ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    An Open Label, Phase Ia/Ib Trial of the DNA-PK Inhibitor
Previous Study | Return to List | Next Study

Phase 1 Trial of MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Combination With Radiotherapy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02516813
Recruitment Status : Recruiting
First Posted : August 6, 2015
Last Update Posted : November 14, 2018
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Brief Summary:
MSC2490484A or M3814 is an investigational drug that is being evaluated for the treatment of subjects with locally advanced tumors. The main purposes of this study are to determine the safety, the tolerability and the efficacy of MSC2490484A in combination with radiotherapy and in combination with chemoradiotherapy (Radiotherapy + cisplatin).

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: MSC2490484A Radiation: Fractionated RT Drug: Cisplatin Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 82 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label, Phase Ia/Ib Trial of the DNA-PK Inhibitor MSC2490484A in Combination With Radiotherapy in Patients With Advanced Solid Tumors
Actual Study Start Date : September 15, 2015
Estimated Primary Completion Date : July 19, 2019
Estimated Study Completion Date : January 8, 2021

Arm Intervention/treatment
Experimental: Phase Ia Arm A: MSC2490484A +Fractionated RT
Subjects will receive MSC2490484A tablet once daily up to 10 times, for two consecutive weeks in concomitance with fractionated radiotherapy (RT) (5 fractions /week).
Drug: MSC2490484A
Phase Ia: Subjects will receive a starting dose of 100 milligram (mg) or 50 mg of MSC2490484A as Capsule or tablet orally once daily 1.5 hours prior each RT.
Other Name: M3814

Radiation: Fractionated RT
Phase Ia: Subjects will receive fractionated palliative RT (3 Gray [Gy] * 10 in Arm A and 2 Gy * 33 to 35, 5 fractions per week [F/W]) in Arm B.

Experimental: Phase Ia Arm B: MSC2490484A+Fractionated RT
Subjects will receive MSC2490484A capsule once daily up to 35 times, for 7 consecutive weeks in concomitance with fractionated RT and Cisplatin (5 fractions/week).
Drug: MSC2490484A
Phase Ia: Subjects will receive a starting dose of 100 milligram (mg) or 50 mg of MSC2490484A as Capsule or tablet orally once daily 1.5 hours prior each RT.
Other Name: M3814

Radiation: Fractionated RT
Phase Ia: Subjects will receive fractionated palliative RT (3 Gray [Gy] * 10 in Arm A and 2 Gy * 33 to 35, 5 fractions per week [F/W]) in Arm B.

Drug: Cisplatin
Cisplatin will be given twice at a dose of 100 milligram per square meter (mg/m^2) or weekly at a dose of 40 (mg/m^2).

Experimental: Phase Ib Arm A Expansion: MSC2490484A+Fractionated RT
Subjects will receive MSC2490484A tablet once daily up to 35 times in concomitance with fractionated RT (5 fractions /week).
Drug: MSC2490484A
Phase Ib: Subjects will receive the assigned dose of MSC2490484A once daily orally.

Radiation: Fractionated RT
Phase Ib: Subjects will receive fractionated RT (2 Gy x 33, 5 F/W).

Experimental: Phase Ib Arm B Expansion: MSC2490484A+Fractionated RT
Subjects will receive MSC2490484A tablet once daily up to 35 times in concomitance with fractionated RT (5 fractions /week) and cisplatin.
Drug: Cisplatin
Cisplatin will be given twice at a dose of 100 milligram per square meter (mg/m^2) or weekly at a dose of 40 (mg/m^2).

Drug: MSC2490484A
Phase Ib: Subjects will receive the assigned dose of MSC2490484A once daily orally.

Radiation: Fractionated RT
Phase Ib: Subjects will receive fractionated RT (2 Gy x 33, 5 F/W).

Experimental: cPOP: MSC2490484A+Fractionated RT
Clinical proof-of-principle (cPOP) study, subjects will receive first dose of RT on Day 1, and will receive MSC2490484A capsule within 1.5 hour before the second dose of RT on Day 2.
Drug: MSC2490484A
cPoP Study: Subjects will receive a single oral MSC2490484A capsule on Day 2, 1.5 hours before the start of RT.

Radiation: Fractionated RT
cPoP study: Subjects will receive a single high dose of RT (10-25 Gy) capsule on Day 1 given on Lesion 1 and a single high dose of RT (10-25 Gy) on Day 2 given on Lesion 2.




