A Study to Evaluate Safety, Tolerability, and Preliminary Effect of the GEN1053 Antibody on Malignant Solid Tumors as Monotherapy

Study Overview
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Brief Summary
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The drug that will be investigated in the study is GEN1053. GEN1053 is an antibody designed to (re)activate and increase antitumor immunity. Since this is the first study of GEN1053 in humans, the main purpose is to evaluate safety. Besides safety, the study will determine the recommended GEN1053 dose to be tested in a larger group of participants and assess preliminary clinical activity of GEN1053. GEN1053 will be studied in a broad group of cancer patients, having different kinds of solid tumors. All participants will get GEN1053. The study consists of two parts: Part 1 tests increasing doses of GEN1053 (escalation), followed by Part 2 which tests the recommended phase 2 dose GEN1053 dose from Part 1 (expansion).

Detailed Description
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The trial is a First in Human open-label, multicenter, multinational safety trial in participants with non-central nervous system (non-CNS) metastatic or advanced malignant solid tumors for whom there is no available standard therapy likely to confer clinical benefit, evaluating the safety, tolerability, preliminary antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of GEN1053. The trial will be conducted as follows: The Dose Escalation part (Part 1) will explore the safety of escalating doses of GEN1053 as monotherapy (phase 1) The Expansion part (Part 2) is planned to provide additional safety and initial antitumor activity information of the Recommended Phase 2 dose (RP2D) for GEN1053 monotherapy in selected tumor indications, as well as more detailed data related to the mode of action (MoA).

Official Title
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First-in-Human, Open-label, Dose-Escalation Trial With an Expansion Cohort to Evaluate the Safety of GEN1053 as Monotherapy in Subjects With Malignant Solid Tumors

Conditions
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Solid Tumor, Adult

Intervention / Treatment
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* Biological: GEN1053


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: For both the Dose Escalation and Expansion parts: Be ≥18 years of age. Have measurable disease according to RECIST 1.1 Provide all pre-baseline scans since failure of last prior therapy (ie radiographic PD), if available Have Eastern Cooperative Oncology Group performance status ≤1. Have organ and bone marrow function as follows: Bone marrow / hematological function: Absolute neutrophil count (ANC) ≥1.5×10^9/L Hemoglobin ≥9.0 g/dL Platelet count ≥150×10^9/L Liver function: Total bilirubin ≤ upper limit of normal (ULN) Alanine aminotransferase ≤1.5×ULN Aspartate aminotransferase ≤1.5×ULN Albumin ≥30 g/L Coagulation status: Prothrombin time (PT)/International normalized ratio ≤1.5 Activated partial thromboplastin time (aPTT) ≤1.5×ULN Renal function: Glomerular filtration rate ≥45 mL/min/1.73 m², according to the abbreviated Modification of Diet in Renal Disease equation For Monotherapy Dose Escalation (phase 1) only: Subjects with histologically or cytologically confirmed non-CNS solid tumors that are metastatic or advanced. Subjects who have progressed on standard of care therapy or for whom there is no available standard therapy likely to provide clinical benefit, or who are not candidates for or refuse such available therapy, and for whom, in the opinion of the investigator, experimental therapy with GEN1053 may be beneficial. Fresh biopsies mandatory for all patients in Monotherapy Dose Escalation For the Expansion part Only: •Subjects with histologically or cytologically confirmed diagnosis of recurrent, unresectable or metastatic HNSCC, who have progressed on standard of care therapy or do not have any further available standard therapy or are not candidates for or refuse standard therapy (if subjects had access), and for whom experimental therapy with GEN1053 may be beneficial in the opinion of the investigator. Key Exclusion Criteria (all parts): Has uncontrolled intercurrent illness, including but not limited to: Ongoing or active infection requiring IV treatment with anti-infective therapy administered less than 2 weeks prior to first dose. Symptomatic congestive heart failure (Grade III or IV as classified by the New York Heart Association), unstable angina pectoris or cardiac arrhythmia. Uncontrolled hypertension defined as systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg, despite optimal medical management. Prolonged QTc interval at baseline of ≥470 milliseconds using Fridericia's QT correction formula. Ongoing or recent (within 1 year) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for irAEs. History of grade 3 or higher irAEs that led to treatment discontinuation of a CPI. History of chronic liver disease or evidence of hepatic cirrhosis. Evidence of interstitial lung disease. Ongoing pneumonitis or history of non-infectious pneumonitis that has required steroids. Known platelet function defects Prior therapy: Radiotherapy within 14 days prior to first GEN1053 administration. Palliative radiotherapy will be allowed. Treatment with an anti-cancer agent (within 28 days or after at least 5 half-lives of the drug, whichever is shorter), prior to GEN1053 administration. Subject with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first treatment. Inhaled or topical steroids, and adrenal or pituitary replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

