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

Study Overview
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Brief Summary
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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).

Official Title
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An Open Label, Phase Ia/Ib Trial of the DNA-PK Inhibitor MSC2490484A in Combination With Radiotherapy in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: MSC2490484A (M3814)
* Radiation: Fractionated RT
* Drug: Cisplatin
* Drug: MSC2490484A (M3814)
* Drug: MSC2490484A (M3814)
* Radiation: Fractionated RT
* Radiation: Fractionated RT


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ia Arm A: MSC2490484A +Fractionated RT<br>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)<br>* 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.<br>* Other names: Peposertib;Radiation: Fractionated RT<br>* 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.<br>|
| Experimental: Phase Ia Arm B: MSC2490484A +Fractionated RT<br>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)<br>* 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.<br>* Other names: Peposertib;Radiation: Fractionated RT<br>* 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.<br>Drug: Cisplatin<br>* 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).<br>|
| Experimental: Phase Ib Arm A Expansion: MSC2490484A+Fractionated RT<br>Subjects will receive MSC2490484A tablet once daily up to 35 times in concomitance with fractionated RT (5 fractions /week). | Drug: MSC2490484A (M3814)<br>* Phase Ib: Subjects will receive the assigned dose of MSC2490484A once daily orally.<br>* Other names: Peposertib;Radiation: Fractionated RT<br>* Phase Ib: Subjects will receive fractionated RT (2 Gy x 33, 5 F/W).<br>|
| Experimental: Phase Ib Arm B Expansion: MSC2490484A+Fractionated RT<br>Subjects will receive MSC2490484A tablet once daily up to 35 times in concomitance with fractionated RT (5 fractions /week) and cisplatin. | Drug: Cisplatin<br>* 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).<br>Drug: MSC2490484A (M3814)<br>* Phase Ib: Subjects will receive the assigned dose of MSC2490484A once daily orally.<br>* Other names: Peposertib;Radiation: Fractionated RT<br>* Phase Ib: Subjects will receive fractionated RT (2 Gy x 33, 5 F/W).<br>|
| Experimental: Ancillary cPoP: MSC2490484A+Fractionated RT<br>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)<br>* Ancillary cPoP Study: Subjects will receive a single oral MSC2490484A capsule on Day 2, 1.5 hours before the start of RT.<br>* Other names: Peposertib;Radiation: Fractionated RT<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ia (Arm A): Number of Subjects Experiencing at Least one Dose-limiting Toxicity (DLT) | DLT: any Grade >= 3 nonhematologic AE or Grade >= 4 hematologic AE according to NCI-CTCAE version 4.03, related to any of study treatments & occurs during DLT period of 5 weeks(Phase Ia, Arm A)/12 weeks (Phase Ia, Arm B & Phase Ib. In addition, following are considered DLTs: Grade 3 thrombocytopenia with medically concerning bleeding, Febrile neutropenia, Any toxicity or study treatment-related TEAE ADRs that, in opinion of SMC, is of potential clinical significance, Any toxicity related to study treatments that causes subject to receive less than 80% of planned radiotherapy (RT) dose, Any toxicity related to study treatments leading to an interruption of RT longer than 1 week in Arm B & Evidence of study treatment related hepatocellular injury for more than 3 days. | Up to 5 weeks after first dose of MSC2490484A in combination with palliative fractionated RT | 
| Phase Ib (Arm A expansion Cohort): Number of subjects experiencing at least one DLT | DLT: any Grade >= 3 nonhematologic AE or Grade >= 4 hematologic AE according to NCI-CTCAE version 4.03, related to any of study treatments & occurs during DLT period of 5 weeks(Phase Ia, Arm A)/12 weeks (Phase Ia, Arm B & Phase Ib. In addition, following are considered DLTs: Grade 3 thrombocytopenia with medically concerning bleeding, Febrile neutropenia, Any toxicity or study treatment-related TEAE ADRs that, in opinion of SMC, is of potential clinical significance, Any toxicity related to study treatments that causes subject to receive less than 80% of planned radiotherapy (RT) dose, Any toxicity related to study treatments leading to an interruption of RT longer than 1 week in Arm B & Evidence of study treatment related hepatocellular injury for more than 3 days. | Up to 12 weeks after first dose of MSC2490484A in combination with curatively intended fractionated RT | 
| Phase Ia (Arm B): Number of Subjects Experiencing at Least one DLT | 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. | up to 12 weeks after first dose of MSC2490484A in combination with standard CRT (with cisplatin) | 
| Phase Ib: Number of subjects experiencing treatment emergent adverse events (TEAEs) | 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. | From first dose of investigational medicinal product administration up to 12 months days after the end of therapy | 
| Phase Ib: Number of Subjects With Clinically Significant Vital signs, Electrocardiogram (ECG) and Laboratory Abnormalities |  | From first dose of investigational medicinal product administration up to 12 months after the end of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ia: Number of Subjects with Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Treatment Discontinuation, and TEAEs Leading to Death |  | Up to 12 months after end of therapy | 
| Phase Ia: Number of Subjects With Clinically Significant Vital signs, Electrocardiogram (ECG) and Laboratory Abnormalities |  | From first dose of investigational medicinal product administration up to 12 months after the end of therapy | 
| Best Overall Response Rate | 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. | Time from first dose to disease progression or death, whichever occurs first, assessed until 1 year after end of RT or CRT | 
| Tumor Size Measurement |  | Time from first dose to disease progression or death, whichever occurs first, assessed until 1 year after end of RT or CRT | 
| Progression-free Survival (PFS) Time | PFS time will be evaluated according to RECIST Version 1.1. | Time from first dose to disease progression or death, whichever occurs first, assessed until 1 year after end of RT or CRT | 
| Overall Survival (OS) Time | Overall Survival (OS) Time will be evaluated according to RECIST Version 1.1. | Time from first dose to death, assessed until 1 year after end of RT or CRT | 
| Phase Ia: Maximum plasma concentration (Cmax) of MSC2490484A |  | 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 | 
| Phase Ia: Time to reach maximum plasma concentration (tmax) of MSC2490484A |  | 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 | 
| Phase Ia: Area under the plasma concentration curve from zero to last sampling time AUC (0-t) of MSC2490484A |  | 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 | 
| Phase Ia: Area under the plasma concentration curve from zero to infinity AUC (0-inf) of MSC2490484A |  | 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 | 
| Phase Ia: Terminal half life (t1/2) of MSC2490484A |  | 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 | 
| Phase Ia: Apparent total body clearance (CL/f) of MSC2490484A |  | Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on FD1 and FD6; Pre-dose on FD2 and FD7 | 
| Phase Ia: Volume of distribution (Vz/F) of MSC2490484A |  | Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on FD1 and FD6; Pre-dose on FD2 and FD7 | 
| Phase Ia: Area under the plasma concentration-time curve over the dosing interval after multiple dosing (AUC0-tau) of MSC2490484A |  | Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 | 
| Phase Ia: Oral clearance of MSC2490484A at steady state (CLss/f) in Plasma |  | Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 | 
| Phase Ia: Apparent volume of distribution at steady state (Vss/f) of MSC2490484A in plasma |  | Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 | 
| Phase Ia: Accumulation ratio for area under the concentration-time curve (Racc[AUC]) |  | Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 | 
| Phase Ia: Accumulation ratio for maximum concentration (Racc[Cmax]) |  | Pre-dose, 0.5, 1, 2, 4 hours post-dose on FD10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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M3814, Advanced solid tumors, DNA-PK Inhibitor, Radiotherapy, Chemotherapy