Brief Summary
M3814 was an investigational drug that is being evaluated for the treatment of participants with locally advanced tumors. The main purposes of this study was to determine the safety, the tolerability and the efficacy of M3814 in combination with radiotherapy and in combination with chemoradiotherapy (Radiotherapy + cisplatin).
Brief Title
Phase 1 Trial of MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Combination With Radiotherapy
Completion Date
Completion Date Type
Actual
Conditions
Advanced Solid Tumors
Eligibility Criteria
Inclusion Criteria:
* Phase Ia part: advanced solid tumors or metastases including lymphoma localized in the head and neck region or thorax with an indication for fractionated palliative RT (Arm A); or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B)
* Phase Ib part: treatment-naïve Stage III A/B NSCLC not eligible for surgical resection or concurrent chemoradiation (Arm A expansion cohort) or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B expansion cohort)
* Ancillary cPoP Part: any tumor with at least 2 (sub)cutaneous tumor/metastases at least 2 cm apart which are RT naïve with an indication for high dose palliative RT
* Availability of archival tumor material, either as a block or slides (Phase Ia and Ib). If no archival material is available then a fresh biopsy should be taken
* Willing to have tumor biopsies collected in Ancillary cPoP
* Measurable or evaluable disease by RECIST v1.1 (not required for ancillary cPoP part of the study)
* Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1
* Life expectancy of ≥ 3 months (Phase Ia, Arm A) or ≥ 6 months (Phase Ia, Arm B and Phase Ib)
* Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy.
Exclusion Criteria:
* Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anticancer therapy or investigational medicinal product (IMP) within 28 days of first trial drug intake for Phase Ia subjects, and any prior therapy for Phase Ib subjects. For subjects with rapidly growing tumors localized in the head and neck region or thorax where the treating physician cannot wait for 28 days, inclusion may take place if there is no residual toxicity from previous treatment (maximum CTCAE Grade 1)
* Prior RT to the same region within 12 months (Phase Ia, Arm A; subjects with tumors localized in the head and neck region or thorax) or at any time previously (Phase Ia, Arm B; treatment-naïve subjects with SCCHN and Phase Ib; treatment-naïve subjects with Stage III A/B NSCLC or SCCHN)
* Extensive prior RT on ≥30% of bone marrow reserve as judged by the investigator or prior bone marrow/stem cell transplantation within 5 years before trial start.
* Poor vital organ functions defined as:
* Bone marrow impairment as evidenced by hemoglobin \<10.0 g/dL, neutrophil count \<1.0 × 109/L, platelets \<100 × 109/L
* Renal impairment as evidenced by serum creatinine \>1.5 × upper limit of normal (ULN)
* Liver function abnormality as defined by total bilirubin \>1.5 × ULN or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>2.5 × ULN (except for subjects with liver involvement, who can have AST/ALT \>5 × ULN)
* History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP, use of percutaneous endoscopic gastrostomy (PEG) tubes
* Significant cardiac conduction abnormalities, including a history of long QTc syndrome and/or pacemaker, or impaired cardiovascular function such as New York Heart Association classification score \>2.
* Subjects currently receiving (or unable to stop using prior to receiving the first dose of trial drug) medications or herbal supplements known to be potent inhibitors of cytochrome P450 (CYP)3A or CYP2C19 (must stop at least 1 week prior), potent inducers of CYP3A or CYP2C19 (must stop at least 3 weeks prior), or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least one day prior).
* Subjects currently receiving H2-blocker or proton pump inhibitors (or unable to stop at least 5 days prior to the first treatment).
* If the planned radiation field includes any part of the esophagus and the subject has symptoms of ongoing esophagitis, the subject is not eligible, unless an esophageal endoscopy rules out the presence of esophagitis
* Subjects where more than 10% of the total esophagus volume receives more than 50% of the prescribed RT dose
Main exclusion criteria for Ancillary Clinical Proof-of-Principle Part:
* History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP
* History of any other significant medical disease such as major gastric or small bowel surgery, recent drainage of significant volumes of ascites or pleural effusion (as per Investigator's judgement) or a psychiatric condition that might impair the subject's well-being or preclude full participation in the trial
* Subjects currently receiving (or unable to stop using prior to receiving the first dose of study drug) medications or herbal supplements known to be potent inhibitors of CYP3A or CYP2C19 must stop at least 1 week prior to taking MSC2490484A. Subjects receiving potent inducers of CYP3A or CYP2C19 must stop at least 3 weeks prior to taking MSC2490484A. Those receiving drugs mainly metabolized by CYP3A with a narrow therapeutic index as judged by the Investigator (and after optional consultation with the Sponsor) must stop at least one day prior to taking MSC2490484A.
* Phase Ia part: advanced solid tumors or metastases including lymphoma localized in the head and neck region or thorax with an indication for fractionated palliative RT (Arm A); or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B)
* Phase Ib part: treatment-naïve Stage III A/B NSCLC not eligible for surgical resection or concurrent chemoradiation (Arm A expansion cohort) or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B expansion cohort)
* Ancillary cPoP Part: any tumor with at least 2 (sub)cutaneous tumor/metastases at least 2 cm apart which are RT naïve with an indication for high dose palliative RT
* Availability of archival tumor material, either as a block or slides (Phase Ia and Ib). If no archival material is available then a fresh biopsy should be taken
* Willing to have tumor biopsies collected in Ancillary cPoP
* Measurable or evaluable disease by RECIST v1.1 (not required for ancillary cPoP part of the study)
* Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1
* Life expectancy of ≥ 3 months (Phase Ia, Arm A) or ≥ 6 months (Phase Ia, Arm B and Phase Ib)
* Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy.
Exclusion Criteria:
* Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anticancer therapy or investigational medicinal product (IMP) within 28 days of first trial drug intake for Phase Ia subjects, and any prior therapy for Phase Ib subjects. For subjects with rapidly growing tumors localized in the head and neck region or thorax where the treating physician cannot wait for 28 days, inclusion may take place if there is no residual toxicity from previous treatment (maximum CTCAE Grade 1)
* Prior RT to the same region within 12 months (Phase Ia, Arm A; subjects with tumors localized in the head and neck region or thorax) or at any time previously (Phase Ia, Arm B; treatment-naïve subjects with SCCHN and Phase Ib; treatment-naïve subjects with Stage III A/B NSCLC or SCCHN)
* Extensive prior RT on ≥30% of bone marrow reserve as judged by the investigator or prior bone marrow/stem cell transplantation within 5 years before trial start.
* Poor vital organ functions defined as:
* Bone marrow impairment as evidenced by hemoglobin \<10.0 g/dL, neutrophil count \<1.0 × 109/L, platelets \<100 × 109/L
* Renal impairment as evidenced by serum creatinine \>1.5 × upper limit of normal (ULN)
* Liver function abnormality as defined by total bilirubin \>1.5 × ULN or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>2.5 × ULN (except for subjects with liver involvement, who can have AST/ALT \>5 × ULN)
* History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP, use of percutaneous endoscopic gastrostomy (PEG) tubes
* Significant cardiac conduction abnormalities, including a history of long QTc syndrome and/or pacemaker, or impaired cardiovascular function such as New York Heart Association classification score \>2.
* Subjects currently receiving (or unable to stop using prior to receiving the first dose of trial drug) medications or herbal supplements known to be potent inhibitors of cytochrome P450 (CYP)3A or CYP2C19 (must stop at least 1 week prior), potent inducers of CYP3A or CYP2C19 (must stop at least 3 weeks prior), or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least one day prior).
* Subjects currently receiving H2-blocker or proton pump inhibitors (or unable to stop at least 5 days prior to the first treatment).
* If the planned radiation field includes any part of the esophagus and the subject has symptoms of ongoing esophagitis, the subject is not eligible, unless an esophageal endoscopy rules out the presence of esophagitis
* Subjects where more than 10% of the total esophagus volume receives more than 50% of the prescribed RT dose
Main exclusion criteria for Ancillary Clinical Proof-of-Principle Part:
* History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP
* History of any other significant medical disease such as major gastric or small bowel surgery, recent drainage of significant volumes of ascites or pleural effusion (as per Investigator's judgement) or a psychiatric condition that might impair the subject's well-being or preclude full participation in the trial
* Subjects currently receiving (or unable to stop using prior to receiving the first dose of study drug) medications or herbal supplements known to be potent inhibitors of CYP3A or CYP2C19 must stop at least 1 week prior to taking MSC2490484A. Subjects receiving potent inducers of CYP3A or CYP2C19 must stop at least 3 weeks prior to taking MSC2490484A. Those receiving drugs mainly metabolized by CYP3A with a narrow therapeutic index as judged by the Investigator (and after optional consultation with the Sponsor) must stop at least one day prior to taking MSC2490484A.
