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.

Pimasertib

Medical Responsible

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.

Oral Bioavailability and Mass Balance Trial With Pimasertib

A Phase I, Open-Label, Single Center Trial to Investigate the Mass Balance, Metabolite Profile and Oral Bioavailability of Pimasertib in Cancer Patients With Locally Advanced or Metastatic Solid Tumors

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.

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 concentration of the Pimasertib metabolite M445 and M554 were presented for the outcome measure.

Identification and profiling of the metabolites was done. The total number of metabolites and the number of metabolites identified as major were reported.

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 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) was calculated using the formula=Dose/C0

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).

Unit of assessment was nanogram equivalent per milliliter (ng eq/mL).

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 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.

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.

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).

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) for the metabolites M445 and M554 was calculated.

Time to reach maximum plasma concentration (Tmax) for the metabolites M445 and M554 was calculated.

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.

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 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.

Fraction of unbound drug (fu) is defined as the ratio of unbound drug concentration to the total drug concentration multiplied by 100.

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.

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.

Merck KGaA, Darmstadt, Germany

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.

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.

Age, Continuous

Sex: Female, Male

Safety analysis set included all subjects who received at least one administration of trial medication and had at least one subsequent safety assessment.

Merck KGaA Communication Center

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.

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.

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

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

Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of [14C]-Pimasertib Following IV Administration 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

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.

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.

Oral Bioavailability of Pimasertib After Single Oral Dose of Unlabeled Pimasertib and Intravenous (IV) Single Tracer Dose of [14C] Pimasertib

Urine

Feces

Total

Part A: For assessment of mass balance, subjects received 60 mg unlabeled pimasertib capsules spiked with a dose of 2.6 MBq (70 mcgCi) of \[14C\] pimasertib orally on Day 8.

Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t)

Predose

Hour 1

Hour 2.0

Hour 4.0

Hour 10.0

Hour 24.0

Part A: Subjects received 60 mg unlabeled Pimasertib capsules spiked with a dose of 2.6 MBq (70 mcgCi) of \[14C\] Pimasertib orally on Day 8.

Plasma Concentrations of [14C] Pimasertib

M445 (Predose)(n=6)

M445 (Hour 1.0)(n=6)

M445 (Hour 2.0)(n=6)

M445 (Hour 4.0)(n=6)

M445 (Hour 10.0)(n=5)

M445 (Hour 24.0)(n=3)

M554(Predose)(n=6)

M554(Hour 1.0)(n=6)

M554 (Hour 2.0)(n=6)

M554 (Hour 4.0)(n=6)

M554 (Hour 10.0) (n=5)

M554 (Hour 24.0) (n=3)

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.

Plasma Concentrations of Pimasertib Metabolites

Overall

Major

Number of Metabolites Identified Overall and as Major

Maximum Observed Plasma Concentration (Cmax) of Unlabeled Pimasertib

Maximum Observed Plasma Concentration (Cmax) of Intravenous [14C] Pimasertib

Unlabeled pimasertib

[14C] intravenous pimasertib

Time to Reach Maximum Plasma Concentration (Tmax) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib

Intravenous [14C] pimasertib

Apparent Terminal Elimination Rate Constant (λz) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib

Total Body Clearance of Unlabeled Pimasertib (CL/f) and Intravenous [14C] Pimasertib (CL)

The Volume of Distribution of the Central or Plasma Compartment (Vc) of Intravenous [14C] 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

Maximum Observed Plasma Concentration (Cmax) of Total [14C] Radioactivity

Time to Reach Maximum Plasma Concentration (Tmax) 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 (AUC0-t) of Total [14C] Radioactivity

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Total [14C] Radioactivity

Apparent Terminal Elimination Rate Constant (λz) of Total [14C] Radioactivity

Apparent Terminal Half-life (t1/2) of Total [14C] Radioactivity

Total Body Clearance of Total [14C] Radioactivity From Plasma Following Oral Administration (CL/f)

Apparent Volume of Distribution of Total [14C] Radioactivity During the Terminal Phase Following Oral Administration (Vz/f)

M445

M554

Part A: For assessment of metabolites, subjects received 60 mg unlabeled pimasertib capsules spiked with a dose of 2.6 MBq (70 mcgCi) of \[14C\] pimasertib orally on Day 8.

Maximum Observed Plasma Concentration (Cmax) of M445 and M554

Time to Reach Maximum Plasma Concentration (Tmax) of M445 and M554

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 Infinity (AUC0-inf) of M445 and M554

Apparent Terminal Elimination Rate Constant (λz) of M445 and M554

Apparent Terminal Half-life (t1/2) of M445 and M554

Fraction Unbound of [14C] Pimasertib

Blood/ Plasma Concentration Ratios of Total [14C] Radioactivity

Stable disease

Progressive disease

Confirmed Response

Partial Response

Non evaluable

Part B : Subjects received 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.

Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD)

TEAEs

Serious TEAEs

TEAEs leading to death

TEAEs leading to discontinuation

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 \[μCi\]) 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.

The safety analysis set included all subjects who received at least one administration of trial medication and have at least one subsequent safety assessment.

Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation

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.

Spots Global Cancer Trial Database for Oral Bioavailability and Mass Balance Trial With Pimasertib

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Study Description

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