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

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.

Study Overview

• Status: Completed
• Conditions: Locally Advanced or Metastatic Solid Tumors
• Intervention / Treatment: Drug: Pimasertib

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• Hungary
  • Budapest, Hungary
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Pimasertib

Drug: Pimasertib; 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.; Other Names: AS703026; MSC19363639B

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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)	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

Secondary Outcome Measures

Outcome Measure	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		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

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, Merck Serono SA, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2012
• Primary Completion (Actual): July 31, 2014
• Study Completion (Actual): July 31, 2014

Study Registration Dates

• First Submitted: September 13, 2012
• First Submitted That Met QC Criteria: October 23, 2012
• First Posted (Estimate): October 24, 2012

Study Record Updates

• Last Update Posted (Actual): August 15, 2017
• Last Update Submitted That Met QC Criteria: July 6, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Mass balance, bioavailability, cancer, 14C
• Other Study ID Numbers: EMR 200066-008; 2012-002562-12 (EudraCT Number)