Clinical trial NCT02699515: MSB0011359C (M7824) in Participants With Metastatic or Locally Advanced Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Keywords: MSB0011359C
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2016-03-04
Enrollment: 114
Sex: ALL
Minimum age (years): 20
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 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.


Eligibility criteria: 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)

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicity (DLT)
timeFrame: Baseline up to Week 3
measure: 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
timeFrame: First study drug administration up to 30 days after the last drug administration assessed up to approximately 5 years
measure: Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03
timeFrame: First study drug administration up to 30 days after the last drug administration assessed up to approximately 5 years
Secondary outcomes:
measure: Dose-Escalation Phase: Maximum Serum Concentration (Cmax) of M7824
timeFrame: Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43
measure: Dose-Escalation Phase: Terminal Half Life (t1/2) of M7824
timeFrame: Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43
measure: Dose-Escalation Phase: Area Under the Serum Concentration Time Curve From Zero to Last Sampling Time (AUC0-t) of M7824
timeFrame: Pre-dose, 0, 4 hour post dose on Day 1, 2, 8, 15, 29, 43
measure: Dose-Escalation Phase: Area Under The Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M7824
timeFrame: Pre-dose, 0, 4 hour post dose on Day 1, 2, 8, 15, 29, 43
measure: Dose-Escalation Phase: Number of Participants With Positive Serum Titers of Anti-Drug Antibodies of M7824
timeFrame: Predose, Day 15, 43, 85 and every 6-weekly until progression or end of the treatment whichever occur first, assessed up to 3 years
measure: Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator
timeFrame: Date of randomization up to 2 years
measure: Expansion Part: Best Overall Response (BOR) As Assessed By Investigator
timeFrame: Date of randomization up to 2 years
measure: Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC)
timeFrame: Up to 2 years
measure: Expansion Part: Duration of Response (DOR)
timeFrame: Up to 2 years
measure: Expansion Part: Disease Control Rate
timeFrame: Up to 2 years
measure: Expansion Part: Progression Free Survival (PFS) Time
timeFrame: Date of randomization until death or progressive disease assessed up to 2 years
measure: Expansion Part: Overall Survival (OS) Time
timeFrame: Date of randomization until death assessed up to 2 years
Other outcomes:
Locations:
city: Fukuoka
country: Japan
facility: NHO Kyushu Cancer Center
city: Kashiwa
country: Japan
facility: National Cancer Center East, Department of Experimental Therapeutics
city: Kashiwa
country: Japan
facility: National Cancer Center East, Department of hepatobiliary and pancreatic oncology
city: Kitaadachi-gun
country: Japan
facility: Saitama Cancer Center
city: Matsuyama
country: Japan
facility: NHO Shikoku Cancer Center
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
city: Osakasayama
country: Japan
facility: Kinki University Hospital
city: Tokyo
country: Japan
facility: National Cancer Center, Department of Experimental Therapeutics
city: Tokyo
country: Japan
facility: National Cancer Center, Department of hepatobiliary and pancreatic oncology
city: Yokohama
country: Japan
facility: Kanagawa Cancer Center, Department of Gastroenterology
city: Yokohama
country: Japan
facility: Kanagawa Cancer Center, Department of Gastrointestinal Surgery
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: Mackay Memorial Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital; Linkou
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
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.
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.