GEN1047 for Solid Tumors - First in Human (FIH) Trial

Study Overview
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Brief Summary
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The drug investigated in the study is an antibody, GEN1047. Since this is the first study of GEN1047 in humans, the main purpose is to evaluate safety. Besides safety, the study will determine the recommended GEN1047 dose to be tested in a larger group of participants and assess preliminary clinical activity of GEN1047. GEN1047 will be studied in a broad group of cancer participants, having different kinds of solid tumors. All participants will get GEN1047. The study consists of two parts: Part 1 tests increasing doses of GEN1047 (escalation), followed by Part 2 (expansion) which tests the recommended GEN1047 dose from Part 1.

Detailed Description
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The trial is an open-label, multi-center safety trial of GEN1047. The trial consists of two parts: a dose escalation part (escalation - phase 1) and an expansion part (expansion - phase 2a). The goal of the dose escalation part is to find out if GEN1047 is safe in participants with specific solid tumors and to find the best dose(s). In the expansion part of the trial up to two doses of GEN1047 will be tested.

Official Title
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First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety of GEN1047 in Subjects With Malignant Solid Tumors

Conditions
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Breast Cancer, Breast Neoplasms, Endometrial Cancer, Endometrial Neoplasm, Ovarian Cancer, Ovarian Neoplasms, Squamous Non Small Cell Lung Cancer (NSCLC-SCC)

Intervention / Treatment
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* Biological: GEN1047 is a bispecific antibody that induces T-cell mediated cytotoxicity of B7H4-positive cells.


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Criteria - Escalation Part: Participant must have histologically or cytologically confirmed solid tumor(s) in any of the following selected indications for which there is no further available standard therapy likely to confer clinical benefit (or participant is not a candidate or has previously refused such earlier available therapy), and for whom, in the opinion of the investigator, experimental therapy with GEN1047 may be beneficial (breast cancer, endometrial cancer, ovarian cancer, squamous non-small-cell lung cancer [NSCLC-SCC]). Participants with ovarian cancer must have documented progressive disease (PD) on or after last prior treatment and within 60 days of screening. Must be at least 18 years of age (or the legal age of consent in the jurisdiction in which the trial is taking place) on the day of signing informed consent. Must have either recurrence after, or progression on or lack of response to available relevant standard of care (SoC) anticancer therapies; or are deemed intolerant to or ineligible for, standard curative therapy in the recurrent setting. Must have at least 1 measurable lesion per RECIST v1.1. The measurable lesion(s) must be outside the field of radiation therapy (RT) if there was prior treatment with RT. Must have an Eastern Cooperative Oncology Group performance status (ECOGPS) score of 0 to 1 at Screening and on C1D1 pretreatment. Should provide a tumor tissue sample during the Screening period and prior to C1D1. Provide all tumor-assessing pre-trial CT scans since failure of last prior therapy. Criteria - Expansion Part: Participants must have documented PD according to RECIST v1.1 on or after last prior treatment with latest scan performed a maximum of 28 days prior to the first dose. Participant must have advanced (unresectable) or metastatic, histologically confirmed diagnosis (breast cancer, endometrial cancer, ovarian cancer. Must be a female and at least 18 years of age (or the legal age of consent in the jurisdiction in which the trial is taking place) at the time of consent. Must have at least 1 measurable lesion per RECIST v1.1 as assessed by local investigator. Must have an ECOG- PS score of 0 to 1 at Screening and on Cycle 1 Day 1 (C1D1) pretreatment. Should provide a tumor tissue sample during the Screening period and prior to C1D1. Provide all tumor-assessing pre-trial CT scans since failure of last prior therapy. Key Exclusion Criteria: Significant cardiovascular impairment within 6 months of the first dose of trial drug. Participant with new or progressive brain metastases or spinal cord compression. Participant has a history of bowel obstruction related to underlying disease. Participant has been exposed to any prior therapy with a compound targeting CD3 and/or B7H4 or cell based therapies. Current pneumonitis (any grade) including any radiological change of ongoing pneumonitis at baseline or history of non-infectious drug-, immune-, or radiation-related pneumonitis that required steroid.

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: GEN1047<br> | Biological: GEN1047 is a bispecific antibody that induces T-cell mediated cytotoxicity of B7H4-positive cells.<br>* GEN1047 will be administered as an intravenous infusion. 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: Number of Participants with Dose Limiting Toxicities | To determine the maximum tolerated dose (MTD) and/or maximum administered dose (MAD) and recommended phase 2 dose (RP2D) or doses, to be studied in expansion part. DLT will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria version 5.0. | From the first Cycle (Cycle length=21 days) in each cohort | 
| Escalation: Number of Participants with Treatment Emergent Adverse Events (TEAEs) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. TEAE is defined as an AE occurring or worsening between the first dose of study drug and 30 days after the last dose received. | From first dose date up to end of the safety follow up period, 30 days after last dose | 
| Expansion: Objective Response Rate (ORR) | ORR is defined as percentage of participants with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Escalation and Expansion: Clearance |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=21 days) | 
| Escalation and Expansion: Volume of Distribution (Vd) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=21 days) | 
| Escalation and Expansion: Area Under the Concentration-time Curve from Time 0 to Time of Last Dose (AUClast) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=21 days) | 
| Escalation and Expansion: Maximum (Peak) Plasma Concentration (Cmax) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=21 days) | 
| Escalation and Expansion: Time to Reach Cmax (Tmax) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=21 days) | 
| Escalation and Expansion: Plasma Trough (Pre-dose) Concentrations (Cthrough) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=21 days) | 
| Escalation and Expansion: Elimination half-life (t 1/2) |  | Predose and postdose at multiple timepoints of each Cycle (Cycle length=21 days) | 
| Escalation and Expansion: Number of Participants with Anti-Drug Antibody (ADA) |  | Up to 5 years | 
| Escalation: ORR | ORR is defined as percentage of participants with BOR of confirmed CR or confirmed PR based on RECIST v1.1. | Up to 5 years | 
| Escalation and Expansion: Duration of Response (DOR) | DOR is defined as the time from the first documented response to the first documented progression or death due to any cause. | Up to 5 years | 
| Escalation and Expansion: Time to response (TTR) | Time to response (TTR) is defined as the time from the date of Cycle 1 Day 1 (C1D1) to the first documented response of either confirmed CR or confirmed PR. | Up to 5 years | 
| Escalation and Expansion: Disease control rate (DCR) | The disease control rate (DCR) is defined as the percentage of participants with BOR of confirmed CR, confirmed PR, or SD according to RECIST v1.1 | Up to 5 years | 
| Expansion: Progression Free Survival (PFS) | PFS is defined as the time from the date of C1D1 to the date of the first documented progression or death due to any cause, whichever occurs earlier according to RECIST v1.1. | Up to 5 years | 
| Expansion: Overall Survival (OS) | OS is defined as the time from date of C1D1 to date of death due to any cause. | Up to 5 years | 
| Expansion: Number of Participants with TEAEs | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. TEAE is defined as an AE occurring or worsening between the first dose of study drug and 30 days after the last dose received. | From first dose date up to end of the safety follow up period, 30 days after last dose |