Tolerability and Pharmacokinetics of Toripalimab in Combination With Axitinib in Patients With Kidney Cancer and Melanoma

Study Overview
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Brief Summary
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This is a phase Ib, open, mono-center, dose-escalation, tolerability and pharmacokinetic study evaluating the Recombinant Humanized Anti-PD-1 mAb for Injection in combination with Axitinib in patients with advanced kidney cancer and melanoma who have failed in routine systemic treatment.

Detailed Description
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This is a phase Ib, open, mono-center, dose-escalation, tolerability and pharmacokinetic study evaluating the Recombinant Humanized Anti-PD-1 mAb for Injection in combination with Axitinib in patients with advanced kidney cancer and melanoma who have failed in routine systemic treatment.The study will be conducted in 2 parts: dose escalation and cohort expansion. 18 to 24 patients will be enrolled in dose escalation part.This part is to analyze safety and efficacy of the humanized anti-PD-1 antibody in combination with axitinib and to confirm dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD). After finishing the dose escalation part, we will enroll other patients for each tumor types of recommended dose group to ensure each group have 10 patients. This part is to further analyze safety and efficacy of the humanized anti-PD-1 antibody.

Official Title
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A Phase Ib,Open,Mono-center,Dose-escalation,Tolerability and Pharmacokinetic Study of Recombinant Humanized Anti-PD-1 mAb for Injection in Combination With Axitinib in Patients With Advanced Kidney Cancer and Melanoma

Conditions
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Kidney Cancer Stage Iv, Advanced Melanoma

