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| ID | Type | Description | Link |
|---|---|---|---|
| 2012-002562-12 | EudraCT Number |
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This is a Phase 1, open-label, single centered trial to evaluate the mass balance, bioavailability and metabolism of pimasertib in cancer subjects with locally advanced or metastatic solid tumors.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pimasertib | Experimental |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pimasertib | Drug | Part A: Subjects will receive unlabeled pimasertib capsules orally at a single dose of 60 milligram (mg) on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kilobecquerel (kBq) [14C] pimasertib will be administered as a bolus injection. On Days 3-21 (except Day 8), subjects will receive unlabeled pimasertib capsules orally at a dose of 60 mg twice daily (BID). In the morning of Day 8, subjects will receive 60 mg unlabeled pimasertib capsules spiked with a dose of 2.6 megabecquerel (MBq) (70 microcuries [mcgCi]) of [14C] pimasertib orally. In the evening of Day 8, subjects will receive the evening dose of 60 mg pimasertib as unlabeled pimasertib capsules orally. Part B : Subjects will be administered with 60 mg BID unlabeled pimasertib as oral capsules continuously in cycles of 21 days until progression of the disease, unacceptable toxicity, withdrawal of consent by the subject, loss to follow-up or death. |
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time Point (AUC0-t) of [14C]-Pimasertib Following Intravenous (IV) Administration on Day 1 | Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1 | |
| Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time Point (AUC0-t) of Pimasertib Following Oral Administration on Day 1 | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1 | |
| Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of [14C]-Pimasertib Following IV Administration on Day 1 | Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1 | |
| Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib Following Oral Administration on Day 1 | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1 | |
| Oral Bioavailability of Pimasertib After Single Oral Dose of Unlabeled Pimasertib and Intravenous (IV) Single Tracer Dose of [14C] Pimasertib | Oral bioavailability (F) was calculated using the formula=AUC0-inf oral/dose oral) / (AUC0-inf iv/dose iv) * 100%, where AUC0-inf is the area under the concentration time curve (AUC) from time zero to infinity. | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] labeled pimasertib dose on Day 1 |
| Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t) |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Unlabeled Pimasertib | Pre-dose 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1 | |
| Maximum Observed Plasma Concentration (Cmax) of Intravenous [14C] Pimasertib |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck Serono SA, an affiliate of Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Budapest | Hungary |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27934635 | Result | Scheible H, Kraetzer F, Marx A, Johne A, Wimmer E. Metabolism of the MEK1/2 Inhibitor Pimasertib Involves a Novel Conjugation with Phosphoethanolamine in Patients with Solid Tumors. Drug Metab Dispos. 2017 Feb;45(2):174-182. doi: 10.1124/dmd.116.072934. Epub 2016 Dec 1. | |
| 27483391 | Derived | von Richter O, Massimini G, Scheible H, Udvaros I, Johne A. Pimasertib, a selective oral MEK1/2 inhibitor: absolute bioavailability, mass balance, elimination route, and metabolite profile in cancer patients. Br J Clin Pharmacol. 2016 Dec;82(6):1498-1508. doi: 10.1111/bcp.13078. Epub 2016 Sep 19. |
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A total of 11 male subjects with locally advanced or metastatic solid cancer were screened for this trial. Six (6) subjects were enrolled and received the trial medication. Of them, 5 subjects completed Part A and further continued in Part B and completed the study.
First/last subject (informed consent): Nov 2012/Apr 2013. Clinical data cutoff: Jun 2013, Study completion date: Jul 2014 (Part B)
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| ID | Title | Description |
|---|---|---|
| FG000 | Pimasertib | Part A: Subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 milligram (mg) on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kilobecquerel (kBq) [14C] pimasertib was administered as a bolus injection. On Days 3-21 (except Day 8), subjects received unlabeled pimasertib capsules orally at a dose of 60 mg twice daily (BID). In the morning of Day 8, subjects received 60 mg unlabeled pimasertib capsules spiked with a dose of 2.6 megabecquerel (MBq) (70 microcuries [mcgCi]) of [14C] pimasertib orally. In the evening of Day 8, subjects received the evening dose of 60 mg pimasertib as unlabeled pimasertib capsules orally. Part B : Subjects were administered with 60 mg BID unlabeled pimasertib as oral capsules continuously in cycles of 21 days until progression of the disease, unacceptable toxicity, withdrawal of consent by the subject, loss to follow-up or death. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Safety analysis set included all subjects who received at least one administration of trial medication and had at least one subsequent safety assessment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Pimasertib | Part A: Subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq [14C] pimasertib was administered as a bolus injection. On Days 3-21 (except Day 8), subjects received unlabeled pimasertib capsules orally at a dose of 60 mg twice daily (BID). In the morning of Day 8, subjects received 60 mg unlabeled pimasertib capsules spiked with a dose of 2.6 MBq (70 mcgCi) of [14C] pimasertib orally. In the evening of Day 8, subjects received the evening dose of 60 mg pimasertib as unlabeled pimasertib capsules orally. Part B: Subjects were administered with 60 mg BID unlabeled pimasertib as oral capsules continuously in cycles of 21 days until progression of the disease, unacceptable toxicity, withdrawal of consent by the subject, loss to follow-up or death. |
| Units | Counts |
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| Participants |
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| 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 | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time Point (AUC0-t) of [14C]-Pimasertib Following Intravenous (IV) Administration on Day 1 | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | hour*picogram equivalent/milliliter | Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1 |
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Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
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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 | Pimasertib | Part A: Subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the IV tracer dose of 9 kBq [14C] pimasertib was administered as a bolus injection. On Days 3-21 (except Day 8), subjects received unlabeled pimasertib capsules orally at a dose of 60 mg twice daily (BID). In the morning of Day 8, subjects received 60 mg unlabeled pimasertib capsules spiked with a dose of 2.6 MBq (70 μCi) of [14C] pimasertib orally. In the evening of Day 8, subjects received the evening dose of 60 mg pimasertib as unlabeled pimasertib capsules orally. Part B: Subjects were administered with 60 mg BID unlabeled pimasertib as oral capsules continuously in cycles of 21 days until progression of the disease, unacceptable toxicity, withdrawal of consent by the subject, loss to follow-up or death. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bronchopneumonia | Infections and infestations | MedDRA (18.0) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Merck KGaA Communication Center | Merck KGaA | +49-6151-72-5200 | service@merckgroup.com |
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| ID | Term |
|---|---|
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| C550600 | N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide |
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Recovery of total [14C]-radioactivity was determined in excreta, i.e., urine and feces at each sampling period subsequent to oral administration of [14C]-pimasertib on Day 8. Cumulative recovery of total [14C]-radioactivity in terms of percentage of dose recovered in urine and feces and total percentage of dose recovered was reported for the outcome measure. |
| Urine: 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours post [14C]-labeled pimasertib dose on Day 8; Feces: 0-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours post [14C]-labeled pimasertib dose on Day 8 |
| Plasma Concentrations of [14C] Pimasertib | Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8 |
| Plasma Concentrations of Pimasertib Metabolites | Plasma concentration of the Pimasertib metabolite M445 and M554 were presented for the outcome measure. | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
| Number of Metabolites Identified Overall and as Major | Identification and profiling of the metabolites was done. The total number of metabolites and the number of metabolites identified as major were reported. | Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8 |
| Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1 |
| Time to Reach Maximum Plasma Concentration (Tmax) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib | Pre-dose 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1 |
| Apparent Terminal Elimination Rate Constant (λz) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib | Apparent terminal elimination rate constant (λz) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1 |
| Total Body Clearance of Unlabeled Pimasertib (CL/f) and Intravenous [14C] Pimasertib (CL) | The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the Dose with area under the plasma concentration time curve from time zero to infinity (AUC0 inf)=Dose/AUC0- inf. | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1 |
