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| Name | Class |
|---|---|
| Merck KGaA, Darmstadt, Germany | INDUSTRY |
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The purpose of this study was to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) (if reached) and early signs of efficacy of M4076 monotherapy in participants with solid tumors in dose escalation (Part 1A). Once the recommended dose for expansion (RDE) was declared in Part 1A, a preliminary food effect cohort, Part 1B, will follow at the RDE determined from Part 1A.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part 1A Dose Escalation: M4076 100 mg | Experimental | Participants received M4076 film coated tablets at a dose of 100 milligrams (mg), orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study |
|
| Part 1A Dose Escalation: M4076 200 mg | Experimental | Participants received M4076 film coated tablets at a dose of 200 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
|
| Part 1A Dose Escalation: M4076 300 mg | Experimental | Participants received M4076 film coated tablets at a dose of 300 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
|
| Part 1A Dose Escalation: M4076 400 mg | Experimental | Participants received M4076 film coated tablets at a dose of 400 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| M4076 | Drug | M4076 was administered orally. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | A DLT was defined as the occurrence of any of following events that were judged by the study investigator, received at least 80% of the planned cumulative dose during the DLT period of each study intervention and completed the DLT period or additionally, participants who did not receive 80% of the planned total dose of study intervention, but at least 80% dosing of a different dose cohort and finished the DLT period are eligible for the DLT analysis set to be analyzed in the highest dose cohort for which they received 80% of dosing. | Day 1 to Day 21 of Cycle 1 (21-day cycle) |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs | An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (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 or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. | From the first dose of study drug administration until 30 days after the last dose of study drug administration (up to 603 days) |
| Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Vital sign assessments included assessments of heart rate, diastolic blood pressure, systolic blood pressure, weight, respiratory rate and temperature. Clinical significance was assessed by the investigator. Number of participants who with clinically significant changes from baseline in vital signs were reported. | Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days) |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | Confirmed objective response was defined as the number of participants with a confirmed objective response of complete response (CR) or partial response (PR). 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. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). |
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Inclusion Criteria:
Exclusion Criteria:
Clinically significant (i.e., active) uncontrolled intercurrent illness including, but not limited to:
Has known ataxia telangiectasia
Participants with tumors harboring previously identified ATM mutations
Participants with hypersensitivity to the active substance or to any of the excipients of M4076
Other protocol defined exclusion criteria could apply
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| MD Anderson Center | Houston | Texas | 77030 | United States | ||
| NEXT Oncology |
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| Label | URL |
|---|---|
| Trial Awareness and Transparency website | View source |
| US Medical Information website, Medical Resources | View source |
| DDRiver website |
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We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website http://bit.ly/IPD21
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This study was to be conducted in 2 parts; Part 1A was the dose escalation phase and Part 1B was the expansion phase. However, the sponsor decided not to conduct the expansion phase (Part 2).
A total of 31 participants were screened, of which 22 participants received the study drug.
