A Phase I Trial of SIM1811-03 in Subjects With Advanced Tumors

Study Overview
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Brief Summary
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This is a first in human, open-label, dose escalation and expansion Phase I study of SIM1811-03 in adult patients with advanced tumors. SIM1811-03 is a first-in-class IgG1-based humanized anti-tumor necrosis factor type 2 receptor (TNFR2) monoclonal antibody for the treatment of malignant tumors.

Detailed Description
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This is a phase I trial to evaluate the safety, efficacy, and pharmacokinetic/ pharmacodynamic characteristics of SIM1811-03 in participants with advanced tumors. The trial is composed of two parts, Part I and Part II. Part I is a dose escalation part to determine the MTD and/or RD of SIM1811-03 or SIM1811-03 in combination with Sintilimab Injection . Part II is a dose expansion part at RD level SIM1811-03 determined in Part I to assess the anti-tumor activity of SIM1811-03 or SIM1811-03 in combination with Sintilimab Injection in participants with advanced solid tumors or CTCL. The tumor types in Part II will be adjusted based on the response observed in Part I.

Official Title
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An Open-label, Phase I Trial of SIM1811-03 to Assess the Safety, Efficacy and Pharmacokinetics/Pharmacodynamics in Subjects With Advanced Tumors

Conditions
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Advanced Solid Tumor, Cutaneous T Cell Lymphoma

Intervention / Treatment
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* Drug: SIM1811-03 or in combination with Sintilimab injectiont


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Written informed consent must be obtained prior to any procedures that are not considered standard of care. ≥18 years old on the day of signing informed consent, male or female; Histologically and/or cytologically documented advanced/metastatic solid tumors or histologically confirmed CTCL; Have relapsed or refractory advanced solid tumors or CTCL, whose disease has progressed during or after standard therapy At least one measurable tumor lesion (RECIST 1.1) for participants with solid tumors. Tumor lesions previously treated with radiotherapy or local therapy should not be considered as measurable unless progression is documented. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 Life expectancy of ≥ 12 weeks. Adequate organ and marrow functions 9） Provide archived or fresh biopsy tumor tissue samples or tissue sections 10) Females of childbearing potential require strict contraception during the study. Exclusion Criteria: 1) Participated in an interventional clinical trial or has used investigational devices within 28 days prior to first dose of study drug or received systemic anti-cancer treatments. 2）Toxicity due to previous antineoplastic therapy has not recovered to grade 0 or 1 unless such AEs are not considered to pose safety risks. 3) Required use of corticosteroids for more than 7 consecutive days within 14 days prior to the first dose of study treatment. 4) Participated with active or history of or risk of autoimmune disease 5) Major surgery (except biopsy) or unhealed wound within 4 weeks prior to first dose of study drug. 6) Other known malignancies within 2 years prior to enrollment. 7) Has known active central nervous system (CNS) metastases. 8) History of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis, symptomatic interstitial lung disease or evidence of active pneumonia that is not considered appropriate by the investigator. 9) Participants with a history of active pulmonary tuberculosis infection within 1 year prior to first dose of study drug. 10) History of hemorrhagic disease requiring transfusion within the last 3 months.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SIM1811-03 monotherapy or SIM1811-03 in combination with Sintilimab injection<br>All participants receive SIM1811-03 or SIM1811-03 in combination with Sintilimab injection | Drug: SIM1811-03 or in combination with Sintilimab injectiont<br>* SIM1811-03 is a first-in-class igG-1 based humanized anti-tumor necrosis factor type 2 receptor (TNFR2) monoclonal antibody for the treatment of malignant tumor. Sintilimab is an IgG4 humanized monoclonal antibody against programmed cell death protein 1 (PD-1)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I The maximum tolerated dose (MTD) or recommended dose (RD) | Part I (dose escalation): To estimate the maximum tolerated dose (MTD) or recommended dose (RD) of SIM1811-03 Monotherapy or in combination with sintilimab | Within 28 days after the first dose in Q2W; Within 21 days after the first dose in Q3W | 
| Part II ORR for Solid Tumor | Solid tumors: objective response rate (ORR) assessed by Investigator per RECIST 1.1 from baseline to disease progression | Q2W: Participants will be evaluated every 8 weeks from baseline to Treatment Cycle 12 (an average of 1 year); Q3W:Participants will be evaluated every 6 weeks from baseline to Treatment Cycle 12 (an average of 1 year) | 
| Part II ORR for CTCL | CTCL: ORR assessed by Investigator per global response score | Q2W:Participants will be evaluated every 8 weeks from baseline to Treatment Cycle 12 (an average of 1 year); Q3W:Participants will be evaluated every 6 weeks from baseline to Treatment Cycle 12 (an average of 1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety and tolerability (incidence of AE and SAE) | Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) | All AEs/SAEs will be collected in this study from the time the subject signs the informed consent form until 90 days after the last dose | 
| Pharmacokinetics profile of SIM1811-03 and in combination with Sintilimab | Serum concentrations of study drugs | from Cycle 1 to Last dose (an average of 1 year) | 
| Pharmacokinetics profile of SIM1811-03 and in combination with Sintilimab | Area under the concentration-time curve (AUC) | from Cycle 1 to Last dose (an average of 1 year) | 
| Pharmacokinetics profile of SIM1811-03 and in combination with Sintilimab | Maximum concentration (Cmax) | from Cycle 1 to Last dose (an average of 1 year) | 
| Pharmacokinetics profile of SIM1811-03 and in combination with Sintilimab | Pre-dose (trough) concentration (Ctrough) | from Cycle 1 to Last dose (an average of 1 year) | 
| Pharmacokinetics profile of SIM1811-03 and in combination with Sintilimab | Time to maximum concentration (Tmax) | from Cycle 1 to Last dose (an average of 1 year) | 
| Pharmacokinetics profile of SIM1811-03 and in combination with Sintilimab | Half-life (T1/2) | Collection point would Predose, 0 hour, 24 hours, 168hours, 336 hours post-dose from Cycle 1 to Last dose (an average of 1 year) | 
| Antidrug antibodies of SIM1811-03 and Sintilimab | Incidence of serum antidrug antibodies. | before staring the treatment for the first 7 treatment cycles (each cycle would be 28 days/21 days) | 
| Neutralizing antibodies of SIM1811-03 and Sintilimab | Incidence of neutralizing antibodies to study drugs. | before staring the treatment for the first 7 treatment cycles (each cycle would be 28 days/21 days) |