Clinical trial NCT03917381: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: Genmab
Sponsor class: INDUSTRY
First posted: 2019-04-17
Enrollment: 429
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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 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 other chemotherapy) or docetaxel.

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.

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.

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.

Primary outcomes:
measure: Dose Escalation: Number of Participants With Dose Limiting Toxicity (DLT)
timeFrame: During first cycle (21 days) for each cohort
measure: Dose Escalation and Monotherapy Expansion Cohorts: Number of Participants With Adverse Events (AEs)
timeFrame: From first dose until the end of the study (up to 60 days after the last dose)
measure: Dose Escalation and Monotherapy Expansion Cohorts: Number of Participants With Shifts From Baseline in Safety Laboratory Parameters
timeFrame: From first dose until the end of the study (up to 60 days after the last dose)
measure: Expansion Cohort 1: Objective Response Rate (ORR)
timeFrame: Up to 3 years
Secondary outcomes:
measure: Expansion Cohort 1: Number of Participants With AEs
timeFrame: From first dose until the end of the study (up to 60 days after the last dose)
measure: Expansion Cohort 1: Number of Participants With Shifts From Baseline in Safety Laboratory Parameters
timeFrame: From first dose until the end of the study (up to 60 days after the last dose)
measure: Combination Therapy Expansion Cohorts: Number of Participants With AEs
timeFrame: From first dose until the end of the study (up to 60 days after the last dose)
measure: Combination Therapy Expansion Cohorts: Number of Participants With Shifts From Baseline in Safety Laboratory Parameters
timeFrame: From first dose until the end of the study (up to 60 days after the last dose)
measure: All Parts: Total Body Clearance (CL) of GEN1046
timeFrame: Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose)
measure: All Parts: Volume of Distribution (Vd) of GEN1046
timeFrame: Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose)
measure: All Parts: Area Under the Concentration-Time Curve from Time Zero to Day 21 (AUC21days) of GEN1046
timeFrame: Predose and postdose at multiple timepoints for 21 days up to end of safety follow up (up to 60 days after last dose)
measure: All Parts: Area Under the Concentration-Time Curve from Time Zero to Infinity (AUCinf) of GEN1046
timeFrame: Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose)
measure: All Parts: Area Under the Concentration-Time Curve from Time Zero to Last Quantifiable Concentration (AUClast) of GEN1046
timeFrame: Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose)
measure: All Parts: Maximum Observed Plasma Concentration (Cmax) of GEN1046
timeFrame: Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose)
measure: All Parts: Time to Reach Cmax (Tmax) of GEN1046
timeFrame: Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose)
measure: All Parts: Elimination Half-life (t½) of GEN1046
timeFrame: Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose)
measure: All Parts: Number of Participants with Anti-drug Antibodies (ADAs)
timeFrame: Up to 3 years
measure: Dose Escalation and Expansion Cohorts 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13: ORR
timeFrame: Up to 3 years
measure: Dose Escalation and Expansion Cohorts 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13: Disease Control Rate (DCR)
timeFrame: Up to 3 years
measure: All Parts: Duration of Response (DoR)
timeFrame: Up to 3 years
measure: Expansion Cohort 1: Progression Free Survival (PFS)
timeFrame: Up to 3 years
measure: Expansion Cohort 1: Overall survival (OS)
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: New Haven
country: United States
facility: Yale University Cancer Center
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Hospitals
state: Iowa
city: Louisville
country: United States
facility: Norton Healthcare Inc
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: START Midwest
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: NYU Langone
state: New York
city: Chapel Hill
country: United States
facility: UNC Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Levine Cancer Institute, Atrium Health
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Brno
country: Czechia
facility: University Hospital Brno
city: Nový Jičín
country: Czechia
facility: Nemocnice AGEL Ostrava-Vítkovice a.s.
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Batumi
country: Georgia
facility: High Technology Hospital Medcenter
city: Tbilisi
country: Georgia
facility: LLC "TIM - Tbilisi Institute of Medicine"
city: Tbilisi
country: Georgia
facility: LTD Consilium Medulla
city: Tbilisi
country: Georgia
facility: Tbilisi State Medical University and Ingorovka High Medical Technology University Clinic Ltd
city: Debrecen
country: Hungary
facility: Onkologiai Klinika
city: Kecskemét
country: Hungary
facility: BKMK Hospital
city: Törökbálint
country: Hungary
facility: Pulmonology Hospital Törökbálinti
city: Haifa
country: Israel
facility: Rambam Health Care Campus RHCC - Rambam Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Organization HMO - Sharett Institute of Oncology
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Tel HaShomer
country: Israel
facility: Sheba Medical Center, Ramat Gan
city: Bologna
country: Italy
facility: Policlinico San'Orsola
city: Milan
country: Italy
facility: IRCCS - Istituto Europeo di Oncologia IEO
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori - Fondazione Pascale Italy
city: Parma
country: Italy
facility: Azienda Ospedaliero Universitaria di Parma
city: Ravenna
country: Italy
facility: AUSL Romagno-Ravenna
city: Roma
country: Italy
facility: Policlinico Uni. Campus Bio-Medico
city: Rome
country: Italy
facility: Regina Elena National Cancer Institute
city: Varese
country: Italy
facility: ASST Sette Laghi "Ospedale di Circolo e Fondazione Macchi "
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Poznań
country: Poland
facility: Medpolonia Sp. z o.o.
city: Prabuty
country: Poland
facility: Specialist Hospital in Prabuty
city: Szczecin
country: Poland
facility: Dom Lekarski SA
city: Warsaw
country: Poland
facility: Maria Sklodowska Curie National Research Instutute of Oncology
city: Barcelona
country: Spain
facility: Hospital Universitario Vall dHebron
city: Barcelona
country: Spain
facility: IOB-Hospital Quironsalud Barcelona
city: Madrid
country: Spain
facility: START Madrid-FJD, Hospital Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: START Madrid-CIOCC
city: Madrid
country: Spain
facility: NEXT Oncology Madrid
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Madrid
country: Spain
facility: MD Anderson Cancer Center Madrid
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Valencia
country: Spain
facility: Hospital Clinico De Valencia
city: Ankara
country: Turkey
facility: Gulhane Training and Research Hospital
city: Edirne
country: Turkey
facility: Trakya University Hospital
city: Karsiyaka
country: Turkey
facility: Medical Point Izmir Hospital
city: Kyiv
country: Ukraine
facility: ARENSIA Exploratory Medicine LLC
Study officials:
affiliation: Genmab
name: Study Official
role: STUDY_DIRECTOR
References:
citation: 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.