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).

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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) - Ancillary cPoP Part: 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 Ancillary cPoP - Measurable or evaluable disease by RECIST v1.1 (not required for ancillary cPoP part of the study) - Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1 - 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) - 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 Ancillary Clinical Proof-of-Principle Part: - 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.

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
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 (M3814)
    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 names:
    • Peposertib
  • 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 (M3814)
    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 names:
    • Peposertib
  • 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 (M3814)
    Phase Ib: Subjects will receive the assigned dose of MSC2490484A once daily orally.
    Other names:
    • Peposertib
  • 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 (M3814)
    Phase Ib: Subjects will receive the assigned dose of MSC2490484A once daily orally.
    Other names:
    • Peposertib
  • Radiation: Fractionated RT
    Phase Ib: Subjects will receive fractionated RT (2 Gy x 33, 5 F/W).
Experimental
Ancillary cPoP: MSC2490484A+Fractionated RT
Ancillary Clinical proof-of-principle (cPOP) study, subjects will receive first dose of RT on Day 1, and will receive MSC2490484A capsule or Tablet formulation within 1.5 hour before the second dose of RT on Day 2.
  • Drug: MSC2490484A (M3814)
    Ancillary cPoP Study: Subjects will receive a single oral MSC2490484A capsule on Day 2, 1.5 hours before the start of RT.
    Other names:
    • Peposertib
  • Radiation: Fractionated RT
    Ancillary 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.

More Details

Status
Completed
Sponsor
EMD Serono Research & Development Institute, Inc.

Study Contact

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.