GEN1046 Safety Trial in Patients With Malignant Solid Tumors

Study Overview
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Brief Summary
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The purpose of the trial is to evaluate the safety of acasunlimab (also known as GEN1046) as monotherapy and in combination therapies in patients with malignant solid tumors

Detailed Description
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The trial is an open-label, multi-center safety trial of acasunlimab (GEN1046). The trial consists of two parts, a dose escalation part (phase 1, first-in-human (FIH) and an expansion part (phase 2a)). The expansion part of the trial will be initiated once the Recommended Phase 2 Dose (RP2D) has been determined.

Official Title
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First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety of GEN1046 in Subjects With Malignant Solid Tumors

Conditions
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Solid Tumors, Non-small Cell Lung Cancer, Urothelial Carcinoma, Endometrial Carcinoma, Triple Negative Breast Cancer, Squamous Cell Carcinoma of the Head and Neck, Cervical Cancer

Intervention / Treatment
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* Biological: Acasunlimab
* Biological: Acasunlimab in combination with docetaxel (in a single expansion cohort)
* Biological: Acasunlimab in combination with pembrolizumab (in a separate expansion cohort)
* Biological: Acasunlimab in combination with pembrolizumab and standard chemotherapy (in separate expansion cohorts)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: For Dose Escalation: • Have a histologically or cytologically confirmed non-CNS solid tumor that is metastatic or unresectable and for whom there is no available standard therapy For Expansion: • Have histologically or cytological confirmed diagnosis of relapsed or refractory, advanced and/or metastatic NSCLC, EC, UC, TNBC, SCCHN, or cervical cancer who are not anymore candidates for standard therapy For separate expansion cohorts: metastatic NSCLC without prior systemic treatment regimens for metastatic disease. For Both Dose Escalation and Expansion Have measurable disease according to RECIST 1.1 Have Eastern Cooperative Oncology Group (ECOG) 0-1 Have an acceptable hematological status Have acceptable liver function Have an acceptable coagulation status Have acceptable renal function Key Exclusion Criteria: Have uncontrolled intercurrent illness, including but not limited to: Ongoing or active infection requiring intravenous treatment with antiinfective therapy 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 mmHg and/or diastolic blood pressure ≥ 100 mmHg, despite optimal medical management Ongoing or recent evidence of autoimmune disease History of irAEs that led to prior checkpoint treatment discontinuation Prior history of myositis, Guillain-Barré syndrome, or myasthenia gravis of any grade History of chronic liver disease or evidence of hepatic cirrhosis History of non-infectious pneumonitis that has required steroids or currently has pneumonitis History of organ allograft (except for corneal transplant) or autologous or allogeneic bone marrow transplant, or stem cell rescue within 3 months prior to the first dose of acasunlimab Serious, non-healing wound, skin ulcer (of any grade), or bone fracture Any history of intracerebral arteriovenous malformation, cerebral aneurysm, new (younger than 6 months) or progressive brain metastases or stroke Prior therapy: Radiotherapy: Radiotherapy within 14 days prior to first acasunlimab 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 acasunlimab administration. Accepted exceptions are bisphosphonates (e.g., pamidronate, zoledronic acid, etc.) and denosumab Toxicities from previous anti-cancer therapies that have not adequately resolved 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation<br>Acasunlimab will be administered as monotherapy | Biological: Acasunlimab<br>* Acasunlimab will be administered intravenously once every 21 days (in selected expansion cohorts acasunlimab will be administered intravenously once every 21 days for the first 2 cycles, and every 42 days in subsequent cycles)<br>* Other names: DuoBody®-PD-L1x4-1BB;|
