A Study of WJ05129 in Advanced Malignant Solid Tumors

Study Overview
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Brief Summary
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This study was an open, multicenter Phase I/II clinical study of WJ05129 in patients with locally advanced or metastatic malignant solid tumors in China, which was divided into three stages: dose escalation, dose extension and efficacy extension. The study included screening, treatment and follow-up periods. Dose escalation phase: adopt 3 + 3 dose escalation mode, preset 5 dose groups: 1.25mg, 2.5mg, 5mg, 7.5mg, 10mg, oral, twice a day (only once on the first day), planned to include a maximum of 30 subjects; Dose expansion phase: 2 dose groups will be planned in this phase, and the specific dose will be determined according to the trial data in the dose escalation phase. The maximum number of participants in each dose group will be 12. Efficacy expansion phase: It is preliminarily planned to expand three cohorts of Rb negative TNBC and SCLC and NB with high Myc expression, and recruit about 24 people in each cohort.

Official Title
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A Phase I/II Clinical Study of WJ05129 Tablets in Patients With Locally Advanced or Metastatic Malignant Solid Tumors

Conditions
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Locally Advanced or Metastatic Malignant Solid Tumors

Intervention / Treatment
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* Drug: WJ05129


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to participate in the clinical trial of this drug, able to understand and sign informed consent, willing and able to comply with the planned visit and study procedures; Age ≥18 to 75 years old, male and female; Locally advanced (except for patients who can be treated with radical therapy) or metastatic malignant solid tumors (only for dose escalation or dose extension phase) confirmed by histology or cytology; Patients who have failed standard treatment, cannot tolerate standard treatment or have no standard treatment; Note: At least one line of standard chemotherapy, no more than four lines of treatment; Eastern Cooperative Oncology Group (ECOG) Physical status score (Annex 2) 0 to 1; Expected survival ≥ 12 weeks; According to the Response evaluation criteria in solid Tumors (RECIST) 1.1 (Annex 4), there is at least one measurable lesion; Voluntarily and informed consent to provide fresh biopsy samples before treatment. For patients unable to provide fresh biopsy samples before treatment, archived samples within 2 years can be provided (dose escalation stage is optional, dose expansion and efficacy expansion stage is mandatory); Have sufficient important organ functions, and meet the following standards in laboratory examination ≤ 7 days before the first drug administration: A: Blood system (transfusion and cytokine support therapy are not allowed within 14 days prior to initial administration) : Hemoglobin ≥ 90 g/L; Platelet count ≥ 100×109/L; Absolute neutrophil count ≥ 1.5×109/L B: Kidney function: Serum albumin ≥30g/L. (Albumin infusion is not allowed within 14 days before administration) Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤ 2.5 × Upper limit of normal (ULN); If liver metastasis occurred, AST/ALT ≤ 5 × ULN; Serum total bilirubin ≤ 1.5 × ULN; TBIL≤3×ULN in patients with liver metastasis or Gilbert syndrome; Serum creatinine (Cr) ≤1.5 TIMES ULN or creatinine clearance (calculated using the Cockcroft and Gault formula [Appendix 1]) ≥ 50 mL/min; C: Coagulation function: International standardized ratio (INR), prothrombin time (PT) and activated partial thrombin time (aPTT) ≤ 1.5ULN for patients who did not receive anticoagulant therapy; For those receiving anticoagulant therapy (e.g., low molecular weight heparin or warfarin), the anticoagulant dose should be stable for at least 4 weeks without dose adjustment; A pregnancy test must be performed within 7 days before the first use of the study drug for premenopausal women who are likely to have children. The blood pregnancy test must be negative and must be non-lactation; All enrolled patients (male or female) should take adequate contraceptive measures throughout the treatment period and within 3 months after the end of treatment; Patients diagnosed with locally advanced or metastatic malignant solid tumors by histopathological and/or cytological tests, and meeting the following criteria (only for the efficacy expansion phase) : There is evidence of rB-negative SCLC patients who fail platinum therapy; There is evidence of RB-negative TNBC in patients who failed standard therapy; There is evidence of refractory NB patients with high Myc expression. Aged 2 to 21 years and with active disease in at least one site of bone, bone marrow or soft tissue, advanced age patients are preferred; Exclusion Criteria: Persons already known to be allergic to the active ingredients or excipients of the study drugs (WJ05129 tablets) Patients previously treated with AURORA A kinase inhibitors (Alisertib, LY3295668, etc.); Subjects who received a potent cytochrome CYP3A inhibitor or inducer within 14 days prior to initial administration and who needed to take these drugs throughout the study period; Participate in other clinical studies within 4 weeks prior to initial administration, except during the follow-up period of observational (non-interventional) clinical studies or interventional studies; Inability to swallow drugs orally, or having a condition that seriously affects gastrointestinal absorption as judged by the investigator; Pregnant or lactating women; Two or more malignancies within 5 years prior to first administration. Except for early stage malignant neoplasms (carcinoma in situ or stage I neoplasms) that have been eradicated, such as adequately treated carcinoma in situ of the cervix, basal cell or squamous cell carcinoma, etc.; Underwent major surgery (as determined by the investigator) or was undergoing surgical recovery within 4 weeks prior to initial dosing. Anti-tumor chemotherapy (eluting for 6 weeks for the last chemotherapy with nitrosourea or mitomycin), radiotherapy, targeted therapy, hormone therapy, immunotherapy, or biotherapy within 4 weeks prior to initial administration. Receive anti-tumor or immunomodulatory TCM or Chinese adult medicine preparations within 2 weeks before the first administration; Patients with symptoms of central nervous system metastasis (if asymptomatic and not currently receiving corticosteroid treatment, they are allowed to be enrolled) or primary tumor disease of the central nervous system; Spinal cord compression that cannot be treated radically by surgery and/or radiotherapy, or for previously diagnosed spinal cord compression that is treated without clinical evidence of disease stability ≥1 week prior to randomization; No remission of toxicity after previous antitumor therapy, i.e., no regression to the level specified in baseline, nCI-CTCAE5.0 level 0 1 (except hair loss), or inclusion/exclusion criteria. Irreversible toxicity not reasonably expected to be aggravated by the study drug (e.g., hearing loss) may be included after consultation with the medical monitor ; Repeated drainage is required for third space effusion with clinical symptoms, such as pericardial effusion, pleural effusion and abdominal effusion that cannot be controlled by drainage or other treatment; Patients with active hepatitis B (chronic or acute, defined as patients with HBsAg positive at baseline and HBV DNA copy number greater than the upper limit of the normal value in the laboratory of the study center), or HCV positive (HCV Ab positive and HCV RNA positive); Patients with prior HBV infection or cured hepatitis B (defined as HBcAb positive and HBsAg negative) can be enrolled. These patients should be tested for HBV DNA expression at the same time before randomization, and the copy number of HBV DNA should be lower than the upper limit of the normal value in the laboratory department of the research center; Patients with POSITIVE HCV antibodies can only be enrolled if HCV RNA PCR test results are negative. Known human immunodeficiency virus (HIV) positive persons; Active tuberculosis patients; Suffering from other serious complications (such as uncontrollable infection, uncontrollable hypokalemia, hypomagnesia, hypocalcemia, hypertension and thromboembolic diseases, etc.); The patient has a history of major upper gastrointestinal surgery, active gastrointestinal disease or other diseases that may significantly affect drug absorption, metabolism or excretion; Patients with grade 2 or more neuropathy; Have a history of serious cardiovascular disease, including but not limited to: myocardial infarction or cerebrovascular accident within 6 months before enrollment, New York Cardiology > class II congestive heart failure, unstable angina pectoris, arrhythmia, etc.; Prior allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation; Receive live or attenuated live vaccine within 30 days of initial administration, or plan to receive live vaccine during the study period; Mental illness, alcohol, drug or substance abuse are known As determined by the investigator, the subject has other factors that may lead to the termination of the study, such as non-compliance with the protocol, other serious diseases requiring combined treatment, serious abnormal laboratory examination, family or social factors, etc., which may affect the safety of the subject, or the collection of data and samples.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental： WJ05129 tablets<br>Twice daily (except for single dose), 12 hours apart, fixed time is recommended | Drug: WJ05129<br>* WJ05129:Twice daily (except for single dose), 12 hours apart, fixed time is recommended<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | It is suitable for dose escalation and dose extension.DLT is defined as any of the following toxic reactions that SMC considers to have occurred during the DLT observation period and may be causally related to WJ05129. | 2 years | 
| The incidence of adverse events (AE) and serious adverse events (SAE) were assessed | It is suitable for dose escalation and dose extension.Incidence and severity of adverse events (AE) and serious adverse events (SAE) as assessed according to NCI-CTCAE 5.0, as well as abnormalities in physical examination, ECOG score, vital signs, electrocardiogram, ophthalmic tests and laboratory tests. | 2 years | 
| MTD | It is suitable for dose escalation and dose extension.If the number of DLT patients is 0 and the next higher dose is unacceptable, the current dose is declared MTD. | 2 years | 
| RP2D | It is suitable for dose escalation and dose extension.RP2D will be determined based on a combination of safety, tolerability, PK and/or pharmacodynamic studies . | 2 years | 
| Incidence of Treatment-Emergent Adverse Events | It is suitable for the curative effect development stage.Incidence and severity of adverse events (AE) and serious adverse events (SAE) as assessed according to NCI-CTCAE 5.0, as well as abnormalities in physical examination, ECOG score, vital signs, electrocardiogram, ophthalmic tests and laboratory tests. | 2 years | 
| ORR | It is suitable for the curative effect development stage.Objective Response Rate by RECIST 1.1,IMWG,RANO,IWG and Lugano 2014. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | It is suitable for dose escalation and dose extension.Maximum Plasma Concentration | 2 years | 
| Tmax | It is suitable for dose escalation and dose extension.Time to Cmax | 2 years | 
| AUC0-t | It is suitable for dose escalation and dose extension.Area under the concentration versus time curve from time 0 to the last measurable concentration | 2 years | 
| AUC0-inf | It is suitable for dose escalation and dose extension.AUC from time 0 to infinity | 2 years | 
| t1/2 | It is suitable for dose escalation and dose extension.Elimination half life time | 2 years | 
| CL/F | It is suitable for dose escalation and dose extension.Clearance | 2 years | 
| Vd/F | It is suitable for dose escalation and dose extension.Apparent volume of distribution | 2 years | 
| λz | It is suitable for dose escalation and dose extension.elimination rate constant | 2 years | 
| DOR | Duration of response | 2 years | 
| DCR | Disease Control Rate | 2 years | 
| PFS | Progression-free survival | 2 years | 
| OS | Overall survival | 2 years | 
| ORR | It is suitable for dose escalation and dose extension.Objective Response Rate by RECIST 1.1,IMWG,RANO,IWG and Lugano 2014. | 2 years | 
| Patient's blood drug concentration after taking the study drug. | It is suitable for the curative effect development stage | 2 years |