MSB0011359C (M7824) in Subjects With Metastatic or Locally Advanced Solid Tumors

A Phase I, Open-label, Multiple-ascending Dose Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of MSB0011359C (M7824) in Subjects With Metastatic or Locally Advanced Solid Tumors With Expansion to Selected Indications in Asia

The main purpose of this study is assess the safety and tolerability of MSB0011359C. Study consists of dose-escalation part and an expansion part in subjects with metastatic or locally advanced solid tumors, for which no standard effective therapy exists or a standard therapy has failed.

Study Overview

• Status: Completed
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: MSB0011359C

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Fukuoka, Japan
    • NHO Kyushu Cancer Center
  • Kashiwa, Japan
    • National Cancer Center East, Department of Experimental Therapeutics
  • Kashiwa, Japan
    • National Cancer Center East, Department of hepatobiliary and pancreatic oncology
  • Kitaadachi-gun, Japan
    • Saitama Cancer Center
  • Matsuyama, Japan
    • Nho Shikoku Cancer Center
  • Nagoya, Japan
    • Aichi Cancer Center Hospital
  • Osakasayama, Japan
    • Kinki University Hospital
  • Tokyo, Japan
    • National Cancer Center, Department of Experimental Therapeutics
  • Tokyo, Japan
    • National Cancer Center, Department of hepatobiliary and pancreatic oncology
  • Yokohama, Japan
    • Kanagawa Cancer Center, Department of Gastroenterology
  • Yokohama, Japan
    • Kanagawa Cancer Center, Department of Gastrointestinal Surgery
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Severance Hospital
• Taiwan
  • Tainan, Taiwan
    • National Cheng Kung University Hospital
  • Taipei, Taiwan
    • Mackay Memorial Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
  • Taoyuan, Taiwan
    • Chang Gung Memorial Hospital; Linkou

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Able and willing to give written informed consent and has signed the appropriate written informed consent form (ICF), prior to performance of any trial activities
• Eligible male and female subjects aged greater than or equal to (>=)20 years
• Histologically or cytologically proven metastatic or locally advanced solid tumors, for which no effective standard therapy exists or standard therapy has failed
• Eastern Cooperative Oncology Group performance status (ECOG) performance status of 0 to 1 at trial entry
• Life expectancy >=12 weeks as judged by the Investigator.
• Adequate hematological function defined by white blood cell (WBC) count >=3*10^9/Liter with absolute neutrophil count (ANC) >=1.5*10^9/Liter, lymphocyte count >=0.5* 10^9/Liter, platelet count >=75*10^9/Liter, and Hemoglobin (Hgb) >= 9 grams per deciliter (g/dL) (in absence of blood transfusion).
• Adequate hepatic function defined by a total bilirubin level <=1.5 × Upper limit of normal (ULN), an AST level <= 2.5 × ULN, and an ALT level <= 2.5 × ULN.
• Adequate renal function defined by an estimated creatinine clearance >50 milliliter per minute (mL/min) according to the Cockcroft-Gault formula or by measure of creatinine clearance from 24 hour urine collection.

Other protocol-defined exclusion 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 bone directed radiotherapy), immune therapy, or cytokine therapy
• Major surgery within 28 days before the start of trial treatment (excluding prior diagnostic biopsy)
• 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 with the exception of cervical carcinoma in situ and superficial or non invasive bladder cancer (treated with curative intent) within the last 5 years or basal cell or squamous cell carcinoma in situ within the last 3 years
• Rapidly progressive disease which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or trial procedures
• Active or history of central nervous system metastases, except as in the melanoma-specific Central nervous system (CNS) criteria listed above
• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MSB0011359C (M7824)	Drug: MSB0011359C; Subjects with metastatic or locally advanced solid tumors will receive intravenous infusion of MSB0011359C over 1 hour once every two weeks for up to 12 months until confirmed progressive disease (PD), unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product (IMP) occurs.; Other Names: M7824

