Neoplasms

Symptoms and General Pathology

All Conditions

Neoplasm Metastasis

Neoplastic Processes

intensity modulated radiotherapy (IMRT) 10 x 3 Gy

fractionated conventional external beam RT 10×3 Gy

Intensity modulated Raiotherapy (IMRT) of the involved spinal bone metastasis

IMRT

external beam Radiotherapy of the involved spinal bone metastasis

fractionated RT

Harald Rief, MD, PhD

Jürgen Debus, MD, PhD

The aim of this explorative trial is to verify the comparability of a fractionated intensity modulated radiotherapy with a conventional radiotherapy related to quality of life on the one hand and to evaluate toxicity, re-calcification and stability of vertebral body as well as pain relief and local response for palliative patients with painful spinal bone metastases on the other hand. This is a single-center, prospective randomized controlled trial with parallel-group design to determine the quality of life after RT in patients with spinal bone metastases. Two different techniques were evaluated: intensity modulated radiotherapy (IMRT) and fractionated conventional external beam RT with 10×3 Gy each.

Experimental intervention:

IMRT 10 x 3 Gy

Control intervention:

3D-RT 10 x 3 Gy

The aim of this explorative trial is to verify the comparability of a fractionated intensity modulated radiotherapy with a conventional radiotherapy related to quality of life on the one hand and to evaluate toxicity, re-calcification and stability of vertebral body as well as pain relief and local response for palliative patients with painful spinal bone metastases on the other hand. This is a single-center, prospective randomized controlled trial with parallel-group design to determine the quality of life after RT in patients with spinal bone metastases. Two different techniques were evaluated: intensity modulated radiotherapy (IMRT) and fractionated conventional external beam RT with 10×3 Gy each.

Experimental intervention:

IMRT 10 x 3 Gy

Control intervention:

3D-RT 10 x 3 Gy After the baseline measurements have been recorded, the patients will be randomly assigned to one of the two groups: IMRT 10×3 Gy (n = 30) or fractionated conventional 3D-RT 10×3 Gy (n = 30). The RT will be applied daily (mondy to Friday).

Follow-up per patient:

The target parameters will be measured and recorded at baseline, at the end of RT (t1), and at 12 weeks (t2) and 6 months (t3) after the end of the irradiation period.

Image-guided and Intensity-modulated Radiotherapy Versus External Beam Radiotherapy for Patients With Spine Metastases

improvement of more than 10% according to the EORTC BM22 questionaire measured at the 3-months-time-point after the end of RT (t2).

bone density is assessed 12 weeks post completion of radiotherapy using follow-up CT scan of the spine

pain is evaluated using the VAS pain scale (0-100 points) at completion and 12/ 24 weeks post completion of radiation

Fatigue is assessed using the EORTC FA13 questionnaire

Heidelberg University

Antineoplastic Agents

All Drugs and Chemicals

Cisplatin

Peposertib

Protein Kinase Inhibitors

Enzyme Inhibitors

Subjects will receive MSC2490484A tablet once daily up to 10 times, for two consecutive weeks in concomitance with fractionated radiotherapy (RT) (5 fractions /week).

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).

Subjects will receive MSC2490484A tablet once daily up to 35 times in concomitance with fractionated RT (5 fractions /week).

Subjects will receive MSC2490484A tablet once daily up to 35 times in concomitance with fractionated RT (5 fractions /week) and cisplatin.

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.

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.

MSC2490484A (M3814)

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.

Fractionated RT

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).

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

Ancillary cPoP Study: Subjects will receive a single oral MSC2490484A capsule on Day 2, 1.5 hours before the start of RT.

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

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.

Medical Responsible

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).

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

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

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.

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.

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.

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.

PFS time will be evaluated according to RECIST Version 1.1.

Overall Survival (OS) Time will be evaluated according to RECIST Version 1.1.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Image-guided and Intensity-modulated Radiotherapy Versus External Beam Radiotherapy for Patients With Spine Metastases	NCT02832830	Vertebral Bony ...	IMRT fractionated RT	18 Years - 85 Years	Heidelberg University
Phase 1 Trial of MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Combination With Radiotherapy	NCT02516813	Advanced Solid ...	MSC2490484A (M3... Fractionated RT Cisplatin MSC2490484A (M3... MSC2490484A (M3... Fractionated RT Fractionated RT	18 Years -	EMD Serono
Phase 1 Trial of MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Combination With Radiotherapy	NCT02516813	Advanced Solid ...	MSC2490484A (M3... Fractionated RT Cisplatin MSC2490484A (M3... MSC2490484A (M3... Fractionated RT Fractionated RT	18 Years -	EMD Serono

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