| The Volume of Distribution of the Central or Plasma Compartment (Vc) of Intravenous [14C] Pimasertib | The volume of distribution of the central or plasma compartment (Vc) was calculated using the formula=Dose/C0 | Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] pimasertib dose on Day 1 |
| Apparent Volume of Distribution During the Terminal Phase Following Oral Administration (Vz/f) and the Apparent Volume of Distribution During the Terminal Phase Following Intravenous Administration (Vz) of [14C] Pimasertib | The apparent volume of distribution during the terminal phase following oral administration (Vz/f) and the apparent volume of distribution during the terminal phase following intravenous administration was calculated by using the formula=Dose/( AUC0-inf* λz). | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] labeled pimasertib dose on Day 1 |
| Maximum Observed Plasma Concentration (Cmax) of Total [14C] Radioactivity | Unit of assessment was nanogram equivalent per milliliter (ng eq/mL). | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
| Time to Reach Maximum Plasma Concentration (Tmax) of Total [14C] Radioactivity | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
| Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Total [14C] Radioactivity | Area under the plasma concentration time curve from time zero to the last sampling time at which the concentration is at or above the lower limit of quantification was calculated by using mixed log linear trapezoidal rule. Unit of assessment was hour*nanogram equivalent per milliliter (hr*ng eq/mL). | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Total [14C] Radioactivity | Area under the concentration time curve (AUC) from time zero to infinity (AUC0-inf) was calculated from AUC0-t + AUCextra, where AUCextra = Clast calc/λz. Clast calc was the calculated plasma concentration at the last sampling time point at which plasma concentration was at or above the lower limit of quantification was measured and λz represents apparent terminal elimination rate constant. | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
| Apparent Terminal Elimination Rate Constant (λz) of Total [14C] Radioactivity | λz of total [14C] radioactivity was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
| Apparent Terminal Half-life (t1/2) of Total [14C] Radioactivity | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
| Total Body Clearance of Total [14C] Radioactivity From Plasma Following Oral Administration (CL/f) | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/f was influenced by the fraction absorbed. Apparent body clearance of total radioactivity from plasma was calculated by dividing the dose with area under the plasma concentration time curve from zero to infinity (Dose/AUC0inf). | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
| Apparent Volume of Distribution of Total [14C] Radioactivity During the Terminal Phase Following Oral Administration (Vz/f) | 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. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Vz/f of total radioactivity during the terminal phase was calculated by dividing the dose with the product of area under the plasma concentration time curve and apparent terminal rate constant (dose/AUC0inf*λz). | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
| Maximum Observed Plasma Concentration (Cmax) of M445 and M554 | Maximum observed plasma concentration (Cmax) for the metabolites M445 and M554 was calculated. | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
| Time to Reach Maximum Plasma Concentration (Tmax) of M445 and M554 | Time to reach maximum plasma concentration (Tmax) for the metabolites M445 and M554 was calculated. | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M445 and M554 | Area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) at which the concentration is at or above the lower limit of quantification. | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M445 and M554 | AUC from time 0 to infinity (AUC0-inf), was calculated from AUC0-t + AUCextra, where AUCextra = Clast calc/lambda z (λz). Clast calc was the calculated plasma concentration at the last sampling time point at which plasma concentration was at or above the lower limit of quantification was measured and λz represents apparent terminal elimination rate constant. | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
| Apparent Terminal Elimination Rate Constant (λz) of M445 and M554 | The λz of M445 and M554 was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
| Apparent Terminal Half-life (t1/2) of M445 and M554 | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
| Fraction Unbound of [14C] Pimasertib | Fraction of unbound drug (fu) is defined as the ratio of unbound drug concentration to the total drug concentration multiplied by 100. | 1.5 hour post [14C]-labeled pimasertib dose on Day 8 |
| Blood/ Plasma Concentration Ratios of Total [14C] Radioactivity | 1.5 hour post [14C]-labeled pimasertib dose on Day 8 |
| Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) | Anti tumor activity defined as CR, PR, or stable disease and PD based on the investigator tumor evaluations performed every 2 cycles in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. CR =Disappearance of all target lesions except lymph nodes (LN); LN must have a decrease in the short axis to less than (<)10 millimeter (mm); PR = 30% decrease in sum of diameters of target lesions taking as reference the baseline sum diameters; Progressed Disease (PD) = 20% increase in sum of diameters of target lesions; the appearance of >=1 new lesions; SD= Neither shrinkage to qualify for PR nor increase to qualify for PD taking the smallest sum diameters on study as reference. For non-target lesions a CR = Disappearance of all non-target lesions and all LN must be non-pathological in size <10 mm; Non-CR/Non PD: persistence of one or more non-target lesions; PD = unequivocal progression of existing non-target lesions or appearance of new ones. | From the screening every 2 cycles until end of the treatment, assessed up to 18 months |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug administration until 30+/-2 days after the last dose of study drug administration that were absent before treatment or that worsened relative to pre treatment state. | Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months |
