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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

Study Description
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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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Chronic Lymphocytic Leukemia Drug: MSC2490484A Phase 1

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 31 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 31, 2014
Actual Primary Completion Date : June 29, 2017
Actual Study Completion Date : June 29, 2017

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Arms and Interventions
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Arm Intervention/treatment
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.
 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


Outcome Measures
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Primary Outcome Measures :
  1. Number of Dose limiting toxicities (DLTs) occurring in Cycle 1 [ Time Frame: up to Day 21 of Cycle 1 ]

Secondary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  2. Time to Maximum Observed Plasma Concentration (tmax) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  3. Minimum Observed Plasma Concentration During a Complete Dosing Interval (Cmin) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  4. Average Observed Plasma Concentration (Cavg) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  5. Fluctuation Index [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  6. 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) ]
  7. 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) ]
  8. 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) ]
  9. 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) ]
  10. 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) ]
  11. Apparent Terminal Half-Life (t1/2) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  12. Terminal Rate Constant (λz) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  13. Oral Clearance (CL/f) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  14. Apparent Volume of Distribution During Terminal Phase (Vz/f) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  15. Apparent Volume of Distribution at Steady State (Vss/f) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  16. Accumulation Ratio for Area Under The Concentration-Time Curve (Racc[AUC]) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  17. Accumulation Ratio for Maximum Concentration (Racc[Cmax]) [ Time Frame: Day 1 of Cycle 1 (cycle length = 21 days) ]
  18. 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 ]
  19. Clinical benefit rate defined as the proportion of subjects with CR, PR, or stable disease at Week 12 [ Time Frame: Week 12 ]
  20. 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 ]

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:

  • 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
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): NCT02316197


Locations
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Germany
Please contact the Merck KGaA Communication Center
Darmstadt, Germany
Sponsors and Collaborators
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible Merck KGaA, Darmstadt, Germany
More Information
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Responsible Party: Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier: NCT02316197     History of Changes
Other Study ID Numbers: EMR100036-001
2014-003099-22 ( EudraCT Number )
First Posted: December 12, 2014    Key Record Dates
Last Update Posted: April 13, 2018
Last Verified: April 2018
Keywords provided by Merck KGaA, Darmstadt, Germany:
DNA-PK Inhibitor
Advanced solid tumors
Chronic lymphocytic Leukemia
Phase I, first-in-human
Dose escalation
Dose expansion
 Safety profile
Tolerability
PK
Antitumor activity
Maximum tolerated dose
M3814
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
 Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell