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Trial record 1 of 1 for:    M8891
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M8891 First in Human in Solid Tumors (M8891)

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ClinicalTrials.gov Identifier: NCT03138538
Recruitment Status : Recruiting
First Posted : May 3, 2017
Last Update Posted : April 7, 2020
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 maximum tolerated dose (MTD), safety, tolerability, Pharmacokinetic and antitumor activity of M8891 as single agent in subjects with solid tumors.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: M8891 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Phase I Dose Escalation Trial of Methionine Aminopeptidase 2 Inhibitor M8891 in Subjects With Advanced Solid Tumors
Actual Study Start Date : August 8, 2017
Estimated Primary Completion Date : July 9, 2020
Estimated Study Completion Date : July 9, 2020

Arm Intervention/treatment
Experimental: M8891 Drug: M8891
Subjects will receive M8891 orally once daily or twice daily at escalated dose levels for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.




Primary Outcome Measures :
  1. Number of Subjects Experienced Any Dose-Limiting Toxicity (DLT) Over the DLT period [ Time Frame: From Cycle Day 1 up to Cycle 1 Day 21 ]
    DLTs are defined as any pre-defined set of adverse events (AEs) which are defined in the protocol, observed in the first 21-day treatment cycle and judged to be M8891 related or clinically relevant (excluding events to be related to underlying disease, medical history or concomitant medications/ procedures in the opinion of the safety monitoring committee).


Secondary Outcome Measures :
  1. Number of Subjects With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Discontinuation and Death [ Time Frame: Up to 7 months ]
    AE is defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE is any untoward medical occurrence that at any dose results in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or considered medically important.

  2. Number of Subjects With Clinical Significant Changes in Laboratory, Electrocardiogram measures, vital signs, Eastern Cooperative Oncology Group Performance status (ECOG PS) [ Time Frame: Up to 8 months ]
    Clinical laboratory assessments will include hematology, biochemistry and coagulation parameters. Vital sign assessments will include assessments of heart rate, diastolic blood pressure, systolic blood pressure, weight and temperature, ECG and ECOG PS will also be assessed.

  3. Maximum Observed Plasma Concentration (Cmax) of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    Cmax will be obtained directly from the concentration versus time curve.

  4. Time to Reach Maximum Plasma Concentration (Tmax) of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    Time to reach the maximum plasma concentration (Tmax) will be obtained directly from the concentration versus time curve.

  5. Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLQ). AUC0-t will be to be calculated according to the mixed log-linear trapezoidal rule.

  6. Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    AUC0-inf will be calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.

  7. Area under the plasma concentration versus time curve within one dosing interval (AUC0-tau) of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    AUC 0-tau is defined as the area under the concentration-time curve from 0 to dosing interval.

  8. Apparent Terminal Half-life (t1/2) of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    Terminal half-life is the time measured for the concentration of drug to decrease by one half.

  9. Apparent Body Clearance From Plasma Following Extravascular Administration (CL/f) of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.

  10. Apparent Volume of Distribution Following Extravascular Administration of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.

  11. Apparent Terminal Rate Constant of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    Apparent Terminal Rate Constant is defined as the rate at which drug is cleared from the body.

  12. Accumulation ratio for AUCtau (Racc(AUCtau)) of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    Accumulation ratio will be calculated from AUCtau at steady state and AUCtau after single dosing.

  13. Accumulation ratio for Cmax (Racc(Cmax))of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    Accumulation ratio will be calculated from Cmax at steady state and Cmax after single dosing.

  14. Apparent Body Clearance of Drug Following Extravascular Administration at Steady State (CLss/F) of M8891 [ Time Frame: Day 1, 2, 8, 15, 16 of Cycle 1; Day 1 of Cycle 2 and Cycle 3 ]
    Clearance (CLss/F) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes at steady state.

  15. Best Overall Response (BOR) [ Time Frame: Time from date of randomization up to end of the treatment or until disease progression (assessed up to 8 months) ]
    BOR will be determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by investigators. BOR is defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  16. Number of Subjects With Clinical Benefit [ Time Frame: Time from date of randomization up to end of the treatment or until disease progression (assessed up to 8 months) ]
    Clinical benefit defined as Complete Response [CR], Partial Response [PR] or Stable Disease [SD] for >= 12 weeks. Clinical benefit will be assessed according to RECIST Version 1.1. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: defined as at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Progressive disease (PD) :defined as at least a 20% increase in sum of longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of longest diameter while on study.

  17. Progression-free survival [ Time Frame: Time from date of randomization until disease progression or death (assessed up to 8 months) ]
    Progression-free survival time (PFS) is defined as the time from first study drug administration to either first observation of disease progression (as assessed by RECIST v 1.1) or occurrence of death due to any cause, whichever occurs first.



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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:

  • Subjects must be refractory to or intolerant of existing cancer therapy(ies) known to provide clinical benefit.
  • Histologically confirmed advanced solid tumors with no clear curative treatment options available after at least 1 prior systemic anticancer therapy.
  • Tumor accessible for biopsies and agreement to conduct pre-dose and post-dose fresh tumor biopsies.
  • Male or female subjects at least 18 years of age.

Exclusion Criteria:

  • ECOG PS >= 2
  • Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years of study start.
  • Severe bone marrow, renal or liver impairment.
  • Presence of deep vein thrombosis based on screening lower extremity Doppler ultrasonography.

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): NCT03138538


Contacts
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Contact: US Medical Information 888-275-7376 service@emdgroup.com

Locations
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United States, Connecticut
Smilow Cancer Hospital - Yale Recruiting
New Haven, Connecticut, United States, 06510
United States, Indiana
Indiana University Health Hospital Active, not recruiting
Indianapolis, Indiana, United States, 46202
United States, Maryland
Sidney Kimmel Cancer Center - Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21205-1911
United States, Michigan
Henry Ford Health System Recruiting
Detroit, Michigan, United States, 48202
United States, Nevada
Comprehensive Cancer Centers of Nevada Terminated
Las Vegas, Nevada, United States, 89169
United States, New Jersey
Rutgers Cancer Institute of New Jersey Completed
New Brunswick, New Jersey, United States, 08901
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible EMD Serono Research & Development Institute, Inc., a business of Merck KGaA, Darmstadt, Germany

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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT03138538    
Other Study ID Numbers: MS100015_0019
First Posted: May 3, 2017    Key Record Dates
Last Update Posted: April 7, 2020
Last Verified: April 2020

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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. ):
Advanced Solid Tumors
M8891
Methionine Aminopeptidase 2 Inhibitor
Additional relevant MeSH terms:
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Neoplasms