Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as MSC2490484A, M3814, MSC2490484A (M3814), MSC2490484
Peposertib · 5 trials · 6 indications
DLT is defined as any of following treatment emergent adverse events (TEAEs) considered possibly related to study treatment by Investigator and/or Sponsor up to completion of assigned chemoradiotherapy treatment. DLT were based on SMC: Adverse drug reaction that, in the opinion of SMC, is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any occurrence of drug-induced liver injury meeting the Hy's law criteria; Any Grade 3 toxicity excluding diarrhea, neutropenia lasting for ≤ 5 days, nausea \& vomiting, Grade 3 thrombocytopenia without bleeding; Grade ≥ 4 AEs at least possibly related to study drug, irrespective of duration, excluding: Isolated Grade 4 lymphocytopenia without clinical symptoms; Neutropenia lasting for ≤ 5 days and not associated with fever; Any toxicity related to study drug that causes participant to receive \> 80% of planned peposertib, capecitabine or RT dose.
A DLT was defined as any Grade more than or equal to \>= 3 nonhematologic Adverse Event(AE) or any Grade\>= 4 hematologic,, occurring during the DLT period that is related to any of the study interventions. In addition, a DLT is considered: Grade 3 thrombocytopenia with medically concerning bleeding, Any febrile neutropenia. A study intervention-related Treatment emergent Adverse Event(TEAE) is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. Any toxicity related to study intervention that causes the participant to receive less than 80% of M3814 during DLT period, evidence of study treatment-related hepatocellular injury for more than 3 days, such as\> 5-fold elevations above the Upper Limits of Normal (ULN) of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase(AST) with or without elevation of serum total bilirubin to \> 2 × ULN. Number of Participants with DLT Grade \>= 3 were reported.
A DLT was defined as any Grade more than or equal to \>= 3 nonhematologic Adverse Event(AE) or any Grade\>= 4 hematologic,, occurring during the DLT period that is related to any of the study interventions. In addition, a DLT is considered: Grade 3 thrombocytopenia with medically concerning bleeding, Any febrile neutropenia. A study intervention-related Treatment emergent Adverse Event(TEAE) is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. Any toxicity related to study intervention that causes the participant to receive less than 80% of M3814 during DLT period, evidence of study treatment-related hepatocellular injury for more than 3 days, such as\> 5-fold elevations above the Upper Limits of Normal (ULN) of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase(AST) with or without elevation of serum total bilirubin to \> 2 × ULN. Number of Participants with DLT Grade \>= 3 were reported.
Area under the plasma concentration versus time curve from time zero to 6 hours post dosing for M3814 was reported.
Cmax was obtained directly from the concentration versus time curve.
DLT: any Grade (Gr) greater than or equal to (\>=) 3 nonhematologic adverse event (AE)/any Gr\>=4 hematologic AE that is related to any of study treatments and occurs during the DLT period of 5 weeks (Phase Ia, Arm A) after the first dose of M3814. Following are considered as DLTs: Gr3 thrombocytopenia with medically concerning bleeding; Febrile neutropenia; Any toxicity/study treatment-related adverse event (TEAE) that, in opinion of Safety Monitoring Committee (SMC), is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any toxicity related to study treatments that causes participant to receive less than 80 percent (%) of the planned RT dose; Evidence of study treatment-related hepatocellular injury for \> 3 days.
DLT: any Grade (Gr) greater than or equal to (\>=) 3 nonhematologic AE/any Gr\>=4 hematologic AE that is related to any of study treatments and occurs during the DLT period of 12 weeks (Phase Ia, Arm B) after the first dose of M3814. Following are considered as DLTs: Gr3 thrombocytopenia with medically concerning bleeding; Febrile neutropenia; Any toxicity/study treatment-related adverse event (TEAE) that, in opinion of Safety Monitoring Committee (SMC), is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any toxicity related to study treatments that causes participant to receive less than 80 percent (%) of the planned 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 \> 3 days.
