Safety and Efficacy Study of GEN1046 as a Single Agent or in Combination With Pembrolizumab for Treatment of Recurrent (Non-small Cell) Lung Cancer

Study Overview
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Brief Summary
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The purpose of this trial is to investigate the safety and efficacy of acasunlimab (also known as GEN1046) as monotherapy and in combination with pembrolizumab in patients with non-small cell lung cancer who have progressed during or after treatment of previous standard of care

Detailed Description
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This trial is a randomized, open-label trial evaluating the safety and efficacy of acasunlimab (GEN1046) as monotherapy and in combination therapy with pembrolizumab. The trial consists of two parts; a safety phase and an extension phase. The extension phase will be initiated once the safety phase is completed.

Official Title
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A Phase 2, Multicenter, Randomized, Open-Label Trial of GEN1046 as Monotherapy and in Combination Pembrolizumab Therapy in Subjects With Relapsed/Refractory Metastatic Non-Small Cell Lung Cancer After Treatment With Standard of Care Therapy With an Immune Checkpoint Inhibitor

Conditions
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Non Small Cell Lung Cancer Metastatic

Intervention / Treatment
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* Biological: Acasunlimab
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Have signed an informed consent form (ICF) Be at least 18 years of age. Have histologically or cytologically confirmed diagnosis of stage 4 NSCLC with at least 1 prior line of systemic therapy containing an anti-PD-1/PD-L1 mAb for metastatic disease Have a tumor PD-L1 expression result available prior to first treatment demonstrating PD-L1 expression in ≥1% of tumor cells as assessed by a central or local laboratory during screening. Have measurable disease per RECIST v1.1. Have Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1. Have life expectancy of at least 3 months. Have adequate organ and bone marrow function as defined in the protocol. Key Exclusion Criteria: Documentation of known EGFR, KRAS, RET, ROS1, BRAF mutations, NTRK gene infusions, RET arrangement, ALK gene rearrangements, high-level MET amplification, or METex 14 skipping. Note: Subjects harboring such mutations, gene rearrangements or amplifications may be enrolled in the trial, if subjects have received prior approved targeted therapy for such mutations, the subject may still be eligible for this trial. Treatment with an anti-cancer agent within 28 days prior to acasunlimab administration. Any investigational agent for the treatment of stage 4 NSCLC. Radiotherapy within 14 days prior to first acasunlimab administration or received lung radiation therapy of >30 Gy within 6 months of the first dose of trial treatment. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Chronic systemic immunosuppressive corticosteroid doses, ie, prednisone >10 mg daily or a cumulative dose >150 mg prednisone within 14 days before the first acasunlimab administration. Subject has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. Subject has contraindications to the use of pembrolizumab per local prescribing information. Subject has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis (interstitial lung disease). Ongoing or active infection requiring intravenous treatment with anti-infective therapy that has been administered <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 mmHg and/or diastolic blood pressure ≥100 mmHg, despite optimal medical management. Ongoing or recent (within 6 months) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for irAEs. Subject has a known history of any of the following: Grade 3 or higher irAEs that led to treatment discontinuation of a prior immunotherapy treatment. Myositis, Guillain-Barré syndrome, or myasthenia gravis of any grade. Liver disease (eg, alcoholic hepatitis or non-alcoholic steatohepatitis, drug-related or autoimmune hepatitis, or evidence of hepatic cirrhosis). 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. Grade 3 or higher allergic reactions to monoclonal antibody therapy as well as known or suspected allergy or intolerance to any agent given in the course of this trial. 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Treatment with acasunlimab once every 21 days for the first 2 cycles and then every 42 days in subsequent cycles | Biological: Acasunlimab<br>* Acasunlimab will be administered intravenously (IV)<br>* Other names: DuoBody®-PD-L1×4-1BB;|
| Experimental: Arm B<br>Treatment with acasunlimab + pembrolizumab once every 21 days | Biological: Acasunlimab<br>* Acasunlimab will be administered intravenously (IV)<br>* Other names: DuoBody®-PD-L1×4-1BB;Biological: Pembrolizumab<br>* Pembrolizumab will be administered IV<br>|
| Experimental: Arm C<br>Treatment with acasunlimab+ pembrolizumab once every 42 days | Biological: Acasunlimab<br>* Acasunlimab will be administered intravenously (IV)<br>* Other names: DuoBody®-PD-L1×4-1BB;Biological: Pembrolizumab<br>* Pembrolizumab will be administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | ORR will be measured as the proportion of subjects with a confirmed response of complete response (CR) or partial response (PR) as per RECIST v1.1 | Throughout the trial 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 |
| --- | --- | --- |
| Duration of response (DOR) | DOR will be measured as the time from initial onset of CR or PR to first radiographic progression as per RECIST v. 1.1 or death from any cause, whichever occurs first. | From onset date of response 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) | 
| Time to response (TTR) | TTR will be measured as the time from first treatment to onset of initial response (CR or PR) as per RECIST v.1.1 | From first treatment to date of onset of initial response (CR or PR) as per RECIST v.1.1 (an expected average of 6 months) | 
| Progression-free survival (PFS) | PFS will be measured from date of first treatment until date of radiographic progression as per RECIST v.1.1 or until death from any cause, whichever occurs first | From first treatment to first documented progression or death due to any cause (an expected average of 6 months) | 
| Overall survival (OS) | Defined as time to death from of any cause | From first treatment to date of death (assessed up to 3 years after the last participant's first dose in the trial) | 
| Incidence and severity of adverse events (AEs) and laboratory abnormalities | Incidence of treatment-emergent AEs as assessed by CTCAE v5.0. Laboratory parameters graded by CTCAE v5.0 | Throughout the trial until end of safety follow-up period (60 days or 90 days after last dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DuoBody®, Bispecific antibody, PD-L1, 4-1BB