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

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

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.

Study Overview

• Status: Unknown
• Conditions: Advanced Melanoma; Kidney Cancer Stage Iv
• Intervention / Treatment: Biological: humanized anti-PD-1 monoclonal antibody Toripalimab

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.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100142
      • Beijing Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: JS001, TAB001

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
correlation analysis of PD-L1 expression of tumor and ORR	correlation analysis of PD-L1 expression of tumor and objective response rate	3 years
correlation analysis of PD-L1 expression of tumor and DOR	correlation analysis of PD-L1 expression of tumor and duration of response	3 years
correlation analysis of PD-L1 expression of tumor and DCR	correlation analysis of PD-L1 expression of tumor and disease control rate	3 years
correlation analysis of PD-L1 expression of tumor and TTR	correlation analysis of PD-L1 expression of tumor and time to response	3 years
correlation analysis of PD-L1 expression of tumor and PFS	correlation analysis of PD-L1 expression of tumor and progression-free survival	3 years
correlation analysis of PD-L1 expression of tumor and OS	correlation analysis of PD-L1 expression of tumor and overall survival	3 years

Collaborators and Investigators

• Sponsor: Shanghai Junshi Bioscience Co., Ltd.

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 31, 2017
• Primary Completion (ACTUAL): December 31, 2019
• Study Completion (ANTICIPATED): December 1, 2020

Study Registration Dates

• First Submitted: March 9, 2017
• First Submitted That Met QC Criteria: March 15, 2017
• First Posted (ACTUAL): March 22, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 30, 2020
• Last Update Submitted That Met QC Criteria: September 28, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: kidney cancer; melanoma; advanced; anti-PD-1 monoclonal antibody
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Kidney Neoplasms; Carcinoma, Renal Cell; Melanoma; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Antibodies, Monoclonal
• Other Study ID Numbers: Junshi-JS001-008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No