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The study was terminated early per sponsor decision to halt further development of M3541 due to pharmaceutical and PK/pharmacodynamics properties that precluded further clinical development.
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| Name | Class |
|---|---|
| Merck KGaA, Darmstadt, Germany | INDUSTRY |
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This dose-escalation study evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and explore antitumor activity of M3541 in combination with fractionated palliative radiotherapy (RT) in participants with solid tumors with malignant lesions in the thorax, abdominal cavity, head and neck region, or extremities likely to benefit from palliative RT.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| M3541 50 mg + RT | Experimental | Participants received 50 milligrams (mg) M3541 orally once per fraction day (FD) in combination with palliative radiotherapy (RT) administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10, for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
|
| M3541 100 mg + RT | Experimental | Participants received 100 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
|
| M3541 200 mg + RT | Experimental | Participants received 200 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
|
| M3541 300 mg + RT | Experimental | Participants received 300 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| M3541 | Drug | Participants received M3541 orally once per fraction day (FD) for two consecutive calendar weeks (that is, Monday through Friday, with Saturday and Sunday as M3541 holidays). |
| Measure | Description | Time Frame |
|---|---|---|
| M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs) | DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) >=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for >3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for >5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time. | Baseline up to 5 weeks (including 2 weeks of treatment and 3 weeks of follow-up period) |
| M3541 300 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs) | DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) >=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for >3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for >5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time. | Baseline up to 4 weeks (including 2 weeks of treatment and 2 weeks of the follow-up period) |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Grade >=3 Adverse Events (AEs), Serious TEAEs and Deaths According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03 (CTCAE V4.03) | An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE 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 or was otherwise considered medically important. TEAEs are events with start date on or after the date of first dose of study treatment and up to and including 30 days after the last dose of study treatment, or events with start date prior to the date of first dose of study treatment, and worsened in severity or become serious during treatment. TEAEs include both Serious TEAEs and non-serious TEAEs. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| IU Simon Cancer Center | Indianapolis | Indiana | 46202 | United States | ||
| Washington University |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35150356 | Derived | Waqar SN, Robinson C, Olszanski AJ, Spira A, Hackmaster M, Lucas L, Sponton L, Jin H, Hering U, Cronier D, Grinberg M, Seithel-Keuth A, Diaz-Padilla I, Berlin J. Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors. Invest New Drugs. 2022 Jun;40(3):596-605. doi: 10.1007/s10637-022-01216-8. Epub 2022 Feb 12. |
| Label | URL |
|---|---|
| Trial Awareness and Transparency website | View source |
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This dose-escalation study was planned to be conducted as per 3 dosing schedules for M3541 including M3541 once per Fraction Day daily, M3541 twice and thrice weekly in combination with fractionated RT given in 10 fractions. However, due to early termination of the study, 2 intermittent schedules (thrice weekly and twice weekly) were never opened and did not enroll any participants.
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| ID | Title | Description |
|---|---|---|
| FG000 | M3541 50 mg + RT | Participants received 50 milligrams (mg) M3541 orally once per fraction day (FD) in combination with palliative radiotherapy (RT) administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10, for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| FG001 | M3541 100 mg + RT | Participants received 100 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| FG002 | M3541 200 mg + RT | Participants received 200 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| FG003 | M3541 300 mg + RT | Participants received 300 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
Safety analysis set included all participants who received at least 1 dose of M3541.
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| ID | Title | Description |
|---|---|---|
| BG000 | M3541 50 mg + RT | Participants received 50 milligrams (mg) M3541 orally once per fraction day (FD) in combination with palliative radiotherapy (RT) administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10, for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs) | DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) >=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for >3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for >5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time. | DLT analysis set included participants who received at least 1 dose of M3541and met at least one of the following criteria: Experienced at least 1 DLT during the DLT evaluation period, regardless of the number of doses of M3541 administered or received at least 80% of planned dose of each treatment, that is, 8 fractions of RT and 8 of 10 M3541 administrations during the treatment period | Posted | Count of Participants | Participants | Baseline up to 5 weeks (including 2 weeks of treatment and 3 weeks of follow-up period) |
Baseline up to 749 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | M3541 50 mg + RT | Participants received 50 milligrams (mg) M3541 orally once per fraction day (FD) in combination with palliative radiotherapy (RT) administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10, for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Urinary tract infection | Infections and infestations | MedDRA version 22.1 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA version 22.1 | Non-systematic Assessment |
The study was terminated early per sponsor decision to halt further development of M3541 due to pharmaceutical and PK/pharmacodynamics properties that precluded further clinical development.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Communication Center | Merck KGaA, Darmstadt, Germany | +49-6151-72-5200 | service@emdgroup.com |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 4, 2019 | Jan 27, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 4, 2019 | Jan 27, 2022 | SAP_001.pdf |
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Subsequent cohorts of patients treated at different dose levels.
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|
| Palliative Radiotherapy (RT) | Radiation | Participants received RT dose of 30 Gray (Gy) given in 10 fractions (3 Gy given per fraction day) administered over two consecutive calendar weeks (that is, Monday through Friday, with Saturday and Sunday as RT holidays). |
|
| Baseline up to 749 days |
| Number of Participants With Grade 3 or Higher Laboratory Abnormalities Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | The laboratory assessment included measurements hematology and biochemistry parameters. It had been graded according to NCI-CTCAE version 4.03 into Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 = death. Participants with grade 3 or higher were reported. | Baseline up to Day 44 |
| Number of Participants With Abnormalities in Vital Signs | Vital signs assessment included blood pressure, pulse rate, body temperature, respiratory rate, and body weight. Notably abnormal vital signs were: Blood pressure: systolic blood pressure >= 140 millimeter of mercury (mmHg) & diastolic blood pressure >=90 mmHg on treatment; Pulse rate >100 beats/min; Body temperature >= 38 degree Celsius (°C) on treatment; Respiratory rate >= 20 breaths/min; Weight (kilogram) > +/-20% from baseline. Number of Participants with abnormalities in vital signs were reported. | Baseline up to 379 days |
| Number of Participants With Abnormalities in Physical Examination Reported as Adverse Events (AEs) | Number of participants with any clinically significant abnormalities in physical examination reported as adverse events with National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade >=3 were presented. | Baseline up to 379 days |
| Number of Participants With Abnormal Change From Baseline in Electrocardiogram (ECG) | The 12-lead ECG was recorded after the participant was in semi-supine position for at least 5 minutes. The ECG was obtained using a Holter recorder. Number of Participants with abnormal change from baseline in ECG were reported. | Baseline up to 15 days |
| Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | BOR was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). BOR is defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | Time from randomization to 964 days |
| Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator | PFS is defined as the time (in months) from first administration of M3541 until the first date of progressive disease (PD) or death due to any cause. PFS was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participant wise data reported for this outcome measure. | From first dose of study drug to disease progression or death from any cause, assessed up to 964 days |
| Maximum Observed Plasma Concentration (Cmax) of M3541 | Cmax was obtained directly from the plasma concentration versus time curve. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3541 | Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of M3541 | Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Apparent Terminal Half-Life (t1/2) of M3541 | Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Area Under Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]) of M3541 | AUC(0-last) is defined as the area under the concentration-time curve from dosing (time 0) to the time of the last measured concentration. AUC(0-last) will be estimated using the Linear Up Log Down calculation method. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Dose Normalized Area Under the Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]/Dose) of M3541 | The Dose normalized AUC from time zero to the last sampling time (0-last) at which the concentration is at or above the lower limit of quantification. Normalized using the actual dose, using the formula AUC0-last/Dose. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Area Under the Concentration-Time Curve From Time Zero to 6 Hour Postdose (AUC[0-6h]) of M3541 | Area under the drug concentration-time curve from 0 to 6 hour post dosing for M3541. AUC0-6 was calculated according to the mixed log-linear trapezoidal rule. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of M3541 | AUC0-inf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Dose Normalized Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]/Dose) of M3541 | Dose normalized was calculated as area under the plasma concentration-time curve from time zero to 8 h postdose divided by dose. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Oral Clearance (CL/F) of M3541 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. CL/f = Dose /AUC0-inf. Predicted AUC0-inf should be used. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Oral Clearance at Steady-State (CLss/F) of M3541 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of M3541 | The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf)* Lambda(z). | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Apparent Volume of Distribution at Steady-State (Vss/F) of M3541 | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Accumulation Ratio for Area Under Plasma Concentration-Time Curve From Time Zero to 6 Hour (Racc[AUC0-6]) of M3541 | The accumulation ratio to assess the increase in exposure via AUC0-6h. Racc(AUC0-6h)= (AUC0-6h after multiple dose) / (AUC0-6h after single dose). | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Accumulation Ratio for Maximum Observed Plasma Concentration (Racc[Cmax]) | The accumulation ratio is to assess the increase in maximum concentration with multiple dosing. Racc(Cmax) = (Cmax after multiple dose)/ (Cmax after single dose). | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Pre-dose Plasma Concentration (Ctrough) of M3541 | Ctrough is the concentration prior to study drug administration. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Minimum Observed Plasma Concentration (Cmin) of M3541 | Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| Average Plasma Concentration (Cavg) of M3541 | Cavg was defined as average plasma concentration. | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
| St Louis |
| Missouri |
| 63110 |
| United States |
| Hackensack University Medical Center | Hackensack | New Jersey | 07601 | United States |
| Fox Chase Cancer Center | Philadelphia | Pennsylvania | 19111 | United States |
| Vanderbilt-Ingram Cancer Center | Nashville | Tennessee | 37212 | United States |
| US Medical Information website, Medical Resources | View source |
| Death |
|
| Study termination per Sponsor Decision |
|
| BG001 |
| M3541 100 mg + RT |
Participants received 100 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| BG002 | M3541 200 mg + RT | Participants received 200 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| BG003 | M3541 300 mg + RT | Participants received 300 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| BG004 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
|
|
|
| Secondary | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Grade >=3 Adverse Events (AEs), Serious TEAEs and Deaths According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03 (CTCAE V4.03) | An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE 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 or was otherwise considered medically important. TEAEs are events with start date on or after the date of first dose of study treatment and up to and including 30 days after the last dose of study treatment, or events with start date prior to the date of first dose of study treatment, and worsened in severity or become serious during treatment. TEAEs include both Serious TEAEs and non-serious TEAEs. | Safety analysis set included all participants who received at least 1 dose of M3541. | Posted | Count of Participants | Participants | Baseline up to 749 days |
|
|
|
| Secondary | Number of Participants With Grade 3 or Higher Laboratory Abnormalities Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | The laboratory assessment included measurements hematology and biochemistry parameters. It had been graded according to NCI-CTCAE version 4.03 into Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 = death. Participants with grade 3 or higher were reported. | Safety analysis set included all participants who received at least 1 dose of M3541. | Posted | Count of Participants | Participants | Baseline up to Day 44 |
|
|
|
| Secondary | Number of Participants With Abnormalities in Vital Signs | Vital signs assessment included blood pressure, pulse rate, body temperature, respiratory rate, and body weight. Notably abnormal vital signs were: Blood pressure: systolic blood pressure >= 140 millimeter of mercury (mmHg) & diastolic blood pressure >=90 mmHg on treatment; Pulse rate >100 beats/min; Body temperature >= 38 degree Celsius (°C) on treatment; Respiratory rate >= 20 breaths/min; Weight (kilogram) > +/-20% from baseline. Number of Participants with abnormalities in vital signs were reported. | Safety analysis set included all participants who received at least 1 dose of M3541. | Posted | Count of Participants | Participants | Baseline up to 379 days |
|
|
|
| Secondary | Number of Participants With Abnormalities in Physical Examination Reported as Adverse Events (AEs) | Number of participants with any clinically significant abnormalities in physical examination reported as adverse events with National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade >=3 were presented. | Safety analysis set included all participants who received at least 1 dose of M3541. | Posted | Count of Participants | Participants | Baseline up to 379 days |
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|
| Secondary | Number of Participants With Abnormal Change From Baseline in Electrocardiogram (ECG) | The 12-lead ECG was recorded after the participant was in semi-supine position for at least 5 minutes. The ECG was obtained using a Holter recorder. Number of Participants with abnormal change from baseline in ECG were reported. | Safety analysis set included all participants who received at least 1 dose of M3541. Here "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure with normal ECG at baseline. | Posted | Count of Participants | Participants | Baseline up to 15 days |
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| Secondary | Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | BOR was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). BOR is defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | Safety analysis set included all participants who received at least 1 dose of M3541. | Posted | Count of Participants | Participants | Time from randomization to 964 days |
