Advanced Malignant Solid Tumors
Conditions
Keywords
Solid Tumors
Brief summary
This study is an open-label, dose-escalation and expansion, Phase I clinical study to evaluate the safety, tolerability, PK characteristics and preliminary antitumor activity of WJ47156 monotherapy and in combination with toripalimab in patients with advanced malignant solid tumors. The study consists of two parts, including monotherapy (Part 1) and combination therapy (Part 2).
Interventions
DRUGWJ47156
Monotherapy study: participate will recepit WJ47156 monotherpy with 3 dose groups; Combination therapy study: participate will recepit WJ47156 and other study drug if in the combination therapy period
DRUGJS001+Bevacizumab
Participants in Cohort1 of combination therapy phase will receive WJ47156 plus toripalimab and bevacizumab.Toripalimab and bevacizumab are administered intravenously.
DRUGJS207
Participants in Cohort2 of combination therapy phase will receive WJ47156 plus JS207. JS207 is administered intravenously.
Sponsors
Sponsor GmbH
Shanghai Junshi Bioscience Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, 18 to 75 years old (inclusive) at the time of signing the ICF; 2. Patients with histologically or cytologically confirmed advanced malignant solid tumors； 3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; 4. Life expectancy ≥ 12 weeks; 5. At least one measurable lesion according to RECIST 1.1; 6. Adequate organ function ； 7. Female or male patients of childbearing potential must agree that they have no intention to become pregnant during the study and for 6 months after the last dose, and to use highly effective contraceptive methods with their partners; ); 8. Voluntary participation with full informed consent by signing an written informed consent, and with good compliance.
Exclusion criteria
1. CNS metastasis； 2. Pleural effusion, peritoneal effusion or pericardial effusion with clinical symptoms or requiring repeated treatment (e.g., puncture or drainage); 3. Unable to swallow tablets, intestinal obstruction, or other factors affecting the administration and gastrointestinal absorption of tablets 4. For the combination therapy, patients will not be enrolled in this study if they meet any of the following criteria: （1）Imaging findings at screening showing tumor encasement of a major vessel or significant necrosis and cavity, which may lead to a hemorrhagic risk as judged by the investigator; （2）Patients with active autoimmune diseases requiring systemic treatment (e.g., corticosteroids or immunosuppressive drugs) within 2 years prior to the first dose, including but not limited to systemic systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, vasculitis, etc. However, hypothyroidism, hypoadrenalism or hypopituitarism controlled only by hormone replacement therapy, Type I diabetes mellitus not requiring systemic treatment, psoriasis or vitiligo are allowed; （3）Previously treated with anti-PD-1/L1 therapy; （4）History of interstitial lung disease or previous history of non-infectious pneumonia treated with corticosteroids, or evidence of active pneumonia on imaging at screening; （5）Gastrointestinal perforation, fistula, abdominal abscess and ulcerative disease or history of digestive system ulcerative disease within 6 months prior to the first dose (patients with stable ulcer as assessed by the investigator may be considered for enrollment); （6）Presence of serious, unhealed, or open wounds, active ulcers, or untreated fractures; （7）History of gastrointestinal bleeding within 6 months prior to enrollment, or clear tendency of gastrointestinal bleeding (including hemorrhagic risk of severe esophageal-gastric varices, locally active digestive tract ulcerative lesion, and persistent positive fecal occult blood); （8）Clinically significant hemoptysis or tumor bleeding for any reason within one month prior to the first dose; （9）History of obvious bleeding tendency or severe coagulation dysfunction; （10）Severe drug-related adverse events leading to permanent discontinuation of the drug product or bevacizumab or its analogues; （11）Use of antiplatelet therapy or anticoagulant therapy for treatment within 14 days prior to the first dose; （12）Long-term treatment with nonsteroidal anti-inflammatory drugs is permitted for brief periods of time to relieve symptoms such as fever or pain. 5\. Uncontrolled hypertension (systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure \> 100 mmHg) or history of hypertensive crisis or hypertensive encephalopathy; 6. Severe cardiovascular disease, including but not limited to, myocardial infarction, severe/unstable angina, congestive heart failure (New York Heart Association \[NYHA\] class ≥ 2), clinically significant supraventricular or ventricular arrhythmia requiring drug intervention, aortic aneurysm requiring surgical repair, any arterial thrombosis/embolism event, Grade 3 or higher (Common Terminology Criteria for Adverse Events \[CTCAE\] v5.0) venous thrombosis/embolism event, transient ischemic attack, cerebral vascular accident; Left ventricular ejection fraction (LVEF) \< 50% by echocardiography. Corrected QT interval (QTc) \> 480 ms (calculated using the Fridericia method; if QTc is abnormal, measure 3 times at an interval of 2 minutes and use the average). 7\. Serious infection (CTCAE Grade \> 2) within 28 days prior to the first dose, such as serious pneumonia, bacteremia, infection and complications requiring hospitalization; or active infection or unknown cause of fever (\>38.5℃) requiring systemic anti-infection treatment within 2 weeks prior to the first dose (as judged by the investigator, patients with tumor-induced fever can be enrolled); 8\. Presence of active tuberculosis, hepatitis B (positive for hepatitis B surface antigen \[HBsAg\] and HBV DNA higher than the lower limit of detection in the study site), hepatitis C (positive for HCV antibody \[HCVAb\] and HCV RNA higher than the lower limit of detection in the study site); 9\. History of immunodeficiency, including human immunodeficiency virus (HIV) positive test, or history of known allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation; 10\. History of another primary malignant tumor, with the exception of malignant tumors (e.g., basal cell carcinoma of skin and squamous cell carcinoma of skin) who have received potentially curative therapy (more than 5 years) without known active disease prior to the first dose, without potential risk for recurrence ; 11\. Toxicity of previous antitumor therapy has not been recovered to CTCTAE Grade ≤ 1 or to the level specified in the inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 4.MTD | 1 year | Maximum tolerated dose (MTD) |
| 3、SAE | 2.5 years | Safety endpoints: incidence and severity of serious adverse events (SAE); Abnormal changes in laboratory and other tests with clinical significance |
| 5.RP2D | 1 year | Recommended dose for phase II trial |
| 1.DLT | 1 years | Safety endpoints: incidence and severity of DLT |
| 2、AE | 2.5 years | Safety endpoints: incidence and severity of adverse events (AE); Abnormal changes in laboratory and other tests with clinical significance |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 10.OS | 2.5 years | Efficacy endpoints: Overall survival (OS) |
| 11.Peak concentration（Cmax） | 2 years | The pharmacokinetic parameters of WJ47156：peak concentration (Cmax) |
| 12.The time to receive Cmax（Tmax） | 2 years | The pharmacokinetic parameters of WJ47156 ：the time to receive Cmax（Tmax） |
| 13. Area under the plasma concentration-time curve (AUC0-t, AUC0-∞) | 2 years | The pharmacokinetic parameters of WJ47156 ：area under the plasma concentration-time curve (AUC0-t, AUC0-∞) |
| 14.Apparent volume of distribution (Vd/F) | 2 years | The pharmacokinetic parameters of WJ47156 ：apparent volume of distribution (Vd/F) |
| 15.Apparent clearance (CL/F) | 2 years | The pharmacokinetic parameters of WJ47156 ：apparent clearance (CL/F) |
| 17.Steady-state peak concentration(Cmax,ss) | 2 years | The pharmacokinetic parameters of WJ47156 ：steady-state peak concentration(Cmax,ss) for the main PK parameters for multiple dose |
| 18.Plasma trough concentration at steady state(Cmin,ss) | 2 years | The pharmacokinetic parameters of WJ47156 ：Plasma trough concentration at steady state(Cmin,ss) for the main PK parameters for multiple dose |
| 19.Mean plasma concentration at steady state(Cav,ss) | 2 years | The pharmacokinetic parameters of WJ47156 ：mean plasma concentration at steady state for the main PK parameters for multiple dose |
| 20.The time to receive Cmax at steady state（Tmax,ss） | 2 years | The pharmacokinetic parameters of WJ47156 ：the time to receive Cmax at steady state（Tmax,ss）for the main PK parameters for multiple dose) |
| 21.Area under the plasma concentration-time curve at steady state (AUC0-t, ss) | 2 years | The pharmacokinetic parameters of WJ47156 ：area under the plasma concentration-time curve at steady state (AUC0-t, ss)for the main PK parameters for multiple dose) |
| 22.Accumulation factor(RAC) | 2 years | The pharmacokinetic parameters of WJ47156 ：accumulation factor(RAC) at steady state for the main PK parameters for multiple dose) |
| 23.Fluctuation coefficient(FD) | 2 years | The pharmacokinetic parameters of WJ47156 ：fluctuation coefficient(FD) at steady state for the main PK parameters for multiple dose) |
| 16.Terminal half-life (t1/2) | 2 years | The pharmacokinetic parameters of WJ47156 ：terminal half-life (t1/2) |
| 6.ORR | 2 years | Efficacy endpoints: Objective response rate (ORR) per RECIST v1.1 |
| 7.DOR | 2 years | Efficacy endpoints: Duration of response (DOR) per RECIST v1.1 |
| 8.DCR | 2 years | Efficacy endpoints: Disease control rate (DCR) per RECIST v1.1 |
| 9.PFS | 2 years | Efficacy endpoints: Progression-free survival (PFS) per RECIST v1.1 |
Other
| Measure | Time frame | Description |
|---|---|---|
| QT interval | 2 years | To evaluate the correlation between plasma concentration of WJ47156 and QT interval (only applicable to the dose group of 30 mg and above of WJ47156 monotherapy) |
| Blood concentration | 2 years | Blood concentration of toripalimab and JS207 |
| Anti-drug antibody (ADA) | 2 years | To evaluate the immunogenicity of toripalimab and JS207, including the incidence and titer of anti-drug antibody (ADA), if ADA positive, the neutralizing antibody (Nab) as needed |
Countries
China
Contacts
Primary ContactNIannian Wang, Master
Outcome results
None listed