Locally Advanced or Metastatic Solid Tumors
Conditions
Keywords
Mass balance, bioavailability, cancer, 14C
Brief summary
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.
Interventions
DRUGPimasertib
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.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male subject with pathologically confirmed solid tumor preferentially including, but not limited to pancreatic, thyroid, colorectal, lung, and renal cancer, or melanoma which is locally advanced or metastatic, and either refractory to the respective standard therapy for the disease or for which no effective standard therapy is available * Subject has measurable and evaluable disease as defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v.1.1) * Age greater than or equal to 18 years and less than or equal to 65 years * Body mass index greater than or equal to 19 and less than or equal to 30 kilogram per meter square (kg/m\^2) * Subject has Eastern Cooperative Oncology Group Performance Status (ECOG PS) of less than or equal to 1 * Male subjects with female partners of childbearing potential must be willing to use an adequate method of contraception during and for 4 weeks after the last dose of the trial medication. During this time, female partners should use a contraceptive method with a failure rate of less than 1 percent * Subject has read and understood the informed consent form and is willing and able to give written informed consent before any trial related procedures are performed
Exclusion criteria
* Bone marrow impairment as evidenced by hemoglobin less than 10.0 gram per deciliter (g/dL), neutrophil count less than 1.5 \* 10\^9 per liter (/L), and/or platelets less than 100 \* 10\^9/L * Renal impairment as evidenced by serum creatinine greater than 1.5 \* upper limit of normal (ULN) and calculated creatinine clearance less than 60 milliliter per minute (mL/min) (Cockcroft Gault formula) * Liver function and liver cell integrity abnormality as defined by total bilirubin greater than 1.5 \* ULN, or aspartate transaminase (AST)/alanine transaminase (ALT) greater than 2.5 \* ULN, for subjects with liver metastases AST/ALT greater than 5 \* ULN * Primary brain tumors or clinical evidence of active brain metastasis. Subjects with a history of previously treated brain tumor are eligible provided that 1 month following treatment they were stable by computed tomography (CT) scan without evidence of cerebral edema, and have no requirements for anticonvulsants or high doses of corticosteroids * History of gastrointestinal disease, malabsorption syndrome or difficulty in swallowing, which in the investigator's opinion might impair the absorption of pimasertib * Any gastric, small or large bowel surgery that may impact the absorption of pimasertib * Known human immunodeficiency virus (HIV) positivity, active hepatitis * Chemotherapy, radiotherapy, immunotherapy, or molecular targeted cancer therapy within the past 4 weeks or within 5 half-lives of the given drug, whatever is longer, prior to start of trial medication or concomitantly within this trial. This restriction does not apply to steroids and bisphosphonates * Major surgical procedure within the last 8 weeks prior to start of trial medication * History of uveitis and scleritis. Retinal pathology beyond normal age-related processes * History of glaucoma. Subjects are excluded if intraocular pressure is above 21 millimeter of mercury (mmHg) * Evidence of a retinal vein occlusion (RVO) on fluorescein angiogram or a history of RVO. Subjects are also excluded if on examination an ophthalmologist finds that their optic disc is at risk for a central RVO * Life expectancy of less than 12 weeks * Clinically relevant non-malignant disease which in the investigator's opinion would exclude the subject from the trial, such as significant cardiovascular, pulmonary, endocrine, renal and neurological disease or psychiatric disorder * Treatment with strong inhibitors and/or inducers of cytochrome P450 2C19 (CYP2C19) and cytochrome P450 3A4 (CYP3A4). Consumption of CYP3A4 enzyme inducing or inhibiting herbal drugs, fruit juices and beverages (example, grapefruit, grapefruit juice, quinine \[tonic water\], star fruit, St John's Wort) within 2 weeks prior to start of trial medication until the end of Day 21 * Participation in a drug trial within 30 days prior to start of trial medication. Participation in a trial involving administration of \[14C\] labeled compound(s) within last 6 months prior to start of trial medication * Known hypersensitivity to any of the excipients used * Inability to understand the protocol requirements, instructions and trial-related restrictions, the nature, scope, and possible consequences of the trial * Legal incapacity or limited legal capacity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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. |
| Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t) | 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 | 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. |
| 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 | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 | Plasma concentration of the Pimasertib metabolite M445 and M554 were presented for the outcome measure. |
| Number of Metabolites Identified Overall and as Major | Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8 | Identification and profiling of the metabolites was done. The total number of metabolites and the number of metabolites identified as major were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 was calculated by using mixed log linear trapezoidal rule. Unit of assessment was hour\*nanogram equivalent per milliliter (hr\*ng eq/mL). |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) 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 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. |
| Apparent Terminal Elimination Rate Constant (λz) 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 | 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. |
| 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) | 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 | 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). |
| Apparent Volume of Distribution of Total [14C] Radioactivity During the Terminal Phase Following Oral Administration (Vz/f) | 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 | 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). |