Inclusion Criteria
Inclusion Criteria:
* Phase Ia part: advanced solid tumors or metastases including lymphoma localized in the head and neck region or thorax with an indication for fractionated palliative RT (Arm A); or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B)
* Phase Ib part: treatment-naïve Stage III A/B NSCLC not eligible for surgical resection or concurrent chemoradiation (Arm A expansion cohort) or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B expansion cohort)
* Ancillary cPoP Part: any tumor with at least 2 (sub)cutaneous tumor/metastases at least 2 cm apart which are RT naïve with an indication for high dose palliative RT
* Availability of archival tumor material, either as a block or slides (Phase Ia and Ib). If no archival material is available then a fresh biopsy should be taken
* Willing to have tumor biopsies collected in Ancillary cPoP
* Measurable or evaluable disease by RECIST v1.1 (not required for ancillary cPoP part of the study)
* Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1
* Life expectancy of ≥ 3 months (Phase Ia, Arm A) or ≥ 6 months (Phase Ia, Arm B and Phase Ib)
* Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy.
inclusion may take place if there is no residual toxicity from previous treatment (maximum CTCAE Grade 1)
* Prior RT to the same region within 12 months (Phase Ia, Arm A; subjects with tumors localized in the head and neck region or thorax) or at any time previously (Phase Ia, Arm B; treatment-naïve subjects with SCCHN and Phase Ib; treatment-naïve subjects with Stage III A/B NSCLC or SCCHN)
* Extensive prior RT on ≥30% of bone marrow reserve as judged by the investigator or prior bone marrow/stem cell transplantation within 5 years before trial start.
* Poor vital organ functions defined as:
* Bone marrow impairment as evidenced by hemoglobin \<10.0 g/dL, neutrophil count \<1.0 × 109/L, platelets \<100 × 109/L
* Renal impairment as evidenced by serum creatinine \>1.5 × upper limit of normal (ULN)
* Liver function abnormality as defined by total bilirubin \>1.5 × ULN or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>2.5 × ULN (except for subjects with liver involvement, who can have AST/ALT \>5 × ULN)
* History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP, use of percutaneous endoscopic gastrostomy (PEG) tubes
* Significant cardiac conduction abnormalities, including a history of long QTc syndrome and/or pacemaker, or impaired cardiovascular function such as New York Heart Association classification score \>2.
* Subjects currently receiving (or unable to stop using prior to receiving the first dose of trial drug) medications or herbal supplements known to be potent inhibitors of cytochrome P450 (CYP)3A or CYP2C19 (must stop at least 1 week prior), potent inducers of CYP3A or CYP2C19 (must stop at least 3 weeks prior), or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least one day prior).
* Subjects currently receiving H2-blocker or proton pump inhibitors (or unable to stop at least 5 days prior to the first treatment).
* If the planned radiation field includes any part of the esophagus and the subject has symptoms of ongoing esophagitis, the subject is not eligible, unless an esophageal endoscopy rules out the presence of esophagitis
* Subjects where more than 10% of the total esophagus volume receives more than 50% of the prescribed RT dose
* Phase Ia part: advanced solid tumors or metastases including lymphoma localized in the head and neck region or thorax with an indication for fractionated palliative RT (Arm A); or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B)
* Phase Ib part: treatment-naïve Stage III A/B NSCLC not eligible for surgical resection or concurrent chemoradiation (Arm A expansion cohort) or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B expansion cohort)
* Ancillary cPoP Part: any tumor with at least 2 (sub)cutaneous tumor/metastases at least 2 cm apart which are RT naïve with an indication for high dose palliative RT
* Availability of archival tumor material, either as a block or slides (Phase Ia and Ib). If no archival material is available then a fresh biopsy should be taken
* Willing to have tumor biopsies collected in Ancillary cPoP
* Measurable or evaluable disease by RECIST v1.1 (not required for ancillary cPoP part of the study)
* Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1
* Life expectancy of ≥ 3 months (Phase Ia, Arm A) or ≥ 6 months (Phase Ia, Arm B and Phase Ib)
* Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy.
inclusion may take place if there is no residual toxicity from previous treatment (maximum CTCAE Grade 1)
* Prior RT to the same region within 12 months (Phase Ia, Arm A; subjects with tumors localized in the head and neck region or thorax) or at any time previously (Phase Ia, Arm B; treatment-naïve subjects with SCCHN and Phase Ib; treatment-naïve subjects with Stage III A/B NSCLC or SCCHN)
* Extensive prior RT on ≥30% of bone marrow reserve as judged by the investigator or prior bone marrow/stem cell transplantation within 5 years before trial start.
* Poor vital organ functions defined as:
* Bone marrow impairment as evidenced by hemoglobin \<10.0 g/dL, neutrophil count \<1.0 × 109/L, platelets \<100 × 109/L
* Renal impairment as evidenced by serum creatinine \>1.5 × upper limit of normal (ULN)
* Liver function abnormality as defined by total bilirubin \>1.5 × ULN or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>2.5 × ULN (except for subjects with liver involvement, who can have AST/ALT \>5 × ULN)
* History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP, use of percutaneous endoscopic gastrostomy (PEG) tubes
* Significant cardiac conduction abnormalities, including a history of long QTc syndrome and/or pacemaker, or impaired cardiovascular function such as New York Heart Association classification score \>2.
* Subjects currently receiving (or unable to stop using prior to receiving the first dose of trial drug) medications or herbal supplements known to be potent inhibitors of cytochrome P450 (CYP)3A or CYP2C19 (must stop at least 1 week prior), potent inducers of CYP3A or CYP2C19 (must stop at least 3 weeks prior), or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least one day prior).
* Subjects currently receiving H2-blocker or proton pump inhibitors (or unable to stop at least 5 days prior to the first treatment).
* If the planned radiation field includes any part of the esophagus and the subject has symptoms of ongoing esophagitis, the subject is not eligible, unless an esophageal endoscopy rules out the presence of esophagitis
* Subjects where more than 10% of the total esophagus volume receives more than 50% of the prescribed RT dose
Gender
All
Gender Based
false
Keywords
M3814
Advanced solid tumors
DNA-PK Inhibitor
Radiotherapy
Chemotherapy
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02516813
Org Class
Industry
Org Full Name
EMD Serono
Org Study Id
100036-002
Overall Status
Completed
Phases
Phase 1
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
An Open Label, Phase Ia/Ib Trial of the DNA-PK Inhibitor MSC2490484A in Combination With Radiotherapy in Patients With Advanced Solid Tumors
Primary Outcomes
Outcome Description
DLT: any Grade (Gr) greater than or equal to (\>=) 3 nonhematologic adverse event (AE)/any Gr\>=4 hematologic AE that is related to any of study treatments and occurs during the DLT period of 5 weeks (Phase Ia, Arm A) after the first dose of M3814. Following are considered as DLTs: Gr3 thrombocytopenia with medically concerning bleeding; Febrile neutropenia; Any toxicity/study treatment-related adverse event (TEAE) that, in opinion of Safety Monitoring Committee (SMC), is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any toxicity related to study treatments that causes participant to receive less than 80 percent (%) of the planned RT dose; Evidence of study treatment-related hepatocellular injury for \> 3 days.
Outcome Measure
Phase 1a (Arm A): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
Outcome Time Frame
Time from first dose of study treatment up to 5 weeks
Outcome Description
DLT: any Grade (Gr) greater than or equal to (\>=) 3 nonhematologic AE/any Gr\>=4 hematologic AE that is related to any of study treatments and occurs during the DLT period of 12 weeks (Phase Ia, Arm B) after the first dose of M3814. Following are considered as DLTs: Gr3 thrombocytopenia with medically concerning bleeding; Febrile neutropenia; Any toxicity/study treatment-related adverse event (TEAE) that, in opinion of Safety Monitoring Committee (SMC), is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any toxicity related to study treatments that causes participant to receive less than 80 percent (%) of the planned RT dose; Any toxicity related to study treatments leading to an interruption of RT longer than 1 week in Arm B; Evidence of study treatment-related hepatocellular injury for \> 3 days.
