MSB0011359C (M7824) in Metastatic or Locally Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT02517398
• Recruitment Status: Completed
• First Posted: August 7, 2015
• Last Update Posted: June 15, 2022
• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborator: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Tracking Information

• First Submitted Date: July 30, 2015
• First Posted Date: August 7, 2015
• Last Update Posted Date: June 15, 2022
• Actual Study Start Date: August 31, 2015
• Actual Primary Completion Date: May 23, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 6, 2018)

• Dose-escalation Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Up to 10 weeks after last treatment ]
  An Adverse Event (AE) is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. Serious Adverse Event (SAE) is 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. AEs (SAEs and non-SAEs) will be considered TEAEs when emerging on treatment period defined as the time from the first trial drug administration up to 10 weeks after the last drug administration date.
• Dose-escalation Part: Number of Subjects With Treatment-Related AEs [ Time Frame: Up to 10 weeks after last treatment ]
  Treatment related AEs are any untoward medical occurrence in a subject who received study drug with causal relationship with the investigational product as assessed by the investigator. AEs will be assessed according to severity; mild (not causing any significant problem, dose adjustment not required), moderate (caused problem that does not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event) and severe (caused problem that interferes significantly with usual activities or the clinical status, study drug stopped due to adverse event).
• Dose-escalation Part: Number of Treatment Emergent Adverse Events (TEAEs) and Related TEAEs by Severity [ Time Frame: Up to 10 weeks after last treatment ]
• Dose-escalation Part: Duration of Treatment Emergent Adverse Events (TEAEs) and Related TEAEs [ Time Frame: Up to 10 weeks after last treatment ]
• Dose-escalation Part: Number of Subjects With Dose Limiting Toxicities (DLT) [ Time Frame: Up to Week 3 ]
  A DLT is defined as any grade greater than or equal to (>=) 3 AE suspected to be related to investigational medicinal product (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.
• Dose-expansion Part: Best Overall Response (BOR) as Assessed by Independent Endpoint Review Committee (IRC) [ Time Frame: Date of randomization up to Week 52 ]
  BOR according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and as adjudicated by the Independent Endpoint Review Committee (IRC).The BOR per IRC adjudication will be determined according to RECIST 1.1 and modified immune related response criteria (irRC), respectively. 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. Overall immune-related complete response: Complete disappearance of all lesions (whether measurable or not) and no new lesions. All measurable lymph nodes also must have a reduction in short axis to 10 mm or less. Overall immune-related partial response (irPR): Sum of the longest diameters of target and new measurable lesions decreases >= 30 percent (%).
• Dose-expansion Part: Disease Control Rate According to Response Assessment in Neuro-Oncology (RANO) as Adjudicated by the IRC for Subjects With Glioblastoma [ Time Frame: Up to Week 52 ]
  The primary efficacy endpoint for the dose expansion part of the trial is the confirmed BOR according to RECIST 1.1 as adjudicated by the Independent Endpoint Review Committee (IRC) and will be evaluated by confirmed objective response rate (ORR). For glioblastoma, the primary endpoint will be disease control according to RANO as adjudicated by the IRC.

Original Primary Outcome Measures (submitted: August 4, 2015)

• Number of subjects with treatment emergent adverse events (TEAEs) [ Time Frame: Time from the first trial drug administration up to 29 days after the last drug administration date ]
  An Adverse Event (AE) is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A Serious Adverse Event (SAE) is 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. AEs (SAEs and non-SAEs) will be considered TEAEs when emerging on treatment period defined as the time from the first trial drug administration up to 29 days after the last drug administration date or the earliest date of subsequent anticancer drug therapy minus 1 day, whichever occurs first, unless otherwise stated.
• Number of subjects with dose limiting toxicities (DLT) [ Time Frame: 21 days after first administration of MSB0011359C ]
  A DLT is defined as any Grade greater than or equal to (>=) 3 AE suspected to be related to investigational medicinal product (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.
• Number of subjects With treatment-related AEs [ Time Frame: Time from the first trial drug administration up to 29 days after the last drug administration date ]
  Treatment related AEs are any untoward medical occurrence in a subject who received study drug with causal relationship with the investigational product as assessed by the investigator. AEs will be assessed according to severity; mild (not causing any significant problem, dose adjustment not required), moderate (caused problem that does not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event) and severe (caused problem that interferes significantly with usual activities or the clinical status, study drug stopped due to adverse event).

Current Secondary Outcome Measures (submitted: September 6, 2018)