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
Interventional Model Description: Sequential assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GEN1053 Monotherapy<br> | Biological: GEN1053<br>* GEN1053 will be administered as an intravenous (IV) infusion every 3rd week. The dose levels will be determined by the starting dose and the escalation steps taken in the trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Escalation: Dose Limiting Toxicities (DLTs) | To evaluate the safety of GEN1053 as monotherapy and determine the Maximum tolerated Dose(MTD)/ Maximum Administered Dose(MAD) / RP2D | DLTs are evaluated during the first cycle (21 days) in each cohort | 
| Adverse Events (AEs) by incidence and severity | To evaluate the safety and tolerability of GEN1053 as monotherapy throughout the treatment period of trial participants | Throughout the trial until the end of the safety follow-up period (60 days after last dose) | 
| Number of participants with clinically significant shifts from baseline in clinical laboratory parameters | Clinical laboratory parameters assessed: Hematology, biochemistry, coagulation, urinalysis, hepatitis B, T3 and T4, CA-125 (Cancer-antigen 125; only participants with ovarian cancer) | Throughout the trial until the end of the safety follow-up period (60 days after last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate at which the drug is removed from the body (clearance) | Characterize the PK properties of GEN1053 as monotherapy | Throughout the trial until the end of the safety follow-up period (60 days after last dose) | 
| Amount of drug in the body (volume of distribution) | Characterize the PK properties of GEN1053 as monotherapy | Throughout the trial until the end of the safety follow-up period (60 days after last dose) | 
| Area-under-the-concentration-time curve (AUC0-C last) and from time 0 to last quantifiable sample (AUC0-C infinity) | Characterize the PK properties of GEN1053 as monotherapy | Throughout the trial until the end of the safety follow-up period (60 days after last dose) | 
| Maximum (peak) concentration (Cmax) after dosing | Characterize the PK properties of GEN1053 as monotherapy | Collected throughout the trial until the end of the safety follow-up period (60 days after last dose) | 
| Time after dosing at which Cmax was observed (Tmax) | Characterize the PK properties of GEN1053 as monotherapy | Throughout the trial until the end of the safety follow-up period (60 days after last dose) | 
| Time after dosing at which the lowest drug concentration is observed before the next dose is administered, pre-dose trough concentration (CTrough) | Characterize the PK properties of GEN1053 as monotherapy | Throughout the trial until the end of the safety follow-up period (60 days after last dose) | 
| Elimination half-life of the drug (T1/2) | Characterize the PK properties of GEN1053 as monotherapy | Throughout the trial until the end of the safety follow-up period (60 days after last dose) | 
| Anti-drug antibody response (ADA) | Immunogenicity: ADA of GEN1053 as monotherapy | Collected throughout the trial until the end of the safety follow-up period (60 days after last dose) | 
| Reduction in tumor size according to response assessment by Objective Response (ORR) | Anti-tumor activity of GEN1053 as monotherapy according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Evaluated through trial completion, up to 5 years after the first visit of the last participant | 
| Disease control rate (DCR) | Anti-tumor activity of GEN1053 as monotherapy according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Evaluated through trial completion, up to 5 years after the first visit of the last participant | 
| Duration of response (DOR) | Anti-tumor activity of GEN1053 as monotherapy according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Evaluated through trial completion, up to 5 years after the first visit of the last participant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Monoclonal antibody