Prospective registration

A Study of SYS6043 in Patients with Advanced/Metastatic Solid Tumors

A Phase I Clinical Study of Dose Escalation, PK Expansion, and Cohort Expansion to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of SYS6043 in Patients with Advanced/Metastatic Solid Tumors

Clinical Trials Information Group 

Li Zhang 

No.896 East Zhongshan Road, Shijiazhuang, Hebei Province, China.

No. 651, Dongfeng East Road, Yuexiu District, Guangzhou

CSPC Megalith Biopharmaceutical Co., Ltd

Sun Yat-sen University Cancer Prevention Center

Yes

Ethics Committee of Sun Yat-sen University Cancer Center

Pan Xuzhi

Room 316, Cuiyuan Building, 23 Xianlie South Road, Yuexiu District, Guangzhou City, Guangdong Province

Ethics Committee of Sun Yat-sen University Cancer Center

No. 651, Dongfeng East Road, Yuexiu District, Guangzhou

CSPC Megalith Biopharmaceutical Co., Ltd

Advanced/Metastatic Solid Tumors

Interventional study

1

Single arm 

Primary objectives: To evaluate the safety and tolerability of SYS6043 treatment in patients with advanced/metastatic solid tumors; Determine the maximum tolerated dose (MTD, if available) and/or the recommended dose for phase 2 clinical trials (RP2D) for the SYS6043; To assess the preliminary effectiveness of SYS6043 for the treatment of patients with advanced/metastatic solid tumors. Secondary objectives: To evaluate the pharmacokinetic profile of SYS6043 in patients with advanced/metastatic solid tumors. To assess the immunogenicity of SYS6043 in patients with advanced/metastatic solid tumors. Preliminary evaluation of the anti-tumor activity of SYS6043 in patients with advanced/metastatic solid tumors. The expression levels of B7-H3 and PD-L1 proteins, as well as the correlation between gene variation and efficacy, were preliminarily evaluated.

