NCT07833735尚未招募1 期
An Open-label, Multicenter Phase I/II Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics and Preliminary Efficacy of SYS6043 With or Without Bevacizumab, With or Without Chemotherapy in Participants With Advanced Solid Tumors
CSPC Megalith Biopharmaceutical Co.,Ltd.0 个研究点目标入组 400 人开始时间: 2026年10月15日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 400
- 主要终点
- Incidence of dose-limiting toxicities (DLTs) -(Phase I: Safety Run-in Study)
研究概览
简要总结
This is a multicenter, open-label, safety run-in, dose-expansion and cohort-expansion Phase I/II study designed to evaluate the safety, tolerability, PK profile and preliminary anti-tumor efficacy of SYS6043 (a B7-H3-targeted ADC) in participants with advanced/metastatic solid tumors. The trial consists of two phases: the Phase I component is the safety run-in study, and the Phase II component includes the dose-expansion study and cohort-expansion study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years (inclusive), as of the date of signing the Informed Consent Form (ICF).
- •Phase I Safety Run in Cohort: Participants with solid tumors whose disease has relapsed or progressed during or following standard of care systemic therapy, or who are intolerant to standard of care therapy and for whom no available standard of care treatment exists.
- •Phase II Dose expansion Stage: Participants with solid tumors whose disease has relapsed or progressed during or following standard of care systemic therapy, or who are intolerant to standard of care therapy and for whom no available standard of care treatment exists.
- •Phase II Cohort Expansion Stage: Participants with histologically or cytologically confirmed epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, with histological subtypes of high grade serous carcinoma or grade 2 3 endometrioid carcinoma:
- •Cohorts 1/2/3: Platinum sensitive recurrence (platinum sensitive recurrence is defined as disease progression or relapse ≥ 183 days after the last platinum containing chemotherapy).
- •Cohort 1: Participants with platinum sensitive recurrence who achieved clinical complete response (CR) or partial response (PR) following platinum containing chemotherapy combined with bevacizumab. A minimum of 3 cycles of bevacizumab plus platinum based chemotherapy are required. For participants who have undergone interval secondary cytoreductive surgery, administration of only 2 cycles of bevacizumab during the final 3 cycles of second line platinum triplet therapy is permitted. If participants carry germline or somatic BRCA1/2 mutations, prior exposure to PARP inhibitors is required; alternatively, participants may have BRCA wild type or unknown BRCA status. The maximum interval between the last dose of prior triplet therapy (defined as Day 1 of the last cycle of second line platinum containing triplet combination therapy) and Cycle 1 Day 1 (C1D1) of maintenance therapy with bevacizumab or SYS6043 combined with bevacizumab shall be 10 weeks. No clinical evidence of disease progression (by physical examination, imaging, or CA 125) shall be present prior to trial randomization.
- •Cohort 2: Participants with platinum sensitive recurrence who achieved clinical CR or PR following platinum containing chemotherapy without bevacizumab. If participants carry germline or somatic BRCA1/2 mutations, prior exposure to PARP inhibitors is required; alternatively, participants may have BRCA wild type or unknown BRCA status. The maximum interval between the last dose of prior triplet therapy (defined as Day 1 of the last cycle of second line platinum containing triplet combination therapy) and C1D1 of SYS6043 maintenance therapy shall be 10 weeks. No clinical evidence of disease progression (by physical examination, imaging, or CA 125) shall be present prior to trial randomization.
- •Cohort 3: Participants with platinum sensitive recurrence who have not received prior systemic therapy.
- •Cohort 4: First line treatment setting (no neoadjuvant therapy; newly diagnosed FIGO stage non I disease).
- •Cohort 5: Participants who achieved CR/PR after first line platinum containing chemotherapy with bevacizumab; BRCA1/2 wild type / HRD negative or unknown status. The maximum interval between the last dose of prior triplet therapy (defined as Day 1 of the last cycle of first line platinum containing triplet combination therapy) and C1D1 of maintenance therapy shall be 10 weeks. No clinical evidence of disease progression (by physical examination, imaging, or CA 125) shall be present prior to trial randomization.
