A Phase I Trial of SIM1811-03 in Subjects With Advanced Solid Tumors and Cutaneous T-cell Lymphoma

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 1 study of SIM1811-03 in adult patients with advanced solid tumors and cutaneous T-cell lymphoma. 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 subjects with advanced solid tumors and subjects with CTCL. The trial is composed of two parts, phase Ia and phase Ib. Phase Ia is a dose escalation part to determine the MTD and/or RD of SIM1811-03. Phase Ib is a dose expansion part at RD level SIM1811-03 determined in phase Ia to primarily assess the anti-tumor activity of SIM1811-03 in subjects with solid tumors or CTCL. The tumor types in PhIb will be adjusted based on the response observed in PhIa. Approximately 50 subjects will be enrolled in this phase. Cohort 1: Patients with CTCL (approximately 20 patients). Cohort 2: Patients with advanced/metastatic solid tumors, including ovarian cancer (approximately 10 patients), NSCLC (approximately 10 patients), and hepatocellular carcinoma etc. Each subject will undergo Screening, Treatment, Safety Follow-up, and survival Follow-up periods. Any subject who has discontinued from study treatment other than disease progression will also enter PFS follow up period and to continue to have tumor assessments until disease progression, initiation of subsequent anticancer therapies, or death, whichever occurs first. Upon completion of the safety follow up and PFS follow-up, as applicable, all patients, except those who died, withdrew consent or were lost to follow-up, will be followed for survival. Eligible subjects will receive intravenous infusion of SIM1811-03 on Days 1 and 15 of each 28-day cycle.

Official Title
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A Phase I Trial of SIM1811-03 in Subjects With Advanced Solid Tumors and Cutaneous T-cell Lymphoma

Conditions
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Advanced Solid Tumor, Cutaneous T-cell Lymphoma (CTCL)

Intervention / Treatment
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* Drug: SIM1811-03


Participation Criteria
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Eligibility Criteria
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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. Patients with lymphoma other than CTCL are not eligible. 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 patients with solid tumors. Tumor lesions previously treated with radiotherapy or local therapy should not be considered as measurable unless progression is documented. For patients with CTCL, the following criteria must be met: Have at least one measurable lesion (mSWAT criteria) , the lesion that has previously been treated with local therapy should not be considered as measurable unless progression is documented; Provide tissue from a punch biopsy of the skin at screening (except for patients in phase Ia dose escalation phase, for whom skin biopsies is recommended only). Mycosis fungoides (MF) or Sézary Syndrome (SS) (Stage IIb-IV based on Tumor Node Metastasis Blood [TNMB] staging system for SS and MF diagnosed at screening) failed of at least 2 prior systemic therapies Meet clinical criteria for systemic treatment (patients that can be treated with radiotherapy and/or skin-directly therapies only are to be excluded) No current large cell transformation Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 Life expectancy of ≥ 12 weeks Adequate organ and marrow functions Provide archival tumor samples or fresh tumor biopsy (mandatory for Phase Ib, and recommended for Phase Ia) Females of childbearing potential require strict contraception during the study Exclusion Criteria: Participated in an interventional clinical trial or has used investigational devices within 28 days prior to first dose of study drug or received any following systemic anti-cancer treatments: cytotoxic chemotherapy, targeted therapy, immune checkpoint inhibitor within 4 weeks (such as PD-1 inhibitor, PD-L1 inhibitor, or CTLA-4 inhibitor); radiotherapy within 2 weeks (palliative radiotherapy is allowed at least 1 week before the study drug treatment). Toxicity and side effects (due to previous anticancer treatments) have not recovered to ≤ grade 1, unless such AE is not considered to pose safety risks (such as hair loss and neuropathy ≤ grade 2 caused by chemotherapy). Required use of corticosteroids for more than 7 consecutive days within 14 days prior to the first dose of study treatment (> 10 mg daily prednisone equivalent for solid tumors; > 20 mg daily prednisone equivalent for CTCL) Patients with active or history of or risk of autoimmune disease Major surgery (except biopsy) or unhealed wound within 4 weeks prior to first dose of study drug Any other current or previous malignancy within the past 2 years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, c) carcinoma in situ of the breast d) local prostate cancer after radical resection and/ or definitive radiotherapy with stable prostate specific antigen (PSA) levels for 1 years Has known active central nervous system (CNS) metastases 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 History of immunodeficiency (including HIV infection) Known active hepatitis B or C infection Patients with clinically significant cardiovascular diseases History of severe allergic reaction to the study drug or excipients used in the protocol Has had an allogeneic tissue/solid organ transplant or graft-versus-host disease Other conditions that researchers consider inappropriate for inclusion

