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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03086174
Recruitment Status : Active, not recruiting
First Posted : March 22, 2017
Last Update Posted : September 30, 2020
Sponsor:
Information provided by (Responsible Party):
Shanghai Junshi Bioscience Co., Ltd.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Kidney Cancer Stage Iv Advanced Melanoma Biological: humanized anti-PD-1 monoclonal antibody Toripalimab Phase 1

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 31, 2017
Actual Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: humanized anti-PD-1monoclonal antibody
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
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.
Other Name: JS001, TAB001




Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 3 years ]
    Safety assessments including vital signs, laboratory tests, and adverse event monitoring


Secondary Outcome Measures :
  1. PD-1 receptor occupancy of blood [ Time Frame: 3 years ]
    To test the PD - 1 receptor share in the blood

  2. Objective Response Rate (ORR) by irRC and RECIST 1.1 [ Time Frame: 3 years ]
    The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine tumor response.

  3. Duration of Response (DOR) by irRC and RECIST 1.1 [ Time Frame: 3 years ]
    The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine duration of response.

  4. Disease Control Rate (DCR) by irRC and RECIST 1.1 [ Time Frame: 3 years ]
    The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine disease control rate.

  5. Time to response (TTR) by irRC and RECIST 1.1 [ Time Frame: 3 years ]
    The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine time to response.

  6. Progression-free survival(PFS) by irRC and RECIST 1.1 [ Time Frame: 3 years ]
    The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine progression-free survival time.

  7. Overall survival (OS) by irRC and RECIST 1.1 [ Time Frame: 3 years ]
    The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine overall survival.

  8. PK Parameter: Maximum Plasma Concentration (Cmax) [ Time Frame: 3 years ]
    Maximum Plasma Concentration (Cmax) after single dose injection of Anti-PD-1 Monoclonal Antibody (mAb) in combination with axitinib

  9. PK Parameter: Peak Time (Tmax) [ Time Frame: 3 years ]
    Peak Time (Tmax) after single dose injection of Anti-PD-1 mAb in combination with axitinib

  10. PK Parameter: t1/2 [ Time Frame: 3 years ]
    t1/2 after single dose injection of Recombinant Humanized Anti-PD-1 mAb in combination with axitinib

  11. PK Parameter: Area Under the Curve (AUC) [ Time Frame: 3 years ]
    Area Under the Curve (AUC) after single dose injection of Anti-PD-1 mAb in combination with axitinib

  12. PK Parameter: Plasma clearance (CL) [ Time Frame: 3 years ]
    Plasma clearance (CL) after single dose injection of Anti-PD-1 mAb in combination with axitinib

  13. PK Parameter: Apparent volume of distribution (V) [ Time Frame: 3 years ]
    Apparent volume of distribution (V) after single dose injection of Anti-PD-1 mAb in combination with axitinib

  14. PK Parameter: Minimum Plasma Concentration (Cmin) [ Time Frame: 3 years ]
    Minimum Plasma Concentration (Cmin) of steady state after multiple dose injection of Anti-PD-1 mAb in combination with axitinib

  15. PK Parameter: Average Plasma Concentration (Cav) [ Time Frame: 3 years ]
    Average Plasma Concentration (Cav) of steady state after multiple dose injection of Anti-PD-1 mAb in combination with axitinib

  16. PK Parameter: degree of fluctuation (DF) [ Time Frame: 3 years ]
    degree of fluctuation (DF) of steady state after multiple dose injection of Anti-PD-1 mAb in combination with axitinib

  17. PK Parameter: Apparent volume of distribution of steady state (Vss) [ Time Frame: 3 years ]
    Apparent volume of distribution of steady state (Vss) after multiple dose injection of Anti-PD-1 mAb in combination with axitinib


Other Outcome Measures:
  1. correlation analysis of PD-L1 expression of tumor and ORR [ Time Frame: 3 years ]
    correlation analysis of PD-L1 expression of tumor and objective response rate

  2. correlation analysis of PD-L1 expression of tumor and DOR [ Time Frame: 3 years ]
    correlation analysis of PD-L1 expression of tumor and duration of response

  3. correlation analysis of PD-L1 expression of tumor and DCR [ Time Frame: 3 years ]
    correlation analysis of PD-L1 expression of tumor and disease control rate

  4. correlation analysis of PD-L1 expression of tumor and TTR [ Time Frame: 3 years ]
    correlation analysis of PD-L1 expression of tumor and time to response

  5. correlation analysis of PD-L1 expression of tumor and PFS [ Time Frame: 3 years ]
    correlation analysis of PD-L1 expression of tumor and progression-free survival

  6. correlation analysis of PD-L1 expression of tumor and OS [ Time Frame: 3 years ]
    correlation analysis of PD-L1 expression of tumor and overall survival



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03086174


Locations
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China, Beijing
Beijing Cancer Hospital
Beijing, Beijing, China, 100142
Sponsors and Collaborators
Shanghai Junshi Bioscience Co., Ltd.
Investigators
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Principal Investigator: Jun Guo Beijing Cancer Hospital
Publications:
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Responsible Party: Shanghai Junshi Bioscience Co., Ltd.
ClinicalTrials.gov Identifier: NCT03086174    
Other Study ID Numbers: Junshi-JS001-008
First Posted: March 22, 2017    Key Record Dates
Last Update Posted: September 30, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Shanghai Junshi Bioscience Co., Ltd.:
anti-PD-1 monoclonal antibody
advanced
melanoma
kidney cancer
Additional relevant MeSH terms:
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Melanoma
Kidney Neoplasms
Carcinoma, Renal Cell
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Antibodies
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs