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 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

Study Overview

• Status: Active, not recruiting
• Conditions: Cervical Cancer; Squamous Cell Carcinoma of the Head and Neck; Triple Negative Breast Cancer; Non-small Cell Lung Cancer; Solid Tumors; Endometrial Carcinoma; Urothelial Carcinoma
• 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 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.

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

Contacts and Locations

• Study Contact: Name: Genmab Trial Information; Phone Number: +4570202728; Email: clinicaltrials@genmab.com

Study Locations

• Czechia
  • Brno, Czechia
    • Fakultní 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 HaShomer, Israel, 52621
    • Sheba Medical Center, Ramat Gan
• Italy
  • Bologna, Italy
    • Policlinico San'Orsola
  • Milan, Italy
    • IRCCS - Istituto Europeo di Oncologia IEO
  • Napoli, 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
  • Gdańsk, Poland
    • Uniwersyteckie Centrum Kliniczne
  • Poznań, 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
  • Ankara, Turkey
    • Gulhane Training and Research Hospital
  • Edirne, Turkey
    • Trakya University Hospital
  • Karsiyaka, Turkey
    • Medical Point İzmir 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
    • Saint 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: 16 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 docetaxel or in combination with pembrolizumab or in combination with pembrolizumab and 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 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)

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 (Estimated): June 1, 2024
• Study Completion (Estimated): December 1, 2024

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 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Breast Diseases; Head and Neck Neoplasms; Carcinoma, Squamous Cell; Breast Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Carcinoma; Endometrial Neoplasms; Squamous Cell Carcinoma of Head and Neck; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Docetaxel; Pembrolizumab
• Other Study ID Numbers: GCT1046-01; 2018-003402-63 (EudraCT Number); MOH_2019-05-08_006011 (Registry Identifier: Clinical Research Site - mytrial)

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