| Maximum Observed Plasma Concentration (Cmax) of M445 and M554 | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 | Maximum observed plasma concentration (Cmax) for the metabolites M445 and M554 was calculated. |
| Time to Reach Maximum Plasma Concentration (Tmax) of M445 and M554 | 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) for the metabolites M445 and M554 was calculated. |
| 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 | — |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M445 and M554 | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 | 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. |
| Apparent Terminal Elimination Rate Constant (λz) of M445 and M554 | Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8 | 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. |
| 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 | 1.5 hour post [14C]-labeled pimasertib dose on Day 8 | Fraction of unbound drug (fu) is defined as the ratio of unbound drug concentration to the total drug concentration multiplied by 100. |
| 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) | From the screening every 2 cycles until end of the treatment, assessed up to 18 months | 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. |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation | 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 | 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. |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M445 and M554 | 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) at which the concentration is at or above the lower limit of quantification. |
| Maximum Observed Plasma Concentration (Cmax) of Intravenous [14C] Pimasertib | 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 | 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) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. |
| Total Body Clearance of Unlabeled Pimasertib (CL/f) and Intravenous [14C] Pimasertib (CL) | 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 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 Volume of Distribution of the Central or Plasma Compartment (Vc) of Intravenous [14C] Pimasertib | 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 | The volume of distribution of the central or plasma compartment (Vc) was calculated using the formula=Dose/C0 |
| 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 | 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 | 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). |
| Maximum Observed Plasma Concentration (Cmax) 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 | Unit of assessment was nanogram equivalent per milliliter (ng eq/mL). |
| 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 | — |
Countries
Hungary
Participant flow
Recruitment details
First/last subject (informed consent): Nov 2012/Apr 2013. Clinical data cutoff: Jun 2013, Study completion date: Jul 2014 (Part B)
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | Pimasertib |
|---|---|
| Age, Continuous | 56.2 years STANDARD_DEVIATION 8.54 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 2 / 6 |
Outcome results
Primary
Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of [14C]-Pimasertib Following IV Administration on Day 1
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of [14C]-Pimasertib Following IV Administration on Day 1 | 37.4 hour*picogram equivalent/milliliter |
Primary
Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib Following Oral Administration on Day 1
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib Following Oral Administration on Day 1 | 957.4 hour*nanogram/milliliter |
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
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | 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 | 36.0 hour*picogram equivalent/milliliter |
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
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | 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 | 937.2 hour*nanogram/milliliter |
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.
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Pimasertib | Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t) | Urine | 52.8 percentage of dose recovered |
| Pimasertib | Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t) | Feces | 30.7 percentage of dose recovered |
| Pimasertib | Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t) | Total | 85.1 percentage of dose recovered |
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.
Time frame: Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pimasertib | Number of Metabolites Identified Overall and as Major | Overall | 14 metabolites |
| Pimasertib | Number of Metabolites Identified Overall and as Major | Major | 2 metabolites |
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.
Time frame: 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
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pimasertib | Oral Bioavailability of Pimasertib After Single Oral Dose of Unlabeled Pimasertib and Intravenous (IV) Single Tracer Dose of [14C] Pimasertib | 73 percentage bioavailability |
Primary
Plasma Concentrations of [14C] Pimasertib
Time frame: Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pimasertib | Plasma Concentrations of [14C] Pimasertib | Predose | 0.0 nanogram equivalent per milliliter | Standard Deviation 0 |
| Pimasertib | Plasma Concentrations of [14C] Pimasertib | Hour 1 | 695.2 nanogram equivalent per milliliter | Standard Deviation 213.5 |
| Pimasertib | Plasma Concentrations of [14C] Pimasertib | Hour 2.0 | 691.2 nanogram equivalent per milliliter | Standard Deviation 164.8 |
| Pimasertib | Plasma Concentrations of [14C] Pimasertib | Hour 4.0 | 379.3 nanogram equivalent per milliliter | Standard Deviation 108.7 |
| Pimasertib | Plasma Concentrations of [14C] Pimasertib | Hour 10.0 | 165.6 nanogram equivalent per milliliter | Standard Deviation 62.58 |
| Pimasertib | Plasma Concentrations of [14C] Pimasertib | Hour 24.0 | 46.62 nanogram equivalent per milliliter | Standard Deviation 14.57 |
Primary
Plasma Concentrations of Pimasertib Metabolites
Plasma concentration of the Pimasertib metabolite M445 and M554 were presented for the outcome measure.
Time frame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M445 (Predose)(n=6) | 0.0 Nanogram equivalent per milliliter | Standard Deviation 0 |
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M445 (Hour 1.0)(n=6) | 285.2 Nanogram equivalent per milliliter | Standard Deviation 64.1 |
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M445 (Hour 2.0)(n=6) | 262.2 Nanogram equivalent per milliliter | Standard Deviation 42.35 |
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M445 (Hour 4.0)(n=6) | 85.05 Nanogram equivalent per milliliter | Standard Deviation 14.01 |
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M445 (Hour 10.0)(n=5) | 28.58 Nanogram equivalent per milliliter | Standard Deviation 9.454 |
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M445 (Hour 24.0)(n=3) | 0.0 Nanogram equivalent per milliliter | Standard Deviation 0 |
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M554(Predose)(n=6) | 0.0 Nanogram equivalent per milliliter | Standard Deviation 0 |
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M554(Hour 1.0)(n=6) | 87.53 Nanogram equivalent per milliliter | Standard Deviation 55.52 |
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M554 (Hour 2.0)(n=6) | 167.6 Nanogram equivalent per milliliter | Standard Deviation 76.72 |
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M554 (Hour 4.0)(n=6) | 169.1 Nanogram equivalent per milliliter | Standard Deviation 45.85 |
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M554 (Hour 10.0) (n=5) | 108.8 Nanogram equivalent per milliliter | Standard Deviation 24.8 |
| Pimasertib | Plasma Concentrations of Pimasertib Metabolites | M554 (Hour 24.0) (n=3) | 51.33 Nanogram equivalent per milliliter | Standard Deviation 12.46 |
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.
Time frame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Pimasertib | Apparent Terminal Elimination Rate Constant (λz) of M445 and M554 | M445 | 0.2542 per hour |
| Pimasertib | Apparent Terminal Elimination Rate Constant (λz) of M445 and M554 | M554 | 0.07021 per hour |
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.
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | Apparent Terminal Elimination Rate Constant (λz) of Total [14C] Radioactivity | 0.04084 per hour |
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.
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Pimasertib | Apparent Terminal Elimination Rate Constant (λz) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib | Intravenous [14C] pimasertib | 0.1994 per hour |
| Pimasertib | Apparent Terminal Elimination Rate Constant (λz) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib | Unlabeled pimasertib | 0.1096 per hour |
Secondary
Apparent Terminal Half-life (t1/2) of M445 and M554
Time frame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib | Apparent Terminal Half-life (t1/2) of M445 and M554 | M445 | 2.653 hour |
| Pimasertib | Apparent Terminal Half-life (t1/2) of M445 and M554 | M554 | 10.81 hour |
Secondary
Apparent Terminal Half-life (t1/2) of Total [14C] Radioactivity
Time frame: 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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pimasertib | Apparent Terminal Half-life (t1/2) of Total [14C] Radioactivity | 14.41 hour |
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).
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Pimasertib | 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 | Unlabeled pimasertib | 571.77 Liter |
| Pimasertib | 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 | Intravenous [14C] pimasertib | 229.35 Liter |
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).
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | Apparent Volume of Distribution of Total [14C] Radioactivity During the Terminal Phase Following Oral Administration (Vz/f) | 253.5 Liter |
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.
Time frame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Pimasertib | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M445 and M554 | M445 | 1134.72 hr*ng eq/mL |
| Pimasertib | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M445 and M554 | M554 | 3135.61 hr*ng eq/mL |
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.
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Total [14C] Radioactivity | 5711 hr*ng eq/mL |
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).