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| Secondary | Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator | PFS is defined as the time (in months) from first administration of M3541 until the first date of progressive disease (PD) or death due to any cause. PFS was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participant wise data reported for this outcome measure. | Safety analysis set included all participants who received at least 1 dose of M3541. The summarized data was not available for this outcome measure, therefore individual data was presented. "Number Analyzed" signifies participants evaluable in respective arm. | Posted | Number | Months | From first dose of study drug to disease progression or death from any cause, assessed up to 964 days |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) of M3541 | Cmax was obtained directly from the plasma concentration versus time curve. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3541 | Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Time to Reach Maximum Observed Plasma Concentration (Tmax) of M3541 | Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Apparent Terminal Half-Life (t1/2) of M3541 | Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Area Under Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]) of M3541 | AUC(0-last) is defined as the area under the concentration-time curve from dosing (time 0) to the time of the last measured concentration. AUC(0-last) will be estimated using the Linear Up Log Down calculation method. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Dose Normalized Area Under the Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]/Dose) of M3541 | The Dose normalized AUC from time zero to the last sampling time (0-last) at which the concentration is at or above the lower limit of quantification. Normalized using the actual dose, using the formula AUC0-last/Dose. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Area Under the Concentration-Time Curve From Time Zero to 6 Hour Postdose (AUC[0-6h]) of M3541 | Area under the drug concentration-time curve from 0 to 6 hour post dosing for M3541. AUC0-6 was calculated according to the mixed log-linear trapezoidal rule. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of M3541 | AUC0-inf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Dose Normalized Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]/Dose) of M3541 | Dose normalized was calculated as area under the plasma concentration-time curve from time zero to 8 h postdose divided by dose. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Oral Clearance (CL/F) of M3541 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. CL/f = Dose /AUC0-inf. Predicted AUC0-inf should be used. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Oral Clearance at Steady-State (CLss/F) of M3541 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Apparent Volume of Distribution During Terminal Phase (Vz/F) of M3541 | The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf)* Lambda(z). | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Apparent Volume of Distribution at Steady-State (Vss/F) of M3541 | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Accumulation Ratio for Area Under Plasma Concentration-Time Curve From Time Zero to 6 Hour (Racc[AUC0-6]) of M3541 | The accumulation ratio to assess the increase in exposure via AUC0-6h. Racc(AUC0-6h)= (AUC0-6h after multiple dose) / (AUC0-6h after single dose). | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Accumulation Ratio for Maximum Observed Plasma Concentration (Racc[Cmax]) | The accumulation ratio is to assess the increase in maximum concentration with multiple dosing. Racc(Cmax) = (Cmax after multiple dose)/ (Cmax after single dose). | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Pre-dose Plasma Concentration (Ctrough) of M3541 | Ctrough is the concentration prior to study drug administration. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Minimum Observed Plasma Concentration (Cmin) of M3541 | Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Secondary | Average Plasma Concentration (Cavg) of M3541 | Cavg was defined as average plasma concentration. | As per changes in planned analysis, the outcome measure related to pharmacokinetic parameters was not assessed. | Posted | Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10 |
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| Primary | M3541 300 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs) | DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) >=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for >3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for >5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time. | DLT analysis set included participants who received at least 1 dose of M3541and met at least one of the following criteria: Experienced at least 1 DLT during the DLT evaluation period, regardless of the number of doses of M3541 administered or received at least 80% of planned dose of each treatment, that is, 8 fractions of RT and 8 of 10 M3541 administrations during the treatment period | Posted | Count of Participants | Participants | Baseline up to 4 weeks (including 2 weeks of treatment and 2 weeks of the follow-up period) |
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| 0 |
| 3 |
| 0 |
| 3 |
| 3 |
| 3 |
| EG001 | M3541 100 mg + RT | Participants received 100 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). | 4 | 4 | 1 | 4 | 4 | 4 |
| EG002 | M3541 200 mg + RT | Participants received 200 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). | 2 | 5 | 1 | 5 | 5 | 5 |
| EG003 | M3541 300 mg + RT | Participants received 300 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). | 0 | 3 | 0 | 3 | 3 | 3 |
| Blood creatinine increased | Investigations | MedDRA version 22.1 | Non-systematic Assessment |
