Inclusion Criteria:
1. Both male and female subjects who are at least 18 years old at the time of signing
the consent form;
2. Inclusion of patients with advanced malignancies confirmed histologically or
cytologically and meeting the following requirements:
- - Single-agent dose escalation and expansion phase to include patients with
advanced malignant tumors who have failed or are intolerant of standard
treatment, or have no standard treatment options;
- Therapeutic effect expansion stage of single drug:
1.
NSCLC: histologically or cytologically confirmed, unresectable locally
advanced, relapsed, or distant metastatic NSCLC that has progressed after
prior treatment with PD-(L)1 antibody and platinum-containing chemotherapy
(except after the last dose > Progression of adjuvant and neoadjuvant
therapy within 6 months). Subjects with EGFR or ALK mutations will need to
progress with prior treatment with appropriate kinase inhibitors.
2. Melanoma: histologically unresectable stage III or IV melanoma that has
progressed after prior chemotherapy and treatment with PD-(L)1 inhibitors
(except after the last dose > Adjuvant and neoadjuvant therapy that
progresses within 6 months); Mucosal melanoma does not require prior
PD-(L)1 inhibitor therapy.
3. CRC: colorectal adenocarcinoma or rectal adenocarcinoma with
histologically confirmed PD-L1 composite positive score [CPS] ≥1, failure
or intolerance of standard treatment, or no standard treatment options.
PD-L1 expression levels in tumor tissues are based on the results of the
central laboratory tests designated by the sponsor (the inclusion criteria
for PD-L1 expression levels can also be adjusted according to previous
data during the study).
4. RCC: Histologically confirmed metastatic or unresectable clear cell type
of RCC with disease progression after previous treatment with targeted
anti-angiogenesis therapy and PD-(L)1 inhibitors.
5. Other advanced malignancies: patients with advanced malignancies who have
failed or been intolerant to standard treatment or have no standard
treatment options.
NSCLC: histologically or cytologically confirmed, unresectable locally
advanced, relapsed, or distant metastatic NSCLC that has not progressed
after prior treatment with PD-(L)1 antibody and platinum-containing
chemotherapy (except after the last dose > Progression of adjuvant and
neoadjuvant therapy within 6 months). Subjects carrying EGFR or ALK
mutations were allowed to progress on kinase inhibitor therapy with a
previous ≤1 line.
2. CRC: Histologically confirmed PD-L1 CPS≥1 colorectal adenocarcinoma or
rectal adenocarcinoma without prior systemic therapy (except after the
last dose of medication > Adjuvant therapy that progresses within 6
months); In patients with MSI-H/dMMR, previous treatment with PD-(L)1
inhibitors is permitted. PD-L1 expression levels in tumor tissues are
based on the results of the central laboratory tests designated by the
sponsor (the inclusion criteria for PD-L1 expression levels can also be
adjusted according to previous data during the study).
3. RCC: Histologically confirmed metastatic or unresectable clear cell RCC
with disease progression after previous treatment with anti-angiogenesis
targeted therapy and PD-(L)1 inhibitors.
4. Melanoma: histologically unresectable stage III or IV melanoma that has
progressed after prior chemotherapy and treatment with PD-(L)1 inhibitors
(except after the last dose > Adjuvant therapy that progresses within 6
months).
5. HCC: Histologically/cytologically confirmed or cirrhotic patients meet the
clinical diagnostic criteria for HCC in AASLD, are identified as having
stage B (intermediate) or stage C (advanced) BCLC HCC and are not
candidates for radical surgery and/or local therapy, and have previously
received PD-(L)1 inhibitors and anti-angiogenic targeted therapy
progression.
6. Other advanced malignancies: patients with advanced malignancies who have
failed or been intolerant to standard treatment, or have no standard
treatment options.
3. ECOG score is 0 or 1;
4. Expected survival ≥12 weeks;
5. Have at least one measurable lesion according to RECIST 1.1 evaluation criteria;
6. Good organ function;
7. Fertile female or male subjects must agree to be childfree during the study period
until 6 months after the end of the last dose and voluntarily take highly effective
contraception with their partner; The serum pregnancy test for WOCBP must be
negative within 7 days prior to the first dose and must be non-lactation (specific
contraceptive methods and WOCBP definitions are set out in section 10.3);
8. Patients participate voluntarily, give full informed consent, sign written informed
consent, and have good compliance.
Exclusion Criteria:
1. Received the following drugs or treatments before the first dose:
1. received chemotherapy, immunotherapy and other anti-tumor therapy or other
investigational drugs within 21 days before the first dose, or received oral
fluorouracil, small molecule targeted drugs or Chinese medicines with
anti-tumor indications within 14 days before the first dose;
2. Major surgery or radiotherapy within 28 days before the first dose (palliative
radiotherapy for local bone/brain lesions allowed within 14 days before the
first dose), coarse needle puncture biopsy or other minor surgery within 7 days
before the start of study therapy, excluding placement of vascular infusion
devices;
3. In combination therapy, patients who have been systematically treated with
corticosteroids (> 10 mg prednisone per day or equivalent) or other
immunosuppressants for more than 1 week within 2 weeks prior to initial
administration are allowed to be treated with inhaled or topical steroids or
≤10 mg/ day systemic prednisone and equivalent doses of similar drugs;
2. There is active central nervous system metastasis. If the patient has received
radiotherapy or surgery in the past, imaging examination within 4 weeks before the
first medication indicates stable brain metastases without aggravation or new
neurological symptoms, hormone therapy has been discontinued 2 weeks before the
first medication, and screening is allowed; For meningeal and brainstem metastases,
screening is not allowed regardless of treatment.