Primary Outcome Measures :
  1. Phase Ia (Arm A): Number of Subjects Experiencing at Least one Dose-limiting Toxicity (DLT) [ Time Frame: Up to 5 weeks after first dose of MSC2490484A in combination with palliative fractionated RT ]
    DLT is defined as any of the following toxicities assessed as at least possibly related to MSC2490484A by the Investigator and/or the Sponsor up to 5 weeks after the end of radiotherapy (RT): A treatment-emergent adverse event (TEAE) of potential clinical significance; evidence of possible treatment-related hepatocellular injury for more than 3 days as defined in the protocol; any Grade greater than or equal to (>=) 3 toxicity, but excluding the conditions mentioned in the protocol; any Grade 4 neutropenia of greater than (>)5 days duration or Grade >=3 febrile neutropenia; any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding; any toxicity related to trial drug that causes the subject to receive less than 80 percent (%) of planned MSC2490484A and/or RT dose.

  2. Phase Ib (Arm A expansion Cohort): Number of subjects experiencing at least one DLT [ Time Frame: Up to 12 weeks after first dose of MSC2490484A in combination with curatively intended fractionated RT ]
    DLT is defined as any of the following toxicities assessed as at least possibly related to MSC2490484A by the Investigator and/or the Sponsor up to 12 weeks after the end of radiotherapy (RT): A Treatment-Emergent Adverse Event (TEAE) of potential clinical significance; evidence of possible treatment-related hepatocellular injury for more than 3 days as defined in the protocol; any Grade greater than or equal to (>=) 3 toxicity, but excluding the conditions mentioned in the protocol; any Grade 4 neutropenia of greater than (>)5 days duration or Grade >=3 febrile neutropenia; any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding; any toxicity related to trial drug that causes the subject to receive less than 80 percent (%) of planned MSC2490484A and/or RT dose. Assessment only to be done in first 3 subjects of the phase 1b.

  3. Phase Ia (Arm B): Number of Subjects Experiencing at Least one DLT [ Time Frame: up to 12 weeks after first dose of MSC2490484A in combination with standard CRT (with cisplatin) ]
    DLT is defined as any of the following toxicities assessed as at least possibly related to MSC2490484A by the Investigator and/or the Sponsor up to 12 weeks after irst dose of MSC2490484A in combination with standard chemoradiotherapy (CRT) (with cisplatin): A treatment-emergent adverse event (TEAE) of potential clinical significance; evidence of possible treatment-related hepatocellular injury for more than 3 days as defined in the protocol; any Grade greater than or equal to (>=) 3 toxicity, but excluding the conditions mentioned in the protocol; any Grade 4 neutropenia of greater than (>)5 days duration or Grade >=3 febrile neutropenia; any Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding; any toxicity related to trial drug that causes the subject to receive less than 80 percent (%) of planned MSC2490484A and/or RT dose and/or CRT.

  4. Phase Ib: Number of subjects experiencing treatment emergent adverse events (TEAEs) [ Time Frame: From first dose of investigational medicinal product administration up to 12 months days after the end of therapy ]
    An Adverse Event (AE) is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A Serious AE (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.

  5. Phase Ib: Number of Subjects With Clinically Significant Vital signs, Electrocardiogram (ECG) and Laboratory Abnormalities [ Time Frame: From first dose of investigational medicinal product administration up to 12 months after the end of therapy ]

Secondary Outcome Measures :
  1. Phase Ia: Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Treatment Discontinuation, and TEAEs Leading to Death [ Time Frame: Up to 12 months after end of therapy ]
  2. Phase Ia: Number of Subjects With Clinically Significant Vital signs, Electrocardiogram (ECG) and Laboratory Abnormalities [ Time Frame: From first dose of investigational medicinal product administration up to 12 months after the end of therapy ]
  3. Best Overall Response Rate [ Time Frame: Time from first dose to disease progression or death, whichever occurs first, assessed until 1 year after end of RT or CRT ]
    Best overall response is defined as occurrence of complete response (CR) or partial response (PR) based on the Investigator's assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 confirmed at a repeat assessment performed no less than 28 days after the criteria for response are first met. Complete response (CR) is defined as disappearance of all target and non-target lesions. Partial response (PR) is defined as at least 30% decrease in the sum of the diameters of target or non-target lesions taking as reference the baseline sum diameters, with no evidence of progressive disease (PD). PD is defined as at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on trial, or unequivocal progression of existing non-target lesions.

  4. Tumor Size Measurement [ Time Frame: Time from first dose to disease progression or death, whichever occurs first, assessed until 1 year after end of RT or CRT ]
  5. Progression-free Survival (PFS) Time [ Time Frame: Time from first dose to disease progression or death, whichever occurs first, assessed until 1 year after end of RT or CRT ]
    PFS time will be evaluated according to RECIST Version 1.1.

