Sym023 (Anti-TIM-3) in Patients With Advanced Solid Tumor Malignancies or Lymphomas

Study Overview
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Brief Summary
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This was the first study to test Sym023 in humans. The primary purpose of this study was to see if Sym023 is safe and tolerable for patients with locally advanced/unresectable or metastatic solid tumor malignancies or lymphomas that are refractory to available therapy or for which no standard therapy is available.

Detailed Description
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This study evaluated the preliminary safety, tolerability, and dose-limiting toxicities (DLTs) of Sym023, a recombinant, fully human, anti-T-cell immunoglobulin and mucin-domain containing-3 (anti-TIM-3) monoclonal antibody (mAb). The goal was to establish the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of sequential escalating doses of Sym023 when administered once every 2 weeks (Q2W) by intravenous (IV) infusion to patient cohorts with locally advanced/unresectable or metastatic solid tumor malignancies or lymphomas that are refractory to available therapy or for which no standard therapy is available. If an MTD was not identified, a maximum administered dose (MAD) was to be determined. Sym023 was given to patients in escalating dose cohorts; each patient was given one fixed dose level.

Official Title
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A Phase 1, Open-Label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Antineoplastic Activity of Sym023 (Anti-TIM-3) in Patients With Advanced Solid Tumor Malignancies or Lymphomas

Conditions
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Metastatic Cancer, Solid Tumor, Lymphoma

Intervention / Treatment
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* Drug: Sym023