3. Immune-related adverse events that led to permanent discontinuation occurred during
previous immunosuppressive therapy (such as anti-PD -(L)1, CTLA-4, LAG-3 inhibitors,
etc.);
4. There are pleural effusion, abdominal effusion or pericardial effusion with clinical
symptoms that require repeated treatment (puncture or drainage, etc.);
5. There is a history of interstitial lung disease or a history of non-infectious
pneumonia treated with corticosteroids, or imaging evidence of active pneumonia
during the screening period;
6. The presence of severe, unhealed or split wounds, active ulcers, or untreated
fractures (other than old fractures assessed by the investigator without clinical
intervention);
7. Obvious bleeding tendency or severe coagulation dysfunction;
8. Have poorly controlled hypertension (systolic blood pressure ≥150 mmHg and/or
diastolic blood pressure > 100 mmHg), or have a history of hypertensive crisis or
hypertensive encephalopathy;
9. The toxicity of previous antitumor therapy did not return to the level ≤ Class 1
prescribed by CTCAE v5.0 or the level specified by the inclusion/exclusion criteria,
except in the following cases: The related toxicity judged by the investigator to be
well controlled and does not affect the safety and compliance of patients using the
investigational drugs can be screened after confirmation with the sponsor;
10. Severe infection occurred within 28 days prior to administration in the first study
(CTCAE v5.0> Grade 2), such as severe pneumonia, bacteremia, infection
complications that require hospitalization; Active infection requiring intravenous
anti-infective therapy or fever of unknown origin > 38.5℃ occurred within 2 weeks
prior to the first study administration (as determined by the investigators,
subjects with fever due to tumors could be enrolled);
11. Clinically significant hemoptysis for any reason (such as blood loss reaching or
exceeding 50 ml/ day, or accompanied by clinical symptoms such as dyspnea and
shortness of breath) or tumor bleeding (such as significant bleeding caused by
tumor, manifested as hemoptysis, hematemesis, bloody stool, etc., and the blood loss
reaching 50 ml/ day or more) within 1 month before the first medication, Or
accompanied by anemia, hypotension, shock and other symptoms);
12. Gastrointestinal perforation, fistula, abdominal abscess, bleeding, or definite
bleeding tendency (including but not limited to: severe esophagofundus varicose
veins with bleeding risk, locally active digestive ulcer lesions [may be considered
in investigators' assessment of ulcer stability], persistent positive stool occult
blood, etc.) within 6 months before randomization; For patients with persistent
positive stool occult blood, if they are patients with colorectal cancer or gastric
cancer, and the positive occult blood test is believed to be related to tumor after
detailed evaluation (such as local bleeding, ulcers, etc.), gastrointestinal
bleeding is stable and does not cause clinical symptoms (such as anemia,
hypotension, etc.) under tumor treatment or disease control, they can be considered
for inclusion;
13. Severe cardiovascular and cerebrovascular diseases, including but not limited to,
History of myocardial infarction, severe/unstable angina pectoris, congestive heart
failure (NYHA cardiac function rating ≥2), clinically significant
supratrioventricular or ventricular arrhythmia requiring pharmacological
intervention, aortic aneurysm requiring surgical repair, any arterial
thromboembolism/embolism event, grade 3 or higher (CTCAE) within 6 months prior to
administration v5.0) Venous thrombosis/embolism events, transient ischemic attacks,
cerebrovascular accidents; Left ventricular ejection fraction (LVEF) by color
Doppler ultrasound < 50%. Corrected QTc> 480ms (using the Fridericia method,
if the QTc is abnormal, it can be detected three times at an interval of 2 minutes,
and the average value is calculated);
14. Active autoimmune diseases requiring systemic treatment (such as corticosteroids or
immunosuppressive drugs) are present within 2 years prior to initial medication,
including but not limited to systemic systemic lupus erythematosus, multiple
sclerosis, rheumatoid arthritis, inflammatory bowel disease, vasculitis, etc.
However, only thyroid, adrenal, or hypopituitarism, type 1 diabetes that can be
controlled with hormone replacement therapy, psoriasis or vitiligo that does not
require systemic treatment, and childhood asthma/allergies that have resolved are
eligible for screening;
15. Had suffered from another malignant tumor within 5 years before the first
medication; However, local tumors that have been cured are excluded, including
cervical carcinoma in situ, skin basal cell carcinoma and prostate carcinoma in
situ;
16. Active tuberculosis, hepatitis B (HBsAg positive with HBV DNA higher than 1000
copies /ml or 200 IU/ml), hepatitis C (HCVAb positive with HCV RNA higher than the
lower limit of detection);
17. A history of immunodeficiency, including HIV testing positive, or a known history of
allogeneic organ transplantation or allogeneic hematopoietic stem cell
transplantation;
18. The presence of other serious physical or mental illnesses or abnormalities in
laboratory tests that may increase the risk of participation in the study, affect
treatment compliance, or interfere with the study results, patients who are judged
by the investigator to be unsuitable for participation in the study.