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | 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 | 5318 hr*ng eq/mL |
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.
Time frame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Pimasertib | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M445 and M554 | M445 | 976.39 hr*ng eq/mL |
| Pimasertib | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M445 and M554 | M554 | 1410.30 hr*ng eq/mL |
Secondary
Blood/ Plasma Concentration Ratios of Total [14C] Radioactivity
Time frame: 1.5 hour post [14C]-labeled pimasertib dose on Day 8
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pimasertib | Blood/ Plasma Concentration Ratios of Total [14C] Radioactivity | 0.687 Ratio | Standard Deviation 0.0786 |
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.
Time frame: 1.5 hour post [14C]-labeled pimasertib dose on Day 8
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pimasertib | Fraction Unbound of [14C] Pimasertib | 6.702 percentage of unbound drug | Standard Deviation 0.6623 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Intravenous [14C] Pimasertib
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | Maximum Observed Plasma Concentration (Cmax) of Intravenous [14C] Pimasertib | 12.67 picogram equivalent per milliliter |
Secondary
Maximum Observed Plasma Concentration (Cmax) of M445 and M554
Maximum observed plasma concentration (Cmax) for the metabolites M445 and M554 was calculated.
Time frame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Pimasertib | Maximum Observed Plasma Concentration (Cmax) of M445 and M554 | M445 | 300.93 Nanogram equivalent per milliliter |
| Pimasertib | Maximum Observed Plasma Concentration (Cmax) of M445 and M554 | M554 | 174.64 Nanogram equivalent per milliliter |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Total [14C] Radioactivity
Unit of assessment was nanogram equivalent per milliliter (ng eq/mL).
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | Maximum Observed Plasma Concentration (Cmax) of Total [14C] Radioactivity | 774.1 ng eq/mL |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Unlabeled Pimasertib
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | Maximum Observed Plasma Concentration (Cmax) of Unlabeled Pimasertib | 265 ng/mL |
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.
Time frame: 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
Population: The safety analysis set included all subjects who received at least one administration of trial medication and have at least one subsequent safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pimasertib | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation | Serious TEAEs | 2 subjects |
| Pimasertib | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation | TEAEs leading to death | 1 subjects |
| Pimasertib | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation | TEAEs | 6 subjects |
| Pimasertib | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation | TEAEs leading to discontinuation | 3 subjects |
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.
Time frame: From the screening every 2 cycles until end of the treatment, assessed up to 18 months
Population: Safety analysis set included all subjects who received at least one administration of trial medication and had at least one subsequent safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pimasertib | Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) | Confirmed Response | 0 subjects |
| Pimasertib | Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) | Stable disease | 3 subjects |
| Pimasertib | Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) | Progressive disease | 1 subjects |
| Pimasertib | Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) | Partial Response | 0 subjects |
| Pimasertib | Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) | Non evaluable | 1 subjects |
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
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | The Volume of Distribution of the Central or Plasma Compartment (Vc) of Intravenous [14C] Pimasertib | 83.668 Liter |
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.
Time frame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib | Time to Reach Maximum Plasma Concentration (Tmax) of M445 and M554 | M445 | 1.5 hour |
| Pimasertib | Time to Reach Maximum Plasma Concentration (Tmax) of M445 and M554 | M554 | 4 hour |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Total [14C] Radioactivity
Time frame: 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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pimasertib | Time to Reach Maximum Plasma Concentration (Tmax) of Total [14C] Radioactivity | 1.5 hour |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib | Time to Reach Maximum Plasma Concentration (Tmax) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib | Unlabeled pimasertib | 0.75 hours |
| Pimasertib | Time to Reach Maximum Plasma Concentration (Tmax) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib | [14C] intravenous pimasertib | 0.5 hours |
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).
Time frame: 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
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Pimasertib | Total Body Clearance of Total [14C] Radioactivity From Plasma Following Oral Administration (CL/f) | 10.35 liter per hour |
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.
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Pimasertib | Total Body Clearance of Unlabeled Pimasertib (CL/f) and Intravenous [14C] Pimasertib (CL) | Unlabeled pimasertib | 62.67 liter per hour |
| Pimasertib | Total Body Clearance of Unlabeled Pimasertib (CL/f) and Intravenous [14C] Pimasertib (CL) | Intravenous [14C] pimasertib | 45.73 liter per hour |