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| Dehydration | Metabolism and nutrition disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Hyponatraemia | Metabolism and nutrition disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Tachycardia | Cardiac disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Visual impairment | Eye disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Abdominal pain lower | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Colitis | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Dysphagia | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Enterocolitis | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Odynophagia | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Proctitis | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Stomatitis | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Face oedema | General disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Facial pain | General disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Fatigue | General disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Influenza like illness | General disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Non-cardiac chest pain | General disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Oedema peripheral | General disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Pain | General disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Pyrexia | General disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Swelling face | General disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Candida infection | Infections and infestations | MedDRA version 22.1 | Non-systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA version 22.1 | Non-systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA version 22.1 | Non-systematic Assessment |
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| Contusion | Injury, poisoning and procedural complications | MedDRA version 22.1 | Non-systematic Assessment |
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| Eye contusion | Injury, poisoning and procedural complications | MedDRA version 22.1 | Non-systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | MedDRA version 22.1 | Non-systematic Assessment |
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| Radiation skin injury | Injury, poisoning and procedural complications | MedDRA version 22.1 | Non-systematic Assessment |
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| Activated partial thromboplastin time prolonged | Investigations | MedDRA version 22.1 | Non-systematic Assessment |
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| Alanine aminotransferase increased | Investigations | MedDRA version 22.1 | Non-systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | MedDRA version 22.1 | Non-systematic Assessment |
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| Blood creatinine increased | Investigations | MedDRA version 22.1 | Non-systematic Assessment |
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| International normalised ratio increased | Investigations | MedDRA version 22.1 | Non-systematic Assessment |
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| Neutrophil count decreased | Investigations | MedDRA version 22.1 | Non-systematic Assessment |
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| Platelet count decreased | Investigations | MedDRA version 22.1 | Non-systematic Assessment |
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| Decreased appetite | Metabolism and nutrition disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Dehydration | Metabolism and nutrition disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Gout | Metabolism and nutrition disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Hyponatraemia | Metabolism and nutrition disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Flank pain | Musculoskeletal and connective tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Hypoaesthesia | Nervous system disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Peripheral sensory neuropathy | Nervous system disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Dyspareunia | Reproductive system and breast disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Haemoptysis | Respiratory, thoracic and mediastinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Productive cough | Respiratory, thoracic and mediastinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Wheezing | Respiratory, thoracic and mediastinal disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Blister | Skin and subcutaneous tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Dry skin | Skin and subcutaneous tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Erythema | Skin and subcutaneous tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Rash erythematous | Skin and subcutaneous tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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| Urticaria | Skin and subcutaneous tissue disorders | MedDRA version 22.1 | Non-systematic Assessment |
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Not provided
Not provided
| Participants with Grade >=3 AEs |
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| Participants with Serious TEAEs |
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| Participants with Death |
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| Biochemistry |
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| Pulse rate |
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| Body temperature |
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| Respiratory rate |
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| Weight |
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| Partial Response |
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| Stable Disease |
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| Progressive Disease |
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| Participant-2 |
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| Participant-3 |
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| Participant-4 |
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| Participant-5 |
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| Participant-6 |
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| Participant-7 |
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| Participant-8 |
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| Participant-9 |
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| Participant-10 |
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| Participant-11 |
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| Participant-12 |
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| Participant-13 |
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| Participant-14 |
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| Participant-15 |
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