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| ID | Title | Description |
|---|---|---|
| FG000 | Part 1A Dose Escalation: M4076 100 mg | Participants received M4076 film coated tablets at a dose of 100 milligrams (mg), orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study |
| FG001 | Part 1A Dose Escalation: M4076 200 mg | Participants received M4076 film coated tablets at a dose of 200 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
| FG002 | Part 1A Dose Escalation: M4076 300 mg | Participants received M4076 film coated tablets at a dose of 300 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
| FG003 | Part 1A Dose Escalation: M4076 400 mg | Participants received M4076 film coated tablets at a dose of 400 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Part 1A Dose Escalation: M4076 100 mg | Participants received M4076 film coated tablets at a dose of 100 milligrams (mg), orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study |
| 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 | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | A DLT was defined as the occurrence of any of following events that were judged by the study investigator, received at least 80% of the planned cumulative dose during the DLT period of each study intervention and completed the DLT period or additionally, participants who did not receive 80% of the planned total dose of study intervention, but at least 80% dosing of a different dose cohort and finished the DLT period are eligible for the DLT analysis set to be analyzed in the highest dose cohort for which they received 80% of dosing. | Dose escalation set included all participants who received at least 80 percent (%) of the planned cumulative dose during the DLT period (Period 1) and have completed the DLT Period or experienced at least one DLT during the DLT period, regardless of administered number of doses of study intervention. | Posted | Count of Participants | Participants | Day 1 to Day 21 of Cycle 1 (21-day cycle) |
|
Up to 603 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 | Part 1A Dose Escalation: M4076 100 mg | Participants received M4076 film coated tablets at a dose of 100 milligrams (mg), orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA 25.1 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 25.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Communication Center | Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | +49-6151-72-5200 | service@emdgroup.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 27, 2022 | Jul 22, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Dec 19, 2022 | Jul 22, 2024 | SAP_001.pdf |
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| Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with change from baseline to grade 3 or higher values for the hematology and biochemistry were reported. | Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days) |
| Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Values | ECG parameters included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, QT intervals, and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically significant change from baseline in 12-lead ECG were reported. | Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days) |
| Time from first study treatment up to 603 days |
| Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: 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 first documentation of objective response to the date of first documentation of PD or death due to any cause, assessed up to 603 days |
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators | PFS is defined as the time (in months) from date of first administration of study intervention to the date of the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was to be estimated using Kaplan-Meier (KM) plots. | Time from the first dose of study intervention until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 603 days) |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076 | Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-tlast was to be calculated according to the mixed log-linear trapezoidal rule. | Day 1 and Day 8 |
| Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4076 | The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. AUC0-inf = AUC0-tlast +Clast pred/ lambda z (single dose only) | Day 1 and Day 8 |
| Maximum Observed Plasma Concentration (Cmax) of M4076 | Cmax was obtained directly from the concentration versus time curve. | Day 1 and Day 8 |
| Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM | Phosphorylated ataxia-telangiectasia mutated (p-ATM) is measured by flow cytometry and immunohistochemistry. Absolute change from baseline was to be reported. | Baseline up to Day 23 |
| Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2 | p-CHK2 is measured by flow cytometry and immunohistochemistry. Absolute change from baseline was to be reported. | Baseline up to Day 23 |
| Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM | Phosphorylated ataxia-telangiectasia mutated (p-ATM) is measured by flow cytometry and immunohistochemistry. Relative change from baseline was to be reported. | Baseline up to Day 23 |
| Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2 | p-CHK2 is measured by flow cytometry and immunohistochemistry. Relative change from baseline was to be reported. | Baseline up to Day 23 |
| Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | gamma-H2AX is measured by flow cytometry and immunohistochemistry. Absolute values were reported for each participant as descriptive data for this outcome measure was not calculated. P= Part, D=Day, H=Hour in the below mentioned categories. Mean Fluorescent Intensity (MFI) is a number generated by the flow cytometer; an instrument that measures the fluorescent signal emitted by a sample. The stronger the fluorescent signal, the higher the MFI value detected by the instrument's acquisition software. The values displayed in the system represent each MFI measurement at different time points, with the MFI value for the blank sample subtracted. | Baseline up to Day 23 |
| San Antonio |
| Texas |
| 78229 |
| United States |
| Princess Margaret Cancer Centre | Toronto | Ontario | M5G 1Z5 | Canada |
| Withdrawal by Subject |
|
| COVID-19-related and COVID-19-non-related |
|
| BG001 |
| Part 1A Dose Escalation: M4076 200 mg |
Participants received M4076 film coated tablets at a dose of 200 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
| BG002 | Part 1A Dose Escalation: M4076 300 mg | Participants received M4076 film coated tablets at a dose of 300 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
| BG003 | Part 1A Dose Escalation: M4076 400 mg | Participants received M4076 film coated tablets at a dose of 400 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
| BG004 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | Participants |
|
| OG000 | Part 1A Dose Escalation: M4076 100 mg | Participants received M4076 film coated tablets at a dose of 100 milligrams (mg), orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study |
| OG001 | Part 1A Dose Escalation: M4076 200 mg | Participants received M4076 film coated tablets at a dose of 200 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
| OG002 | Part 1A Dose Escalation: M4076 300 mg | Participants received M4076 film coated tablets at a dose of 300 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
| OG003 | Part 1A Dose Escalation: M4076 400 mg | Participants received M4076 film coated tablets at a dose of 400 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. |
|
|
| Primary | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment Related TEAEs | An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (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 or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. | Safety analysis set included all participants who were administered at least one dose of any study intervention. | Posted | Count of Participants | Participants | From the first dose of study drug administration until 30 days after the last dose of study drug administration (up to 603 days) |
|
|
|
| Primary | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Vital sign assessments included assessments of heart rate, diastolic blood pressure, systolic blood pressure, weight, respiratory rate and temperature. Clinical significance was assessed by the investigator. Number of participants who with clinically significant changes from baseline in vital signs were reported. | Safety analysis set included all participants who were administered at least one dose of any study intervention. | Posted | Count of Participants | Participants | Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days) |
|
|
|
| Primary | Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 5.0 | The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with change from baseline to grade 3 or higher values for the hematology and biochemistry were reported. | Safety analysis set included all participants who were administered at least one dose of any study intervention. | Posted | Count of Participants | Participants | Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days) |
|
|
|
| Primary | Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) Values | ECG parameters included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, QT intervals, and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically significant change from baseline in 12-lead ECG were reported. | Safety analysis set included all participants who were administered at least one dose of any study intervention. | Posted | Count of Participants | Participants | Baseline (Day 1) up to 30 days after the last dose of study drug administration (up to 603 days) |
|
|
|
| Secondary | Number of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | Confirmed objective response was defined as the number of participants with a confirmed objective response of complete response (CR) or partial response (PR). 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. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). | Full analysis set included all participants who were administered at least one dose of any study intervention. | Posted | Count of Participants | Participants | Time from first study treatment up to 603 days |
|
|
|
| Secondary | Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: 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. | None of the participants showed objective response. | Posted | Time from first documentation of objective response to the date of first documentation of PD or death due to any cause, assessed up to 603 days |
|
|
| Secondary | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators | PFS is defined as the time (in months) from date of first administration of study intervention to the date of the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was to be estimated using Kaplan-Meier (KM) plots. | Full analysis set included all participants who were administered at least one dose of any study intervention. | Posted | Median | 95% Confidence Interval | months | Time from the first dose of study intervention until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 603 days) |
|
|
|
| Secondary | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUClast) of M4076 | Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-tlast was to be calculated according to the mixed log-linear trapezoidal rule. | Pharmacokinetic Analysis Set included all participants who were administered at least one dose of study intervention. Here, "Number analyzed" signifies those participants who were evaluable for this outcome measure at specified timepoints. | Posted | Geometric Mean | Geometric Coefficient of Variation | hour*nanograms per milliliter | Day 1 and Day 8 |
|
|
|
| Secondary | Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4076 | The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. AUC0-inf = AUC0-tlast +Clast pred/ lambda z (single dose only) | Pharmacokinetic Analysis Set included all participants who were administered at least one dose of study intervention. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Day 1 and Day 8 |
|
|
|
| Secondary | Maximum Observed Plasma Concentration (Cmax) of M4076 | Cmax was obtained directly from the concentration versus time curve. | Pharmacokinetic Analysis Set included all participants who were administered at least one dose of study intervention, have no clinically important protocol deviations or important events affecting pharmacodynamics, and provide the baseline and at least one measurable pharmacodynamics endpoint post dose. Here, "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram per milliliter (ng/mL) | Day 1 and Day 8 |
|
|
|
| Secondary | Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM | Phosphorylated ataxia-telangiectasia mutated (p-ATM) is measured by flow cytometry and immunohistochemistry. Absolute change from baseline was to be reported. | Data for p-ATM was not generated due to insufficient samples as all Peripheral Blood Mononuclear Cells (PBMC) samples were exhausted in gamma-H2AX analysis. Hence no data was collected. | Posted | Baseline up to Day 23 |
|
|
| Secondary | Absolute Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2 | p-CHK2 is measured by flow cytometry and immunohistochemistry. Absolute change from baseline was to be reported. | Data for p-CHK2 was not generated as no fresh tumor biopsies were collected. Hence no data was collected. | Posted | Baseline up to Day 23 |
|
|
| Secondary | Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-ATM | Phosphorylated ataxia-telangiectasia mutated (p-ATM) is measured by flow cytometry and immunohistochemistry. Relative change from baseline was to be reported. | Data for p-ATM was not generated due to insufficient samples as all Peripheral Blood Mononuclear Cells (PBMC) samples were exhausted in gamma-H2AX analysis. Hence no data was collected. | Posted | Baseline up to Day 23 |
|
|
| Secondary | Relative Changes From Baseline in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: p-CHK2 | p-CHK2 is measured by flow cytometry and immunohistochemistry. Relative change from baseline was to be reported. | Data for p-CHK2 was not generated as no fresh tumor biopsies were collected. Hence no data was collected. | Posted | Baseline up to Day 23 |
|
|
| Secondary | Absolute Values in Ataxia-Telangiectasia Mutated (ATM) Pathway Readouts Assessed by Flow Cytometry and Immunohistochemistry: Gamma-H2AX | gamma-H2AX is measured by flow cytometry and immunohistochemistry. Absolute values were reported for each participant as descriptive data for this outcome measure was not calculated. P= Part, D=Day, H=Hour in the below mentioned categories. Mean Fluorescent Intensity (MFI) is a number generated by the flow cytometer; an instrument that measures the fluorescent signal emitted by a sample. The stronger the fluorescent signal, the higher the MFI value detected by the instrument's acquisition software. The values displayed in the system represent each MFI measurement at different time points, with the MFI value for the blank sample subtracted. | The pharmacodynamics (Pd) Analysis Set consisted of all participants, who received at least one dose of study intervention, had no clinically important protocol deviations or important events affecting Pd, and provide the baseline and at least one measurable Pd endpoint postdose. Participants will be analyzed per the actual study intervention they received. | Posted | Number | Mean fluorescence intensity | Baseline up to Day 23 |
|
|
|
| 0 |
| 2 |
| 0 |
| 2 |
| 2 |
| 2 |
| EG001 | Part 1A Dose Escalation: M4076 200 mg | Participants received M4076 film coated tablets at a dose of 200 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. | 4 | 7 | 4 | 7 | 7 | 7 |
| EG002 | Part 1A Dose Escalation: M4076 300 mg | Participants received M4076 film coated tablets at a dose of 300 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. | 1 | 9 | 2 | 9 | 9 | 9 |
| EG003 | Part 1A Dose Escalation: M4076 400 mg | Participants received M4076 film coated tablets at a dose of 400 mg, orally once daily in 21-day cycles, starting from Day 1 of each cycle disease progression, death, AE leading to discontinuation of study intervention(s), or withdrawal of consent, whichever occurred first, or End of Study. | 0 | 4 | 3 | 4 | 4 | 4 |
| Nausea | Gastrointestinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Immune system disorder | Immune system disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Enterocolitis infectious | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Liver abscess | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Spontaneous bacterial peritonitis | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Urinary tract stoma complication | Injury, poisoning and procedural complications | MedDRA 25.1 | Non-systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| Lymphocyte count decreased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Eye irritation | Eye disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Small intestinal obstruction | Gastrointestinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Gait disturbance | General disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| COVID-19 | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Cystitis | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Enterocolitis infectious | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Liver abscess | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Oral candidiasis | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Osteomyelitis | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Skin infection | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Spontaneous bacterial peritonitis | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 25.1 | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| Lymphocyte count decreased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| Neutrophil count decreased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| Platelet count decreased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| White blood cell count increased | Investigations | MedDRA 25.1 | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Squamous cell carcinoma of skin | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 25.1 | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Peripheral sensory neuropathy | Nervous system disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Confusional state | Psychiatric disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Dysuria | Renal and urinary disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Urinary tract obstruction | Renal and urinary disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA 25.1 | Non-systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 25.1 | Non-systematic Assessment |
|
Not provided
Not provided
| Treatment Related TEAEs |
|
| Grade>=3 Aspartate Aminotransferase High |
|
| Grade>=3 Alkaline Phosphatase High |
|
| Grade>=3 Gamma Glutamyl Transferase High |
|
| Grade>=3 Bilirubin High |
