A Study Explore WJB001 Capsules in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a phase I/II study to evaluate the safety and tolerability, DLT(Dose limited toxicity), MTD(Maximum tolerated dose), and RP2D(Recommended phase II dose) of WJB001 capsules in patients with advanced solid tumors, including dose escalation phase, dose expansion phase and cohort expansion phase.The study includes screening, treatment and follow-up periods. In the Dose Escalation phase:Accelerated titration (the first two dose groups) and BOIN combination (the subsequent dose group) were used for dose escalation. In the Dose Expansion phase:Based on the previous data, 1 to 2 doses were selected to further evaluate the initial efficacy, safety, tolerability and pharmacokinetic characteristics to confirm RP2D. In the Cohort Expansion phase:The preliminary plan of cohort expansion phase uses the Simon two-stage optimal method to expand 2 to 3 cohorts.

Official Title
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A Phase I/II Study to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics and Preliminary Efficacy of WJB001 Capsules in Dose Escalation, Dose Expansion, and Efficacy Expansion in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: WJB001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years or older at the time of informed consent； Patient with advanced malignant solid tumors clearly diagnosed pathologically and/or cytologically, who have failed to receive standard treatment, or who currently no have standard treatment, or who are intolerant to standard treatment; Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score ≤1; Life expectancy ≥ 12 weeks; Adequate hematologic and organ function； All acute toxic effects from previous antineoplastic therapy or surgery ； Fertile women must confirm a negative blood pregnancy test within 7 days prior to the first administration of study drug;and they required to use adequate and effective contraceptive measures throughout the treatment period and within 3 months after the end of treatment;Fertile women in this protocol were defined as sexually mature women: 1) not undergoing hysterectomy or bilateral oophorectomy; 2) 24 months without a continuous period of spontaneous menopause (i.e., having had a period at any time in the previous 24 consecutive months; Amenorrhea after cancer treatment does not exclude fertility). Male participants with a sexual partner who was a woman of reproductive age had to agree to use an effective contraceptive method while using the study drug and for 3 months after the last dose. Specific inclusion criteria 8. Patient must have at least one measurable lesion as defined per RECIST v1.1;Have not biopsy history of the target lesion within the previous two weeks (mainly applicable to the dose expansion phase and the efficacy expansion phase) 9. Patient with advanced endometrial serous carcinoma or high-grade serous ovarian cancer with special biomarker (mainly applicable to the efficacy expansion phase); Exclusion Criteria: 1.General condition Pregnant or lactating women; Any known allergies to or contraindications to components of the study drug; History of substance abuse; History of alcohol abuse or consumption of more than 28 units of alcohol per week (1 unit =285 ml beer or 25 ml spirits (40%v/v) or 100 ml wine). 2.Previous or current treatment: Previous or current treatment with Wee1 inhibitors; Received cytotoxic chemotherapy drugs,anti-tumor traditional Chinese medicine orother anti-tumor therapies (such as small molecule targeted therapy, etc.)within 4 weeks prior to the first administration of study drug;Or received the investigational drug, macromolecular drug with anti-tumor effect (e.g., monoclonal antibody, antibody-drug conjugate, or bispecific antibody, etc.) within 28 days prior to the first administration of study drug; Or need to continue receiving these medications during the study; The use of a medium or strong inhibitor or inducer of CYP3A or other product (e.g., grapefruit juice) or P-gp inhibitor or inducer was discontinued less than the time before the first dose of WJB001 was administered 5 half-lives of the drug or 14 days, whichever is shorter; Patients with a known organ transplant or stem cell transplant; Major surgery or major trauma (excluding needle biopsy for sample collection) within 4 weeks prior to the first administration of study drug; Radiation therapy was administered within 21 days prior to the first administration of study drug; (except the radiation was delivered to ≤5% of bone marrow volume). 3. Past medical history, present medical history and abnormal laboratory indicators: Having active GI abnormalities including, but not limited to, inability to take oral medication, need for intravenous nutritional support, peptic ulcer, chronic diarrhea (e.g., Crohn's disease, irritable bowel syndrome), or vomiting or other factors that the investigator believes may significantly affect drug absorption, metabolism, or excretion; History of severe ocular disease (except permanent blindness due to disease) that has not recovered to grade 1 or less; Patients with active brain metastases (except if they had CNS metastases confined to the supratentorial or cerebellar region, had been adequately treated (surgery or radiotherapy), had maintained radiological stability for at least 4 weeks, and did not require corticosteroids for symptom control); Patients with current cancer meningitis or spinal cord compression; Severe or poorly controlled hypertension, including previous history of hypertensive crisis or hypertensive encephalopathy; Adjustment of antihypertensive medication due to poor blood pressure control within 2 weeks before the first dose;Systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg during the screening period; Patients with clinically significant bleeding symptoms or obvious bleeding tendency within 4 weeks before the first dose, such as gastrointestinal bleeding, gastric ulcer bleeding, obvious gross hematuria, or angiitis; Patients with active HBV and HCV infection: if HBsAg is positive or/and anti-HBc is positive, blood HBV DNA should be tested to confirm that it is above the limit of quantitative detection; If anti-HCV is positive, it is necessary to detect HCV RNA to confirm that the HCV virus copy number exceeds the quantitative detection limit. Known history of human immunodeficiency virus infection or seropositivity for HIV; History of syphilis (both treponema pallidum specific and non-specific antibodies were positive); History of other primary solid tumor (except a cured solid tumor that has been inactive for ≥5 years before screening and has a very low risk of recurrence）; Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease recurrence; Adequately treated carcinoma in situ with no evidence of disease recurrence, such as carcinoma in situ of the cervix); history of severe or what the investigators considered clinically significant cardiac disease affected the safety assessment； Severe active infectious diseases or other diseases that seriously affect the safety of the first medication occurred during the screening period; There are other factors that the investigator considers may affect the results of the study and interfere with the patient's participation in the study.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Sequential
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: WJB001 capsules<br>Once a day (QD). | Drug: WJB001<br>* Dose Escalation: Accelerated titration (the first two dose groups) and BOIN combination (the subsequent dose group) were used for dose escalation. Dose Expansion: Based on the previous data, 1 to 2 doses were selected to further evaluate the initial efficacy, safety, tolerability and pharmacokinetic characteristics to confirm RP2D. Cohort Expansion: The preliminary plan of cohort expansion phase uses the Simon two-stage optimal method to expand 2 to 3 cohorts.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1.Dose limited toxicity (DLT) | incidence of Dose limited toxicity(DLT); | 3 years | 
| 2.Adverse event (AE) | incidence and severity of adverse event (AE), Abnormal changes in laboratory and other tests of clinical significance; | 3 years | 
| 3.Serious adverse event (SAE) | incidence and severity of Serious adverse event (SAE); | 3 years | 
| 4.Maximum tolerated dose (MTD) | Maximum tolerated dose (MTD) | 2 years | 
| 5.Recommended phase II dose (RP2D) | Recommended phase II dose (RP2D) | 2 years | 
| 6.Objective response rate(ORR) | Efficacy endpoints: Objective response rate(ORR) per RECIST v1.1 | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 7. Peak time(Tmax) | Pharmacokinetic (PK) parameter : Peak time(Tmax) after a single dose; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 8.Maximum plasma concentration (Cmax) | Pharmacokinetic (PK) parameter : Maximum plasma concentration (Cmax) after a single dose; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 9. (AUC 0-t) | Pharmacokinetic (PK) parameter : Area under blood concentration - time curve(AUC 0-t) after a single dose; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 10. (AUC 0-∞) | Pharmacokinetic (PK) parameter : Area under blood concentration - time curve(AUC 0-∞) after a single dose; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 11.Apparent volume of distribution (Vd/F) | Pharmacokinetic (PK) parameter : Apparent volume of distribution (Vd/F) after a single dose; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 12.Clearance rate (CL/F) | Pharmacokinetic (PK) parameter : Clearance rate (CL/F) after a single dose; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 13. Elimination half-life time ( t1/2) | Pharmacokinetic (PK) parameter : Elimination half-life time ( t1/2) | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 14.Steady state peak concentration(Cmax,ss) | Pharmacokinetic (PK) parameter : Steady state peak concentration(Cmax,ss) after repeated administration; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 15.Steady state valley concentration(Cmin,ss) | Pharmacokinetic (PK) parameter : Steady state valley concentration(Cmin,ss) after repeated administration; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 16.Average steady-state plasma concentration(Cav,ss) | Pharmacokinetic (PK) parameter : Average steady-state plasma concentration(Cav,ss) after repeated administration; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 17. Steady state peak time(Tmax,ss) | Pharmacokinetic (PK) parameter : Steady state peak time(Tmax,ss) after repeated administration; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 18.Steady state Area under blood concentration - time curve(AUC0-t,ss) | Pharmacokinetic (PK) parameter : Steady state Area under blood concentration - time curve(AUC0-t,ss) after repeated administration; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 19.Accumulation Index ( RAC) | Pharmacokinetic (PK) parameter :Accumulation Index ( RAC) after repeated administration; | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 20.Fluctuation coefficient (FD) | Pharmacokinetic (PK) parameter : Fluctuation coefficient (FD) | Prior to dose on day 1,5,8,12 and at 0.5,1,1.5, 2,3, 4, 6,8,10 and 24 hours post dose on day 1 and day 12 of Cycle 1 | 
| 21.Duration of response (DOR) | Efficacy endpoints: Duration of response (DOR) per RECIST v1.1 | 3 years | 
| 22.Disease control rate (DCR) | Efficacy endpoints: Disease control rate (DCR) per RECIST v1.1 | 3 years | 
| 23.Progression-free survival (PFS) | Efficacy endpoints: Progression-free survival (PFS) per RECIST v1.1 | 2 years | 
| 24. Overall survival (OS) | Efficacy endpoints: Overall survival (OS) per RECIST v1.1 | 3 years |