Unless otherwise noted, the inclusion criteria listed below apply to both Phase Ia and Phase Ib studies. Participants must meet all of the following criteria to be selected: 1. Age 18-75 (inclusive) years old (subject to the day of signing the informed consent form). 2. Histologically or cytologically confirmed advanced/unresectable or metastatic solid tumors with disease recurrence or progression during or after standard systemic therapy, or intolerance to standard therapy for which no standard therapy is available. 3. At least one measurable lesion according to the Efficacy Evaluation Criteria for Solid Tumors (RECIST v1.1). Participants with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases will discuss the evaluation with the sponsor's medical monitor on a case-by-case basis before determining whether they are suitable for enrollment. 4. Participant expected survival>= 3 months. 5. ECOG score 0-1 with no score deterioration found within 28 days prior to enrollment. 6. ECHO or MUGA within 28 days prior to enrollment showing LVEF>=50%. 7. Vital organ function meeting the following requirements within 7 days prior to enrollment: a. Routine blood count (no whole blood, red blood cells, platelet transfusions within 7 days prior to sampling, and no drugs such as hematopoietic stimulating factor [G-CSF or GM-CSF], erythropoietin [EPO], thrombopoietin [TPO] to correct blood cell count): Neutrophil count ANC >=1.5×109/L; Platelet count PLT >=100×109/L; Hemoglobin HGB >=9 g/dL. b. Blood biochemistry: Creatinine clearance should be >=60 mL/min (calculated according to the Cockcroft-Gault formula); ? Serum total bilirubin TBIL <=1.5×ULN (relaxed to 3×ULN in participants with Gilbert's syndrome); Alanine aminotransferase ALT and aspartate aminotransferase AST <=2.5×ULN (hepatocellular carcinoma or liver metastases <=5.0×ULN). Serum albumin > = 30 g/L. c. Coagulation function: Activated partial thromboplastin time (APTT) and international normalized ratio (INR) <=1.5× ULN (no anticoagulation; Patients receiving anticoagulation should be within the target range of treatment and at a stable dose). 8. Toxicities induced by any prior therapy have returned to CTCAE 5.0 standard <=1 grade or baseline level (except for alopecia, fatigue, peripheral neuropathy, and other toxicities that the investigator considers not to be a safety risk to the participant). 9. Adequate treatment washout period of prior anti-tumor therapy, defined as in the table below, prior to the first dose: Chemotherapy >=3 weeks (5-fluorouracil, leucovorin, and/or weekly paclitaxel treatment >=2 weeks) nitrosourea or mitomycin C treatment >=6 weeks Tyrosine kinase inhibitor (TKI) >=1 week Small molecule targeted drugs (except TKIs) >=5 half-lives Chloroquine/hydroxychloroquine >=2 weeks Immunotherapy >=4 weeks Hormone therapy >=2 weeks, except for gonadotropin-releasing hormone (GnRH) agonists or antagonists for the treatment of prostate cancer, breast cancer, or oral contraceptives Anti-tumor TCM >=2 weeks Major surgery >=4 weeks (or 2 weeks for low-invasive cases [e.g., colostomy]), excluding procedures or procedures that can be recovered within 14 days prior to the first dose and considered to have resumed as assessed by the investigator, e.g., tumor biopsy Radiotherapy >=4 weeks (radical radiation therapy, or palliative radiation therapy to the chest) >=2 weeks (palliative radiotherapy to other sites [including breast]) CAR-T, drainage of pleural effusion, ascites, or pericardial effusion >=2 weeks Autologous transplantation >=3 months 10. Willing to provide a previously resected tumor sample or undergo a fresh tumor biopsy for the determination of B7-H3 levels and other biomarkers (if not contraindicated). Enrollment in the Phase Ia dose escalation phase does not limit B7-H3 expression levels. Enrollment in stage Ia PK amplification and stage Ib cervical cancer, small cell lung cancer, head and neck squamous cell carcinoma, endometrial cancer and prostate adenocarcinoma does not limit the expression level of B7-H3, and enrollment of other indications requires positive B7-H3 expression test by the central laboratory. 11. Female participants of childbearing potential with a negative serum pregnancy test within 7 days prior to randomization. Male and female participants of childbearing potential must agree to use adequate contraception for the duration of the study and for at least 7 months after the last dose of study drug; During this period, females are not lactating, male participants are not allowed to freeze or donate sperm, and female participants are not allowed to donate eggs or retrieve eggs for their own use. 12. Fully understand this clinical trial and voluntarily sign a written informed consent form. 13. Participants with small cell lung cancer (for Phase Ib Phase Ib Cohort 1): 1) Locally advanced or metastatic small cell lung cancer confirmed by pathology. 2) Disease recurrence/progression after treatment with at least one line of platinum-containing regimen (with or without PD-1/PD-L1 inhibitors) for ES-SCLC that has failed standard systemic therapy, with at least 2 cycles of platinum-containing chemotherapy without chemotherapy > 30 days. 3) No prior receipt of irinotecan, topotecan, or any other topoisomerase I inhibitor (including investigational TOP1 inhibitors) 14. Participants with squamous cell carcinoma of the lung (for Phase Ib Phase 2 Cohort): 1) Locally advanced or metastatic squamous cell carcinoma of the lung confirmed by pathology. 2) Positive B7-H3 expression by central laboratory test. 3) Failure of standard systemic therapy, including platinum-containing chemotherapy and/or PD-1/PD-L1 inhibitor therapy for advanced/metastatic stages. 15. Participants with esophageal squamous cell carcinoma (for Phase Ib cohort 3): 1) Locally advanced or metastatic esophageal or esophagogastric junction squamous cell carcinoma confirmed by pathology (esophageal adenosquamous cell carcinoma is allowed). 2) Positive B7-H3 expression by central laboratory test. 3) Failure of standard systemic therapy, including platinum-containing chemotherapy and/or PD-1/PD-L1 inhibitor therapy for the advanced/metastatic stage, if disease progression occurs during or within 6 months after adjuvant/neoadjuvant therapy, adjuvant/neoadjuvant therapy is considered to be a first-line systemic treatment for advanced disease. 16. Participants with cervical cancer (for Phase Ib Cohort 4): 1) Locally advanced or metastatic cervical cancer (pathological types including squamous cell carcinoma, adenocarcinoma and adenosquamous cell carcinoma) confirmed by pathology, not suitable for radical surgery or radical radiotherapy. 2) Failure of standard systemic therapy, including previous advanced/metastatic platinum-containing chemotherapy and/or PD-1/PD-L1 inhibitor therapy. 17. Participants with head and neck squamous cell carcinoma (for Phase Ib cohort 5): 1) Locally advanced or metastatic head and neck squamous cell carcinoma (oral, oropharynx, hypopharynx, larynx) confirmed by pathology, not suitable for radical surgery or radical radiotherapy. 2) Failure of standard systemic therapy, including prior disease progression after first-line platinum-containing chemotherapy and/or PD-1/PD-L1 inhibitor therapy, and no more than 2 lines of systemic therapy in the advanced/metastatic stage (progression during neoadjuvant/adjuvant chemotherapy or within 6 months after the last dose can be considered as first-line chemotherapy failure). 3) Imaging studies clearly show that the tumor has not invaded major blood vessels (such as carotid arteries). 4) No tumor-related bleeding events of >=3 (CTCAE 5.0 criteria) within 28 days prior to the first dose. 18. Participants with metastatic castration-resistant prostate cancer (mCRPC) (for Phase Ib cohort 6): 1) Adenocarcinoma of the prostate confirmed by pathology (excluding neuroendocrine differentiation or small cell components). 2) Within 28 days prior to the first dose, there is metastatic disease confirmed by CT, MRI or bone scan imaging. 3) Prostate cancer progression that meets PCWG3 criteria during androgen deprivation therapy (or bilateral scrotal resection). 4) Serum testosterone levels (<50 ng/dL or 1.7 nmol/L) before the first dose. 5) Androgen deprivation therapy (ADT) with LHRH agonists or LHRH antagonists can be continued during the study period or have previously undergone bilateral orchiectomy (surgical castration). 6) Prior treatment with pharmacological androgen deprivation therapy (or bilateral scrotal resection) and novel endocrine therapy (e.g., abiraterone, enzalutamide, apalutamide, darolutamide) and disease progression; 7) Failure of previous docetaxel treatment. 8) Patients with HRR mutations should have been treated with a PARP inhibitor (e.g., olaparib). 19. Hepatocellular carcinoma (for stage Ib cohort 7): 1) Locally advanced or metastatic hepatocellular carcinoma confirmed by pathology, not suitable for curative local therapy. 2) Positive B7-H3 expression by central laboratory test. 3) Failure of standard systemic therapy, including previous late/metastatic PD-1/PD-L1 inhibitors, TKIs (sorafenib, lenvatinib, apatinib, regorafenib, donafenib, etc.), and disease progression. 4) according to the Barcelona Clinical Liver Cancer Staging System (BCLC) stage C or B (not suitable for surgery/local treatment, including ablation therapy, interventional and radiotherapy) or CNLC (Chinese liver cancer staging) stage II-III (not suitable for surgery/local treatment, including ablation therapy, interventional and radiotherapy). 5) Child-Pugh score of A in liver function. 6) Patients with severe esophageal varices need to have been treated and there is no risk of bleeding at present. 20. B7-H3 expression-positive solid tumors (for Phase Ib cohort 8): 1) Locally advanced or metastatic solid tumors confirmed by pathology, mainly HER2-negative breast cancer (including triple-negative breast cancer, HR+/HER2- breast cancer), non-squamous non-small cell lung cancer, colorectal cancer, ovarian cancer, endometrial cancer, soft tissue sarcoma, etc. 2) Positive B7-H3 expression by central laboratory test (except endometrial cancer). 3) Disease recurrence or progression during or after receiving at least one line of standard therapy in the advanced/metastatic phase, or intolerance to standard therapy, or no standard treatment available.

