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First in Human Study of M6223

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ClinicalTrials.gov Identifier: NCT04457778
Recruitment Status : Recruiting
First Posted : July 7, 2020
Last Update Posted : October 22, 2021
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Study Description
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Brief Summary:
The main purpose of this study is to determine the safety, tolerability, pharmacokinetics (PK), immunogenicity and (if observed) the maximum tolerated dose (MTD) of M6223 as a single agent (Part 1A) and of M6223 combined with bintrafusp alfa [Part 1B, for both the every 2 weeks (Q2W) regimen and the every 3 weeks (Q3W) regimen] in participants with metastatic or locally advanced solid unresectable tumors.

Condition or disease Intervention/treatment Phase
Metastatic Solid Tumors Drug: M6223 Drug: Bintrafusp alfa Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I, First-in-Human, Open-Label, Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of M6223, an Inhibitor of TIGIT, as Single Agent and in Combination With Bintrafusp Alfa, Anti-PDL1/ TGFß Trap in, Participants With Metastatic or Locally Advanced Solid Unresectable Tumors
Actual Study Start Date : July 10, 2020
Estimated Primary Completion Date : September 14, 2022
Estimated Study Completion Date : September 14, 2022
Arms and Interventions
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Arm Intervention/treatment
Experimental: Part 1A: M6223 Monotherapy Drug: M6223
Participants will receive an intravenous (IV) infusion of M6223 at escalated doses every 2 weeks (Q2W) on Day 1 of each Cycle (Each cycle is of 14 days) according to the recommendation of the SMC (Safety Monitoring Committee) until the maximum tolerated dose (MTD) has been reached or confirmed disease progression.
Experimental: Part1B: M6223 + Bintrafusp alfa Drug: Bintrafusp alfa
Participants will receive an IV infusion of bintrafusp alfa Q2W on Day 1 of each Cycle (Cycle is 14 days) or Q3W on Day 1 of each Cycle (Cycle is of 21 days) until confirmed disease progression.

Drug: M6223
Participants will receive an IV infusion of M6223 at escalated doses Q3W on Day 1 of each Cycle (Each cycle is of 21 days) according to the recommendation of the SMC until the MTD has been reached or confirmed disease progression. Additionally, an every Q3W regimen of M6223 in combination with bintrafusp alfa will be tested after the MTD of M6223 Q2W in combination with bintrafusp alfa has been defined, or after the highest dose level anticipated in the Q2W combination regimen has been tested in at least 3 participants, whichever comes first.


Outcome Measures
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Primary Outcome Measures :
  1. Part 1A and 1B: Occurrence of Dose Limiting Toxicities (DLTs) During the DLT Observation Period (28 Days) [ Time Frame: Day 1 to Day 28 ]
  2. Part IA and IB: Occurrence of Treatment-Emergent Adverse Events (TEAEs) and Treatment Related Adverse Events (TRAEs) According to the National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE) version 5 [ Time Frame: Time from first study drug administration to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years) ]
  3. Part IA and IB: Occurrence of Treatment-Emergent Adverse Events (TEAEs) as per Severity and Deaths [ Time Frame: Time from first study drug administration to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years) ]
  4. Part IA and IB: Occurrence of Clinically Significant Change From Baseline in Clinical Laboratory Measures [ Time Frame: Time from baseline to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years) ]
  5. Part IA and IB: Occurrence of Clinically Significant Change From Baseline in Electrocardiogram Findings [ Time Frame: Time from baseline to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years) ]
  6. Part IA and IB: Occurrence of Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Time from baseline to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years) ]
  7. Part IA and IB: Occurrence of Change From Baseline in Eastern Cooperative Oncology Group Performance Status [ Time Frame: Time from baseline to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years) ]

