GEN1046 Safety Trial in Patients With Malignant Solid Tumors

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

The goal of this trial is to learn about the antibody acasunlimab (an antibody also known as GEN1046) when it is used alone and when it is used together with standard of care treatment (docetaxel) or another antibody cancer drug, pembrolizumab (with or without chemotherapy), for treatment of patients with certain types of cancer. All subjects will receive active drug; no one will receive placebo.

This trial has 2 parts. The purpose of the first part is to find out if acasunlimab at various doses is safe and to find out the best doses of acasunlimab to use. The purpose of the second part is to give acasunlimab to more subjects to see how well the doses of acasunlimab selected in the first part work against cancer when given alone and how well they work when given with pembrolizumab with or without chemotherapy.

Trial details include:

• The average trial duration for an individual subject will be about 74 weeks.
• The average treatment duration for an individual subject will be about 21 weeks.
• The visit frequency will be weekly at first and lessening over time until visits are only once every 3 weeks.

Study Overview

• Status: Active, not recruiting
• Conditions: Solid Tumors
• Intervention / Treatment: 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)

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 429
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Czechia
  • Brno, Czechia
    • Fakultni nemocnice Brno
  • Brno, Czechia
    • University Hospital Brno
  • Nový Jičín, Czechia
    • Nemocnice AGEL Ostrava-Vítkovice a.s.
  • Olomouc, Czechia
    • Fakultni nemocnice Olomouc
• Georgia
  • Batumi, Georgia
    • High Technology Hospital Medcenter
  • Tbilisi, Georgia
    • LLC "TIM - Tbilisi Institute of Medicine"
  • Tbilisi, Georgia
    • LTD Consilium Medulla
  • Tbilisi, Georgia
    • Tbilisi State Medical University and Ingorovka High Medical Technology University Clinic Ltd
• Hungary
  • Debrecen, Hungary
    • Onkologiai Klinika
  • Kecskemét, Hungary
    • Bkmk Hospital
  • Törökbálint, Hungary
    • Pulmonology Hospital Törökbálinti
• Israel
  • Haifa, Israel
    • Rambam Health Care Campus RHCC - Rambam Medical Center
  • Jerusalem, Israel, 12000
    • Hadassah Medical Organization HMO - Sharett Institute of Oncology
  • Tel Aviv, Israel, 64239
    • Tel Aviv Sourasky Medical Center
  • Tel Litwinsky, Israel, 52621
    • Sheba Medical Center, Ramat Gan
• Italy
  • Bologna, Italy
    • Policlinico San'Orsola
  • Milan, Italy
    • IRCCS - Istituto Europeo di Oncologia IEO
  • Naples, Italy
    • Istituto Nazionale Tumori - Fondazione Pascale Italy
  • Parma, Italy
    • Azienda Ospedaliero Universitaria di Parma
  • Ravenna, Italy
    • AUSL Romagno-Ravenna
  • Roma, Italy
    • Policlinico Uni. Campus Bio-Medico
  • Rome, Italy
    • Regina Elena National Cancer Institute
  • Varese, Italy
    • ASST Sette Laghi "Ospedale di Circolo e Fondazione Macchi "
• Poland
  • Gdansk, Poland
    • Uniwersyteckie Centrum Kliniczne
  • Poznan, Poland
    • Medpolonia Sp. z o.o.
  • Prabuty, Poland
    • Specialist Hospital in Prabuty
  • Szczecin, Poland
    • Dom Lekarski SA
  • Warsaw, Poland
    • Maria Sklodowska Curie National Research Instutute of Oncology
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall dHebron
  • Barcelona, Spain, 8023
    • IOB-Hospital Quironsalud Barcelona
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28040
    • START Madrid-FJD, Hospital Fundacion Jimenez Diaz
  • Madrid, Spain
    • MD Anderson Cancer Center Madrid
  • Madrid, Spain
    • Hospital Universitario La Princesa
  • Madrid, Spain, 28050
    • START Madrid-CIOCC
  • Madrid, Spain, 28223
    • Next Oncology Madrid
  • Málaga, Spain
    • Hospital Universitario Virgen de la Victoria
  • Pamplona, Spain, 31008
    • Clinica Universidad de Navarra
  • Valencia, Spain, 46010
    • Hospital Clinico de Valencia
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye)
    • Gulhane Training and Research Hospital
  • Cordaleo, Turkey (Türkiye)
    • Medical Point Izmir Hospital
  • Edirne, Turkey (Türkiye)
    • Trakya University Hospital
• Ukraine
  • Kyiv, Ukraine
    • ARENSIA Exploratory Medicine LLC
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic
  • Connecticut
    • New Haven, Connecticut, United States, 06520-8028
      • Yale University Cancer Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Norton Healthcare Inc
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Grand Rapids, Michigan, United States, 49546
      • START Midwest
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10016
      • NYU Langone
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Chapel Hill
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute, Atrium Health
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 anti-infective therapy, or any ongoing systemic inflammatory condition requiring further diagnostic work-up or management during screening.
  • 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 within 14 days prior to first dose of acasunlimab. Note: 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation; Acasunlimab will be administered as monotherapy.	Biological: Acasunlimab; 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).; Other Names: GEN1046; DuoBody®-PD-L1x4-1BB
Experimental: Expansion; Acasunlimab will be administered as monotherapy or in combination with either docetaxel, pembrolizumab, or pembrolizumab + standard chemotherapy in separate expansion cohorts.	Biological: Acasunlimab; 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).; Other Names: GEN1046; DuoBody®-PD-L1x4-1BB; Biological: Acasunlimab in combination with docetaxel (in a single expansion cohort); Acasunlimab and docetaxel will be administered intravenously once every 21 days.; Other Names: GEN1046; DuoBody®-PD-L1x4-1BB; Biological: Acasunlimab in combination with pembrolizumab (in a separate expansion cohort); Acasunlimab and pembrolizumab will be administered intravenously once every 21 days or every 42 days, respectively.; Other Names: GEN1046; DuoBody®-PD-L1x4-1BB; Biological: Acasunlimab in combination with pembrolizumab and standard chemotherapy (in separate expansion cohorts); 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.; Other Names: GEN1046; DuoBody®-PD-L1x4-1BB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Escalation: Number of Participants With Dose Limiting Toxicity (DLT)	Toxicities will be graded for severity according to Common Terminology Criteria for Adverse Events (CTCAE) criteria version 5.0.	During first cycle (21 days) for each cohort
Dose Escalation and Monotherapy Expansion Cohorts: Number of Participants With Adverse Events (AEs)		From first dose until the end of the study (up to 60 days after the last dose)
Expansion Cohort 1: Objective Response Rate (ORR)	ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on response evaluation criteria in solid tumours (RECIST).	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expansion Cohort 1: Number of Participants With AEs		From first dose until the end of the study (up to 60 days after the last dose)
Combination Therapy Expansion Cohorts: Number of Participants With AEs		From first dose until the end of the study (up to 60 days after the last dose)
All Parts: Area Under the Concentration-Time Curve from Time Zero to Last Quantifiable Concentration (AUClast) of GEN1046		Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose)
All Parts: Maximum Observed Plasma Concentration (Cmax) of GEN1046		Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose)
All Parts: Number of Participants with Anti-drug Antibodies (ADAs)	Venous blood samples will be collected for measurement of serum concentrations of ADAs.	Up to 3 years
Dose Escalation and Expansion Cohorts 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13: ORR	ORR is defined as the percentage of participants with BOR of CR or PR based on RECIST v1.1.	Up to 3 years
Dose Escalation and Expansion Cohorts 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13: Disease Control Rate (DCR)	The DCR is defined as the percentage of participants with confirmed BOR of CR, PR, or Stable Disease (SD) according to RECIST v1.1.	Up to 3 years
All Parts: Duration of Response (DoR)	DOR is defined as the time from first documentation of response (CR or PR) to the date of the first documented progression or death whichever occurs earlier based on RECIST v1.1.	Up to 3 years
Expansion Cohort 1: Progression Free Survival (PFS)	PFS is defined as the number of days from Day 1 in Cycle 1 to the first documented progression or death due to any cause, whichever occurs first based on RECIST version 1.1.	Up to 3 years
Expansion Cohort 1: Overall survival (OS)	OS is defined as the number of days from Day 1 in Cycle 1 to death due to any cause.	Up to 3 years

Collaborators and Investigators

• Sponsor: Genmab
• Collaborators: BioNTech SE
• Investigators: Study Director: Study Official, Genmab

Publications and helpful links

General Publications

• Muik A, Garralda E, Altintas I, Gieseke F, Geva R, Ben-Ami E, Maurice-Dror C, Calvo E, LoRusso PM, Alonso G, Rodriguez-Ruiz ME, Schoedel KB, Blum JM, Sanger B, Salcedo TW, Burm SM, Stanganello E, Verzijl D, Vascotto F, Sette A, Quinkhardt J, Plantinga TS, Toker A, van den Brink EN, Fereshteh M, Diken M, Satijn D, Kreiter S, Breij ECW, Bajaj G, Lagkadinou E, Sasser K, Tureci O, Forssmann U, Ahmadi T, Sahin U, Jure-Kunkel M, Melero I. Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors. Cancer Discov. 2022 May 2;12(5):1248-1265. doi: 10.1158/2159-8290.CD-21-1345.

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2019
• Primary Completion (Actual): April 1, 2025
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: April 11, 2019
• First Submitted That Met QC Criteria: April 12, 2019
• First Posted (Actual): April 17, 2019

Study Record Updates

• Last Update Posted (Actual): April 6, 2026
• Last Update Submitted That Met QC Criteria: March 31, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Respiratory Tract Diseases; Neoplasms by Histologic Type; Uterine Diseases; Genital Diseases, Female; Lung Diseases; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Genital Neoplasms, Female; Skin Diseases; Breast Diseases; Carcinoma; Uterine Cervical Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Uterine Neoplasms; Carcinoma, Squamous Cell; Breast Neoplasms; Skin and Connective Tissue Diseases; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Non-Small-Cell Lung; Uterine Cervical Neoplasms; Triple Negative Breast Neoplasms; Endometrial Neoplasms; Carcinoma, Transitional Cell; Organic Chemicals; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Taxoids; Cyclodecanes; Diterpenes; Docetaxel; pembrolizumab
• Other Study ID Numbers: GCT1046-01; 2018-003402-63 (EudraCT Number); MOH_2019-05-08_006011 (Registry Identifier: Clinical Research Site - mytrial); 2023-509059-15 (Other Identifier: EU Trial (CTIS) Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No