Unless otherwise noted, the following exclusion criteria apply to both Phase Ia and Phase Ib studies. Participants who meet any of the following criteria will be excluded from this study: 1. Prior treatment with B7-H3 targeted therapy. 2. Prior treatment with topoisomerase inhibitor antibody conjugates (e.g., trastuzumab). 3. History of symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] Class II-IV) or severe arrhythmia requiring treatment. 4. History of myocardial infarction or unstable angina within 6 months prior to enrollment. 5. Mean QT interval (QTcF) corrected by Fredericia's formula for males and females lengthened to >470 milliseconds (ms) based on the results of three 12-lead electrocardiograms (ECGs). 6. Inability or unwillingness to discontinue concomitant medications known to prolong the QT interval. 7. Has a history of interstitial lung disease (e.g., non-infectious interstitial pneumonitis, pneumonia, pulmonary fibrosis, and severe radiation pneumonitis) or current interstitial lung disease or suspected of such disease by imaging at screening. 8. Has a history of underlying pulmonary disease, including but not limited to pulmonary embolism, severe asthma, severe COPD, restrictive lung disease, and other clinically significant lung impairment within 3 months prior to initiation of study treatment or the need for supplemental oxygen. 9. Any autoimmune, connective tissue disease, or inflammatory disease (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.) documented or suspected to involve the lungs at screening. 10. Presence of an uncontrolled infection requiring intravenous antibiotics, antivirals, or antifungals. 11. Known human immunodeficiency virus (HIV) infection. 12. Participants with active viral (any etiology) hepatitis were excluded. However, participants with serological evidence of chronic hepatitis B virus (HBV) infection (defined as a positive hepatitis B surface antigen [HBsAg] test or a positive hepatitis B core antibody test), viral load below the limit of quantification (HBV DNA titer <1000cps/ml or 200IU/ml), and who are not currently receiving antiviral therapy may be eligible to participate in the study and should be discussed with the sponsor's medical monitor. However, for participants with a history of hepatitis C virus (HCV) infection, only those who have completed curative antiviral therapy and have a viral load below the limit of quantification are eligible for enrollment in the study. 13. Lactating females (females who are willing to temporarily interrupt breastfeeding will also be excluded), or those who have been confirmed to be pregnant by pregnancy examination within 7 days prior to enrollment. 14. Presence of spinal cord compression or clinically active brain metastases, defined as untreated, symptomatic, or requiring corticosteroids or anticonvulsants to control related symptoms. Participants with asymptomatic central nervous system metastases who have been on stable radiological and neurological disease for at least 4 weeks after receiving central nervous system-directed therapy and who are on stable or decreasing doses of corticosteroids (equivalent to <=10mg/day prednisone) are eligible for study entry. 15. Multiple primary malignancies within 3 years prior to enrollment, with the exception of adequately resected non-melanoma skin cancer (e.g., resected basal or squamous cell skin cancer), orthotopic disease that has received curative therapy (e.g., cervical or breast carcinoma in situ), and other solid tumors that have received curative therapy (e.g., superficial bladder cancer). 16. Presence of a substance of abuse or any other medical condition that, in the opinion of the investigator, may increase the participant's safety risk or interfere with the participant's participation in the clinical study or clinical study evaluation. 17. Those who have received strong inhibitors or strong inducers of CYP3A4 within 14 days before the first use of the trial drug or need to continue to use such drugs during the trial. 18. Known hypersensitivity to the study drug substance or excipients. 19. Patients who, in the opinion of the investigator, have other reasons that make them unsuitable to participate in this study.

Phase 1b Cohort 1 was randomized at different doses through a randomized system.

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