- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02316197
Clinical Phase I Study Investigating MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Advanced Solid Tumors or Chronic Lymphocytic Leukemia
A Multicenter, Open-Label, Dose-Escalating Phase I Trial of the DNA-PK Inhibitor MSC2490484A in Subjects With Advanced Solid Tumors or Chronic Lymphocytic Leukemia
Study Overview
Status
Intervention / Treatment
Detailed Description
This is a Phase I, first-in-human, open-label, dose escalation, and dose expansion trial designed to explore the safety, tolerability, PK and PD profiles, and clinical activity of MSC2490484A administered daily as a single agent to subjects with advanced solid tumors or CLL likely to have alterations in DNA repair mechanisms.
Dose Escalation : Subjects will receive MSC2490484A continuously at the starting dose of 100 mg once daily. Sequential treatment cohorts will receive ascending doses of MSC2490484A once daily or twice daily (if determined to be appropriate by the Safety Monitoring Committee [SMC]) following a standard "3+3" design. The SMC will make dose escalation decisions based on review of available safety, tolerability, Pharmacokinetic (PK), and Pharmacodynamic (PD) data. Once the maximum tolerated dose (MTD) has been established, an Recommended Phase II Dose (RP2D) will be defined by the SMC, either at the MTD level or another dose level, depending on the available data on safety, efficacy, PK, and PD observed in the trial. The SMC may decide to stop dose escalation at any time during the trial.
Up to 12 subjects will be enrolled at the RP2D/Optimal biologic dose (OBD) to confirm safety and tolerability and explore the PK and PD profile of MSC2490484A.
Expansion cohorts: Once subjects have been evaluated at the RP2D, additional subjects will be enrolled into 2 or more expansion cohorts (20 evaluable subjects per expansion cohort) to evaluate clinical efficacy in tumors likely to have alterations in the DNA repair mechanism (eg, CLL and other tumor types). Subjects are evaluable for efficacy if they have received at least 1 dose of study drug and have radiographic baseline. Subjects who are not evaluable for efficacy will be replaced.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Bruxelles, Belgium
- Institut Jules Bordet
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Leuven, Belgium
- UZ Leuven
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Copenhagen, Denmark
- Rigshospitalet - Onkologisk KFE
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Herlev, Denmark
- Herlev Hospital University of Copenhagen
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Amsterdam, Netherlands
- Antoni van Leeuwenhoek Ziekenhuis
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Amsterdam, Netherlands
- VU Medisch Centrum - Dept of Medical Oncology
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Rotterdam, Netherlands
- Erasmus Medisch Centrum - Parent
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Advanced solid tumors likely to have alterations in DNA repair mechanisms, such as the BRCA and ATM pathways, or CLL, with no other standard surgical, radiation, or systemic anticancer therapies available. Subjects with CLL will be enrolled in 1 of the RP2D expansion cohorts only
- Tumor accessible for biopsies and agree to pretreatment tumor biopsy
- Measurable or evaluable disease in accordance with RECIST v 1.1 for solid tumors or Cheson´s criteria for CLL
- Male or female subjects at least 18 years of age who sign written informed consent.
- Other protocol-defined criteria could apply
Exclusion Criteria:
- Eastern Cooperative Oncology Group performance status > 1
- Prior treatment with chemotherapy, immunotherapy, hormonal therapy, with the exception of luteinizing hormone releasing hormone (LHRH) analogs, biologic therapy, any other anticancer therapy, or any other investigational agent within 28 days of the first dose of MSC2490484A (6 weeks for nitrosoureas or mitomycin C)
- Extensive prior radiotherapy on more than 30% of bone marrow reserves or prior bone marrow/stem cell transplantation within 5 years of study start. The extent of previous radiotherapy to the bone marrow will be determined by the investigator.
- Receiving medications or herbal supplements that are known to be potent inhibitors of cytochrome P450 3A4 or inducers of cytochrome P450 3A4.
