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First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04882917
Recruitment Status : Recruiting
First Posted : May 12, 2021
Last Update Posted : October 19, 2021
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Brief Summary:
The purpose of this study is to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) (if reached) and early signs of efficacy of M4076 monotherapy in participants with solid tumors in dose escalation (Part 1A). Once the recommended dose for expansion (RDE) is declared in Part 1A, a preliminary food effect cohort, Part 1B, will follow at the RDE determined from Part 1A.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: M4076 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A First-in-human, Phase I, Open-label Study of the ATM Inhibitor M4076 in Participants With Advanced Solid Tumors (DDRiver Solid Tumors 410)
Actual Study Start Date : May 24, 2021
Estimated Primary Completion Date : August 1, 2022
Estimated Study Completion Date : August 1, 2022

Arm Intervention/treatment
Experimental: Experimental: Dose Escalation Cohort (Part 1A): M4076 Monotherapy
Participants will receive M4076 film coated tablet at escalated doses orally, once daily under fasting condition until disease progression, death, Adverse events (AEs) leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurs first.
Drug: M4076
M4076 will be administered orally, in Part 1A and Part 1B.

Experimental: Experimental: Preliminary Food Effect Assessment Cohort (Part 1B): M4076
Participants in food effect assessment will receive M4076 at the dose and schedule determined as recommended dose for expansion (RDE) in Part 1A. A single dose of M4076 will be administered on Day -7 under a fed or fasted condition, followed by a 1-week washout period.
Drug: M4076
M4076 will be administered orally, in Part 1A and Part 1B.




Primary Outcome Measures :
  1. Part 1A: Occurrence of Dose Limiting Toxicities (DLTs) During the DLT Observation Period [ Time Frame: Day 1 up to Day 21 ]
  2. Part 1A: Occurrence of Adverse Events (AEs) and Treatment-Related AEs [ Time Frame: Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) ]
  3. Part 1A: Number of Participants With Clinical Significant Changes in Vital Signs, Laboratory Parameters, and 12-Lead Electrocardiogram (ECG) Findings [ Time Frame: Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) ]
  4. Part 1B: Occurrence of Adverse Events (AEs) and Treatment-Related AEs [ Time Frame: Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) ]
  5. Part 1B: Number of Participants With Clinical Significant Changes in Vital Signs, Laboratory Parameters, and 12-Lead Electrocardiogram (ECG) Findings [ Time Frame: Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) ]

Secondary Outcome Measures :
  1. Part 1A and Part 1B: Objective Response According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as Assessed by Investigators [ Time Frame: Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) ]
  2. Part 1A and Part 1B: Duration of Response According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as Assessed by Investigators [ Time Frame: Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) ]
  3. Part 1A and Part 1B: Progression Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as Assessed by Investigators [ Time Frame: Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) ]
  4. Part 1A and Part 1B: Overall Survival (OS) [ Time Frame: Time from randomization to final assessment at end of safety follow-up visit (up to a maximum of approximately 4 years) ]
  5. Part 1A and 1B: Area Under Plasma Concentration-Time Curve (AUC) From Time Zero (= Dosing Time) to the Last Sampling Time (tlast) of M4076 [ Time Frame: Pre-dose up to 51 months post-dose ]
  6. Part 1A and Part 1B: Area Under Plasma Concentration (AUC) From Time Zero (Dosing Time) Extrapolated to Infinity (AUC0-inf) of M4076 [ Time Frame: Pre-dose up to 51 months post-dose ]
  7. Part 1A and Part 1B: Maximum Observed Plasma Concentration (Cmax) of M4076 [ Time Frame: Pre-dose up to 51 months post-dose ]
  8. Part 1A and Part 1B: Absolute and Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry [ Time Frame: Pre-dose up to 51 months post-dose ]
    ATM pathway readouts including phosphorylated ataxia-telangiectasia mutated (p-ATM), gamma histone family member X (gamma-H2AX) and checkpoint kinase 2 protein (p-CHK2) will measure by flow cytometry and immunohistochemistry.



Information from the National Library of Medicine

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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 with advanced solid tumors, for whom no standard of care therapy exists or for whom is not considered sufficiently effective, or who cannot tolerate standard of care
  • Participants with Eastern Cooperative Oncology Group Performance status 0 or 1
  • Adequate hematological, hepatic, and renal function as defined in the protocol
  • Participants in Part 1B (the preliminary food effect assessment) must agree to provide paired tumor biopsies if not contraindicated for medical reasons
  • Other protocol defined inclusion criteria could apply

Exclusion Criteria:

  • Clinically significant (i.e., active) uncontrolled intercurrent illness including, but not limited to:

    1. Active infection (i.e., requiring systemic antibiotics or antifungals)
    2. Uncontrolled arterial hypertension
    3. Severe cardiac arrhythmia requiring medication
    4. Cerebral vascular accident/stroke
  • Has known ataxia telangiectasia
  • Participants with tumors harboring previously identified ATM mutations
  • Participants with hypersensitivity to the active substance or to any of the excipients of M4076
  • Other protocol defined exclusion criteria could apply

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): NCT04882917


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, Texas
MD Anderson Center Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Timothy Yap         
NEXT Oncology Recruiting
San Antonio, Texas, United States, 78229
Contact    210-580-9500    cdeleon@nextoncology.com   
Principal Investigator: Anthony Tolcher         
Canada, Ontario
Princess Margaret Cancer Centre Recruiting
Toronto, Ontario, Canada, M5G 1Z5
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
Additional Information:
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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT04882917    
Other Study ID Numbers: MS201512_0010
First Posted: May 12, 2021    Key Record Dates
Last Update Posted: October 19, 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 https:\\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. ):
M4076
Maximum tolerated dose
Pharmacokinetics
Pharmacodynamics
Additional relevant MeSH terms:
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Neoplasms