  6. Overall Survival (OS) Time [ Time Frame: Time from first dose to death, assessed until 1 year after end of RT or CRT ]
    Overall Survival (OS) Time will be evaluated according to RECIST Version 1.1.

  7. Phase Ia: Maximum plasma concentration (Cmax) of MSC2490484A [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day (FD) 1 and FD6; Pre-dose on FD2 and FD7; Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 ]
  8. Phase Ia: Time to reach maximum plasma concentration (tmax) of MSC2490484A [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on FD1 and FD6; Pre-dose on FD2 and FD7; Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 ]
  9. Phase Ia: Area under the plasma concentration curve from zero to last sampling time AUC (0-t) of MSC2490484A [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on FD1 and FD6; Pre-dose on FD2 and FD7; Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 ]
  10. Phase Ia: Area under the plasma concentration curve from zero to infinity AUC (0-inf) of MSC2490484A [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on FD1 and FD6; Pre-dose on FD2 and FD7; Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 ]
  11. Phase Ia: Terminal half life (t1/2) of MSC2490484A [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on FD1 and FD6; Pre-dose on FD2 and FD7; Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 ]
  12. Phase Ia: Apparent total body clearance (CL/f) of MSC2490484A [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on FD1 and FD6; Pre-dose on FD2 and FD7 ]
  13. Phase Ia: Volume of distribution (Vz/F) of MSC2490484A [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on FD1 and FD6; Pre-dose on FD2 and FD7 ]
  14. Phase Ia: Area under the plasma concentration-time curve over the dosing interval after multiple dosing (AUC0-tau) of MSC2490484A [ Time Frame: Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 ]
  15. Phase Ia: Oral clearance of MSC2490484A at steady state (CLss/f) in Plasma [ Time Frame: Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 ]
  16. Phase Ia: Apparent volume of distribution at steady state (Vss/f) of MSC2490484A in plasma [ Time Frame: Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 ]
  17. Phase Ia: Accumulation ratio for area under the concentration-time curve (Racc[AUC]) [ Time Frame: Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 ]
  18. Phase Ia: Accumulation ratio for maximum concentration (Racc[Cmax]) [ Time Frame: Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Phase Ia part: advanced solid tumors or metastases including lymphoma localized in the head and neck region or thorax with an indication for fractionated palliative RT (Arm A); or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B)
  • Phase Ib part: treatment-naïve Stage III A/B NSCLC not eligible for surgical resection or concurrent chemoradiation (Arm A expansion cohort) or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B expansion cohort)
  • cPoP study: any tumor with at least 2 (sub)cutaneous tumor/metastases at least 2 cm apart which are RT naïve with an indication for high dose palliative RT
  • Availability of archival tumor material, either as a block or slides (Phase Ia and Ib). If no archival material is available then a fresh biopsy should be taken
  • Willing to have tumor biopsies collected in cPoP
  • Measurable or evaluable disease by RECIST v1.1 (not required for the cPoP study)
  • Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2
  • Life expectancy of ≥ 3 months (Phase Ia, Arm A) or ≥ 6 months (Phase Ia, Arm B and Phase Ib)
  • Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy.

Exclusion Criteria:

  • Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anticancer therapy or investigational medicinal product (IMP) within 28 days of first trial drug intake for Phase Ia subjects, and any prior therapy for Phase Ib subjects. For subjects with rapidly growing tumors localized in the head and neck region or thorax where the treating physician cannot wait for 28 days, inclusion may take place if there is no residual toxicity from previous treatment (maximum CTCAE Grade 1)
  • Prior RT to the same region within 12 months (Phase Ia, Arm A; subjects with tumors localized in the head and neck region or thorax) or at any time previously (Phase Ia, Arm B; treatment-naïve subjects with SCCHN and Phase Ib; treatment-naïve subjects with Stage III A/B NSCLC or SCCHN)
  • Extensive prior RT on ≥30% of bone marrow reserve as judged by the investigator or prior bone marrow/stem cell transplantation within 5 years before trial start.
  • Poor vital organ functions defined as:

    • Bone marrow impairment as evidenced by hemoglobin <10.0 g/dL, neutrophil count <1.0 × 109/L, platelets <100 × 109/L
    • Renal impairment as evidenced by serum creatinine >1.5 × upper limit of normal (ULN)
    • Liver function abnormality as defined by total bilirubin >1.5 × ULN or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2.5 × ULN (except for subjects with liver involvement, who can have AST/ALT >5 × ULN)
    • Abnormality in coagulation parameters. Received oral or parenteral anticoagulants or thrombolytic agents within 10 days of the first dose of trial drug. Low dose high molecular weight heparin is permitted if international normalized ratio is within the normal range
  • History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP, use of percutaneous endoscopic gastrostomy (PEG) tubes
  • Significant cardiac conduction abnormalities, including a history of long QTc syndrome and/or pacemaker, or impaired cardiovascular function such as New York Heart Association classification score >2.
  • Subjects currently receiving (or unable to stop using prior to receiving the first dose of trial drug) medications or herbal supplements known to be potent inhibitors of cytochrome P450 (CYP)3A or CYP2C19 (must stop at least 1 week prior), potent inducers of CYP3A or CYP2C19 (must stop at least 3 weeks prior), or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least one day prior).
  • Subjects currently receiving H2-blocker or proton pump inhibitors (or unable to stop at least 5 days prior to the first treatment).
  • If the planned radiation field includes any part of the esophagus and the subject has symptoms of ongoing esophagitis, the subject is not eligible, unless an esophageal endoscopy rules out the presence of esophagitis
  • Subjects where more than 10% of the total esophagus volume receives more than 50% of the prescribed RT dose

Main exclusion criteria for cPoP

  • History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP
  • History of any other significant medical disease such as major gastric or small bowel surgery, recent drainage of significant volumes of ascites or pleural effusion (as per Investigator's judgement) or a psychiatric condition that might impair the subject's well-being or preclude full participation in the trial
  • Subjects currently receiving (or unable to stop using prior to receiving the first dose of study drug) medications or herbal supplements known to be potent inhibitors of CYP3A or CYP2C19 must stop at least 1 week prior to taking MSC2490484A. Subjects receiving potent inducers of CYP3A or CYP2C19 must stop at least 3 weeks prior to taking MSC2490484A. Those receiving drugs mainly metabolized by CYP3A with a narrow therapeutic index as judged by the Investigator (and after optional consultation with the Sponsor) must stop at least one day prior to taking MSC2490484A.

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): NCT02516813


Contacts
Contact: US Medical Information 888-275-7376
Contact: Merck KGaA Communication Center +49-6151-72-5200 service@merckgroup.com

Locations
United States, California
Research site Recruiting
Fresno, California, United States, 93720
United States, Florida
Research site Recruiting
Fort Lauderdale, Florida, United States, 33308
Research site Recruiting
Miami, Florida, United States, 33136-1002
United States, Montana
Research site Recruiting
Billings, Montana, United States, 59101
United States, New York
Research site Recruiting
Bronx, New York, United States, 10461
United States, Pennsylvania
Research site Recruiting
Philadelphia, Pennsylvania, United States, 19107
United States, Texas
Research site Not yet recruiting
Houston, Texas, United States, 77030
United States, Washington
Research site Completed
Tacoma, Washington, United States, 98405
Belgium
Research site Active, not recruiting
Leuven, Belgium
Denmark
Research site Recruiting
Copenhagen, Denmark, 2100
Research site Recruiting
Herlev, Denmark
Germany
Research site Active, not recruiting
Freiburg, Baden Wuerttemberg, Germany, 79106
Research site Recruiting
Heidelberg, Baden Wuerttemberg, Germany
Research site Recruiting
Mannheim, Baden Wuerttemberg, Germany
Research site Recruiting
Tuebingen, Baden Wuerttemberg, Germany, 72076
Research site Recruiting
Mainz, Rhineland-Palatinate, Germany, 55131
Research site Recruiting
Dresden, Sachsen, Germany, 1307
Research site Recruiting
Kiel, Schleswig-Holstein, Germany, 24105
Research site Recruiting
Berlin, Germany, 12200
Netherlands
Research site Recruiting
Amsterdam, Netherlands, 1066 CX
Research site 1 Active, not recruiting
Amsterdam, Netherlands
Norway
Research site Active, not recruiting
Oslo, Norway
Sweden
Research site Recruiting
Solna, Sweden, 17176
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
Study Director: Medical Responsible Merck KGaA, Darmstadt, Germany

Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT02516813     History of Changes
Other Study ID Numbers: 100036-002
2015-000673-12 ( EudraCT Number )
First Posted: August 6, 2015    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: November 2018

Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
M3814
Advanced solid tumors
DNA-PK Inhibitor
Radiotherapy
Chemotherapy

Additional relevant MeSH terms:
Cisplatin
Antineoplastic Agents