| Arm | Type | Description |
|---|---|---|
| Part 1: Peposertib: Treatment Sequence A-B-C | EXPERIMENTAL | Participants will receive single oral dose of peposertib tablet (Treatment A) on Day 1 under fasted condition in period 1, followed by single oral dose of peposertib tablet (Treatment B) on Day 8 under fed condition in period 2, followed by oral suspension dose of peposertib (Treatment C) on Day 15 under fasted condition in period 3. There will be washout period of 7 days between each treatment period. |
| Part 1: Peposertib Treatment Sequence A-C-B | EXPERIMENTAL | Participants will receive single oral dose of peposertib tablet (Treatment A) on Day 1 under fasted condition in period 1, followed by oral suspension dose of peposertib (Treatment C) on Day 8 under fasted condition in period 2, followed by single oral dose of peposertib tablet (Treatment B) on Day 15 under fed condition in period 3. There will be washout period of 7 days between each treatment period. |
| Part 1: Peposertib Treatment Sequence B-A-C | EXPERIMENTAL | Participants will receive single oral dose of peposertib tablet (Treatment B) on Day 1 under fed condition in period 1, followed by single oral dose of peposertib tablet (Treatment A) on Day 8 under fasted condition in period 2, followed by oral suspension dose of peposertib (Treatment C) on Day 15 under fasted condition in period 3. There will be washout period of 7 days between each treatment period. |
| Part 1: Peposertib Treatment Sequence B-C-A | EXPERIMENTAL | Participants will receive single oral dose of peposertib tablet (Treatment B) on Day 1 under fed condition in period 1, followed by oral suspension dose of peposertib (Treatment C) on Day 8 under fasted condition in period 2, followed by single oral dose of peposertib tablet (Treatment A) on Day 15 under fasted condition in period 3. There will be washout period of 7 days between each treatment period. |
| Part 1: Peposertib: Treatment Sequence C-A-B | EXPERIMENTAL | Participants will receive oral suspension dose of peposertib (Treatment C) on Day 1 under fasted condition in period 1, followed by single oral dose of peposertib tablet (Treatment A) on Day 8 under fasted condition in period 2, followed by single oral dose of peposertib tablet (Treatment B) on Day 15 under fed condition in period 3. There will be washout period of 7 days between each treatment period. |
| Part 1: Peposertib Treatment Sequence C-B-A | EXPERIMENTAL | Participants will receive oral suspension dose of peposertib (Treatment C) on Day 1 under fasted condition in period 1, followed by single oral dose of peposertib tablet (Treatment B) on Day 8 under fed condition in period 2, followed by single oral dose of peposertib tablet (Treatment A) on Day 15 under fasted condition in period 3. There will be washout period of 7 days between each treatment period. |
| Part 2: Peposertib Treatment Sequence A-B | EXPERIMENTAL | Participants will receive single oral dose of peposertib tablet (Treatment A) on Day 1 under fasted condition in period 1, followed by single oral dose of peposertib tablet (Treatment B) on Day 8 under fed condition in period 2. There will be washout period of 7 days between each treatment period. |
| Part 2: Peposertib: Treatment Sequence B-A | EXPERIMENTAL | Participants will receive single oral dose of peposertib tablet (Treatment B) on Day 1 under fed condition in period 1, followed by single oral dose of peposertib tablet (Treatment A) on Day 8 under fasted condition in period 2. There will be washout period of 7 days between each treatment period. |
| Peposertib 50 mg + RT + Capecitabine | EXPERIMENTAL | Participants received peposertib 50 milligram (mg) once daily in combination with capecitabine 825 milligram per square meter (mg/m\^2) twice daily 5 days per week and radiotherapy (RT) of 50 to 50.4 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period. |
| Peposertib 100 mg + RT + Capecitabine | EXPERIMENTAL | Participants received peposertib 100 mg once daily in combination with capecitabine 825 mg/m\^2 twice daily 5 days per week and RT of 50 to 50.4 Gy to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period. |
| Peposertib 150 mg + RT + Capecitabine | EXPERIMENTAL | Participants received peposertib 150 mg once daily in combination with capecitabine 825 mg/m\^2 twice daily 5 days per week and RT of 50 to 50.4 Gy to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period. |
| Peposertib 250 mg + RT + Capecitabine | EXPERIMENTAL | Participants received peposertib 250 mg once daily in combination with capecitabine 825 mg/m\^2 twice daily 5 days per week and RT of 50 to 50.4 Gy to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period. |
| Part A: M3814 + Avelumab | EXPERIMENTAL | - |
| Part B: M3814 + Avelumab + Radiotherapy (RT) | EXPERIMENTAL | - |
| Part FE: M3814 + Avelumab (fasted/fed state) | EXPERIMENTAL | - |
| Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | EXPERIMENTAL | Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative radiotherapy (RT) received 100 milligrams (mg) of M3814 as capsule orally once daily on fraction day (FD) 6 in combination with RT (3 Gray \[Gy\] x 10, 5 fractions per week \[F/W\]). |
| Phase 1a (Arm A): M3814 Capsule (200 mg) + RT | EXPERIMENTAL | Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 200 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W). |
| Phase 1a (Arm A): M3814 Capsule (300 mg) + RT | EXPERIMENTAL | Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 300 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W). |
| Phase 1a (Arm A): M3814 Capsule (400 mg) + RT | EXPERIMENTAL | Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 400 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W). |
| Phase 1a (Arm A): M3814 Tablet (100 mg) + RT | EXPERIMENTAL | Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 100 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W). |
