Clinical Trial of WB100 on Advanced Solid Tumor

Study Overview
=================
Brief Summary
-----------------
This is a phase I clinical study of WBC100 in Patients with advanced solid tumor.

Detailed Description
-----------------
This is a phase I open-label, single and dose escalation study to evaluate the safety, cell pharmacokinetics, and preliminary efficacy of WBC100, a drug targeting c-myc, in subjects who have been diagnosed with c-myc positive advanced solid tumor and refractory or intolerant to current standard systemic treatment.

Official Title
-----------------
An Open, Dose Escalation, Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of WBC100 in Patients With Advanced Solid Tumor

Conditions
-----------------
Solid Tumor

Intervention / Treatment
-----------------
* Drug: WBC100


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Sign informed consent, able to follow protocol requirements Aged 18 to 75 years, male or female Dose escalation stage: Histopathology or cytology proven advanced solid tumor with positive C-myc who have developed progressive disease or intolerability after at least one line of standard systemic therapies Dose expansion stage: Histopathology or cytology proven advanced pancreatic cancer with positive C-myc who are not suitable for surgery or local treatment, have developed progressive disease or intolerability after at least one line of standard systemic therapies Positive C-myc refer to C-myc overexpression: more than 10% tumor cells are detected 1+ by immunohistochemistry (IHC) ECOG Performance Status score: 0 to 2 points Expected survival is > 3 months Adequate hematologic and organ functions (without persistent supportive treatment) Absolute Neutrophil Count > 1.5 × 109/L, Platelet count ≥ 75 × 109/L, Hemoglobin > 8.5 g/dL INR and PT ≤ 2 × ULN Alb > 3.0 g/dL, Bilirubin level ≤ 2 × ULN, AST and ALT ≤ 2 × ULN or < 5 × ULN in the presence of liver metastases Calculated creatinine clearance (e.g. Cockcroft-Gault) ≥ 60 ml/min or serum creatinine ≤ 1.5 × ULN f. Left ventricular ejection fraction (LVEF) ≥ 50%. Heart rate (HR) ≥ 60 bpm. QT intervals, male ≤ 450 ms, female ≤ 470 ms According to RECIST 1.1, patients have at least one evaluable target lesion(only for dose expansion stage) Female patients of child-bearing potential or male subjects whose spouses are women of childbearing potential must agree to use a reliable method of contraception (IUD, oral contraceptive, condom) throughout the treatment period and for 3 months after discontinuation of WBC100. Female patients of child-bearing age must undergo a serum pregnancy test before the initiation of the study and the result must be negative. Exclusion Criteria: Allergic to WBC100 or its excipients or with allergic constitution Major surgery, active ulcer or unhealing wound occurred within 4 weeks before first dose Taken drugs in other clinical trials within 4 weeks or still in the safety follow-up period Subjects have Spinal compression, brain metastases and meningeal metastases (subjects who is asymptomatic, stable or with no need for steroid for at least 4 weeks before first dose are allowed) Subjects have history of cardiac insufficiency (NYHA III-IV) or uncontrolled congestive heart failure (NYHA II-IV) within 6 months before consent Subjects have risk factors of QT intervals prolongation or arrhythmia, such as Idiopathic Q-T interval prolongation syndrome or history of drug induced arrhythmia Subject have any condition within 6 months before consent: unstable angina pectoris requiring surgical intervention, uncontrolled hypertension (systolic pressure ≥ 140 mmHg, diastolic pressure ≥ 90 mmHg), myocardial infarction, stroke (lacunar infarction is allowed), Coronary/peripheral artery bypass surgery, pulmonary embolism Infection of HIV, active infection of HBV (HBV-DNA ≥ upper limits of normal) active infection of HC (HCV-RNA ≥ upper limits of normal) History of severe infection within 28 days before enrolled, including uncontrolled infection requiring systemic treatment of bacteria, virus and fungus The side effects caused by the previous treatment of the subjects did not return to grade ≤1 according to CTCAE 5.0 with exception of tolerable events determined by investigator such as hair loss and grade 2 Peripheral neuropathy Subjects with uncontrolled nausea or vomiting, chronic gastrointestinal diseases, unable to swallow pills, enterostomy, uncontrolled diarrhea or any intestinal surgery that cause insufficient absorption of WBC100 Subjects taking any CYP inducers or inhibitors or Chinese medicine within 7 days prior to the first dose of study drug History of malignancy in the last 2 years with the exception of patients with prior history of in situ breast cancer, in situ cervical cancer, basal or squamous cell skin cancer who have already been cured Subjects who have antitumor therapy within 28 days prior to first dose of WBC100, such as monoclonal antibody, chemotherapy, radiotherapy and Chinese medicine Subjects have mental disorders or history of drug abuse that may limit subjects' participation in this trial Unable to tolerate intravenous blood collection According to the investigators' evaluation, patients are unable or unwilling to comply with the requirements of the study protocol