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| Sex: Female, Male | Count of Participants | Participants |
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| Primary | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time Point (AUC0-t) of Pimasertib Following Oral Administration on Day 1 | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | hour*nanogram/milliliter | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1 |
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| Primary | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of [14C]-Pimasertib Following IV Administration on Day 1 | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | hour*picogram equivalent/milliliter | Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1 |
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| Primary | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib Following Oral Administration on Day 1 | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | hour*nanogram/milliliter | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1 |
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| Primary | Oral Bioavailability of Pimasertib After Single Oral Dose of Unlabeled Pimasertib and Intravenous (IV) Single Tracer Dose of [14C] Pimasertib | Oral bioavailability (F) was calculated using the formula=AUC0-inf oral/dose oral) / (AUC0-inf iv/dose iv) * 100%, where AUC0-inf is the area under the concentration time curve (AUC) from time zero to infinity. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with investigational medicinal product (IMP) intake for the complete Part A. | Posted | Number | 90% Confidence Interval | percentage bioavailability | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] labeled pimasertib dose on Day 1 |
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| Primary | Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t) | Recovery of total [14C]-radioactivity was determined in excreta, i.e., urine and feces at each sampling period subsequent to oral administration of [14C]-pimasertib on Day 8. Cumulative recovery of total [14C]-radioactivity in terms of percentage of dose recovered in urine and feces and total percentage of dose recovered was reported for the outcome measure. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | Full Range | percentage of dose recovered | Urine: 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours post [14C]-labeled pimasertib dose on Day 8; Feces: 0-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours post [14C]-labeled pimasertib dose on Day 8 |
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| Primary | Plasma Concentrations of [14C] Pimasertib | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Mean | Standard Deviation | nanogram equivalent per milliliter | Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8 |
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| Primary | Plasma Concentrations of Pimasertib Metabolites | Plasma concentration of the Pimasertib metabolite M445 and M554 were presented for the outcome measure. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. Here 'n' is the number of subjects analysed at each time point. | Posted | Mean | Standard Deviation | Nanogram equivalent per milliliter | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
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| Primary | Number of Metabolites Identified Overall and as Major | Identification and profiling of the metabolites was done. The total number of metabolites and the number of metabolites identified as major were reported. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Number | metabolites | Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8 |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) of Unlabeled Pimasertib | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | ng/mL | Pre-dose 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1 |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) of Intravenous [14C] Pimasertib | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | picogram equivalent per milliliter | Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1 |
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| Secondary | Time to Reach Maximum Plasma Concentration (Tmax) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Median | Full Range | hours | Pre-dose 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1 |
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| Secondary | Apparent Terminal Elimination Rate Constant (λz) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib | Apparent terminal elimination rate constant (λz) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | per hour | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1 |
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| Secondary | Total Body Clearance of Unlabeled Pimasertib (CL/f) and Intravenous [14C] Pimasertib (CL) | The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the Dose with area under the plasma concentration time curve from time zero to infinity (AUC0 inf)=Dose/AUC0- inf. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | liter per hour | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1 |
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| Secondary | The Volume of Distribution of the Central or Plasma Compartment (Vc) of Intravenous [14C] Pimasertib | The volume of distribution of the central or plasma compartment (Vc) was calculated using the formula=Dose/C0 | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | Liter | Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] pimasertib dose on Day 1 |
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| Secondary | Apparent Volume of Distribution During the Terminal Phase Following Oral Administration (Vz/f) and the Apparent Volume of Distribution During the Terminal Phase Following Intravenous Administration (Vz) of [14C] Pimasertib | The apparent volume of distribution during the terminal phase following oral administration (Vz/f) and the apparent volume of distribution during the terminal phase following intravenous administration was calculated by using the formula=Dose/( AUC0-inf* λz). | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | Liter | Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] labeled pimasertib dose on Day 1 |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) of Total [14C] Radioactivity | Unit of assessment was nanogram equivalent per milliliter (ng eq/mL). | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | ng eq/mL | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Time to Reach Maximum Plasma Concentration (Tmax) of Total [14C] Radioactivity | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Median | Full Range | hour | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Total [14C] Radioactivity | Area under the plasma concentration time curve from time zero to the last sampling time at which the concentration is at or above the lower limit of quantification was calculated by using mixed log linear trapezoidal rule. Unit of assessment was hour*nanogram equivalent per milliliter (hr*ng eq/mL). | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | hr*ng eq/mL | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Total [14C] Radioactivity | Area under the concentration time curve (AUC) from time zero to infinity (AUC0-inf) was calculated from AUC0-t + AUCextra, where AUCextra = Clast calc/λz. Clast calc was the calculated plasma concentration at the last sampling time point at which plasma concentration was at or above the lower limit of quantification was measured and λz represents apparent terminal elimination rate constant. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | hr*ng eq/mL | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Apparent Terminal Elimination Rate Constant (λz) of Total [14C] Radioactivity | λz of total [14C] radioactivity was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | per hour | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Apparent Terminal Half-life (t1/2) of Total [14C] Radioactivity | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Median | Full Range | hour | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Total Body Clearance of Total [14C] Radioactivity From Plasma Following Oral Administration (CL/f) | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/f was influenced by the fraction absorbed. Apparent body clearance of total radioactivity from plasma was calculated by dividing the dose with area under the plasma concentration time curve from zero to infinity (Dose/AUC0inf). | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | liter per hour | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Apparent Volume of Distribution of Total [14C] Radioactivity During the Terminal Phase Following Oral Administration (Vz/f) | 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. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Vz/f of total radioactivity during the terminal phase was calculated by dividing the dose with the product of area under the plasma concentration time curve and apparent terminal rate constant (dose/AUC0inf*λz). | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | Liter | Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) of M445 and M554 | Maximum observed plasma concentration (Cmax) for the metabolites M445 and M554 was calculated. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | Nanogram equivalent per milliliter | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Time to Reach Maximum Plasma Concentration (Tmax) of M445 and M554 | Time to reach maximum plasma concentration (Tmax) for the metabolites M445 and M554 was calculated. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Median | Full Range | hour | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M445 and M554 | Area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) at which the concentration is at or above the lower limit of quantification. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | hr*ng eq/mL | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M445 and M554 | AUC from time 0 to infinity (AUC0-inf), was calculated from AUC0-t + AUCextra, where AUCextra = Clast calc/lambda z (λz). Clast calc was the calculated plasma concentration at the last sampling time point at which plasma concentration was at or above the lower limit of quantification was measured and λz represents apparent terminal elimination rate constant. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | hr*ng eq/mL | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Apparent Terminal Elimination Rate Constant (λz) of M445 and M554 | The λz of M445 and M554 was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Geometric Mean | 95% Confidence Interval | per hour | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Apparent Terminal Half-life (t1/2) of M445 and M554 | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Median | Full Range | hour | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Fraction Unbound of [14C] Pimasertib | Fraction of unbound drug (fu) is defined as the ratio of unbound drug concentration to the total drug concentration multiplied by 100. | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Mean | Standard Deviation | percentage of unbound drug | 1.5 hour post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Blood/ Plasma Concentration Ratios of Total [14C] Radioactivity | The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. | Posted | Mean | Standard Deviation | Ratio | 1.5 hour post [14C]-labeled pimasertib dose on Day 8 |
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| Secondary | Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) | Anti tumor activity defined as CR, PR, or stable disease and PD based on the investigator tumor evaluations performed every 2 cycles in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. CR =Disappearance of all target lesions except lymph nodes (LN); LN must have a decrease in the short axis to less than (<)10 millimeter (mm); PR = 30% decrease in sum of diameters of target lesions taking as reference the baseline sum diameters; Progressed Disease (PD) = 20% increase in sum of diameters of target lesions; the appearance of >=1 new lesions; SD= Neither shrinkage to qualify for PR nor increase to qualify for PD taking the smallest sum diameters on study as reference. For non-target lesions a CR = Disappearance of all non-target lesions and all LN must be non-pathological in size <10 mm; Non-CR/Non PD: persistence of one or more non-target lesions; PD = unequivocal progression of existing non-target lesions or appearance of new ones. | Safety analysis set included all subjects who received at least one administration of trial medication and had at least one subsequent safety assessment. | Posted | Number | subjects | From the screening every 2 cycles until end of the treatment, assessed up to 18 months |
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| Secondary | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug administration until 30+/-2 days after the last dose of study drug administration that were absent before treatment or that worsened relative to pre treatment state. | The safety analysis set included all subjects who received at least one administration of trial medication and have at least one subsequent safety assessment. | Posted | Number | subjects | Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months |
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| 2 |
| 6 |
| 6 |
| 6 |
| Diarrhoea | Gastrointestinal disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Pyrexia | General disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Stomatitis | Gastrointestinal disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Ascites | Gastrointestinal disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Retinal detachment | Eye disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Eyelid oedema | Eye disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Retinal exudates | Eye disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Retinal haemorrhage | Eye disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Hypochromic anaemia | Blood and lymphatic system disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Supraventricular tachycardia | Cardiac disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Pyrexia | General disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Face oedema | General disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Oedema peripheral | General disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Bacteriuria | Infections and infestations | MedDRA (18.0) | Non-systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA (18.0) | Non-systematic Assessment |
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| Conjunctivitis | Infections and infestations | MedDRA (18.0) | Non-systematic Assessment |
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| Pharyngitis | Infections and infestations | MedDRA (18.0) | Non-systematic Assessment |
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| Blood creatine phosphokinase increased | Investigations | MedDRA (18.0) | Non-systematic Assessment |
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| Blood lactate dehydrogenase increased | Investigations | MedDRA (18.0) | Non-systematic Assessment |
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| Hepatic enzyme increased | Investigations | MedDRA (18.0) | Non-systematic Assessment |
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| Pancreatic enzymes increased | Investigations | MedDRA (18.0) | Non-systematic Assessment |
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| Amylase increased | Investigations | MedDRA (18.0) | Non-systematic Assessment |
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| Lipase increased | Investigations | MedDRA (18.0) | Non-systematic Assessment |
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| Gamma-glutamyltransferase increased | Investigations | MedDRA (18.0) | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Toxic neuropathy | Nervous system disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Hallucination | Psychiatric disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Acute generalised exanthematous pustulosis | Skin and subcutaneous tissue disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Seborrhoeic dermatitis | Skin and subcutaneous tissue disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Chromaturia | Renal and urinary disorders | MedDRA (18.0) | Non-systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA (18.0) | Non-systematic Assessment |
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Not provided
| Title | Measurements |
|---|---|
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| Title | Measurements |
|---|---|
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| Hour 4.0 |
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| Hour 10.0 |
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| Hour 24.0 |
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| Title | Measurements |
|---|---|
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| M445 (Hour 4.0)(n=6) |
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| M445 (Hour 10.0)(n=5) |
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| M445 (Hour 24.0)(n=3) |
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| M554(Predose)(n=6) |
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| M554(Hour 1.0)(n=6) |
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| M554 (Hour 2.0)(n=6) |
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| M554 (Hour 4.0)(n=6) |
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| M554 (Hour 10.0) (n=5) |
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| M554 (Hour 24.0) (n=3) |
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| Title | Measurements |
|---|---|
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| Partial Response |
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| Non evaluable |
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| Title | Measurements |
|---|---|
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| TEAEs leading to discontinuation |
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