Outcome Measure
Phase 1a (Arm B): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
Outcome Time Frame
Time from first dose of study treatment up to 12 weeks
Secondary Ids
Secondary Id
2015-000673-12
Secondary Outcomes
Outcome Description
Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily have a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious AEs and non-serious AEs. As per NCI-CTCAE v4.03, Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Number of participants with Grade \>=3 TEAEs were reported.
Outcome Time Frame
Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
Outcome Measure
Phase 1a (Arm A and Arm B): Number of Participants With Grade Greater Than or Equal to (>=) 3 Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
Outcome Description
Number of participants with shifts from Baseline values (Grade 0/1/2) to worst post-baseline values (Grade 1/2/3/4) were reported as per NCI-CTCAE, v4.03 graded from Grade 1 to 5. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Shifts in hematology parameter (hemoglobin low, leukocytes low, lymphocytes low, neutrophil count decreased, and platelet count decreased) were reported.
Outcome Time Frame
Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
Outcome Measure
Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Baseline to Worst Post-Baseline Grade in Hematology Parameters According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTC v4.03)
Outcome Description
Number of participants with shifts from Baseline values (Grade 0/1/2) to worst post-baseline values (Grade 1/2/3/4) were reported as per NCI-CTCAE, v4.03 graded from Grade 1 to 5. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Shifts in biochemistry parameter (phosphate low, potassium low, sodium low, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, blood bilirubin increased, glucose high, glucose low, albumin low and creatinine increased) were reported.
Outcome Time Frame
Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
Outcome Measure
Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Baseline to Worst Post-Baseline Grade in Biochemistry Parameters According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
Outcome Description
Vital sign assessments included assessments of heart rate, blood pressure, body weight and body temperature. Abnormal vital sign measurement was decided by Investigator. Number of participants with markedly abnormal vital sign measurements were reported.
Outcome Time Frame
Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
Outcome Measure
Phase 1a (Arm A and Arm B): Number of Participants With Markedly Abnormal Vital Sign Measurements
Outcome Description
Electrocardiograms (ECG) was obtained after the participant has been in a supine position for at least 5 minutes. ECG parameters included heart rate, atrial ventricular conduction, QR and QT intervals (including QTcF), and possible arrhythmias. Any ECG finding that was judged by the investigator as a abnormal (worsening) compared with a baseline value was considered an adverse event. Number of participants with shifts from normal baseline values to abnormal post-baseline values in ECG were reported.
Outcome Time Frame
Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
Outcome Measure
Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Normal Baseline to Abnormal Post-baseline in Electrocardiogram (ECG)
Outcome Description
Confirmed BOR was defined as best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) 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: defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. CR or PR must be confirmed by a subsequent tumor assessment, at least 4 weeks after initial documentation of CR or PR.
Outcome Time Frame
Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
Outcome Measure
Phase 1a (Arm A and Arm B): Number of Participants With Confirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
Outcome Description
Unconfirmed BOR was defined as unconfirmed best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) 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: defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Outcome Time Frame
Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
Outcome Measure
Phase 1a (Arm A and Arm B): Number of Participants With Unconfirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
Outcome Description
The tumor size was defined as the sum of the longest diameters for the target lesions. The sum of lesion diameters was calculated using RECIST v1.1 and was assessed by Investigator.