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: WBC100<br>WBC100 | Drug: WBC100<br>* The first stage: single dose escalation according to classic 3+3 dose escalation method. 6 increasing dose levels were set up, with 3 to 6 cases per dose. The first dose group is 0.5 mg QD. The second dose group is 1mg QD. The third dose group is 1.5 mg QD. The fourth dose group is 2.0 mg QD. The fifth dose group is 2.5 mg QD. The sixth dose group is 3.0 mg QD. In each dose group, patients take WBC100 once on cycle 0. After a washout period of 2 days, patents start subsequent 4 weeks cycles until progression disease or intolerable toxicity. In each cycle, patient was on WBC100 every for 3 weeks and off for 1 week. The second stage: Two dose levels will be chosen according to data from the first stage. Each dose stage enroll 12 pancreatic patients with positive c-myc expression.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Adverse Event and Severe Adverse Event | AEs and SAEs will be assessed by CTCAE v5.0 | 2 years | 
| Dose limited toxicity（DLT） | safety | 28 days | 
| Maximum Tolerated Dose（MTD） | The highest dose level at which < 2 of 6 subjects experienced a dose limiting toxicity during the first 28 days of the treatment period | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Peak plasma concentration after one dose | 28 days | 
| Tmax | Time to peak plasma concentration after one dose | 28 days | 
| AUC0-t | Area under the plasma concentration versus time curve after one dose and multiple dose；time range from 0 to last point when plasma concentration is detectable | 28 days | 
| AUC0-inf | Area under the plasma concentration versus time curve；time range from 0 to infinity | 28 days | 
| T1/2 | half-life period | 28 days | 
| λz | elimination rate constant | 28 days | 
| CL/F | apparent clearance | 28 days | 
| Vz/F | apparent volume of distribution | 28 days | 
| Cmax, ss | Steady peak plasma concentration after multiple dose | 28 days | 
| Cmin, ss | Steady minimal plasma concentration after multiple dose | 28 days | 
| Cavg | Steady averagel plasma concentration after multiple dose | 28 days | 
| Tmax, ss | Time to steady peak plasma concentration after multiple dose | 28 days | 
| CLss/F | steady apparent clearance | 28 days | 
| Vss/F | steady apparent volume of distribution | 28 days | 
| ARCmax | Peak concerntration cumulative coefficient | 28 days | 
| ARAUC | AUC cumulative coefficient | 28 days | 
| DF | degree of fluctuation | 28 days | 
| CA19-9 | Change of CA19-9 | 28 days | 
| CA125 | Change of CA125 | 28 days | 
| Serum ferritin | change of serum ferritin | 28 days | 
| Progression-free survival (PFS) | The period from the day when the subject receives the first study treatment to the first recorded tumor progression (whether treated or not) or death of any cause, which occurs first | 2 years | 
| Duration of response (DOR) | The period from the first evaluation of complete response ( CR) or partial response (PR) to the first evaluation of progressive disease (PD)or death of any cause | 2 years | 
| Objective response rate (ORR) | The number of cases in which tumor size is reduced to partial response (PR) or complete response (CR) / the total number of evaluable cases (%). In the event of partial response( PR) or complete response (CR), the subjects should confirm it no less than 4 weeks after the first evaluation | 2 years | 
| change of tumor size | The major axis change of target lesion relative to baseline | 52 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
C-myc, Solid tumor