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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

Primary Purpose

Advanced Solid Tumors, Chronic Lymphocytic Leukemia

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

MSC2490484A (M3814)

About this trial

This is an interventional treatment trial for Advanced Solid Tumors focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Institut Jules Bordet
UZ Leuven
Rigshospitalet - Onkologisk KFE
Herlev Hospital University of Copenhagen
Antoni van Leeuwenhoek Ziekenhuis
VU Medisch Centrum - Dept of Medical Oncology
Erasmus Medisch Centrum - Parent

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Arm Label

MSC2490484A 100 mg QD

MSC2490484A 200 mg QD

MSC2490484A 150 mg BID

MSC2490484A 200 mg BID

MSC2490484A 300 mg BID

MSC2490484A 400 mg BID

MSC2490484A 400 mg BID RP2D

Arm Description

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.

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Number of Dose limiting toxicities (DLTs) occurring in Cycle 1

Secondary Outcome Measures

Maximum Observed Plasma Concentration (Cmax)

Time to Maximum Observed Plasma Concentration (tmax)

Minimum Observed Plasma Concentration During a Complete Dosing Interval (Cmin)

Average Observed Plasma Concentration (Cavg)

Fluctuation Index

Area Under the Concentration-Time Curve From Time Zero To 24 Hours (AUC0-24)

Area Under the Concentration-Time Curve From Time Zero To 12 Hours (AUC0-12)

Area Under the Concentration-Time Curve From Time Zero To the Time of Last Quantifiable Concentration (AUC0-t)

Area Under the Concentration-Time Curve From Time Zero Extrapolated To Infinity (AUC0-inf)

Area Under the Concentration-Time Curve From Time Zero to Time tau at Steady State (AUCtau)

Apparent Terminal Half-Life (t1/2)

Terminal Rate Constant (λz)

Oral Clearance (CL/f)

Apparent Volume of Distribution During Terminal Phase (Vz/f)

Apparent Volume of Distribution at Steady State (Vss/f)

Accumulation Ratio for Area Under The Concentration-Time Curve (Racc[AUC])

Accumulation Ratio for Maximum Concentration (Racc[Cmax])

Best overall response rate

Clinical benefit rate defined as the proportion of subjects with CR, PR, or stable disease at Week 12

Progression-free survival time (PFS)

Full Information

NCT ID

NCT02316197

First Posted

December 10, 2014

Last Updated

April 24, 2020

Sponsor

Merck KGaA, Darmstadt, Germany

1. Study Identification

Unique Protocol Identification Number

NCT02316197

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2020

Overall Recruitment Status

Completed

Study Start Date

December 31, 2014 (Actual)

Primary Completion Date

June 29, 2017 (Actual)

Study Completion Date

June 29, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Merck KGaA, Darmstadt, Germany

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Advanced Solid Tumors, Chronic Lymphocytic Leukemia

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Enrollment

31 (Actual)

8. Arms, Groups, and Interventions

Arm Title

MSC2490484A 100 mg QD

Arm Type

Experimental

Arm Description

Arm Title

MSC2490484A 200 mg QD

Arm Type

Experimental

Arm Description

Arm Title

MSC2490484A 150 mg BID

Arm Type

Experimental

Arm Description

Arm Title

MSC2490484A 200 mg BID

Arm Type

Experimental

Arm Description

Arm Title

MSC2490484A 300 mg BID

Arm Type

Experimental

Arm Description

Arm Title

MSC2490484A 400 mg BID

Arm Type

Experimental

Arm Description

Arm Title

MSC2490484A 400 mg BID RP2D

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

MSC2490484A (M3814)

Other Intervention Name(s)

M3814, Peposertib

Intervention Description

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.

Primary Outcome Measure Information:

Title

Number of Dose limiting toxicities (DLTs) occurring in Cycle 1

Time Frame

up to Day 21 of Cycle 1

Secondary Outcome Measure Information:

Title

Maximum Observed Plasma Concentration (Cmax)

Time Frame