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

Primary Purpose

Kidney Cancer Stage Iv, Advanced Melanoma

Status
Unknown status
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
humanized anti-PD-1 monoclonal antibody Toripalimab
Sponsored by
Shanghai Junshi Bioscience Co., Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Kidney Cancer Stage Iv focused on measuring anti-PD-1 monoclonal antibody, advanced, melanoma, kidney cancer

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Beijing Cancer Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

humanized anti-PD-1monoclonal antibody

Arm Description

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

PD-1 receptor occupancy of blood
To test the PD - 1 receptor share in the blood
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.
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.
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.
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.
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.
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.
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
PK Parameter: Peak Time (Tmax)
Peak Time (Tmax) after single dose injection of Anti-PD-1 mAb in combination with axitinib
PK Parameter: t1/2
t1/2 after single dose injection of Recombinant Humanized Anti-PD-1 mAb in combination with axitinib
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
PK Parameter: Plasma clearance (CL)
Plasma clearance (CL) after single dose injection of Anti-PD-1 mAb in combination with axitinib
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
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
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
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
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

Full Information

First Posted
March 9, 2017
Last Updated
September 28, 2020
Sponsor
Shanghai Junshi Bioscience Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT03086174
Brief Title
Tolerability and Pharmacokinetics of Toripalimab in Combination With Axitinib in Patients With Kidney Cancer and Melanoma
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Unknown status
Study Start Date
March 31, 2017 (Actual)
Primary Completion Date
December 31, 2019 (Actual)
Study Completion Date
December 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shanghai Junshi Bioscience Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Kidney Cancer Stage Iv, Advanced Melanoma
Keywords
anti-PD-1 monoclonal antibody, advanced, melanoma, kidney cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
humanized anti-PD-1monoclonal antibody
Arm Type
Experimental
Arm Description
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
Intervention Type
Biological
Intervention Name(s)
humanized anti-PD-1 monoclonal antibody Toripalimab
Other Intervention Name(s)
JS001, TAB001
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Description
Safety assessments including vital signs, laboratory tests, and adverse event monitoring
Time Frame
3 years
Secondary Outcome Measure Information:
Title
PD-1 receptor occupancy of blood
Description
To test the PD - 1 receptor share in the blood
Time Frame
3 years
Title
Objective Response Rate (ORR) by irRC and RECIST 1.1
Description
The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine tumor response.
Time Frame
3 years
Title
Duration of Response (DOR) by irRC and RECIST 1.1
Description
The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine duration of response.
Time Frame
3 years
Title
Disease Control Rate (DCR) by irRC and RECIST 1.1
Description
The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine disease control rate.
Time Frame
3 years
Title
Time to response (TTR) by irRC and RECIST 1.1
Description
The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine time to response.
Time Frame
3 years
Title
Progression-free survival(PFS) by irRC and RECIST 1.1
Description
The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine progression-free survival time.
Time Frame
3 years
Title
Overall survival (OS) by irRC and RECIST 1.1
Description
The treatment effect of JS001 in combination with axitinib, will be assessed using irRC and RECIST 1.1 to determine overall survival.
Time Frame
3 years
Title
PK Parameter: Maximum Plasma Concentration (Cmax)
Description
Maximum Plasma Concentration (Cmax) after single dose injection of Anti-PD-1 Monoclonal Antibody (mAb) in combination with axitinib
Time Frame
3 years
Title
PK Parameter: Peak Time (Tmax)
Description
Peak Time (Tmax) after single dose injection of Anti-PD-1 mAb in combination with axitinib
Time Frame
3 years
Title
PK Parameter: t1/2
Description
t1/2 after single dose injection of Recombinant Humanized Anti-PD-1 mAb in combination with axitinib
Time Frame
3 years
Title
PK Parameter: Area Under the Curve (AUC)
Description
Area Under the Curve (AUC) after single dose injection of Anti-PD-1 mAb in combination with axitinib
Time Frame
3 years
Title
PK Parameter: Plasma clearance (CL)
Description
Plasma clearance (CL) after single dose injection of Anti-PD-1 mAb in combination with axitinib
Time Frame
3 years
Title
PK Parameter: Apparent volume of distribution (V)
Description
Apparent volume of distribution (V) after single dose injection of Anti-PD-1 mAb in combination with axitinib
Time Frame
3 years
Title
PK Parameter: Minimum Plasma Concentration (Cmin)
Description
Minimum Plasma Concentration (Cmin) of steady state after multiple dose injection of Anti-PD-1 mAb in combination with axitinib
Time Frame
3 years
Title
PK Parameter: Average Plasma Concentration (Cav)
Description
Average Plasma Concentration (Cav) of steady state after multiple dose injection of Anti-PD-1 mAb in combination with axitinib
Time Frame
3 years
Title
PK Parameter: degree of fluctuation (DF)
Description
degree of fluctuation (DF) of steady state after multiple dose injection of Anti-PD-1 mAb in combination with axitinib
Time Frame
3 years
Title
PK Parameter: Apparent volume of distribution of steady state (Vss)
Description
Apparent volume of distribution of steady state (Vss) after multiple dose injection of Anti-PD-1 mAb in combination with axitinib
Time Frame
3 years
Other Pre-specified Outcome Measures:
Title
correlation analysis of PD-L1 expression of tumor and ORR
Description
correlation analysis of PD-L1 expression of tumor and objective response rate
Time Frame
3 years
Title
correlation analysis of PD-L1 expression of tumor and DOR
Description
correlation analysis of PD-L1 expression of tumor and duration of response
Time Frame
3 years
Title
correlation analysis of PD-L1 expression of tumor and DCR
Description
correlation analysis of PD-L1 expression of tumor and disease control rate
Time Frame
3 years
Title
correlation analysis of PD-L1 expression of tumor and TTR
Description
correlation analysis of PD-L1 expression of tumor and time to response
Time Frame
3 years
Title
correlation analysis of PD-L1 expression of tumor and PFS
Description
correlation analysis of PD-L1 expression of tumor and progression-free survival
Time Frame
3 years
Title
correlation analysis of PD-L1 expression of tumor and OS
Description
correlation analysis of PD-L1 expression of tumor and overall survival
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jun Guo
Organizational Affiliation
Peking University Cancer Hospital & Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Beijing Cancer Hospital
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100142
Country
China

12. IPD Sharing Statement

Plan to Share IPD
Yes
Citations:
PubMed Identifier
22056247
Citation
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. doi: 10.1016/S0140-6736(11)61613-9. Epub 2011 Nov 4. Erratum In: Lancet. 2012 Nov 24;380(9856):1818.
Results Reference
background
PubMed Identifier
26137411
Citation
Du Four S, Maenhout SK, De Pierre K, Renmans D, Niclou SP, Thielemans K, Neyns B, Aerts JL. Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model. Oncoimmunology. 2015 Jan 22;4(4):e998107. doi: 10.1080/2162402X.2014.998107. eCollection 2015 Apr.
Results Reference
background
PubMed Identifier
35193932
Citation
Li S, Wu X, Yan X, Zhou L, Chi Z, Si L, Cui C, Tang B, Mao L, Lian B, Wang X, Bai X, Dai J, Kong Y, Tang X, Feng H, Yao S, Flaherty KT, Guo J, Sheng X. Toripalimab plus axitinib in patients with metastatic mucosal melanoma: 3-year survival update and biomarker analysis. J Immunother Cancer. 2022 Feb;10(2):e004036. doi: 10.1136/jitc-2021-004036.
Results Reference
derived

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

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