Intervention / Treatment
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* Biological: humanized anti-PD-1 monoclonal antibody Toripalimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and Female aged between 18 and 75 years are eligible; Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; At least received first-line treatment but appeared disease progression or intolerance, and a diagnosis of an advanced kidney Cancer and melanoma confirmed by pathology (Remark: Treatment intolerance including 1) The main organ function of the patient is evaluated by the doctor that can not be treated by the first-line standard;2) Patients received a first-line treatment with a 3/4 adverse reaction;3) Patients reject first-line treatment, etc) Providing with tumor specimen (for testing the expression of PD -L1 and the infiltrating lymphocytes); At least 1 measurable lesion (only 1 measurable lymph node lesion is excluded) (routine CT scan >=20mm, spiral CT scan >=10mm, no prior radiation to measurable lesions) Predicted survival >=3 months; Brain or meningeal metastases must be disposed with surgery or radiation, and be stable clinically for at least 3 months (prior systemic steroids was allowed, but concurrent administration of systemic steroids with the study drug is excluded). Screening laboratory values must meet the following criteria（within past 14 days）: hemoglobin ≥ 9.0 g/dL; neutrophils ≥ 1500 cells/ µL; platelets ≥ 100 x 10^3/ µL; total bilirubin ≤ 1.5 x upper limit of normal (ULN); aspartic transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN without, and ≤ 5 x ULN with hepatic metastasis; serum creatinine ≤1╳ULN，creatinine clearance >50ml/min (Cockcroft-Gault equation) INR, aPTT≤1.5 x ULN; Urine protein + 1 or less, if the urine protein > 1 +, need to collect 24 hours urinary protein determination, the total amount should be 1 gram or less Without systemic steroids within past 4 weeks Males or female of childbearing potential must: agree to use using a reliable form of contraception (eg, oral contraceptives, intrauterine device, control sex desire, double barrier method of condom and spermicidal) during the treatment period and for at least 12 months after the last dose of study drug. Must have read, understood, and provided written informed consent voluntarily. Willing to adhere to the study visit schedule and the prohibitions and restrictions specified in this protocol. Exclusion Criteria: Prior treatment with anti-PD-1/PD-L1/PD-L2 antibody and Axitinib Hypersensitivity to recombinant humanized anti-PD-1 monoclonal Abm or its components Prior antitumor therapy (including corticosteroids and immunotherapy) or participation in other clinical trials within past 4 weeks, or have not recovered from toxicities since the last treatment; Pregnant or nursing; Positive tests for HIV, HCV, HBsAg or HBcAb with positive test for HBV DNA (>500IU/ml); HBsAg or HBcAb with positive test for HBV DNA (>500IU/ml) History with active tuberculosis; Associated with clinical symptoms or symptomatic treatment of pleural effusion or ascites; Patients with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, such as hypophysitis, pneumonia, colitis, hepatitis, nephritis, hyperthyroidism or hypothyroidism; Severe, uncontrolled medical condition that would affect patients' compliance or obscure the interpretation of toxicity determination or adverse events, including active severe infection, uncontrolled diabetes, angiocardiopathy (heart failure > class II NYHA, heart block >II grade, myocardial infarction, unstable arrhythmia or unstable angina within past 6 months, cerebral infarction within past 3 months) or pulmonary disease ( interstitial pneumonia, obstructive pulmonary disease or symptomatic bronchospasm). Evidence with active CNS disease; Prior treatment with bone marrow stimulating factors，such as CSF (colony stimulating factor), EPO (erythropoietin), within past 1 weeks; Prior live vaccine therapy within past 4 weeks; Received allogeneic hematopoietic stem cell transplantation or solid organ transplantation; Prior major surgery within past 4 weeks (diagnostic surgery excluded). Psychiatric medicines abuse without withdrawal, or history of psychiatric illness. Prior malignancy active within the previous 5 years except for locally curable cancers that have been apparently cured, such as basal cell skin cancer or carcinoma in situ of the cervix. Underlying medical condition that, in the Investigator's opinion, would increase the risks of study drug administration or obscure the interpretation of toxicity determination or adverse events.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: humanized anti-PD-1monoclonal antibody<br>humanized anti-PD-1 monoclonal antibody is to be injected intravenously 1mg/kg or 3mg/kg Q2w PLUS axitinib 5 mg orally Q2w until disease progresses or unacceptable tolerability occurs | Biological: humanized anti-PD-1 monoclonal antibody Toripalimab<br>* humanized anti-PD-1 monoclonal antibody Toripalimab is a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, which selectively interferes with the combination of PD-1 with its ligands, PD-L1 and PD-L2, resulting in the activation of lymphocytes and elimination of malignancy theoretically.<br>* Other names: JS001, TAB001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Safety assessments including vital signs, laboratory tests, and adverse event monitoring | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PD-1 receptor occupancy of blood | To test the PD - 1 receptor share in the blood | 3 years | 
| Objective Response Rate (ORR) by irRC and RECIST 1.1 | The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine tumor response. | 3 years | 
| Duration of Response (DOR) by irRC and RECIST 1.1 | The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine duration of response. | 3 years | 
| Disease Control Rate (DCR) by irRC and RECIST 1.1 | The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine disease control rate. | 3 years | 
| Time to response (TTR) by irRC and RECIST 1.1 | The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine time to response. | 3 years | 
| Progression-free survival(PFS) by irRC and RECIST 1.1 | The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine progression-free survival time. | 3 years | 
| Overall survival (OS) by irRC and RECIST 1.1 | The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine overall survival. | 3 years | 
| PK Parameter: Maximum Plasma Concentration (Cmax) | Maximum Plasma Concentration (Cmax) after single dose injection of Anti-PD-1 Monoclonal Antibody (mAb) in combination with axitinib | 3 years | 
| PK Parameter: Peak Time (Tmax) | Peak Time (Tmax) after single dose injection of Anti-PD-1 mAb in combination with axitinib | 3 years | 
| PK Parameter: t1/2 | t1/2 after single dose injection of Recombinant Humanized Anti-PD-1 mAb in combination with axitinib | 3 years | 
| PK Parameter: Area Under the Curve (AUC) | Area Under the Curve (AUC) after single dose injection of Anti-PD-1 mAb in combination with axitinib | 3 years | 
| PK Parameter: Plasma clearance (CL) | Plasma clearance (CL) after single dose injection of Anti-PD-1 mAb in combination with axitinib | 3 years | 
| PK Parameter: Apparent volume of distribution (V) | Apparent volume of distribution (V) after single dose injection of Anti-PD-1 mAb in combination with axitinib | 3 years | 
| PK Parameter: Minimum Plasma Concentration (Cmin) | Minimum Plasma Concentration (Cmin) of steady state after multiple dose injection of Anti-PD-1 mAb in combination with axitinib | 3 years | 
| PK Parameter: Average Plasma Concentration (Cav) | Average Plasma Concentration (Cav) of steady state after multiple dose injection of Anti-PD-1 mAb in combination with axitinib | 3 years | 
| PK Parameter: degree of fluctuation (DF) | degree of fluctuation (DF) of steady state after multiple dose injection of Anti-PD-1 mAb in combination with axitinib | 3 years | 
| PK Parameter: Apparent volume of distribution of steady state (Vss) | Apparent volume of distribution of steady state (Vss) after multiple dose injection of Anti-PD-1 mAb in combination with axitinib | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-PD-1 monoclonal antibody, advanced, melanoma, kidney cancer