Secondary Outcome Measures :
  1. Part 1A and Part 1B: Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of M6223 [ Time Frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) ]
  2. Part 1A and Part 1B: Area Under the Serum Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of M6223 [ Time Frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) ]
  3. Part 1A and Part 1B: Area Under Serum Concentration-Time Curve Over a Dosing Interval From Time Zero to Tau (τ) (AUCτ) of M6223 [ Time Frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) ]
  4. Part 1A and Part 1B: Maximum Observed Serum Concentration (Cmax) of M6223 [ Time Frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) ]
  5. Part 1A and Part 1B: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of M6223 [ Time Frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) ]
  6. Part 1A and Part 1B: Time to Reach Maximum Serum Concentration (Tmax) of M6223 [ Time Frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) ]
  7. Part 1A and Part 1B: Apparent Terminal Half-Life (t1/2) of M6223 [ Time Frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) ]
  8. Part 1A and Part 1B: Elimination Rate Constant (Lambda z) of M6223 [ Time Frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) ]
  9. Part 1B: Maximum Observed Serum Concentration (Cmax) of Bintrafusp alfa [ Time Frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) ]
  10. Part 1B: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Bintrafusp alfa [ Time Frame: Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) ]
  11. Part IA and 1B: Immunogenicity of M6223 Measured by Antidrug Antibody (ADA) Assays [ Time Frame: Pre-dose of Day 1 Cycle 1 (Each Cycle is of 14 days in Q2W regimen and 21 days in Q3W regimen) up to end of safety follow-up visit (up to a maximum of 2 years) ]
  12. Part 1B: Immunogenicity of Bintrafusp alfa Measured by Antidrug Antibody (ADA) Assays [ Time Frame: Pre-dose of Day 1 Cycle 1 (Each Cycle is of 14 days in Q2W regimen and 21 days in Q3W regimen) up to end of safety follow-up visit (up to a maximum of 2 years) ]
  13. Part 1A and 1B: Change from Baseline in QT Interval [ Time Frame: From Day 1 Cycle 1 (Baseline) up to Day 1 Cycle 7 (Each Cycle is of 14 days in Q2W regimen and 21 days in Q3W regimen) ]
  14. Part 1A and IB: Best Overall Response According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as per Investigator [ Time Frame: From first study drug administration until documented disease progression or death due to any cause whichever occurs first, (approximately assessed up to 2 years) ]
  15. Part 1A and 1B: Duration of Response According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as per Investigator [ Time Frame: From first study drug administration until documented disease progression or death due to any cause whichever occurs first, (approximately assessed up to 2 years) ]
  16. Part 1A and 1B: Time to Tumor Response According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as per Investigator [ Time Frame: From first study drug administration until documented disease progression or death due to any cause whichever occurs first, (approximately assessed up to 2 years) ]
  17. Part 1A and 1B: Disease Control According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as per Investigator [ Time Frame: From first study drug administration until documented disease progression or death due to any cause whichever occurs first, (approximately assessed up to 2 years) ]
  18. Part 1A and 1B: Progression-free Survival Time According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as per Investigator [ Time Frame: From first study drug administration until documented disease progression or death due to any cause whichever occurs first, (approximately assessed up to 2 years) ]
  19. Part 1A and 1B: Overall Survival [ Time Frame: Time from first treatment to end of study (planned 12 months after last patient started treatment) ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants have histologically or cytologically proven locally advanced or advanced solid malignancies who are refractory to or have progressed under standard treatment and have no other treatment options known to confer clinical benefit
  • Participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening
  • Participant has a formalin-fixed paraffin-embedded block containing tumor tissue or a minimum of 15 (preferably 25) unstained tumor slides suitable for immunohistochemistry-based staining of protein expression
  • Participants with life expectancy of at least 12 weeks
  • Participants with measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
  • Adequate hematological, hepatic and renal function as defined in the protocol
  • Other protocol defined inclusion criteria may apply

Exclusion Criteria:

  • Participants with persisting toxicity related to prior therapy Grade greater than (>) 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, however, alopecia, sensory neuropathy Grade less than or equal to (<=) 2, or other non-immune-related Grade <= 2 not constituting a safety risk
  • Participants with prior organ transplantation including allogeneic stem cell transplantation
  • Participants with prior toxicity related to an immune checkpoint inhibitor Grade greater than equal to (>=) 3 NCI-CTCAE Version 5.0 unless resolved to Grade <= 1 prior to study inclusion
  • Participants with current significant cardiac conduction abnormalities, including corrected QT interval (QTcF, corrected with Fridericia formula) prolongation of > 450 milli seconds (ms) on triplicate 12-lead ECG or impaired cardiovascular function, ventricular tachycardia, hypokalemia or a history of paroxysmal atrial fibrillation, serious cardiac arrhythmia and family history of sudden death or long QT syndrome
  • A history of vascular, cardiovascular or cerebrovascular disease like, cerebral vascular accident/stroke (less than [<] 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class >= II), deep vein thrombosis (< 3 months prior to enrollment) or pulmonary thrombosis/embolism (< 3 months prior to enrollment)
  • Other protocol defined exclusion criteria may apply
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04457778


Contacts
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Contact: US Medical Information 888-275-7376 eMediUSA@emdserono.com
Contact: Communication Center 49 6151 72 5200 service@emdgroup.com

Locations
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United States, Tennessee
Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Contact       j.bendell@tnonc.com   
Principal Investigator: Johanna Bendell         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact       anaing@mdanderson.org   
Principal Investigator: Aung Naing         
Next Oncology Recruiting
San Antonio, Texas, United States, 78229
Contact       atolcher@nextoncology.com   
Principal Investigator: Anthony Tolcher         
Canada
Princess Margaret Cancer Centre Recruiting
Toronto, Canada
Contact       lillian.siu@uhn.on.ca   
Principal Investigator: Lillian Sui         
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
More Information
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Additional Information:

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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT04457778    
Other Study ID Numbers: MS201430_0001
First Posted: July 7, 2020    Key Record Dates
Last Update Posted: October 22, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
M6223
Bintrafusp alfa
Metastatic Solid Tumors