Outcome Time Frame
Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
Outcome Measure
Phase 1a (Arm A and Arm B): Median Percent Change From Baseline in Tumor Size Measurement According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
Outcome Description
Cmax was taken directly from the observed concentration-time curve.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
Outcome Measure
Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose
Outcome Description
tmax was obtained directly from the concentration versus time curve.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
Outcome Measure
Phase 1a (Arm A and Arm B): Time to Reach Maximum Plasma Concentration (Tmax) of M3814 After Single Dose
Outcome Description
AUC0-24 of M3814 was defined as the area under the concentration time curve from time 0 to 24 hours post-dose.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Fraction Day 1 and Fraction Day 6
Outcome Measure
Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose
Outcome Description
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 the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
Outcome Measure
Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose
Outcome Description
t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
Outcome Measure
Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose
Outcome Description
The apparent total body clearance of study intervention following extravascular administration on FD1, taking into account the fraction of dose absorbed. CL/f = Dose oral (p.o.)/AUC0-inf. The predicted AUC0-inf should be used.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
Outcome Measure
Phase 1a (Arm A and Arm B): Total Body Clearance Following Oral Administration (CL/f) of M3814 After Single Dose
Outcome Description
Apparent volume of distribution during the terminal phase following extravascular administration for M8891 was calculated. Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. 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. AUC(0- inf)=AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
Outcome Measure
Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose
Outcome Description
Cmax was taken directly from the observed concentration-time curve.
Outcome Time Frame
Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
Outcome Measure
Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose
Outcome Description
tmax was obtained directly from the concentration versus time curve.
Outcome Time Frame
Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
Outcome Measure
Phase 1a (Arm A and Arm B): Time to Reach Maximum Plasma Concentration (Tmax) of M3814 After Multiple Dose
Outcome Description
AUCtau was defined as area under the plasma concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.
Outcome Time Frame
Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
Outcome Measure
Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUCtau) of M3814 After Multiple Dosing
Outcome Description
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 the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
Outcome Time Frame
Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
Outcome Measure
Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose
Outcome Description
t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.
Outcome Time Frame
Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
Outcome Measure
Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose
Outcome Description
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Outcome Time Frame
Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
Outcome Measure
Phase 1a (Arm A and Arm B): Oral Clearance in Plasma at Steady State (CLss/f) of M3814 After Multiple Dose
Outcome Description
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.
Outcome Time Frame
Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
Outcome Measure
Phase 1a (Arm A and Arm B): Apparent Volume of Distribution at Steady-State (Vss/f) of M3814 After Multiple Dose
Outcome Description
Accumulation ratio for AUC was calculated as AUC, after dosing on fraction Day 10 divided by AUC, after dosing on fraction Day 1 of cycle 1.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4 and 24 hours post-dose on Fraction Day 1 and Fraction Day 10
Outcome Measure
Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose
Outcome Description
Accumulation ratio for Cmax was calculated as Cmax, after dosing on fraction Day 10 divided by Cmax, after dosing on fraction Day 1 of cycle 1.
Outcome Time Frame
Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 1 and Fraction Day 10
Outcome Measure
Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose
Outcome Description
Cmax was taken directly from the observed concentration-time curve.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2
Outcome Measure
Ancillary cPoP: Maximum Observed Plasma Concentration (Cmax) of M3814
Outcome Description
tmax was obtained directly from the concentration versus time curve.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2
Outcome Measure
Ancillary cPoP: Time to Reach Maximum Plasma Concentration (Tmax) of M3814
Outcome Description
AUC0-4hr is the area under the plasma concentration-time curve from time 0 to 4 hours post-dose. This is a measure of the average amount of study drug M3814 in the blood plasma over a period of 4 hours after the dose.
Outcome Time Frame
Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 2
Outcome Measure
Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) of M3814
Outcome Description
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-t was to be calculated according to the mixed log-linear trapezoidal rule.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2
Outcome Measure
Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of M3814
Outcome Description
AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose.
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2
Outcome Measure
Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M3814
Outcome Description
AUC0-4/Dose was defined as AUC from time of dosing to the time zero to 4 hours divided by dose.
Outcome Time Frame
Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 2
Outcome Measure
Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 4 Hours (AUC0-4)/Dose of M3814
Outcome Description
Cmax/Dose was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose. Cmax/dose was measured in nanogram per milliliter per milligram (ng/mL/mg).
Outcome Time Frame
Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2
Outcome Measure
Ancillary cPoP: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3814
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Sanjay Goel
Investigator Email
sgoel@montefiore.org
Investigator Phone
718-405-8404
MeSH Terms
PEPOSERTIB
CISPLATIN
CHLORINE COMPOUNDS
INORGANIC CHEMICALS
NITROGEN COMPOUNDS
PLATINUM COMPOUNDS