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with DLT (Dose limiting Toxicity): dose escalation part	A DLT is defined as any grade greater than or equal to (>=) 3 adverse event 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.	Baseline up to Week 3
Number of Subjects with treatment-emergent adverse events (TEAEs)	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 30 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.	First trial drug administration up to 30 days after the last drug administration assessed up to 2 years
Number of subjects with treatment-related Adverse Events (AE)	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.	First trial drug administration up to 30 days after the last drug administration assessed up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum serum concentration (Cmax) of MSB0011359C		Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43
Minimum serum concentration (Cmin) of MSB0011359C		Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43
Area under the concentration time curve from zero to last sampling time (AUC0-t) of MSB0011359C		Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43
Area under the concentration time curve from time zero to infinity (AUC0-inf) of MSB0011359C		Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43
Terminal half life (t1/2) of MSB0011359C		Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43
Serum titers of anti-MSB0011359C antibodies		Predose, Day 15, 43, 85 and every 6-weekly until progression or end of the treatment whichever occur first, assessed up to 3 years
Best Overall Response (BOR) as assessed by investigator: Dose escalation part	BOR will be assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. 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 percent (%) decrease in the sum of largest diameter (SLD) of the TLs, taking as a reference the baseline SLD.	Date of randomization up to 2 years
Best Overall Response (BOR) as assessed by investigator: Expansion part	BOR will be assessed by investigator according to RECIST Version 1.1. BOR is defined as sum of CR and PR. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30 percent (%) decrease in the SLD of the TLs, taking as a reference the baseline SLD.	Date of randomization up to 2 years
Best Overall Response (BOR) as assessed by Independent Endpoint Review Committee (IRC): Expansion part	The BOR per Independent Endpoint Review Committee (IRC) adjudication will be determined according to RECIST 1.1. BOR is defined as sum of CR and PR. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30 percent (%) decrease in the SLD of the TLs, taking as a reference the baseline SLD.	Date of randomization up to 2 years
Duration of response	Time from first assessment of CR to disease progression or death, for TLs, CR was defined as the disappearance of all TLs	Date of randomization up to 2 years
Disease control rate	The disease control rate is defined as the percentage of subjects with BOR. The BOR per IRC adjudication will be determined according to RECIST 1.1. BOR is defined as sum of CR and PR. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD.	Date of randomization up to 2 years
Progression Free survival (PFS) time	PFS is defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PFS will be assessed as RECIST v1.1 as adjudicated by IRC. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.	Date of randomization until death or progressive disease assessed up to 2 years
Overall Survival (OS) time	OS is defined as the time from randomization to death due to any cause.	Date of randomization until death assessed up to 2 years

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany

Publications and helpful links

General Publications

• Yoo C, Oh DY, Choi HJ, Kudo M, Ueno M, Kondo S, Chen LT, Osada M, Helwig C, Dussault I, Ikeda M. Phase I study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1, in patients with pretreated biliary tract cancer. J Immunother Cancer. 2020 May;8(1):e000564. doi: 10.1136/jitc-2020-000564.
• 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.
• Lin CC, Doi T, Muro K, Hou MM, Esaki T, Hara H, Chung HC, Helwig C, Dussault I, Osada M, Kondo S. Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFbeta and PD-L1, in Patients with Esophageal Squamous Cell Carcinoma: Results from a Phase 1 Cohort in Asia. Target Oncol. 2021 Jul;16(4):447-459. doi: 10.1007/s11523-021-00810-9. Epub 2021 Apr 11.
• 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.

Helpful Links

• INTR@PID Clinical Trial Program
• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2016
• Primary Completion (Actual): February 21, 2022
• Study Completion (Actual): February 21, 2022

Study Registration Dates

• First Submitted: March 1, 2016
• First Submitted That Met QC Criteria: March 3, 2016
• First Posted (Estimate): March 4, 2016

Study Record Updates

• Last Update Posted (Actual): March 21, 2022
• Last Update Submitted That Met QC Criteria: March 7, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: MSB0011359C
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: 200647-0008