A Study on the Safety of GEN1044 (DuoBody®-CD3x5T4) 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, determine the recommended Phase 2 dose (RP2D), and assess preliminary clinical activity of GEN1044 in patients with solid tumors.

Detailed Description
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The trial is an open-label, multi-center safety trial of GEN1044. The trial consists of two parts: a dose-escalation part (Phase 1) and an expansion part (Phase 2a). The expansion part of the trial will be initiated once the RP2D has been determined from Phase 1.

Official Title
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First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety of GEN1044 in Subjects With Malignant Solid Tumors

Conditions
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Bladder Cancer, Triple Negative Breast Cancer (TNBC), Locally Advanced or Metastatic Solid Tumor(s), Prostate Cancer, Esophageal Cancer, Squamous Cell Carcinoma of Head and Neck (SCCHN), Non-small Cell Lung Cancer (NSCLC), Uterine Cancer

Intervention / Treatment
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* Biological: GEN1044 is an immunoglobulin G1 (IgG1) bispecific antibody targeting CD3 and 5T4.


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Dose-escalation part: • Patient with locally advanced or metastatic solid tumor(s) (excluding patients with primary central nervous system [CNS] tumors), who has experienced disease progression while on standard therapy or is intolerant of, or not eligible for, standard therapy. Expansion part: • Must have an advanced or metastatic, pathologically confirmed diagnosis of one of the following tumors: Uterine Cancer, Prostate Cancer, Esophageal Cancer, TNBC, SCCHN, NSCLC (both adenocarcinoma [ACC] and squamous cell carcinoma [SCC], Bladder Cancer. Both parts: Must sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for the trial, and is willing to participate in the trial prior to any trial related assessments or procedures. Must have measurable disease according to response assessment criteria relevant to the tumor type. Must have an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0-1 at Screening and on C1D1. A woman of reproductive potential must agree to use adequate contraception during the trial and for 4 months after the last GEN1044 administration. Adequate contraception is defined as highly effective methods of contraception. Key Exclusion Criteria (both parts): Has an uncontrolled intercurrent illness, including but not limited to: Ongoing or active infection requiring intravenous treatment with anti-infective 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 significant autoimmune disease. Patients with a history of grade 3 or higher immune-related adverse events that led to treatment discontinuation. Patients with a 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 GEN1044. Serious, non-healing wound, skin ulcer (of any grade), or bone fracture. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, new or symptomatic brain metastases or stroke. Prior therapy: Radiotherapy: Radiotherapy within 14 days prior to first GEN1044 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 GEN1044 administration. Toxicities from previous anti-cancer therapies that have not resolved. Has a history of ≥ grade 2 cytokine release syndrome (CRS) with other CD3-based bispecifics, or a history of ≥ grade 3 allergic reactions to monoclonal antibody therapy as well as known or has known allergies, hypersensitivity, or intolerance to GEN1044 or its excipients.

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: GEN1044<br> | Biological: GEN1044 is an immunoglobulin G1 (IgG1) bispecific antibody targeting CD3 and 5T4.<br>* GEN1044 will be administered intravenously in cycles of 21 days.<br>* Other names: DuoBody®-CD3x5T4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | The DLT was defined as Grade (G) >= 3 cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome; any G3 or 4 hematologic and non-hematologic toxicity (with exceptions defined by the protocol); laboratory abnormality that required clinically significant medical intervention, led to hospitalization, persisted for >1 week, or resulted in a drug-induced liver injury; G3 or 4 febrile neutropenia; liver toxicity defined by Hy's law; any treatment-related toxicity that caused treatment discontinuation during Cycle 1; or any G5 toxicity. | From Day 1 to Day 21 of first cycle | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) is defined as an AE that meets one of the following criteria: fatal or life-threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; medically significant (an event that jeopardizes the participant or may require medical or surgical intervention to prevent one of the outcomes listed above [medical and scientific judgment must be exercised in deciding whether an AE is 'medically significant']); required inpatient hospitalization or prolongation of existing hospitalization. A TEAE is defined as an AE occurring or worsening between the first dose of GEN1044 and 30 days after the last dose received. | Day 1 through Day 263 (corresponding to maximum observed duration) | 
| Number of Participants With Abnormal Laboratory Values | Number of participants with laboratory values of Grade >= 3 by NCI-CTCAE v5.0 are reported. The NCI-CTCAE is a descriptive terminology that is used for gradings (Grade 1-5) of Adverse Events (AEs) and of laboratory values; the latter being summarized here. This table reports laboratory values graded only on the numerical value of the reported parameter and is therefore not graded by symptoms or signs. The abnormal laboratory values assessed by the investigator as being AEs are reported also in the AE table. In case a participant reported multiple severity grades for a laboratory value, only the maximum grade was used. | Day 1 through Day 263 (corresponding to maximum observed duration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response (CR) or Partial Response (PR) | The radiological evaluation based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) was performed by investigator using computed tomography (CT) scan/ magnetic resonance imaging (MRI) scan/ positron emission tomography (PET) scan. The CR was defined as disappearance of all target and non-target lesions and all pathological lymph nodes must have decreased to < 10 mm in short axis. The PR was defined as at least a 30% decrease in the sum of the longest diameters of target lesions taking as reference the baseline sum of longest diameters. | Day 1 through Day 233 | 
| Number of Participants With Antidrug Antibodies (ADAs) Positive to GEN1044 | The detection and titer characterization of ADAs was performed using validated, specific, and sensitive electrochemiluminescence immunoassay (ECLIA) methods. Number of participants with ADA positive post baseline to GEN1044 are reported. | Day 1 through Day 263 (predose on Day 1 of Cycles 1, 2, 3, 5, 7, and then on Day 1 of every 4 cycles thereafter, end of treatment [EOT], and 30 days after last study drug) |