- •At least one measurable extracranial target lesion per RECIST Version 1.1 (for Cohort 3 of Phase II only);
- •Participant's expected survival ≥ 3 months;
- •ECOG performance status 0-1 with no deterioration within 28 days prior to enrollment;
- •LVEF ≥ 50% demonstrated by ECHO or MUGA performed within 28 days prior to enrollment;
- •Adequate organ function as defined below, assessed within 7 days prior to enrollment:Major organ function must meet the following criteria within 7 days prior to enrollment:
- •Complete blood count (no whole blood, red blood cell, or platelet transfusion, and no administration of hematopoietic growth factors [G-CSF or GM-CSF], erythropoietin [EPO], or thrombopoietin [TPO] to correct blood cell counts within 7 days before sampling):i. Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L;Platelet count (PLT) ≥ 100 × 10^9/L;Hemoglobin (HGB) ≥ 90 g/L.
- •Blood biochemistry:i. Serum creatinine ≤ 1.5 × ULN;Serum total bilirubin (TBIL) ≤ 1.5 × ULN (participants with Gilbert's syndrome may be allowed up to 3 × ULN);Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5.0 × ULN for participants with hepatocellular carcinoma or liver metastasis);Serum albumin ≥ 30 g/L.
- •Coagulation function:
- •i. Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN (for participants not receiving anticoagulation therapy; for those on anticoagulation therapy, levels must be within the therapeutic range with stable dose).
- •Any toxicities related to prior therapy have resolved to CTCAE version 6.0 grade ≤1 or baseline level, excluding alopecia, fatigue, pigmentation, hypothyroidism stabilized with hormone replacement therapy, grade 2 peripheral neuropathy following chemotherapy, and other toxicities that the investigator deems not to pose a safety risk to participants.
- •A sufficient washout period from prior anti-tumor therapy is required prior to the first study drug administration.
- •Willing to provide a previously excised tumor sample or undergo a fresh tumor biopsy for the assessment of B7-H3 expression level (if no contraindications exist).
- •Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to first administration. Male and female participants with fertility must agree to take adequate contraceptive measures during the study period and for at least 7 months after the last administration of the investigational drug; During this period, women are not breastfeeding, male participants are not allowed to freeze or donate sperm, and female participants are not allowed to donate eggs or retrieve eggs for personal use.
- •Capable and willing to comply with the visits and procedures specified in the protocol.
排除标准
- •Participants with non epithelial ovarian carcinoma, clear cell carcinoma, mucinous carcinoma, carcinosarcoma or sarcoma, mixed tumors containing any of the above histologic subtypes, or low grade / borderline ovarian tumors (Phase II expansion cohort only);
- •Prior exposure to B7 H3 targeted therapy;
- •Prior treatment with topoisomerase 1 inhibitor based antibody drug conjugates (e.g., trastuzumab deruxtecan);
- •History of severe cardiac or cerebrovascular disease, e.g., heart failure with NYHA Class ≥ 2, acute coronary syndrome (e.g., myocardial infarction, unstable angina) within 6 months prior to screening, acute cerebrovascular events (e.g., transient ischemic attack, cerebral infarction, cerebral hemorrhage) within 6 months prior to screening;
- •Mean QT interval corrected by Fredericia formula > 470 ms based on three 12 lead ECG tracings; history of severe arrhythmias (e.g., complete left bundle branch block, third degree atrioventricular block, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter; transient atrial fibrillation/atrial flutter excluded);
- •Inability or unwillingness to discontinue concomitant medications known to prolong the QT interval;
- •History of interstitial lung disease / non infectious pneumonitis requiring corticosteroid therapy (e.g., non infectious interstitial pneumonitis, pulmonary interstitial fibrosis, severe radiation pneumonitis), or active interstitial lung disease / non infectious pneumonitis at present, or radiological suspicion of such disease at screening;