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<br>All participants receive SIM1811-03 alone | Drug: SIM1811-03<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 tumors<br>* Other names: SIM0235, TNFR2 monoclonal antibody;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: Incidence Rate of Dose-Limiting Toxicity (DLT) | To estimate the maximum tolerated dose (MTD) or recommended dose (RD) of SIM1811-03 | Within 28 days after the first dose | 
| Phase 1b: ORR Solid tumors: objective response rate (ORR) assessed by Investigator per RECIST 1.1 CTCL: ORR assessed by Investigator per global response (Olsen 2011) | Phase 1b (dose expansion): To evaluate the anti-tumor activity of SIM1811-03 at the proposed RD | Assessed up to an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events (AEs) | Number of participants with treatment-related adverse events as assessed by CTCAE v5.0. | 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 | 
| Incidence of dose interruptions, delays and discontinuations | To assess the tolerability of SIM1811-03 | 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 | 
| AUC | To evaluate the area under the curve (AUC) plasma-concentration of SIM1811-03 | Days 1, 2, 4, 8, and 15 of Cycle 1 (each cycle is 28 days), then assessed in subsequent cycles, up to an average of 1 year | 
| Cmax | To evaluate the maximum observed concentration (Cmax) of SIM1811-03 in the blood after a dose is given | Days 1, 2, 4, 8, and 15 of Cycle 1 (each cycle is 28 days), then assessed in subsequent cycles, up to an average of 1 year | 
| Ctrough | To evaluate the lowest concentration of a drug just before the next dose of SIM1811-03 | Days 1, 2, 4, 8, and 15 of Cycle 1 (each cycle is 28 days), then assessed in subsequent cycles, up to an average of 1 year | 
| Tmax | To evaluate the time take to reach Cmax of SIM1811-03 | Days 1, 2, 4, 8, and 15 of Cycle 1 (each cycle is 28 days), then assessed in subsequent cycles, up to an average of 1 year | 
| Half-life (T1/2) | To evaluate the time it takes for the concentration of SIM1811-03 in the plasma or the total amount in the body to be reduced by 50% | Days 1, 2, 4, 8, and 15 of Cycle 1 (each cycle is 28 days), then assessed in subsequent cycles, up to an average of 1 year | 
| Incidence of anti-drug antibodies (ADAs) to SIM1811-03 | To assess the occurrence of anti-drug antibodies (ADAs) to SIM1811-03 | Days 1, 2, 4, 8, and 15 of Cycle 1 (each cycle is 28 days), then assessed in subsequent cycles, up to an average of 1 year | 
| Titer of anti-drug antibodies (ADAs) to SIM1811-03 | To evaluate the quasi-quantitative expression of the level of ADA | Days 1, 2, 4, 8, and 15 of Cycle 1 (each cycle is 28 days), then assessed in subsequent cycles, up to an average of 1 year | 
| Overall Response Rate (ORR) | ORR is defined as the proportion of participants who have a partial response (PR) or better per RECIST 1.1 | Assessed up to an average of 1 year | 
| Duration of Response (DOR) | DOR is defined as time from date of initial documentation of a response (PR or better) to date of first documented evidence of PD per RECIST 1.1 | Assessed up to an average of 1 year | 
| Disease Control Rate (DCR) | Disease Control Rate (DCR) is defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents | Assessed up to an average of 1 year | 
| Progression-Free Survival (PFS) | PFS is defined as time from date of first dose of study drug to date of first documented PD, per RACIST 1.1, or death due to any cause, whichever occurs first. | From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to an average of 1 year | 
| Overall survival (OS) | Overall survival is defined as the duration from the date of enrollment to the date of the participant's death | Up to an average of 2 year |