Clinical trial NCT03086174: 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
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Kidney Cancer Stage Iv
Advanced Melanoma
Keywords: anti-PD-1 monoclonal antibody
advanced
melanoma
kidney cancer
Lead sponsor: Shanghai Junshi Bioscience Co., Ltd.
Sponsor class: OTHER
First posted: 2017-03-22
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 3 years
Secondary outcomes:
measure: PD-1 receptor occupancy of blood
timeFrame: 3 years
measure: Objective Response Rate (ORR) by irRC and RECIST 1.1
timeFrame: 3 years
measure: Duration of Response (DOR) by irRC and RECIST 1.1
timeFrame: 3 years
measure: Disease Control Rate (DCR) by irRC and RECIST 1.1
timeFrame: 3 years
measure: Time to response (TTR) by irRC and RECIST 1.1
timeFrame: 3 years
measure: Progression-free survival(PFS) by irRC and RECIST 1.1
timeFrame: 3 years
measure: Overall survival (OS) by irRC and RECIST 1.1
timeFrame: 3 years
measure: PK Parameter: Maximum Plasma Concentration (Cmax)
timeFrame: 3 years
measure: PK Parameter: Peak Time (Tmax)
timeFrame: 3 years
measure: PK Parameter: t1/2
timeFrame: 3 years
measure: PK Parameter: Area Under the Curve (AUC)
timeFrame: 3 years
measure: PK Parameter: Plasma clearance (CL)
timeFrame: 3 years
measure: PK Parameter: Apparent volume of distribution (V)
timeFrame: 3 years
measure: PK Parameter: Minimum Plasma Concentration (Cmin)
timeFrame: 3 years
measure: PK Parameter: Average Plasma Concentration (Cav)
timeFrame: 3 years
measure: PK Parameter: degree of fluctuation (DF)
timeFrame: 3 years
measure: PK Parameter: Apparent volume of distribution of steady state (Vss)
timeFrame: 3 years
Other outcomes:
measure: correlation analysis of PD-L1 expression of tumor and ORR
timeFrame: 3 years
measure: correlation analysis of PD-L1 expression of tumor and DOR
timeFrame: 3 years
measure: correlation analysis of PD-L1 expression of tumor and DCR
timeFrame: 3 years
measure: correlation analysis of PD-L1 expression of tumor and TTR
timeFrame: 3 years
measure: correlation analysis of PD-L1 expression of tumor and PFS
timeFrame: 3 years
measure: correlation analysis of PD-L1 expression of tumor and OS
timeFrame: 3 years
Locations:
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
Study officials:
affiliation: Peking University Cancer Hospital & Institute
name: Jun Guo
role: PRINCIPAL_INVESTIGATOR
References:
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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.
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.