- •History of underlying pulmonary disease, including but not limited to pulmonary embolism within 3 months prior to study treatment initiation, severe asthma, severe chronic obstructive pulmonary disease (COPD), severe restrictive lung disease, other clinically significant pulmonary impairment, or requirement for supplemental oxygen;
- •Presence of active pulmonary tuberculosis. Participants who have received adequate anti tuberculosis therapy and completed anti tuberculosis treatment for ≥ 3 months prior to randomization are eligible;
- •Any autoimmune disease, connective tissue disease, or inflammatory disorder with documented or suspected pulmonary involvement at screening (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis);
- •Thrombotic events requiring therapeutic intervention within 6 months prior to screening, including unstable deep vein thrombosis, arterial thrombosis, pulmonary embolism, myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack. Isolated muscular calf vein thrombosis or catheter related thrombosis may be enrolled if assessed as low risk by the Investigator;
- •Uncontrolled infection requiring intravenous antibacterial, antiviral, or antifungal therapy;
- •Known human immunodeficiency virus (HIV) infection; active syphilis infection (positive treponemal antibody or condition requiring systemic therapy);
- •Participants with active viral hepatitis: positive hepatitis B surface antigen and/or positive hepatitis B core antibody with HBV DNA ≥ 10 000 copies/mL or 2000 IU/mL; positive HCV serology with HCV RNA above the lower limit of quantitation of the assay;
- •Spinal cord compression, clinically active brain metastases, or leptomeningeal metastases. Participants with central nervous system (CNS) metastases are eligible if they have received prior CNS directed therapy and have radiologically and neurologically stable disease for at least 4 weeks before first study drug administration (i.e., no new or progressive metastatic lesions on imaging, no corticosteroid requirement, or stable/decreasing corticosteroid dose equivalent to ≤ 10 mg prednisone per day, and asymptomatic). Untreated asymptomatic CNS metastases are permitted if immediate intervention is not deemed necessary by the Investigator;
- •Active malignancy diagnosed within 3 years prior to randomization, except for radically treated basal cell skin carcinoma, squamous cell skin carcinoma, superficial bladder carcinoma, cervical carcinoma in situ, breast carcinoma in situ, or other radically resected in situ malignancies judged eligible by the Investigator;
- •Moderate or greater pleural, pericardial, or ascitic effusion. Participants may be enrolled if effusion drainage (excluding diagnostic thoracentesis) has been performed and effusion remains stable for at least 2 weeks post drainage;
- •History of female genital tract fistula, genitourinary fistula, enterovaginal fistula, abdominal wall fistula, gastrointestinal perforation, refractory non healed gastric ulcer, or active gastrointestinal bleeding within 6 months prior to enrollment;
- •Bowel obstruction, or signs/symptoms of bowel obstruction, or requirement for parenteral nutrition within 1 month prior to study treatment initiation. Participants may proceed to screening if surgical decompression has been performed with complete resolution of obstruction. Prior enteral stent placement with the stent still in situ at screening;
- •Participants with active bleeding or bleeding diathesis, including known bleeding disorders, coagulopathy, or high bleeding risk tumor involving major blood vessels;
- •Major surgery within 4 weeks prior to screening (biopsy of any type and variceal procedures within 4 weeks are excluded);
- •Unhealed wounds, active ulcers, or fractures. Granulating wounds undergoing secondary intention healing without dehiscence or evidence of infection are permitted; wound assessment shall be performed every 3 weeks;