|
| Grade>=3 Lipase High |
|
| Grade>=3 Sodium Low |
|
| Grade>=3 Potassium High |
|
| Grade>=3 Potassium Low |
|
| Grade>=3 Calcium High |
|
| Grade>=3 Hemoglobin Low |
|
| Grade>=3 Lymphocytes Low |
|
|
| Day 8 |
|
|
|
| Day 8 |
|
|
| Day 8 |
|
|
| Title | Measurements |
|---|---|
|
| Participant1(P1AD1-Predose) |
|
| Participant1(P1AD2-2-4H Postdose) |
|
| Participant1(P1AD2-Predose) |
|
| Participant1(P1A/1BD22-2H Postdose |
|
| Participant1(P1A/1BD22-4H Postdose) |
|
| Participant1(P1A/1BD22-Predose) |
|
| Participant2(P1AD1-6H Postdose) |
|
| Participant2(P1AD2-2-4H Postdose) |
|
| Participant2(P1A/1BD22-2H Postdose) |
|
| Participant2(P1A/1BD22-Predose) |
|
| Participant3(P1AD1-2H Postdose) |
|
| Participant3(P1AD1-4H Postdose) |
|
| Participant3(P1AD2-2H-4H Postdose) |
|
| Participant3(P1AD2-4H Predose) |
|
| Participant4(P1AD1-2H Postdose) |
|
| Participant4(P1AD1-4H Potdose) |
|
| Participant4(P1AD1-6H Postdose) |
|
| Participant4(P1AD1-Predose) |
|
| Participant4(P1AD2-2H-4H Postdose) |
|
| Participant4(P1AD2-Predose) |
|
| Participant5(P1AD1-2H Postdose) |
|
| Participant5(P1AD1-4H Postdose) |
|
| Participant5(P1AD1-6H Postdose) |
|
| Participant5(P1AD1-Predose) |
|
| Participant5(P1AD2-2H-4H Postdose) |
|
| Participant5(P1AD2-Predose) |
|
| Participant6(P1AD1-2H Postdose) |
|
| Participant6(P1AD1-4H Postdose) |
|
| Participant6(P1AD1-6H Postdose) |
|
| Participant6(P1AD1-4H Predose) |
|
| Participant6(P1AD2-2H-4H Postdose) |
|
| Participant6(P1AD2- Predose) |
|
| Participant6(P1A/1BD22-2H Postdose) |
|
| Participant6(P1A/1BD22-4H Postdose) |
|
| Participant6(P1A/1BD22-Predose) |
|
| Participant7(P1A/1BD22-4H Postdose) |
|
| Participant7(P1A/1BD22-2H-4H Postdose) |
|
| Participant7(P1AD2-Predose) |
|
| Participant8(P1AD1-2H Postdose) |
|
| Participant8(P1AD1-4H Postdose) |
|
| Participant8(P1AD1-6H Postdose) |
|
| Participant8(P1AD1-Predose) |
|
| Participant8(P1AD1-2H-4H Postdose) |
|
| Participant8(Part1AD2-Predose) |
|
| Participant9(P1AD1-2H Postdose) |
|
| Participant9(P1AD1-4H Postdose) |
|
| Participant9(P1AD1-6H Postdose) |
|
| Participant9(P1AD1-Predose) |
|
| Participant9(P1AD2-2H-4H Postdose) |
|
| Participant9(P1A/1BD22-2H Postdose) |
|
| Participant9(P1A/1BD22-4H Postdose) |
|
| Participant9(P1A/1BD22-Predose) |
|
| Participant10(P1A/1BD22-2H Postdose) |
|
| Participant10(P1A/1BD22-4H Postdose) |
|
| Participant10(P1A/1BD22-Predose) |
|
| Participant10(P1AD1-2H Postdose) |
|
| Participant10(P1AD1-4H Postdose) |
|
| Participant10(P1AD1-2H-4H Postdose) |
|
| Participant10(P1AD2-Predose) |
|
| Participant11(P1AD1-2H Postdose) |
|
| Participant11(P1AD1-4H Postdose) |
|
| Participant11(P1A/1BD22-2H Postdose) |
|
| Participant11(P1A/1BD22- Predose) |
|
| Participant11(P1A/1BD22-4H Postdose) |
|
| Participant12(P1AD1-2H Postdose) |
|
| Participant12(P1AD1-Predose) |
|
| Participant12(P1AD2-2H-4H Postdose) |
|
| Participant12(P1AD2-Predose) |
|
| Participant13(P1AD2-2H-4H Postdose) |
|
| Participant13(P1AD2-Predose) |
|
| Participant13(P1A/1BD22-2H Postdose) |
|
| Participant13(P1A/1BD22-4H Postdose) |
|
| Participant13(P1A/1BD22 Predose) |
|
| Participant14(P1AD1-2H Postdose) |
|
| Participant14(P1AD1-4H Postdose) |
|
| Participant14(P1AD1-6H Postdose) |
|
| Participant14(P1AD1-Predose) |
|
| Participant14(P1AD2-2H-4H Postdose) |
|
| Participant14(P1AD2-Predose) |
|
| Participant14(P1A/1BD22-Predose) |
|
| Participant15(P1AD1-2H Postdose) |
|
| Participant15(P1AD1-4H Postdose) |
|
| Participant15(P1AD1-6H Postdose) |
|
| Participant15(P1AD1-Predose) |
|
| Participant15(P1AD2-2H-4H Postdose) |
|
| Participant15(P1AD2-2H Predose) |
|
| Participant16(P1AD1-2H Postdose) |
|
| Participant16(P1AD1-4H Postdose) |
|
| Participant16(P1AD1-6H Postdose) |
|
| Participant16(P1AD1-Predose) |
|
| Participant16(P1AD2-2H-4H Postdose) |
|
| Participant17(P1AD1-2H Postdose) |
|
| Participant17(P1AD1-4H Postdose) |
|
| Participant17(P1AD2-2H-4H Postdose) |
|
| Participant17(P1AD2-Predose) |
|
| Participant18(P1AD1-6H Postdose) |
|
| Participant18(P1AD1-Presdose) |
|
| Participant18(P1AD2-2H-4H Postdose) |
|
| Participant19(P1AD1-2H Postdose) |
|
| Participant19(P1AD1-4H Postdose) |
|
| Participant19(P1AD1-6H Postdose) |
|
| Participant19(P1AD1-Predose) |
|
| Participant19(P1AD2-2H-4H Postdose) |
|
| Participant19(P1AD2-Predose) |
|
| Participant20(P1A/1BD22-2H Postdose) |
|
| Participant20(P1AD1-2H Postdose |
|
| Participant20(P1AD1-4H Postdose |
|
| Participant20(P1AD1-6H Postdose |
|
| Participant20(P1AD1-Predose) |
|
| Participant20(P1AD2-2H-4H Postdose) |
|
| Participant20(P1AD2-Predose) |
|
| Participant21(P1AD1-2H Postdose) |
|
| Participant21(P1AD1-4H Postdose) |
|
| Participant21(P1AD1-6H Postdose) |
|
| Participant21(P1AD1 Predose) |
|
| Participant21(P1AD2-2H-4H Postdose) |
|
| Participant21(P1AD2 Predose) |
|