- Not recovered from toxicity due to prior therapy to baseline or an AE CTCAE Grade of 1 or less (except alopecia)
- Poor vital organ function as defined in the protocol
- Significant cardiac conduction abnormalities as defined in the protocol
- Central nervous system metastases unless previously radiotherapy treated, stable by computerized tomography (CT) scan for at least 3 months without evidence of cerebral edema, and no requirements for corticosteroids or anticonvulsants
- Other protocol-defined criteria could apply
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: MSC2490484A 100 mg QD
Participants received MSC2490484A capsules 100 milligram (mg) orally, once daily (QD) from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
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Participants received MSC2490484A capsules at escalated dose from 100 mg to 400 mg orally from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
Other Names:
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Experimental: MSC2490484A 200 mg QD
Participants received MSC2490484A capsules 200 mg orally, QD from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
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Participants received MSC2490484A capsules at escalated dose from 100 mg to 400 mg orally from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
Other Names:
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Experimental: MSC2490484A 150 mg BID
Participants received MSC2490484A capsules 150 mg orally, twice daily (BID) from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
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Participants received MSC2490484A capsules at escalated dose from 100 mg to 400 mg orally from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
Other Names:
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Experimental: MSC2490484A 200 mg BID
Participants received MSC2490484A capsules 200 mg orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
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Participants received MSC2490484A capsules at escalated dose from 100 mg to 400 mg orally from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
Other Names:
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Experimental: MSC2490484A 300 mg BID
Participants received MSC2490484A capsules 300 mg orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
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Participants received MSC2490484A capsules at escalated dose from 100 mg to 400 mg orally from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
Other Names:
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Experimental: MSC2490484A 400 mg BID
Participants received MSC2490484A capsules 400 mg orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
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Participants received MSC2490484A capsules at escalated dose from 100 mg to 400 mg orally from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
Other Names:
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Experimental: MSC2490484A 400 mg BID RP2D
Participants received MSC2490484A capsules 400 mg recommended Phase II dose (RP2D) orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
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Participants received MSC2490484A capsules at escalated dose from 100 mg to 400 mg orally from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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Number of Dose limiting toxicities (DLTs) occurring in Cycle 1
Time Frame: up to Day 21 of Cycle 1
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up to Day 21 of Cycle 1
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
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Maximum Observed Plasma Concentration (Cmax)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Time to Maximum Observed Plasma Concentration (tmax)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Minimum Observed Plasma Concentration During a Complete Dosing Interval (Cmin)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Average Observed Plasma Concentration (Cavg)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Fluctuation Index
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Area Under the Concentration-Time Curve From Time Zero To 24 Hours (AUC0-24)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Area Under the Concentration-Time Curve From Time Zero To 12 Hours (AUC0-12)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Area Under the Concentration-Time Curve From Time Zero To the Time of Last Quantifiable Concentration (AUC0-t)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Area Under the Concentration-Time Curve From Time Zero Extrapolated To Infinity (AUC0-inf)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Area Under the Concentration-Time Curve From Time Zero to Time tau at Steady State (AUCtau)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Apparent Terminal Half-Life (t1/2)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Terminal Rate Constant (λz)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Oral Clearance (CL/f)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Apparent Volume of Distribution During Terminal Phase (Vz/f)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Apparent Volume of Distribution at Steady State (Vss/f)
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Accumulation Ratio for Area Under The Concentration-Time Curve (Racc[AUC])
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Accumulation Ratio for Maximum Concentration (Racc[Cmax])
Time Frame: Day 1 of Cycle 1 (cycle length = 21 days)
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Day 1 of Cycle 1 (cycle length = 21 days)
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Best overall response rate
Time Frame: Time from first dose to disease progression or death, whichever occurs first, assessed until 12 weeks after last patient treated
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Time from first dose to disease progression or death, whichever occurs first, assessed until 12 weeks after last patient treated
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Clinical benefit rate defined as the proportion of subjects with CR, PR, or stable disease at Week 12
Time Frame: Week 12
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Week 12
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Progression-free survival time (PFS)
Time Frame: Time from first dose to disease progression or death, whichever occurs first, assessed until 12 weeks after last patient treated
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Time from first dose to disease progression or death, whichever occurs first, assessed until 12 weeks after last patient treated
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Collaborators and Investigators
Sponsor
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Leukemia, B-Cell
- Leukemia
- Leukemia, Lymphocytic, Chronic, B-Cell
- Leukemia, Lymphoid
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Protein Kinase Inhibitors
- Peposertib
Other Study ID Numbers
- EMR100036-001
- 2014-003099-22 (EudraCT Number)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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