| Experimental: Expansion<br>Acasunlimab will be administered as monotherapy (or in combination with docetaxel or in combination with pembrolizumab or in combination with pembrolizumab and standard chemotherapy in separate expansion cohorts) | Biological: Acasunlimab<br>* Acasunlimab will be administered intravenously once every 21 days (in selected expansion cohorts acasunlimab will be administered intravenously once every 21 days for the first 2 cycles, and every 42 days in subsequent cycles)<br>* Other names: DuoBody®-PD-L1x4-1BB;Biological: Acasunlimab in combination with docetaxel (in a single expansion cohort)<br>* Acasunlimab and docetaxel will be administered intravenously once every 21 days<br>* Other names: DuoBody®-PD-L1x4-1BB;Biological: Acasunlimab in combination with pembrolizumab (in a separate expansion cohort)<br>* Acasunlimab and pembrolizumab will be administered intravenously once every 21 days or every 42 days, respectively<br>* Other names: DuoBody®-PD-L1x4-1BB;Biological: Acasunlimab in combination with pembrolizumab and standard chemotherapy (in separate expansion cohorts)<br>* Acasunlimab and pembrolizumab and standard chemotherapy will be administered intravenously once every 21 days for 4 cycles, followed by treatment with acasunlimab and pembrolizumab once every 21 days<br>* Other names: DuoBody®-PD-L1x4-1BB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) | to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) | DLTs are assessed during the first cycle (21 days) in each cohort] | 
| Adverse events | Incidence of treatment-emergent adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| Safety laboratory parameters (hematology, biochemistry, coagulation, endocrines) | Laboratory parameters graded by CTCAE v5.0 | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| For expansion cohort 1 only: Objective Response Rate (ORR) | Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by Independent Review Committee (IRC) | throughout the study until disease progression/death/lost to follow-up/start of new anticancer therapy or withdrawal of consent, whichever occurs first (an expected average of 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters | Total body clearance of drug from the plasma | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| PK parameters | Volume of distribution | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| PK parameters | The area under the curve (AUC) from time zero to day 21 | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| PK parameters | The AUC from time zero to infinity | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| PK parameters | The AUC from time zero to last quantifiable measurement | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| PK parameters | The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| PK parameters | The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| PK parameters | The elimination half-life associated with the terminal slope of a semi-logarithmic concentration-time curve | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| Anti-Drug Antibody (ADA) response | Number of subjects with ADA response | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| Objective Response Rate (ORR) | Rate of subjects with objective response assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | throughout the study until disease progression/death/lost to follow-up/start of new anticancer therapy or withdrawal of consent, whichever occurs first (an expected average of 6 months) | 
| Disease Control Rate (DCR) | Rate of subjects with disease control assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | throughout the study until disease progression/death/lost to follow-up/start of new anticancer therapy or withdrawal of consent, whichever occurs first (an expected average of 6 months) | 
| Duration of Response (DoR) | Duration of Response assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | throughout the study until disease progression/death/lost to follow-up/start of new anticancer therapy or withdrawal of consent, whichever occurs first (an expected average of 6 months) | 
| Adverse events expansion, cohort 1 only | Incidence of treatment-emergent adverse events as assessed by CTCAE v5.0 | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| Laboratory parameters, cohort 1 only | Laboratory parameters graded by CTCAE v5.0 (Listing of all laboratory data with values flagged and shift tables) | throughout the study and until end of safety follow-up period (60 days after last dose) | 
| Duration of Response (DoR), cohort 1 only | Duration of Response assessed by independent review committee using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | throughout the study until disease progression/death/lost to follow-up/start of new anticancer therapy or withdrawal of consent, whichever occurs first (an expected average of 6 months) | 
| Progression free survival (PFS), cohort 1 only | Progression free survival assessed by independent review committee and assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | throughout the study until disease progression/death/lost to follow-up/start of new anticancer therapy or withdrawal of consent, whichever occurs first (an expected average of 6 months) | 
| Overall survival (OS), cohort 1 only | Overall survival | throughout the study until disease progression/death/lost to follow-up/start of new anticancer therapy or withdrawal of consent, whichever occurs first (an expected average of 6 months) |