Phase 1 First-in-human Study of JS014

Study Overview
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Brief Summary
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This phase 1, first-in-human study uses a BOIN design to assess the safety and potential efficacy of JS014 at different dose levels as a single agent and in combination with fixed dose of pembrolizumab in subjects with advanced cancer.

Detailed Description
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This study has two parts: 1a and Ib. Ia is a single agent study, and Ib is a combination study, testing the safety of JS014 with 200 mg of pembrolizumab. After being informed about the study and the potential risks, all subjects giving written informed consent will receive at most 4-week screening procedures to ensure the eligibility of the study entry. Once eligible, the subjects will receive JS014 infusion at the designated dose levels once every week until disease progression. In Ia study, only JS014 is given. In Ib study, JS014 will be given once a week with pembrolizumab at 200 mg once every three weeks until disease progression. The subjects will receive safety evaluation, pharmacokinetic and pharmacodynamic studies, as well as efficacy evaluation at regular interval. The maximum number in each part of the study is 30 subjects. The Ia study will be conducted in Taiwan, and Ib study will be conducted in both Taiwan and the United States.

Official Title
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A Phase 1 Study of JS014, a Recombinant Fusion Protein of Interleukin-21 and Humanized Anti-human Serum Albumin VHH Antibody as a Single Agent or in Combination With Pembrolizumab in Subjects With Advanced Cancer

Conditions
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Neoplasm Malignant, Neoplasm, Experimental, Solid Tumor, Adult, Lymphoma

Intervention / Treatment
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* Biological: JS014, Interleukin 21 and humanized anti-human serum albumin VHH antibody
* Biological: Pembrolizumab - anti-PD-1 antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Older 18 years of age or per local regulation Subjects with advanced cancer or lymphoma who have no standard therapy available, ineligible for standard therapy or unwilling to receive cytotoxic therapy . ECOG PS 0-1 A life expectancy longer than three months Adequate organ functions Able to adopt effective contraceptive measures Exclusion Criteria: Known history of allergies to JS014 or IL-21 or human serum albumin or pembrolizumab (Ib only) Subjects who have received major surgery less than 4 weeks before 1st infusion of JS014 Subjects who has a history of immune-related adverse events in prior immunotherapy. Subjects who have received immunosuppressive therapy less than 4 weeks before 1st infusion of JS014. Subjects who have two or more primary cancers in the past 5 years. Newly diagnosed or symptomatic brain metastases. Subjects who have received prior anti-cancer therapy with residual toxicities greater than grade 2. Subjects who have a history of autoimmune disease in 2 years. Subjects who have active infection, or uncontrollable hypertension, unstable angina, active peptic ulcer, recent acute myocardial infarction, severe congestive heart failure, or unhealed wound. Subjects with active hepatitis B or hepatitis C. Subjects who are pregnant or breast feeding. Subjects who primary immune deficiency.

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Interventional Model Description: Single group assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Dose escalation<br>A open-label single arm of JS014 alone or in combination with pembrolizumab | Biological: JS014, Interleukin 21 and humanized anti-human serum albumin VHH antibody<br>* Weekly infusion at the designated dose level until disease progression, withdrawal or up to two years<br>Biological: Pembrolizumab - anti-PD-1 antibody<br>* 200 mg, once every three weeks until disease progression, withdrawal or up to two years<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The numbers of participants with treatment-related adverse events assessed by CTCAE 5.0 | To determine the percentage of various toxicities assessed by CTCAE at different dose levels alone or in combination with pembrolizumab | 24 months | 
| Maximum tolerated dose (MTD) of JS014 | To determine the MTD of JS014 alone or in combination with pembrolizumab | 24 months | 
| Recommended phase-2 dose (RP2D) of JS014 | To determine of the RP2D of JS014 alone or in combination of pembrolizumab | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of JS014 | To estimate the AUC of JS014 at different dose levels alone or in combination with pembrolizumab | 24 months | 
| Maximum concentration (Cmax) of JS014 | To measure the Cmax after 1st and repeat dose of JS014 alone or in combination with pembrolizumab | 24 months | 
| Clearance of JS014 | To estimate the clearance of JS014 after 1st and repeat dose of JS014 alone or in combination with pembrolizumab | 24 months | 
| Half life (T1/2) of JS014 | To estimate the T1/2 at terminal phase of JS014 after 1st and repeat dose of JS014 alone or in combination with pembrolizumab | 24 months | 
| Volume of distribution (Vd) of JS014 | To estimate Vd of JS014 after 1st and repeat dose alone or in combination with pembrolizumab | 24 months | 
| Time to reach maximum concentration (Tmax) of JS014 | To estimate Tmax of JS014 after 1st and repeat dose of JS014 alone or in combination with pembrolizumab | 24 months | 
| Overall response rate (ORR) alone or in combination with pembrolizumab | The assess the ORR of JS014 alone or in combination with pembrolizumab at different dose levels | 24 months | 
| Duration of response (DoR) alone or in combination with pembrolizumab | To estimate the DoR at different dose levels alone or in combination with pembrolizumab | 24 months | 
| Prevalence of anti-JS014 antibody | To estimate prevalence of anti-JS014 antibody at different dose levels alone or in combination with pembrolizumab | 24 months | 
| Titers of anti-JS014 antibody | To measure the titer of anti-JS014 antibody alone or in combination with pembrolizumab at different dose levels during the study | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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phase 1, JS014, first-in-human