MSB0011359C (M7824) in Participants 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 was to assess the safety and tolerability of MSB0011359C. Study consists of dose-escalation part and an expansion part in participants with metastatic or locally advanced solid tumors, for which no standard effective therapy exists or a standard therapy had 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

Description

Inclusion Criteria:

• Able and willing to give written informed consent and had signed the appropriate written informed consent form (ICF), prior to performance of any trial activities
• Eligible male and female participants 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 had 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 received 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 Participants With Dose Limiting Toxicity (DLT)	A DLT was 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 Participants With Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.03	An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. 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.	First study drug administration up to 30 days after the last drug administration assessed up to approximately 5 years
Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03	An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. 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. Treatment-related TEAEs: reasonably related to the study intervention. Number of participants with TEAEs and treatment related TEAEs were reported.	First study drug administration up to 30 days after the last drug administration assessed up to approximately 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-Escalation Phase: Maximum Serum Concentration (Cmax) of M7824	Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.	Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43
Dose-Escalation Phase: Terminal Half Life (t1/2) of M7824	t1/2 was the time measured for the concentration to decrease by one half, determined as 0.693/Lambda z, here Lambda z was the terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.	Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43
Dose-Escalation Phase: Area Under the Serum Concentration Time Curve From Zero to Last Sampling Time (AUC0-t) of M7824	Area under the serum concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated by linear trapezoidal summation.	Pre-dose, 0, 4 hour post dose on Day 1, 2, 8, 15, 29, 43
Dose-Escalation Phase: Area Under The Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M7824	The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.	Pre-dose, 0, 4 hour post dose on Day 1, 2, 8, 15, 29, 43
Dose-Escalation Phase: Number of Participants With Positive Serum Titers of Anti-Drug Antibodies of M7824	The detection of antibodies to M7824 was performed using a validated electrochemiluminescence (ECL) immunoassay with tiered testing of screening, confirmatory and titration. Number of participants with positive anti-drug antibody (ADA) of M7824 were reported.	Predose, Day 15, 43, 85 and every 6-weekly until progression or end of the treatment whichever occur first, assessed up to 3 years
Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator	BOR was assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. BOR was 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
Expansion Part: Best Overall Response (BOR) As Assessed By Investigator	BOR was assessed by investigator according to RECIST Version 1.1. BOR was 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
Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC)	The BOR per Independent Endpoint Review Committee (IRC) adjudication was 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.	Up to 2 years
Expansion Part: Duration of Response (DOR)	Duration of response according to RECIST 1.1 as adjudicated by the IRC was defined as the time from first confirmed response until the first documented disease progression that was subsequently confirmed. It was analyzed using Kaplan-Meier method.	Up to 2 years
Expansion Part: Disease Control Rate	The disease control rate was defined as the percentage of participants with BOR. The BOR per IRC adjudication was 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.	Up to 2 years
Expansion Part: Progression Free Survival (PFS) Time	PFS was 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 was 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
Expansion Part: Overall Survival (OS) Time	OS was 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
• Investigators: Study Director: Medical Responsible, 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

• 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 (Estimated): March 4, 2016

Study Record Updates

• Last Update Posted (Actual): November 18, 2024
• Last Update Submitted That Met QC Criteria: September 26, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

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