MSB0011359C (M7824) in Metastatic or Locally Advanced Solid Tumors

Solid Tumors Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02517398
• Other study ID #: EMR 200647-001
• Secondary ID: 2015-004366-28
• Status: Completed
• Phase: Phase 1
• Start date: August 31, 2015
• Est. completion date: May 23, 2022

Study information

• Verified date: November 2023
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 600
• Est. completion date: May 23, 2022
• Est. primary completion date: May 23, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumors

Intervention

Drug:
• MSB0011359C
Subjects would receive intravenous infusion of MSB0011359C once every 2 weeks in a dose escalation fashion until confirmed progression, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product (IMP) occurs.

Locations

Country	Name	City	State
Australia	Blacktown Hospital	Blacktown	New South Wales
Australia	Peter MacCallum Cancer Centre-East Melbourne	East Melbourne	Victoria
Australia	Gallipoli Medical Research Foundation Ltd	Greenslopes	Queensland
Australia	St George Hospital	Kogarah	New South Wales
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Cabrini Hospital Malvern	Malvern	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Linear Clinical Research Limited	Nedlands	Western Australia
Australia	Port Macquarie Base Hospital	Port Macquarie	New South Wales
Australia	Tasman Oncology Research Ltd	Southport	Queensland
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	Calvary Mater Newcastle	Waratah	New South Wales
Australia	Border Medical Oncology Research Unit	Wodonga	Victoria
Australia	The Queen Elizabeth Hospital	Woodville South	South Australia
Belgium	Cliniques Universitaires Saint-Luc	Bruxelles
Belgium	Institut Jules Bordet	Bruxelles
Belgium	Grand Hôpital de Charleroi	Charleroi
Belgium	UZ Antwerpen	Edegem
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	Centre Hospitalier de l'Ardenne	Libramont
Belgium	C. H. U. Sart Tilman	Liège
Belgium	GZA Ziekenhuizen - Campus Sint-Augustinus	Wilrijk
Canada	Cross Cancer Institute	Edmonton	Alberta
France	CHU Bordeaux - Hôpital Saint André	Bordeaux cedex	Gironde
France	Hôpital Henri Mondor	Créteil Cedex	Val De Marne
France	Centre Georges François Leclerc	Dijon cedex	Côte-d'Or
France	CHU de Grenoble - Hôpital Nord	Grenoble cedex 9	Isere
France	Centre Oscar Lambret	Lille cedex	Nord
France	Centre Léon Bérard	Lyon	Rhone
France	Centre Hospitalier de la Croix Rousse	Lyon Cedex 04	Rhone
France	Hôpital de la Timone#	Marseille cedex 5	Bouches-du-Rhône
France	Institut Régional du Cancer de Montpellier	Montpellier
France	Centre Antoine Lacassagne	Nice cedex 02	Alpes Maritimes
France	Institut Curie - Centre de Lutte Contre le Cancer (CLCC) de Paris	Paris Cedex 05	Paris
France	Hôpital Saint-Louis	Paris Cedex 10	Paris
France	Groupe Hospitalier Pitie-Salpetriere	Paris cedex 12	Paris
France	ICO - Site René Gauducheau	Saint Herblain	Loire Atlantique
France	Centre Paul Strauss	Strasbourg Cedex	Bas Rhin
France	Institut Claudius Regaud-Oncopole	Toulouse cedex 09	Haute Garonne
Germany	Charite Universitaetsmedizin Berlin - Campus Charite Mitte	Berlin
Germany	Universitaetsklinikum Carl Gustav Carus TU Dresden	Dresden	Sachsen
Germany	Medizinische Hochschule Hannover	Hannover	Niedersachsen
Germany	Cellex Koeln	Koeln	Nordrhein Westfalen
Italy	Fondazione del Piemonte per l'Oncologia IRCC Candiolo	Candiolo	Torino
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano
Italy	IEO Istituto Europeo di Oncologia	Milano
Italy	Ospedale San Raffaele	Milano
Italy	Istituto Nazionale Tumori Fondazione G. Pascale	Napoli
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Azienda Ospedaliero Universitaria Pisana	Pisa
Italy	Policlinico Universitario Agostino Gemelli	Roma
Italy	A.O.U. Senese Policlinico Santa Maria alle Scotte	Siena
Japan	National Cancer Center Hospital East	Kashiwa-shi	Chiba-Ken
Japan	Kindai University Hospital	Osakasayama-shi	Osaka-Fu
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Chungbuk National University Hospital	Cheongju-si	Chungcheongbuk-do
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Spain	Hospital Infanta Cristina	Badajoz
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Centro Integral Oncologico Clara Campal	Madrid
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Clinico San Carlos	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Taiwan	Mackay Memorial Hospital	Taipei
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Medical University Hospital	Taipei
United Kingdom	Queen Elizabeth Hospital	Birmingham	West Midlands
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow	Strathclyde
United Kingdom	Guy's Hospital	London	Greater London
United Kingdom	University College London Hospitals	London	Greater London
United Kingdom	The Christie	Manchester	Greater Manchester
United Kingdom	Northern Centre for Cancer Care	Newcastle upon Tyne	Tyne & Wear
United Kingdom	Southampton General Hospital	Southampton	Hampshire
United States	University Cancer & Blood Center, LLC	Athens	Georgia
United States	Texas Oncology, P.A. - Austin	Austin	Texas
United States	National Cancer Institute	Bethesda	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	UC Health Clinical Trials Office	Cincinnati	Ohio
United States	Case Comprehensive Cancer Center	Cleveland	Ohio
United States	Mary Crowley Cancer Research Centers	Dallas	Texas
United States	Rocky Mountain Cancer Centers, LLP	Denver	Colorado
United States	Henry Ford Health System	Detroit	Michigan
United States	Pacific Oncology Associates	Escondido	California
United States	Virginia Cancer Specialists, PC	Fairfax	Virginia
United States	Texas Oncology, P.A. - Fort Worth	Fort Worth	Texas
United States	Greenville Hospital System University Medical Center (ITOR)	Greenville	South Carolina
United States	Penn State University Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Oncology Consultants, P.A.	Houston	Texas
United States	University of Texas M. D. Anderson Cancer Center - Investigational Cancer Therapeutics	Houston	Texas
United States	Tennessee Cancer Specialists	Knoxville	Tennessee
United States	Michigan State University	Lansing	Michigan
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Metairie Oncologists, LLC	Metairie	Louisiana
United States	Sylvester Cancer Center	Miami	Florida
United States	Southeastern Regional Medical Center	Newnan	Georgia
United States	Virginia Oncology Associates - Hampton	Norfolk	Virginia
United States	Eastern Connecticut Hematology/Oncology Assoc.	Norwich	Connecticut
United States	Hematology - Oncology Associates of Treasure Coast	Port Saint Lucie	Florida
United States	Rhode Island Hospital	Providence	Rhode Island
United States	University of California Davis Health System	Sacramento	California
United States	Washington University	Saint Louis	Missouri
United States	South Texas Accelerated Research Therapeutics, LLC	San Antonio	Texas
United States	California Pacific Medical Center	San Francisco	California
United States	Arizona Clinical Research Center	Tucson	Arizona
United States	Texas Oncology, P.A. - Tyler	Tyler	Texas
United States	Compass Oncology	Vancouver	Washington
United States	Innovative Clinical Research Institute	Whittier	California

Sponsors (2)

Lead Sponsor	Collaborator
EMD Serono Research & Development Institute, Inc.	Merck KGaA, Darmstadt, Germany

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Spain,  Taiwan,  United Kingdom, 

References & Publications (5)

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 — View 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 — View 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 — View 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 — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose-escalation: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs	Adverse event (AE): any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs.	From start of study drug administration up to 139 weeks
Primary	Dose-escalation: Number of Participants With Treatment-Related TEAEs, Treatment-Related Serious TEAEs and Treatment-related TEAEs Leading to Death	Treatment-related TEAEs are any untoward medical occurrence in a participant who received study drug with causal relationship with the investigational product as assessed by the investigator. Related TEAEs were events with relationship missing, unknown or yes. Number of participants With treatment-related TEAEs, treatment-related serious TEAEs and treatment-related TEAE leading to death were reported.	From start of study drug administration up to 139 weeks
Primary	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	AEs were graded according to severity using NCI-CTCAE Version 4.03. Severity of TEAEs were graded as Grade 1: mild (not causing any significant problem, dose adjustment not required), Grade 2: moderate (caused problem that does not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event), Grade 3: Severe (caused problem that interferes significantly with usual activities or the clinical status, study drug stopped due to adverse event), Grade 4: Life-threatening, Grade 5: Death. Number of Participants with TEAEs and Related TEAEs Based on Severity having Grade greater than or equal to (>=) 3 and Grade >=4 were reported.	From start of study drug administration up to 139 weeks
Primary	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	A DLT was defined as any grade >= 3 Adverse Event (AE) suspected to be related to IMP by the Investigator and / or Sponsor occurring in the DLT evaluation period confirmed by the Safety Monitoring Committee (SMC) to be relevant for the IMP treatment. According to the NCI-CTCAE, v4.03, occurring in the DLT evaluation period and assessed to be related to study treatment by the Investigator and / or Sponsor confirmed by the safety monitoring committee to be relevant for the study treatment.	From start of study drug administration up to 21 days
Primary	Dose-expansion: Number of Participants With Best Overall Response (BOR) as Assessed by Independent Endpoint Review Committee (IRC)	BOR according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and as adjudicated by the Independent Endpoint Review Committee (IRC). BOR is defined as sum of complete response and partial response (CR+PR). For target lesions (TLs), CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the sum of largest diameter (SLD) of the TLs, taking as a reference the baseline SLD.	From date of randomization up to Week 66
Primary	Dose-expansion: Disease Control Rate According to Response Assessment in Neuro-Oncology (RANO) as Adjudicated by the IRC for Participants With Glioblastoma	DCR is defined as the percentage of participants with a confirmed CR+PR+SD+ Non-CR/non-PD at any time as per RANO criteria. A responder is a participant with a Complete Response (CR) or Partial Response (PR), and a non-responder is a participant with Stable Disease (SD) or Progressive Disease (PD) assessed by the RANO criteria. CR is no T1 gadolinium enhancing disease, no new lesions, or corticosteroids, and stable or decreasing T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR). PR is =50% decrease in T1 gadolinium enhancing disease, no new lesions, stable or decreasing T2/FLAIR or corticosteroids, and stable or increasing clinical status. SD is <50% decrease in T1 gadolinium enhancing disease but < 25% increase, no new lesions, stable or decreasing T2/FLAIR or corticosteroids, and stable or increase in clinical status. PD is =25% increase in T1 gadolinium enhancing disease.	From date of randomization up to Week 66
Secondary	Maximum Concentration (Cmax) of M7824 in Plasma	Cmax was obtained directly from the concentration versus time curve.	0 hours (pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
Secondary	Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUCtau) of M7824	Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (336 hours).	0 hours (pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose post-dose
Secondary	Apparent Terminal Half Life (t1/2) of M7824	Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base e (Log e) multiplied by (*) 2/ ?z, where '?z' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.	Pre-dose, 0, 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
Secondary	Trough Plasma Concentration (Ctrough) of M7824	Ctrough is the plasma concentration of a drug prior to administration.	0 hours (Pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
Secondary	Apparent Plasma Clearance (CL) of M7824	CL is defined as the time it takes for the study drug to be completely removed from the body's plasma.	0 hours (Pre-dose), 1, 4, 10, 25, 72, 168, 240, 336 hours post-dose
Secondary	Number of Participants With Positive Anti-Drug Antibody (ADA) of M7824	The detection of antibodies to M7824 was performed using a validated immunoassay method with tiered testing of screening, confirmatory and titration. Number of participants with positive ADA of M7824 were reported.	Predose, up to Week 52
Secondary	Number of Participants With Best Overall Response (BOR) as Assessed by Investigator	BOR according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and as adjudicated by the Investigator. BOR is defined as sum of complete response and partial response (CR+PR). For target lesions (TLs), CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the sum of largest diameter (SLD) of the TLs, taking as a reference the baseline SLD.	From date of randomization up to Week 66
Secondary	Dose Expansion: Number of Participants With TEAEs and Serious TEAEs	An Adverse Event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. TEAEs were defined as events with onset date or worsening during the on-treatment period. Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Any TEAE included participants with both serious and non-serious AEs.	From start of study drug administration up to 200 weeks
Secondary	Dose Expansion: Number of Participants With Treatment-Related TEAEs, Treatment-Related Serious TEAEs and Treatment-related TEAE Leading to Death	Treatment-related TEAEs are any untoward medical occurrence in a participant who received study drug with causal relationship with the investigational product as assessed by the investigator. Related TEAEs were events with relationship missing, unknown or yes. Number of participants with treatment-related TEAEs, treatment-related serious TEAEs and treatment-related TEAE leading to death were reported.	From start of study drug administration up to 200 weeks
Secondary	Dose Expansion: Number of Participants With TEAEs and Related TEAEs Based on Severity According to NCI-CTCAE Version 4.03	AEs were graded according to severity using NCI-CTCAE Version 4.03. Severity of TEAEs were graded as Grade 1: mild (not causing any significant problem, dose adjustment not required), Grade 2: moderate (caused problem that does not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event), Grade 3: Severe (caused problem that interferes significantly with usual activities or the clinical status, study drug stopped due to adverse event), Grade 4: Life-threatening, Grade 5: Death. Number of Participants with TEAEs and Related TEAEs Based on Severity having Grade >= 3 and Grade >=4 TEAEs were reported.	From start of study drug administration up to 200 weeks

External Links

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