- •Major traumatic injury within 4 weeks before randomization;
- •Uncontrolled hypertension despite optimal antihypertensive pharmacotherapy, judged by the Investigator to render bevacizumab based therapy inappropriate;
- •History or physical exam evidence of central nervous system disorders, including primary brain tumor, seizures uncontrolled by standard medical therapy, brain metastases, or stroke within 5 years before first study treatment. History of severe psychiatric disorders, including but not limited to dementia, depression, seizure disorder, bipolar affective disorder;
- •Systemic anticoagulation is permitted, with the exception of vitamin K antagonists;
- •Any history of nephrotic syndrome or nephritic syndrome;
- •Clinically significant proteinuria: urine protein to creatinine ratio ≥ 1.0, or urine dipstick protein ≥ 2+, or urinalysis protein ≥ 2+. A 24 hour urine collection must demonstrate ≥ 1 g protein/24 h;
- •Tumor invasion into vital adjacent structures (e.g., mediastinal great vessels, superior vena cava, inferior vena cava, pericardium, heart, trachea, esophagus), or high risk of gastrointestinal / respiratory fistula formation;
- •Current or recent (within 6 months) major gastrointestinal / respiratory disease or condition, including: history of inflammatory bowel disease; post endoprosthesis placement within gastrointestinal or tracheal lumen; Grade ≥ 2 diarrhea within 2 weeks prior to first study drug administration; radiation enteritis;
- •Systemic administration of strong CYP3A4 inhibitors or inducers, or OATP1B1 / OATP1B3 inhibitors within 14 days prior to first study drug dose, or anticipated continued systemic use of such agents during study treatment;
- •Known hypersensitivity to active pharmaceutical ingredient or excipients of study drug;
- •Prior autologous or allogeneic stem cell transplantation;
- •Substance abuse, or any other medical condition that, in the Investigator's opinion, may increase participant safety risk, interfere with study participation, or confound study assessments;
- •Planned live vaccine administration, or receipt of live vaccine within 4 weeks before first study drug dose;
- •Any participant with other severe medical conditions, significant laboratory abnormalities, or poor adherence that may increase risks of study participation or confound study results, and who is deemed unsuitable for this study by the Investigator. Participants with local or systemic non-malignant disorders, or tumor-related sequelae/symptoms associated with substantial medical risk and/or uncertainty in survival assessment, e.g., tumor-related leukemoid reaction (white blood cell count > 20 × 10⁹/L), cachexia.
研究组 & 干预措施
SYS6043
Experimental
In this group, participants will receive SYS6043 ;
干预措施: SYS6043 (Drug)
SYS6043+ bevacizumab
Experimental
In this group, participants will receive SYS6043 with bevacizumab;
干预措施: bevacizumab (Drug)
SYS6043+ carboplatin
Experimental
In this group, participants will receive SYS6043 with carboplatin
干预措施: carboplatin (Drug)
Bevacizumab
Experimental
In this group, participants will receive bevacizumab ;
干预措施: bevacizumab (Drug)
SYS6043+ bevacizumab
Experimental
In this group, participants will receive SYS6043 with bevacizumab;
干预措施: SYS6043 (Drug)
SYS6043+ carboplatin
Experimental
In this group, participants will receive SYS6043 with carboplatin
干预措施: SYS6043 (Drug)
SYS6043 + carboplatin + bevacizumab
Experimental
In this froup, participants will receive SYS6043 with carboplatin and bevacizumab
干预措施: SYS6043 (Drug)
SYS6043 + carboplatin + bevacizumab
Experimental
In this froup, participants will receive SYS6043 with carboplatin and bevacizumab
干预措施: carboplatin (Drug)
SYS6043 + carboplatin + bevacizumab
Experimental
In this froup, participants will receive SYS6043 with carboplatin and bevacizumab
干预措施: bevacizumab (Drug)
结局指标
主要结局
Incidence of dose-limiting toxicities (DLTs) -(Phase I: Safety Run-in Study)
时间窗: 21 days for Arm 1-3.