• Dose Escalation and Expansion Part: Maximum Concentration (Cmax) of MSB0011359C in Plasma [ Time Frame: Predose, 0, 4, and 30 hours post dose ]
• Dose Escalation and Expansion Part: Minimum Concentration (Cmin) of MSB0011359C in Plasma [ Time Frame: Predose, 0, 4, and 30 hours post dose ]
• Dose Escalation and Expansion Part: Area Under the Plasma Concentration Time Curve From Zero to Last Sampling Time (AUC0-t) of MSB0011359C [ Time Frame: Predose, 0, 4, and 30 hours post dose ]
• Dose Escalation and Expansion Part: Terminal Half Life (t1/2) of MSB0011359C [ Time Frame: Predose, 0, 4, and 30 hours post dose ]
• Dose Escalation and Expansion Part: Serum Titers of Anti-MSB0011359C Antibodies [ Time Frame: Predose, Day 15, Day 43, Day 85 and every 6-weekly until progression or end of the treatment whichever occur first, assessed up to Week 52 ]
• Dose Escalation and Expansion Part: Best Overall Response (BOR) as Assessed by Investigator [ Time Frame: Date of randomization up to Week 52 ]
  BOR according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and as adjudicated by the Investigator.The BOR per investigator adjudication will be determined according to RECIST 1.1 and modified immune related response criteria (irRC), respectively. 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. Overall immune-related complete response: Complete disappearance of all lesions (whether measurable or not) and no new lesions. All measurable lymph nodes also must have a reduction in short axis to 10 mm or less. Overall immune-related partial response (irPR): Sum of the longest diameters of target and new measurable lesions decreases >= 30%.
• Dose Expansion Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Time from the first trial drug administration up to 10 weeks last drug administration date ]
  An Adverse Event (AE) is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. Serious Adverse Event (SAE) is 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. AEs (SAEs and non-SAEs) will be considered TEAEs when emerging on treatment period defined as the time from the first trial drug administration up to 29 days after the last drug administration date or the earliest date of subsequent anticancer drug therapy minus 1 day, whichever occurs first, unless otherwise stated.
• Dose Expansion Part: Number of Subjects With Treatment-Related AEs [ Time Frame: Time from the first trial drug administration up to 10 weeks after the last drug administration date ]
  Treatment related AEs are any untoward medical occurrence in a subject who received study drug with causal relationship with the investigational product as assessed by the investigator. AEs will be assessed according to severity; mild (not causing any significant problem, dose adjustment not required), moderate (caused problem that does not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event) and severe (caused problem that interferes significantly with usual activities or the clinical status, study drug stopped due to adverse event).
• Dose Expansion Part: Number of Treatment Emergent Adverse Events (TEAEs) and Related TEAEs by Severity [ Time Frame: Time from the first trial drug administration up to 10 weeks after the last drug administration date ]
• Dose Expansion Part: Duration of Treatment Emergent Adverse Events (TEAEs) and Related TEAEs [ Time Frame: Time from the first trial drug administration up to 10 weeks after the last drug administration date ]

Original Secondary Outcome Measures (submitted: August 4, 2015)

• Cmax of MSB0011359C in plasma [ Time Frame: Predose, 0, 4, and 30 hours post dose ]
• Cmin of MSB0011359C in plasma [ Time Frame: Predose, 0, 4, and 30 hours post dose ]
• Area under the plasma concentration time curve from zero to last sampling time (AUC0-t) of MSB0011359C [ Time Frame: Predose, 0, 4, and 30 hours post dose ]
• Area under the plasma concentration time curve from time zero to infinity (AUC0-inf) of MSB0011359C [ Time Frame: Predose, 0, 4, and 30 hours post dose ]
• Terminal half life (t1/2) of MSB0011359C [ Time Frame: Predose, 0, 4, and 30 hours post dose ]
• Serum titers of anti-MSB0011359C antibodies [ Time Frame: Predose, Day 15, Day 43, Day 85 and every 6-weekly until progression or end of the treatment whichever occur first, assessed up to 4 year' ]
• Best Overall Response (BOR) [ Time Frame: Up to 4 years ]
  BOR according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and as adjudicated by the Independent Endpoint Review Committee (IRC). The BOR per IRC adjudication will be determined according to RECIST 1.1 and modified immune related response criteria (irRC), respectively. 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. Overall immune-related complete response: Complete disappearance of all lesions (whether measurable or not) and no new lesions. All measurable lymph nodes also must have a reduction in short axis to 10 mm or less. Overall immune-related partial response (irPR): Sum of the longest diameters of target and new measurable lesions decreases >= 30%.

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

Descriptive Information

• Brief Title: 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
• Brief Summary: The main purpose of this Phase I study is 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 is composed 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 indications. 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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumors

Intervention

Drug: MSB0011359C

Subjects will 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.

Other Name: M7824

Study Arms

Experimental: MSB0011359C (M7824)

Intervention: Drug: MSB0011359C

Publications *

• 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.
• 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. Erratum In: J Immunother Cancer. 2020 Oct;8(2):
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 10, 2020): 600
• Original Estimated Enrollment (submitted: August 4, 2015): 106
• Actual Study Completion Date: May 23, 2022
• Actual Primary Completion Date: May 23, 2022 (Final data collection date for primary outcome measure)

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

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

Administrative Information

• NCT Number: NCT02517398
• Other Study ID Numbers: EMR 200647-001; 2015-004366-28 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: EMD Serono ( EMD Serono Research & Development Institute, Inc. )
• Original Responsible Party: EMD Serono
• Current Study Sponsor: EMD Serono Research & Development Institute, Inc.
• Original Study Sponsor: EMD Serono
• Collaborators: Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible; EMD Serono Research & Development Institute, Inc, an affiliate of MerckKGaA, Darmstadt, Germany

• PRS Account: EMD Serono
• Verification Date: June 2022