Clinical trial NCT02517398: MSB0011359C (M7824) in Metastatic or Locally Advanced Solid Tumors
Official title: A Phase I, Open-label, Multiple-ascending Dose Trial to Investigate the Safety, Tolerability, PK, Biological and Clinical Activity of MSB0011359C in Subjects With Metastatic or Locally Advanced Solid Tumors and Expansion to Selected Indications
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Keywords: Solid tumor
MSB0011359C (M7824)
Metastatic or Locally Advanced Solid Tumors
Bintrafusp alfa
INTR@PID
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2015-08-07
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The main purpose of this Phase I study was to test MSB0011359C (M7824) at different dose levels to see if it is safe and well tolerated when given once every 2 weeks. Phase I means the study drug has not previously been given to humans or has only been given to a limited number of people, although it has been extensively studied in animals. Based on this information, it is hoped to find out which dose could be best for the treatment of patients. There are two parts of this research study: a dose-escalation part and an expansion part. Dose escalation means that the first people taking part in the study will receive low doses of the study drug, and as more people take part, the additional participants will receive a higher dose. This is done to find the safest dose for the study drug. Expansion means that after the dose-escalation part of the study has looked at the safety and effectiveness of different doses, many more people will be invited to take part in the study and will receive the study drug at the safest dose. Additional purposes of the study are to find out whether the study drug has anti-cancer effects and how the study drug is processed by the body.

Detailed description: This is a Phase I, open-label, dose-escalation trial with consecutive parallel-group expansion in selected solid tumor indications. The current trial wascomposed of a standard dose escalation "3 + 3" cohort design, for which 3 to 6 subjects will be enrolled at each dose level depending on the occurrence of dose limiting toxicities (DLTs), followed by a consecutive parallel-group expansion in selected solid tumor in dications. Cohorts of 3 subjects with metastatic or locally advanced solid tumors, for which no standard effective therapy exists or standard therapy has failed, will receive MSB0011359C (M7824) at escalating dose levels. After determination of the Maximum tolerated dose (MTD), enrollment in several expansion cohorts will be opened to determine the safety, pharmacokinetic (PK) / Pharmacodynamic, and clinical activity of MSB0011359C (M7824). Subjects who have experienced a confirmed complete response (CR) should continue treatment through the end of 12 months, although additional treatment is possible. In the case of progressive disease (PD), subjects should continue treatment through their next tumor assessment. Additional indications will be planned based on emerging data in the field.

Eligibility criteria: Inclusion Criteria:

* Ability to understand the purpose of the study, provide signed and dated informed consent, and able to comply with all procedures
* In Japan, if a subject is \< 20 years, the written informed consent from his/her parent or guardian will be required in addition to the subject's written consent
* Male or female subjects aged greater than or equal to (\>=) 18 years
* Life expectancy \>= 12 weeks as judged by the Investigator
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at trial entry
* Disease must be measurable with at least 1 uni dimensional measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
* Adequate hematological, hepatic and renal function as defined in the protocol
* Effective contraception for both male and female subjects if the risk of conception exists

Other protocol-defined inclusion criteria could apply.

Exclusion Criteria:

* Concurrent treatment with non-permitted drugs and other interventions
* Anticancer treatment within 28 days before the start of trial treatment, for example cyto reductive therapy, radiotherapy (with the exception of palliative radiotherapy delivered in a normal organ-spearing technique), immune therapy, or cytokine therapy
* Major surgery within 28 days before the start of trial treatment (prior diagnostic biopsy is permitted)
* Systemic therapy with immunosuppressive agents within 7 days before the start of trial treatment; or use of any investigational drug within 28 days before the start of trial treatment
* Previous malignant disease (other than the target malignancy to be investigated in this trial) within the last 3 years. Subjects with history of cervical carcinoma in situ, superficial or non invasive bladder cancer or basal cell or squamous cell cancer in situ previously treated with curative intent are NOT excluded. Subjects with other localized malignancies treated with curative intent need to be discussed with the Medical Monitor.
* Rapidly progressive disease which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or trial procedures
* Subjects with active central nervous system (CNS) metastases causing clinical symptoms or metastases that require therapeutic intervention are excluded
* Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (eg, corneal transplant, hair transplant)

