Hg (adjustment of anti-hypertensive drugs
before the start of this study is acceptable, but the average blood pressure of the
most recent three consecutive recordings must = 150/90 mm Hg prior to enrollment of
the study);
17. Adverse reactions to prior anti-tumor therapy have not recovered to Grade = 1 as per
CTCAE Ver 5.0 (except for toxicities that are judged by the investigator to have no
safety risk, such as alopecia, Grade 2 peripheral neurotoxicity, hypothyroidism which
is stable after hormone replacement therapy, etc.);
18. Have received immunotherapy and experienced Grade = 3 irAEs or Grade = 2
immune-related myocarditis;
19. Subjects with clinically significant cardiovascular disorder: including Grade II to IV
cardiac insufficiency defined by the classification criteria of New York Heart
Association (NYHA), congestive cardiac failure, heart block above Grade II, infarct
myocardial within the past 3 months, unstable arrhythmia or unstable angina,
significant QT interval prolongation (>450 ms for male and >470 ms for female); or
cerebral infarction within the past 3 months, or surgical history of percutaneous
transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG)
within the past 6 months;
20. With deep vein thrombosis within 6 months prior to the start of study treatment
(except for the subjects who have not used the anti-coagulation agent of warfarin for
more than 2 weeks prior to the start of the study treatment);
21. Thrombolytic therapy (except for the maintenance of an IV catheter) within 10 days
prior to treatment initiation;
22. Any active infection requiring intravenous anti-infective therapy;
23. Subjects with known or suspected conditions (e.g., alcoholism, drug dependence, or
psychological disorder) which render it impossible for them to comply with the
protocol, or who may be at rick if they participate in this study according to the
opinion of the investigator; or with the conditions in which subject's participation
in this study is not their best option as judged by the investigator, (e.g., causing
harm to health) or that affect, limit, or confound protocol assessments.
Exclusion Criteria:
1. Pregnant or breast-feeding women;
2. Prior treatment with CD47 or SIRPa inhibitors;
3. Prior CAR-T cell therapy;
4. Subjects who have received systemic anti-tumor therapies within 4 weeks prior to the
initiation of treatment or within five half-lives (whichever is shorter) of the study
drug, except for the following;
- Nitrosourea or mitomycin C within 6 weeks prior to the first dose of study drug;
- Oral fluorouracils and small molecule targeted agents are within 2 weeks prior to
the first dose of study drug or within 5 half-lives of the drug, whichever is
longer;
- Traditional Chinese medicine with anti-tumor indications is within 2 weeks prior
to the first dose of study drug.
5. Subjects who had or have two or more primary tumors cannot be enrolled, except for
cured carcinoma in situ and basal cell carcinoma. Subjects with concomitant tumors
that have been stable for more than 5 years before enrollment in the study can be
enrolled;
6. Subjects who have active auto-immune diseases requiring systemic treatment with
immunomodulatory drugs within 12 months prior to treatment initiation, but relevant
alternative therapies are allowed;
7. Subjects who have received systemic treatment with corticosteroids (more than 10
mg/day prednisone equivalent) or other immunosuppressants for more than 7 days within
2 weeks prior to treatment initiation (inhaled or topical steroids or adrenal
replacement therapy in excess of 10 mg prednisone equivalents is permitted in the
absence of active auto-immune disease);
8. Subjects who have participated in clinical trials (including investigational
vaccines), and received interventional and investigational treatment with invasive and
investigational medical devices within 4 weeks prior to the initiation of treatment;
9. Subjects who have experienced major surgery or severe trauma within 4 weeks prior to
treatment initiation, or who are recovering, but which will exert an impact on the
study as judged by the investigator, or who have surgical arrangements during their
participation in the study;
10. Chest radiotherapy or expanded field radiotherapy (defined as more than 50% pelvic
bone mass or equivalent) within 4 weeks prior to the initiation of treatment, or
palliative radiotherapy within 2 weeks prior to the initiation of treatment;
11. Presence of symptomatic metastases to the central nervous system (CNS) and
neurological instability within 2 weeks prior to initiation of dosing or a need to
increase the dose of steroids to control CNS symptoms;
12. HBsAg positive and HBV-DNA copies > 500 IU/ml or lower limit of detection at the site
(only if the lower limit of detection at the site is above 500 IU/ml); HCV antibody
positive and result of HCV-RNA quantitative assay above the ULN;
13. Known positive human immunodeficiency virus (HIV) serum reaction;
14. Subjects with uncontrollable hydrothorax, ascites, or pericardial effusion;
15. Subjects who have or had active interstitial lung disease;
16. Subjects with hypertension that cannot be well controlled with drug therapies.
Hypertension which cannot be controlled clinically is defined as a systolic blood
pressure > 150 mmHg or a diastolic blood pressure > 90 mmHg (adjustment of treatment
medications for hypertension is allowed before the initiation of this study, but the
average blood pressure calculated from the most recent three consecutive recordings
must = 150/90 mmHg prior to his/her entry into the study);
17. Adverse reactions of prior anti-tumor therapy have not recovered to = CTCAE 5.0 Grade
1 (except for alopecia, Grade 2 peripheral neurotoxicity and other toxicities judged
by the investigator to have no safety risk);
18. Subjects with clinically significant cardiovascular disorder: including Grade II to IV
cardiac insufficiency defined by the classification criteria of New York Heart
Association (NYHA), congestive cardiac failure, heart block above Grade II, infarct
myocardial within the past 3 months, unstable arrhythmia or unstable angina,
significant QT interval prolongation (>450 ms for male and >470 ms for female); or
cerebral infarction within the past 3 months, or surgical history of percutaneous
transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG)
within the past 6 months;
19. Deep vein thrombosis within 6 months prior to the initiation of treatment (except for
the case where warfarin has not been used for anti-coagulation for more than 2 weeks
prior to treatment initiation);
20. Thrombolytic therapy (except for the maintenance of an IV catheter) within 10 days
prior to treatment initiation;
21. Any active infection requiring intravenous anti-infective treatment;
22. Subjects with known or suspected conditions (e.g., alcoholism, drug dependence, or
psychological disorder) which render it impossible for them to comply with the
protocol, or who may be at risk if they participate in this study according to the
opinion of the investigator; or with the conditions in which subject's participation
in this study is not their best option as judged by the investigator, (e.g., causing
harm to health) or that affect, limit, or confound protocol assessments.
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