Clinical trial NCT01713036: Oral Bioavailability and Mass Balance Trial With Pimasertib
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Locally Advanced or Metastatic Solid Tumors
Keywords: Mass balance, bioavailability, cancer, 14C
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2012-10-24
Enrollment: 6
Sex: MALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of [14C]-Pimasertib Following IV Administration on Day 1
timeFrame: 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
measure: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib Following Oral Administration on Day 1
timeFrame: 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
measure: Oral Bioavailability of Pimasertib After Single Oral Dose of Unlabeled Pimasertib and Intravenous (IV) Single Tracer Dose of [14C] Pimasertib
timeFrame: 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
measure: Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t)
timeFrame: 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
measure: Plasma Concentrations of [14C] Pimasertib
timeFrame: Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8
measure: Plasma Concentrations of Pimasertib Metabolites
timeFrame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
measure: Number of Metabolites Identified Overall and as Major
timeFrame: Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Unlabeled Pimasertib
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Intravenous [14C] Pimasertib
timeFrame: 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
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib
timeFrame: 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
measure: Apparent Terminal Elimination Rate Constant (λz) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib
timeFrame: 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
measure: Total Body Clearance of Unlabeled Pimasertib (CL/f) and Intravenous [14C] Pimasertib (CL)
timeFrame: 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
measure: The Volume of Distribution of the Central or Plasma Compartment (Vc) of Intravenous [14C] Pimasertib
timeFrame: 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
measure: 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
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Total [14C] Radioactivity
timeFrame: 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
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Total [14C] Radioactivity
timeFrame: 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
measure: 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
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Total [14C] Radioactivity
timeFrame: 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
measure: Apparent Terminal Elimination Rate Constant (λz) of Total [14C] Radioactivity
timeFrame: 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
measure: Apparent Terminal Half-life (t1/2) of Total [14C] Radioactivity
timeFrame: 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
measure: Total Body Clearance of Total [14C] Radioactivity From Plasma Following Oral Administration (CL/f)
timeFrame: 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
measure: Apparent Volume of Distribution of Total [14C] Radioactivity During the Terminal Phase Following Oral Administration (Vz/f)
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of M445 and M554
timeFrame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
measure: Time to Reach Maximum Plasma Concentration (Tmax) of M445 and M554
timeFrame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M445 and M554
timeFrame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M445 and M554
timeFrame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
measure: Apparent Terminal Elimination Rate Constant (λz) of M445 and M554
timeFrame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
measure: Apparent Terminal Half-life (t1/2) of M445 and M554
timeFrame: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8
measure: Fraction Unbound of [14C] Pimasertib
timeFrame: 1.5 hour post [14C]-labeled pimasertib dose on Day 8
measure: Blood/ Plasma Concentration Ratios of Total [14C] Radioactivity
timeFrame: 1.5 hour post [14C]-labeled pimasertib dose on Day 8
measure: Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD)
timeFrame: From the screening every 2 cycles until end of the treatment, assessed up to 18 months
measure: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation
timeFrame: 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
Other outcomes:
Locations:
city: Budapest
country: Hungary
facility: Research Site
Study officials:
affiliation: Merck Serono SA, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.