| Phase 1a (Arm A): M3814 Tablet (200 mg) + RT | EXPERIMENTAL | Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 200 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W). |
| Phase 1a (Arm A): M3814 Tablet (300 mg) + RT | EXPERIMENTAL | Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 300 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W). |
| Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT | EXPERIMENTAL | Participants with local/locally advanced squamous cell carcinoma of the head and neck (SCCHN) received 50 mg of M3814 as capsule orally once daily on FD 6 in combination with fractionated RT (2 Gy x 33 to 35 fractions; 5 F/W) and Cisplatin twice at a dose of 100 milligrams per square meter (mg/m\^2) or weekly at a dose of 40 (mg/m\^2). |
| Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT | EXPERIMENTAL | Participants with squamous cell carcinoma of the head and neck (SCCHN) received 100 mg of M3814 as tablet orally once daily for 7 consecutive weeks in combination with fractionated RT (2 Gy X 33 to 35 fractions; 5 F/W) and Cisplatin twice at a dose of 100 mg/m\^2 or weekly at a dose of 40 (mg/m\^2). |
| Ancillary cPoP: M3814 Capsule (100 mg) + RT | EXPERIMENTAL | Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 centimeters \[cm\] apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 100 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2. |
| Ancillary cPOP: M3814 Capsule (200 mg) + RT | EXPERIMENTAL | Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 cm apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 200 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2. |
| Ancillary cPOP: M3814 Capsule (400 mg) + RT | EXPERIMENTAL | Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 cm apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 400 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2 |
| MSC2490484A 100 mg QD | EXPERIMENTAL | Participants received MSC2490484A capsules 100 milligram (mg) orally, once daily (QD) from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814. |
| MSC2490484A 200 mg QD | EXPERIMENTAL | Participants received MSC2490484A capsules 200 mg orally, QD from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814. |
| MSC2490484A 150 mg BID | EXPERIMENTAL | Participants received MSC2490484A capsules 150 mg orally, twice daily (BID) from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814. |
| MSC2490484A 200 mg BID | EXPERIMENTAL | Participants received MSC2490484A capsules 200 mg orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814. |
| MSC2490484A 300 mg BID | EXPERIMENTAL | Participants received MSC2490484A capsules 300 mg orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814. |
| MSC2490484A 400 mg BID | EXPERIMENTAL | Participants received MSC2490484A capsules 400 mg orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814. |
| MSC2490484A 400 mg BID RP2D | EXPERIMENTAL | Participants received MSC2490484A capsules 400 mg recommended Phase II dose (RP2D) orally, BID from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814. |
| Name | Type | Description |
|---|---|---|
| Peposertib | DRUG | Participants will receive single oral dose of Peposertib tablet under fasting (Treatment A) or fed (Treatment B) conditions. |
| Peposertib 50 mg | DRUG | Participants received peposertib 50 milligram (mg) once daily 5 days per week up to 5.5 weeks. |
| Peposertib 100 mg | DRUG | Participants received peposertib 100 mg once daily 5 days per week up to 5.5 weeks. |
| Peposertib 150 mg | DRUG | Participants received peposertib 150 mg once daily 5 days per week up to 5.5 weeks. |
| Peposertib 250 mg | DRUG | Participants received peposertib 250 mg once daily 5 days per week up to 5.5 weeks. |
| Capecitabine | DRUG | Participants received capecitabine at a dose of 825 milligram per square meter (mg/m\^2) twice daily 5 days per week up to 5.5 weeks. |
| Radiotherapy (RT) | RADIATION | Participants received RT 50 to 50.4 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks. |
| M3814 | DRUG | Participants received M3814 twice daily (BID) continuously starting from Day 1 until progressive disease (PD) or unacceptable toxicity. |
| Avelumab | DRUG | Participants received avelumab once every 2 weeks (Q2W) starting from Day 1 until PD or unacceptable toxicity. |
| Radiotherapy | RADIATION | Participants received radiotherapy at the dose of 3 grays (Gy) per day starting Day 1 for 5 days per week for 2 weeks. |
| M3814 100 mg | DRUG | Participants received 100 mg of M3814 as capsule or tablet orally once daily. |
| M3814 200 mg | DRUG | Participants received 200 mg of M3814 as capsule or tablet orally once daily. |
| M3814 300 mg | DRUG | Participants received 300 mg of M3814 as capsule or tablet orally once daily. |
| M3814 400 mg | DRUG | Participants received 400 mg of M3814 as capsule or tablet orally once daily. |
| M3814 50 mg | DRUG | Participants received 100 mg of M3814 as capsule orally once daily. |
| Fractionated RT | RADIATION | Participants received 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 and received 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 in ancillary CPoP part. |
| Cisplatin | DRUG | Participants received Cisplatin twice at a dose of 100 mg/m\^2 or weekly at a dose of 40 mg/m\^2. |
| MSC2490484A (M3814) | DRUG | Participants received MSC2490484A capsules at escalated dose from 100 mg to 400 mg orally from Day 1 to Day 21 of each treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, and/or occurrence of any criterion for withdrawal from study or M3814. |
Inclusion Criteria: * Participants are overtly healthy as determined by medical evaluation, including medical history, physical examination, laboratory tests, and cardiac monitoring * Participants are nonsmoker for at least 6 months prior to Screening * Participants have a body weight greater than ...