GEN1046 Safety Trial in Patients With Malignant Solid Tumors

• ClinicalTrials.gov Identifier: NCT03917381
• Recruitment Status: Active, not recruiting
• First Posted: April 17, 2019
• Last Update Posted: May 7, 2024
• Sponsor: Genmab
• Collaborator: BioNTech SE
• Information provided by (Responsible Party): Genmab

Tracking Information

• First Submitted Date: April 11, 2019
• First Posted Date: April 17, 2019
• Last Update Posted Date: May 7, 2024
• Actual Study Start Date: May 14, 2019
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 23, 2022)

• Dose limiting toxicity (DLT) [ Time Frame: DLTs are assessed during the first cycle (21 days) in each cohort] ]
  to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D)
• Adverse events [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  Incidence of treatment-emergent adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0
• Safety laboratory parameters (hematology, biochemistry, coagulation, endocrines) [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  Laboratory parameters graded by CTCAE v5.0
• For expansion cohort 1 only: Objective Response Rate (ORR) [ Time Frame: 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) ]
  Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by Independent Review Committee (IRC)

Original Primary Outcome Measures (submitted: April 12, 2019)

• Dose limiting toxicity (DLT) [ Time Frame: DLTs are assessed during the first cycle (21 days) in each cohort] ]
  to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D)
• Adverse events [ Time Frame: AEs are collected throughout the study and up to 2 months after last subject last treatment ]
  Incidence of treatment-emergent adverse events as assessed by CTCAE v5.0
• Safety laboratory parameters (hematology, biochemistry, coagulation, endocrines) [ Time Frame: Safety laboratory data are collected throughout the study and up to 2 months after last subject last treatment ]
  Laboratory parameters graded by CTCAE v5.0

Current Secondary Outcome Measures (submitted: December 23, 2022)

• PK parameters [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  Total body clearance of drug from the plasma
• PK parameters [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  Volume of distribution
• PK parameters [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  The area under the curve (AUC) from time zero to day 21
• PK parameters [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  The AUC from time zero to infinity
• PK parameters [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  The AUC from time zero to last quantifiable measurement
• PK parameters [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration
• PK parameters [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration
• PK parameters [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  The elimination half-life associated with the terminal slope of a semi-logarithmic concentration-time curve
• Anti-Drug Antibody (ADA) response [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  Number of subjects with ADA response
• Objective Response Rate (ORR) [ Time Frame: 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) ]
  Rate of subjects with objective response assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
• Disease Control Rate (DCR) [ Time Frame: 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) ]
  Rate of subjects with disease control assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
• Duration of Response (DoR) [ Time Frame: 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 assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
• Adverse events expansion, cohort 1 only [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  Incidence of treatment-emergent adverse events as assessed by CTCAE v5.0
• Laboratory parameters, cohort 1 only [ Time Frame: throughout the study and until end of safety follow-up period (60 days after last dose) ]
  Laboratory parameters graded by CTCAE v5.0 (Listing of all laboratory data with values flagged and shift tables)
• Duration of Response (DoR), cohort 1 only [ Time Frame: 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 assessed by independent review committee using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
• Progression free survival (PFS), cohort 1 only [ Time Frame: 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 assessed by independent review committee and assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
• Overall survival (OS), cohort 1 only [ Time Frame: 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

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: GEN1046 Safety Trial in Patients With Malignant Solid Tumors
• Official Title: First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety of GEN1046 in Subjects With Malignant Solid Tumors
• Brief Summary: 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
• 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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Solid Tumors
• Non-small Cell Lung Cancer
• Urothelial Carcinoma
• Endometrial Carcinoma
• Triple Negative Breast Cancer
• Squamous Cell Carcinoma of the Head and Neck
• Cervical Cancer

Intervention

• 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

Study Arms

• Experimental: Dose escalation
  Acasunlimab will be administered as monotherapy
  Intervention: Biological: Acasunlimab
• 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)
  Interventions:

  • 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)

• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 7, 2024): 429
• Original Estimated Enrollment (submitted: April 12, 2019): 192
• Estimated Study Completion Date: December 2024
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Czechia, Georgia, Hungary, Israel, Italy, Poland, Spain, Turkey, Ukraine, United States

Administrative Information

• NCT Number: NCT03917381
• Other Study ID Numbers: GCT1046-01; 2018-003402-63 ( EudraCT Number ); MOH_2019-05-08_006011 ( Registry Identifier: Clinical Research Site - mytrial )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Genmab
• Original Responsible Party: Same as current
• Current Study Sponsor: Genmab
• Original Study Sponsor: Same as current
• Collaborators: BioNTech SE

Investigators

• Study Director: Study Official; Genmab

• PRS Account: Genmab
• Verification Date: May 2024