Clinical Trials /

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

NCT02516813

Description:

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).

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Lymphoma
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 100036-002
  • SECONDARY ID: 2015-000673-12
  • NCT ID: NCT02516813

Conditions

  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
MSC2490484AM3814Phase Ia Arm A: MSC2490484A+Fractionated RT
CisplatinPhase Ia Arm B: MSC2490484A+Fractionated RT
MSC2490484APhase Ib Arm A Expansion: MSC2490484A+Fractionated RT
MSC2490484AcPOP: MSC2490484A+Fractionated RT

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Phase Ia Arm A: MSC2490484A+Fractionated RTExperimentalSubjects will receive MSC2490484A once daily up to 10 times, for two consecutive weeks in concomitance with fractionated radiotherapy (RT) (5 fractions /week).
  • MSC2490484A
Phase Ia Arm B: MSC2490484A+Fractionated RTExperimentalSubjects will receive MSC2490484A once daily up to 35 times, for 7 consecutive weeks in concomitance with fractionated RT and Cisplatin (5 fractions/week).
  • MSC2490484A
  • Cisplatin
Phase Ib Arm A Expansion: MSC2490484A+Fractionated RTExperimentalSubjects will receive the recommended dose of MSC2490484A once daily up to 35 times in concomitance with fractionated RT (5 fractions /week).
  • MSC2490484A
Phase Ib Arm B Expansion: MSC2490484A+Fractionated RTExperimentalSubjects will receive the recommended dose of MSC2490484A once daily up to 35 times in concomitance with fractionated RT (5 fractions /week) and cisplatin.
  • Cisplatin
  • MSC2490484A
cPOP: MSC2490484A+Fractionated RTExperimentalClinical proof-of-principle (cPOP) study, subjects will receive a single dose of MSC2490484A (this dose will be administrated 1 day after the first dose of RT on Day 1 and within 1.5 hour before the second single high dose of RT on Day 2.
  • MSC2490484A

Eligibility 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).

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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 21 days 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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:PFS time will be evaluated according to RECIST Version 1.1.
Measure:Overall Survival (OS) Time
Time Frame:Time from first dose to death, assessed until 1 year after end of RT or CRT
Safety Issue:
Description:Overall Survival (OS) Time will be evaluated according to RECIST Version 1.1.
Measure:Phase Ia: Maximum plasma concentration (Cmax) of MSC2490484A
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, 6 (Day 1, 10); 8 hours postdose on Day 1
Safety Issue:
Description:
Measure:Phase Ia: Time to reach maximum plasma concentration (tmax) of MSC2490484A
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, 6 (Day 1, 10); 8 hours postdose on Day 1
Safety Issue:
Description:
Measure:Phase Ia: Area under the plasma concentration curve from zero to last sampling time AUC (0-t) of MSC2490484A
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours postdose on Day 1
Safety Issue:
Description:
Measure:Phase Ia: Area under the plasma concentration curve from zero to infinity AUC (0-inf) of MSC2490484A
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, 6 (Day 1, 10); 8 hours postdose on Day 1
Safety Issue:
Description:
Measure:Phase Ia: Terminal half life (t1/2) of MSC2490484A
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, 6 (Day 1, 10); 8 hours postdose on Day 1
Safety Issue:
Description:
Measure:Phase Ia: Apparent total body clearance (CL/f) of MSC2490484A
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours postdose on Day 1
Safety Issue:
Description:
Measure:Phase Ia: Volume of distribution (Vz/F) of MSC2490484A
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours postdose on Day 1
Safety Issue:
Description:
Measure:Phase Ia: Area under the plasma concentration-time curve over the dosing interval after multiple dosing (AUC0-tau) of MSC2490484A
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, and 6 hours postdose on Day 10
Safety Issue:
Description:
Measure:Phase Ia: Oral clearance of MSC2490484A at steady state (CLss/f) in Plasma
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, and 6 hours postdose on Day 10
Safety Issue:
Description:
Measure:Phase Ia: Apparent volume of distribution at steady state (Vss/f) of MSC2490484A in plasma
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, and 6 hours postdose on Day 10
Safety Issue:
Description:
Measure:Phase Ia: Accumulation ratio for area under the concentration-time curve (Racc[AUC])
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, and 6 hours postdose on Day 10
Safety Issue:
Description:
Measure:Phase Ia: Accumulation ratio for maximum concentration (Racc[Cmax])
Time Frame:Predose, 0.5, 1, 1.5, 2, 3, 4, and 6 hours postdose on Day 10
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:EMD Serono Research & Development Institute, Inc.

Trial Keywords

  • M3814
  • Advanced solid tumors
  • DNA-PK Inhibitor
  • Radiotherapy

Last Updated

February 9, 2017