Other protocol-defined exclusion criteria could apply

Primary outcomes:
measure: Dose-escalation: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: From start of study drug administration up to 139 weeks
measure: Dose-escalation: Number of Participants With Treatment-Related TEAEs, Treatment-Related Serious TEAEs and Treatment-related TEAEs Leading to Death
timeFrame: From start of study drug administration up to 139 weeks
measure: Number of Participants With TEAEs and Related TEAEs Based on Severity According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03
timeFrame: From start of study drug administration up to 139 weeks
measure: Dose-escalation: Number of Participants With Dose-Limiting Toxicities According to the National Cancer Institute Common Terminology Criteria For Adverse Events(NCI-CTCAE), v4.03
timeFrame: From start of study drug administration up to 21 days
measure: Dose-expansion: Number of Participants With Best Overall Response (BOR) as Assessed by Independent Endpoint Review Committee (IRC)
timeFrame: From date of randomization up to Week 66
measure: Dose-expansion: Disease Control Rate According to Response Assessment in Neuro-Oncology (RANO) as Adjudicated by the IRC for Participants With Glioblastoma
timeFrame: From date of randomization up to Week 66
Secondary outcomes:
measure: Maximum Concentration (Cmax) of M7824 in Plasma
timeFrame: 0 hours (pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
measure: Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUCtau) of M7824
timeFrame: 0 hours (pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose post-dose
measure: Apparent Terminal Half Life (t1/2) of M7824
timeFrame: Pre-dose, 0, 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
measure: Trough Plasma Concentration (Ctrough) of M7824
timeFrame: 0 hours (Pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
measure: Apparent Plasma Clearance (CL) of M7824
timeFrame: 0 hours (Pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
measure: Number of Participants With Positive Anti-Drug Antibody (ADA) of M7824
timeFrame: Predose, up to Week 52
measure: Number of Participants With Best Overall Response (BOR) as Assessed by Investigator
timeFrame: From date of randomization up to Week 66
measure: Dose Expansion: Number of Participants With TEAEs and Serious TEAEs
timeFrame: From start of study drug administration up to 200 weeks
measure: Dose Expansion: Number of Participants With Treatment-Related TEAEs, Treatment-Related Serious TEAEs and Treatment-related TEAE Leading to Death
timeFrame: From start of study drug administration up to 200 weeks
measure: Dose Expansion: Number of Participants With TEAEs and Related TEAEs Based on Severity According to NCI-CTCAE Version 4.03
timeFrame: From start of study drug administration up to 200 weeks
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Clinical Research Center
state: Arizona
city: Escondido
country: United States
facility: Pacific Oncology Associates
state: California
city: Sacramento
country: United States
facility: University of California Davis Health System
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Whittier
country: United States
facility: Innovative Clinical Research Institute
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers, LLP
state: Colorado
city: Norwich
country: United States
facility: Eastern Connecticut Hematology/Oncology Assoc.
state: Connecticut
city: Miami
country: United States
facility: Sylvester Cancer Center
state: Florida
city: Port Saint Lucie
country: United States
facility: Hematology - Oncology Associates of Treasure Coast
state: Florida
city: Athens
country: United States
facility: University Cancer & Blood Center, LLC
state: Georgia
city: Newnan
country: United States
facility: Southeastern Regional Medical Center
state: Georgia
city: Metairie
country: United States
facility: Metairie Oncologists, LLC
state: Louisiana
city: Bethesda
country: United States
facility: National Cancer Institute
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Cincinnati
country: United States
facility: UC Health Clinical Trials Office
state: Ohio
city: Cleveland
country: United States
facility: Case Comprehensive Cancer Center
state: Ohio
city: Hershey
country: United States
facility: Penn State University Milton S. Hershey Medical Center
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: Greenville Hospital System University Medical Center (ITOR)
state: South Carolina
city: Knoxville
country: United States
facility: Tennessee Cancer Specialists
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology, P.A. - Austin
state: Texas
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Centers
state: Texas
city: Fort Worth
country: United States
facility: Texas Oncology, P.A. - Fort Worth
state: Texas
city: Houston
country: United States
facility: Oncology Consultants, P.A.
state: Texas
city: Houston
country: United States
facility: University of Texas M. D. Anderson Cancer Center - Investigational Cancer Therapeutics
state: Texas
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics, LLC
state: Texas
city: Tyler
country: United States
facility: Texas Oncology, P.A. - Tyler
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Norfolk
country: United States
facility: Virginia Oncology Associates - Hampton
state: Virginia
city: Vancouver
country: United States
facility: Compass Oncology
state: Washington
city: Blacktown
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Port Macquarie
country: Australia
facility: Port Macquarie Base Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Greenslopes
country: Australia
facility: Gallipoli Medical Research Foundation Ltd
state: Queensland
city: Southport
country: Australia
facility: Tasman Oncology Research Ltd
state: Queensland
city: Woodville South
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre-East Melbourne
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Hospital Malvern
state: Victoria
city: Wodonga
country: Australia
facility: Border Medical Oncology Research Unit
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Nedlands
country: Australia
facility: Linear Clinical Research Limited
state: Western Australia
city: Bruxelles
country: Belgium
facility: Institut Jules Bordet
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Charleroi
country: Belgium
facility: Grand Hôpital de Charleroi
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Libramont
country: Belgium
facility: Centre Hospitalier de l'Ardenne
city: Liège
country: Belgium
facility: C. H. U. Sart Tilman
city: Wilrijk
country: Belgium
facility: GZA Ziekenhuizen - Campus Sint-Augustinus
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Nice cedex 02
country: France
facility: Centre Antoine Lacassagne
state: Alpes Maritimes
city: Strasbourg Cedex
country: France
facility: Centre Paul Strauss
state: Bas Rhin
city: Marseille cedex 5
country: France
facility: Hôpital de la Timone#
state: Bouches-du-Rhône
city: Dijon cedex
country: France
facility: Centre Georges François Leclerc
state: Côte-d'Or
city: Bordeaux cedex
country: France
facility: CHU Bordeaux - Hôpital Saint André
state: Gironde
city: Toulouse cedex 09
country: France
facility: Institut Claudius Regaud-Oncopole
state: Haute Garonne
city: Grenoble cedex 9
country: France
facility: CHU de Grenoble - Hôpital Nord
state: Isere
city: Saint Herblain
country: France
facility: ICO - Site René Gauducheau
state: Loire Atlantique
city: Lille cedex
country: France
facility: Centre Oscar Lambret
state: Nord
city: Paris Cedex 05
country: France
facility: Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris
state: Paris
city: Paris Cedex 10
country: France
facility: Hôpital Saint-Louis
state: Paris
city: Paris cedex 12
country: France
facility: Groupe Hospitalier Pitie-Salpetriere
state: Paris
city: Lyon Cedex 04
country: France
facility: Centre Hospitalier de la Croix Rousse
state: Rhone
city: Lyon
country: France
facility: Centre Léon Bérard
state: Rhone
city: Créteil Cedex
country: France
facility: Hôpital Henri Mondor
state: Val De Marne
city: Montpellier
country: France
facility: Institut Régional du Cancer de Montpellier
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachsen
city: Koeln
country: Germany
facility: Cellex Koeln
state: Nordrhein Westfalen
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus TU Dresden
state: Sachsen
city: Berlin
country: Germany
facility: Charite Universitaetsmedizin Berlin - Campus Charite Mitte
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia IRCC Candiolo
state: Torino
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Milano
country: Italy
facility: IEO Istituto Europeo di Oncologia
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione G. Pascale
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli
city: Siena
country: Italy
facility: A.O.U. Senese Policlinico Santa Maria alle Scotte
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
state: Chiba-Ken
city: Osakasayama-shi
country: Japan
facility: Kindai University Hospital
state: Osaka-Fu
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chungcheongbuk-do
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Badajoz
country: Spain
facility: Hospital Infanta Cristina
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Mackay Memorial Hospital
city: Taipei
country: Taiwan
facility: Taipei Medical University Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
state: Greater London
city: London
country: United Kingdom
facility: University College London Hospitals
state: Greater London
city: Manchester
country: United Kingdom
facility: The Christie
state: Greater Manchester
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: Hampshire
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
state: Strathclyde
city: Newcastle upon Tyne
country: United Kingdom
facility: Northern Centre for Cancer Care
state: Tyne & Wear
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
state: West Midlands
Study officials:
affiliation: EMD Serono Research & Development Institute, Inc, an affiliate of MerckKGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Strauss J, Gatti-Mays ME, Cho BC, Hill A, Salas S, McClay E, Redman JM, Sater HA, Donahue RN, Jochems C, Lamping E, Burmeister A, Marte JL, Cordes LM, Bilusic M, Karzai F, Ojalvo LS, Jehl G, Rolfe PA, Hinrichs CS, Madan RA, Schlom J, Gulley JL. Bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1, in patients with human papillomavirus-associated malignancies. J Immunother Cancer. 2020 Dec;8(2):e001395. doi: 10.1136/jitc-2020-001395.
citation: Cho BC, Daste A, Ravaud A, Salas S, Isambert N, McClay E, Awada A, Borel C, Ojalvo LS, Helwig C, Rolfe PA, Gulley JL, Penel N. Bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort. J Immunother Cancer. 2020 Jul;8(2):e000664. doi: 10.1136/jitc-2020-000664.
citation: Wilkins JJ, Vugmeyster Y, Dussault I, Girard P, Khandelwal A. Population Pharmacokinetic Analysis of Bintrafusp Alfa in Different Cancer Types. Adv Ther. 2019 Sep;36(9):2414-2433. doi: 10.1007/s12325-019-01018-0. Epub 2019 Jul 5.
citation: Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, Lamping E, Marte JL, Donahue RN, Grenga I, Cordes L, Christensen O, Mahnke L, Helwig C, Gulley JL. Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFbeta, in Advanced Solid Tumors. Clin Cancer Res. 2018 Mar 15;24(6):1287-1295. doi: 10.1158/1078-0432.CCR-17-2653. Epub 2018 Jan 3.
citation: Tan B, Khattak A, Felip E, Kelly K, Rich P, Wang D, Helwig C, Dussault I, Ojalvo LS, Isambert N. Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-beta and PD-L1, in Patients with Esophageal Adenocarcinoma: Results from a Phase 1 Cohort. Target Oncol. 2021 Jul;16(4):435-446. doi: 10.1007/s11523-021-00809-2. Epub 2021 May 19.
citation: Vugmeyster Y, Grisic AM, Wilkins JJ, Loos AH, Hallwachs R, Osada M, Venkatakrishnan K, Khandelwal A. Model-informed approach for risk management of bleeding toxicities for bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1. Cancer Chemother Pharmacol. 2022 Oct;90(4):369-379. doi: 10.1007/s00280-022-04468-6. Epub 2022 Sep 6.