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients, ≥ 18 years of age at the time of obtaining informed consent. Documented (histologically- or cytologically-proven) solid tumor malignancy that is locally advanced or metastatic; patients with documented lymphomas. Malignancy (solid tumor or lymphoma) that is currently not amenable to surgical intervention due to either medical contraindications or nonresectability of the tumor. Refractory to or intolerant of existing therapy(ies) known to provide clinical benefit. Measurable or non-measurable disease according to RECIST v1.1 or RECIL 2017. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Not of childbearing potential or who agree to use a highly effective method of contraception during the study beginning within 2 weeks prior to the first dose and continuing until 6 months after the last dose of study drug. Exclusion Criteria: Women who are pregnant or lactating, or intending to become pregnant before, during, or within 6 months after the last dose of study drug. Women of childbearing potential (WOCBP) and fertile men with WOCBP-partner(s) not using and not willing to use a highly effective method of contraception. Known, untreated central nervous system (CNS) or leptomeningeal metastases, or spinal cord compression, patients with any of the above not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required. Hematologic malignancies other than lymphomas. Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 4 weeks prior to Cycle 1/Day 1 (C1/D1) unless adequately treated and considered stable. Active uncontrolled bleeding or a known bleeding diathesis. Clinically significant cardiovascular disease or condition. Significant ocular disease or condition, including history of autoimmune or inflammatory disorder. Significant pulmonary disease or condition. Current or recent (within 6 months) significant gastrointestinal (GI) disease or condition. An active, known, or suspected autoimmune disease, or a documented history of autoimmune disease or syndrome, requiring systemic steroids or other immunosuppressive medications. History of significant toxicities associated with previous administration of immune checkpoint inhibitors that necessitated permanent discontinuation of that therapy. Patients with unresolved > Grade 1 toxicity associated with any prior antineoplastic therapy, with exceptions. Inadequate recovery from any prior surgical procedure, or having undergone any major surgical procedure within 4 weeks prior to C1/D1. Known history of human immunodeficiency virus (HIV) or known active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sym023 0.03 mg/kg<br>Sym023 was administered at a dose of 0.03 mg/kg by intravenous infusion | Drug: Sym023<br>* Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.<br>* Other names: Anti-TIM-3;|
| Experimental: Sym023 0.1 mg/kg<br>Sym023 was administered at a dose of 0.1 mg/kg by intravenous infusion | Drug: Sym023<br>* Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.<br>* Other names: Anti-TIM-3;|
| Experimental: Sym023 0.3 mg/kg<br>Sym023 was administered at a dose of 0.3 mg/kg by intravenous infusion | Drug: Sym023<br>* Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.<br>* Other names: Anti-TIM-3;|
| Experimental: Sym023 1.0 mg/kg<br>Sym023 was administered at a dose of 1.0 mg/kg by intravenous infusion | Drug: Sym023<br>* Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.<br>* Other names: Anti-TIM-3;|
| Experimental: Sym023 3.0 mg/kg<br>Sym023 was administered at a dose of 3.0 mg/kg by intravenous infusion | Drug: Sym023<br>* Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.<br>* Other names: Anti-TIM-3;|
| Experimental: Sym023 10.0 mg/kg<br>Sym023 was administered at a dose of 10.0 mg/kg by intravenous infusion | Drug: Sym023<br>* Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.<br>* Other names: Anti-TIM-3;|
| Experimental: Sym023 20.0 mg/kg<br>Sym023 was administered at a dose of 20.0 mg/kg by intravenous infusion | Drug: Sym023<br>* Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.<br>* Other names: Anti-TIM-3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Treatment Emergent Adverse Events (AEs) Meeting Dose-limiting Toxicity (DLT) Criteria. | Assess the safety and tolerability of Sym023 on a Q2W (once every 2 weeks) schedule to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Assessment based on the occurrence of AEs meeting DLT criteria measured during Cycle 1. The MTD was to be determined by those DLTs that occurred during C1 in either more than 1 patient in a 3 to 6 patient cohort or ≥33.3% of patients in the event of an expanded 7 to 12 patient cohort. One patient in the 10.0 mg/kg dose cohort was not evaluable for MTD as she did not complete C1 for a reason other than drug toxicity (i.e., discontinuation after 1 dose due to patient withdrawal of consent). However, this patient was included in the evaluation of other outcomes. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the Immunogenicity of Sym023. | Serum sampling to assess the potential for anti-drug antibody (ADA) formation. The number of patients with positive samples at indicated visits is presented. | Baseline up to 6-months follow-up, approximately 1 year | 
| Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIST v1.1 | OR or SD Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). The number of patients with confirmed or unconfirmed OR (partial or complete response) is presented. Duration of SD for patients with best overall response = SD was defined as the time from the day of first study treatment to the start of radiologic disease progression or death. If the patient did not have a radiological disease progression or death, the duration of SD was defined as the time from the day of first study treatment to the date of the last SD assessment. | 24 months | 
| Evaluation of Objective Response (OR) or Stable Disease (SD) by iRECIST | OR or SD Assessed by Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST). The number of patients with confirmed or unconfirmed OR (partial or complete response) is presented. Duration of SD for patients with best overall response = SD was defined as the time from the day of first study treatment to the start of radiologic disease progression or death. If the patient did not have a radiological disease progression or death, the duration of SD was defined as the time from the day of first study treatment to the date of the last SD assessment. | 24 months | 
| Evaluation of Objective Response (OR) or Stable Disease (SD) by RECIL 2017. | OR or SD Assessed by Response Evaluation Criteria in Lymphomas 2017 (RECIL 2017) | 24 months | 
| Time to Progression (TTP) of Disease. | Based on time of enrollment to first evidence of progression on imaging studies, as assessed by RECIST v1.1, RECIL 2017, or iRECIST, depending on tumor type. The numbers shown below correspond to the values related to RECIST v1.1. | 24 months | 
| Area Under the Concentration-time Curve in a Dosing Interval (AUC). | The AUC after first dose was estimated using non-compartmental methods. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. | From before the start of the infusion to 168 hours after the end of the infusion | 
| Maximum Concentration (Cmax) | Outcome measure after first dose was derived from observed data. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. | From before the start of the infusion to 168 hours after the end of the infusion | 
| Time to Reach Maximum Concentration (Tmax) | Outcome measure after first dose was derived from observed data. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. | From before the start of the infusion to 168 hours after the end of the infusion | 
| Trough Concentration (Ctrough) | Outcome measure after first dose was derived from observed data. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. | From before the start of the infusion to 168 hours after the end of the infusion | 
| Terminal Elimination Half-life (T½) | Outcome measure after first dose was estimated using non-compartmental methods. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. | From before the start of the infusion to 168 hours after the end of the infusion | 
| Clearance (CL) | Outcome measure after first dose was estimated using non-compartmental methods. Blood samples for PK analysis were taken at the following timepoints: before the start of the infusion, at the end of the infusion and at 2, 4, 8, 24, 48 and 168 hours after the end of the infusion. Actual timepoints were recorded. | From before the start of the infusion to 168 hours after the end of the infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally advanced/unresectable, Metastatic solid tumor, Lymphoma, Anti-TIM-3, TIM-3, TIM3