Incidence of adverse events (AEs) and serious adverse events (SAEs) assessed by CTCAE 6.0-(Phase I: Safety Run-in Study)
时间窗: 2 years
Maximum tolerated dose (MTD) (if any) ) of SYS6043 with or without bevacizumab with or without carboplatin-(Phase I: Safety Run-in Study)
时间窗: Up to 1year
Recommended phase 2 dose (RP2D) of SYS6043 with or without bevacizumab with or without carboplatin-(Phase I: Safety Run-in Study)
时间窗: 2 years
Incidence of adverse events (AEs) and serious adverse events (SAEs) assessed by CTCAE 6.0-(Phase II: Dose-expansion Study)
时间窗: Up to 1year
PFS rate assessed by RECIST Version 1.1(Phase II: Cohort-expansion Study)
时间窗: 2 years
次要结局
- Number of Participants With Anti-Drug Antibodies (ADA): Incidence, titer of anti-SYS6043 antibodies, and incidence of neutralizing antibodies (if applicable) -( Phase II: Cohort expansion Study)(2 years)
- Serum concentrations of toxin-bound antibody of SYS6043-( Phase II: Cohort expansion Study)(2 years)
- Serum concentrations of total antibody of SYS6043-( Phase II: Cohort expansion Study)(2 years)
- Association between B7-H3 expression level and efficacy-(Phase II: Cohort expansion Study)(2 years)
- Association between B7-H3 expression level and safety-(Phase II: Cohort expansion Study)(2 years)
- Association between HRR related gene alterations in tumor tissue and efficacy(Phase II: Cohort expansion Study)(2 years)
- Association between HRR related gene alterations in tumor tissue and safety(Phase II: Cohort expansion Study)(2 years)
- PFS based on RECIST v1.1-(Phase I: Safety Run-in Study)(2 years)
- ORR based on RECIST v1.1-(Phase I: Safety Run-in Study)(2 years)
- DoR based on RECIST v1.1-(Phase I: Safety Run-in Study)(2 years)
- DCR by Blinded Independent Central Review (BICR) based on RECIST v1.1-(Phase I: Safety Run-in Study)(2 years)
- TTR based on RECIST v1.1-(Phase I: Safety Run-in Study)(2 years)
- OS-(Phase I: Safety Run-in Study)(2 years)
- Number of Participants With Anti-Drug Antibodies (ADA): Incidence, titer of anti-SYS6043 antibodies, and incidence of neutralizing antibodies (if applicable) -(Phase I: Safety Run-in Study)(2 years)
- Serum concentrations of toxin-bound antibody of SYS6043-(Phase I: Safety Run-in Study)(2 years)
- Serum concentrations of total antibody of SYS6043-(Phase I: Safety Run-in Study)(2 years)
- Association between B7-H3 expression level and efficacy-(Phase I: Safety Run-in Study)(2 years)
- Association between B7-H3 expression level and safety-(Phase I: Safety Run-in Study)(2 years)
- PFS based on RECIST v1.1-(Phase II: Dose expansion Study)(2 years)
- ORR based on RECIST v1.1-( Phase II: Dose expansion Study)(2 years)
- DoR based on RECIST v1.1-( Phase II: Dose expansion Study)(2 years)
- DCR by Blinded Independent Central Review (BICR) based on RECIST v1.1-( Phase II: Dose expansion Study)(2 years)
- TTR based on RECIST v1.1-( Phase II: Dose expansion Study)(2 years)
- OS-( Phase II: Dose expansion Study)(2 years)
- Number of Participants With Anti-Drug Antibodies (ADA): Incidence, titer of anti-SYS6043 antibodies, and incidence of neutralizing antibodies (if applicable) -( Phase II: Dose expansion Study)(2 years)
- Serum concentrations of toxin-bound antibody of SYS6043-( Phase II: Dose expansion Study)(2 years)
- Serum concentrations of total antibody of SYS6043-( Phase II: Dose expansion Study)(2 years)
- Association between B7-H3 expression level and efficacy-( Phase II: Dose expansion Study)(2 years)
- Association between B7-H3 expression level and safety-( Phase II: Dose expansion Study(2 years)
- PFS based on RECIST v1.1-(Phase II: Cohort expansion Study)(2 years)
- ORR based on RECIST v1.1-( Phase II: Cohort expansion Study)(2 years)
- DoR based on RECIST v1.1-( Phase II: Cohort expansion Study)(2 years)
- DCR based on RECIST v1.1-( Phase II: Cohort expansion Study)(2 years)
- TTR based on RECIST v1.1-( Phase II: Cohort expansion Study)(2 years)
- CA-125 response rate assessed by the investigator-( Phase II: Cohort expansion Study)(2 years)
- OS-( Phase II: Cohort expansion Study)(2 years)
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