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Clinical Phase I Study Investigating MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Advanced Solid Tumors or Chronic Lymphocytic Leukemia

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ClinicalTrials.gov Identifier: NCT02316197
Recruitment Status : Completed
First Posted : December 12, 2014
Last Update Posted : April 13, 2018
Sponsor:
Information provided by (Responsible Party):
Merck KGaA, Darmstadt, Germany

Tracking Information
First Submitted Date  ICMJE December 10, 2014
First Posted Date  ICMJE December 12, 2014
Last Update Posted Date April 13, 2018
Actual Study Start Date  ICMJE December 31, 2014
Actual Primary Completion Date June 29, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 10, 2014)
Number of Dose limiting toxicities (DLTs) occurring in Cycle 1 [ Time Frame: up to Day 21 of Cycle 1 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02316197 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 11, 2017)
  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • Time to Maximum Observed Plasma Concentration (tmax) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • Minimum Observed Plasma Concentration During a Complete Dosing Interval (Cmin) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • Average Observed Plasma Concentration (Cavg) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • Fluctuation Index [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • Apparent Terminal Half-Life (t1/2) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • Terminal Rate Constant (λz) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • Oral Clearance (CL/f) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • Apparent Volume of Distribution During Terminal Phase (Vz/f) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • Apparent Volume of Distribution at Steady State (Vss/f) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • Accumulation Ratio for Area Under The Concentration-Time Curve (Racc[AUC]) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • Accumulation Ratio for Maximum Concentration (Racc[Cmax]) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  • 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 ]
  • Clinical benefit rate defined as the proportion of subjects with CR, PR, or stable disease at Week 12 [ Time Frame: Week 12 ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2014)
  • Pharmacokinetics profile in plasma (Cmax, tmax, Cmin, Cavg, fluctuation indices (peak-to-trough fluctuation and swing), AUC0-24, AUC0-12, AUC0-t, AUC0-∞, AUCτ, t1/2, λz, CL/f, Vz/f, Vss/f, Racc(AUC), and Racc(Cmax) [ Time Frame: Day 1 of Cycle 1 ]
  • 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 ]
  • Clinical benefit rate defined as the proportion of subjects with CR, PR, or stable disease at Week 12 [ Time Frame: Week 12 ]
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clinical Phase I Study Investigating MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Advanced Solid Tumors or Chronic Lymphocytic Leukemia
Official Title  ICMJE 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
Brief Summary MSC2490484A is an investigational drug that is being evaluated for the treatment of subjects with advanced solid tumors or chronic lymphocytic leukemia (CLL) that likely differs from other cancers in how it repairs damaged DNA (genetic material). This is a first-in-man Phase I study, which means that it is the first time the study drug is being used in humans. The main purpose is to determine the highest dose that does not cause unacceptable side effects. The second is to determine the appropriate dose to use in future research for subjects with cancer. Othergoals of the study are to learn about the drug's safety and side effects, how it affects the tumor, and how the body processes the drug.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Solid Tumors
  • Chronic Lymphocytic Leukemia
Intervention  ICMJE Drug: MSC2490484A
Initial starting dose at 100 mg (oral administration), once daily, subsequent doses and treatment regimens will be determined by the SMC (once or twice daily). MSC2490484A will be administered in continuous 21-day cycles in dose escalation or dose expansion cohorts, as long as they do not experience unacceptable toxicity or disease progression.
Other Name: M3814
Study Arms  ICMJE Experimental: MSC2490484A
Initial starting dose at 100 mg (oral administration), once daily, subsequent doses and treatment regimens will be determined by the SMC (once or twice daily). MSC2490484A will be administered in continuous 21-day cycles in dose escalation or dose expansion cohorts, as long as they do not experience unacceptable toxicity or disease progression.
Intervention: Drug: MSC2490484A
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 21, 2017)
31
Original Estimated Enrollment  ICMJE
 (submitted: December 10, 2014)
82
Actual Study Completion Date  ICMJE June 29, 2017
Actual Primary Completion Date June 29, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02316197
Other Study ID Numbers  ICMJE EMR100036-001
2014-003099-22 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Merck KGaA, Darmstadt, Germany
Study Sponsor  ICMJE Merck KGaA, Darmstadt, Germany
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Responsible Merck KGaA, Darmstadt, Germany
PRS Account Merck KGaA, Darmstadt, Germany
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP