Oral Bioavailability and Mass Balance Trial With Pimasertib

Locally Advanced or Metastatic Solid Tumors Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01713036
• Other study ID #: EMR 200066-008
• Secondary ID: 2012-002562-12
• Status: Completed
• Phase: Phase 1
• First received: September 13, 2012
• Last updated: April 17, 2015
• Start date: November 2012
• Est. completion date: July 2014

Study information

• Verified date: April 2015
• Source: Merck KGaA
• Contact: n/a
• Is FDA regulated: No
• Health authority: Hungary: National Institute for Quality and Organizational Development in Healthcare and Medicines
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. 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

2. Subject has measurable and evaluable disease as defined by RECIST v.1.1

3. Age greater than or equal to 18 years and less than or equal to 65 years

4. Body mass index greater than or equal to 19 and less than or equal to 30 kilogram per meter square (kg/m^2)

5. Subject has Eastern Cooperative Oncology Group Performance Status (ECOG PS) of less than or equal to 1

6. 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

7. 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:

1. 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

2. 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)

3. 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

4. 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

5. History of gastrointestinal disease, malabsorption syndrome or difficulty in swallowing, which in the investigator's opinion might impair the absorption of pimasertib

6. Any gastric, small or large bowel surgery that may impact the absorption of pimasertib

7. Known human immunodeficiency virus (HIV) positivity, active hepatitis

8. 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

9. Major surgical procedure within the last 8 weeks prior to start of trial medication

10. History of uveitis and scleritis. Retinal pathology beyond normal age-related processes

11. History of glaucoma. Subjects are excluded if intraocular pressure is above 21 millimeter of mercury (mmHg)

12. 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

13. Life expectancy of less than 12 weeks

14. 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

15. 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

16. 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

17. Known hypersensitivity to any of the excipients used

18. Inability to understand the protocol requirements, instructions and trial-related restrictions, the nature, scope, and possible consequences of the trial

19. Legal incapacity or limited legal capacity

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Locally Advanced or Metastatic Solid Tumors

Intervention

Drug:
• Pimasertib
Unlabeled pimasertib, 60 milligram (mg), will be administered as oral capsules in the morning of Day 1 of Part A of the study (21-day treatment period). After 1 hour, the intravenous tracer dose of [14C] pimasertib (2 microgram [mcg] equaling 9 kilobecquerel [kBq]) will be administered as a bolus injection on Day 1. From Days 3-21, 60 mg unlabeled pimasertib oral capsules will be administered twice a day except on Day 8, on which 60 mg unlabeled pimasertib capsules spiked with 2.6 megabecquerel (MBq) of [14C] pimasertib will be administered orally in morning followed by an evening dose of 60 mg pimasertib as unlabeled pimasertib oral capsules. Unlabeled pimasertib, 60 mg will be administered as oral capsule twice a day in Part B of the study, that is, cycles of 21 days duration until disease progression, unacceptable toxicity, withdrawal by subject, lost to follow up, or death.

Locations

Country	Name	City	State
Hungary	Research Site	Budapest

Sponsors (2)

Lead Sponsor	Collaborator
Merck KGaA	Merck Serono S.A., Switzerland

Country where clinical trial is conducted

Hungary, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Oral bioavailability of pimasertib: Area under the curve (AUC) of unlabeled pimasertib administered per os (PO) and intravenous (IV) single tracer dose of [14C] pimasertib		Day 1	No
Primary	Mass Balance: Recovery of total [14C] radioactivity in excreta, that is, Ae0-t in urine and in feces		Day 8-21	No
Primary	Metabolite Identification: Chemical structure of pimasertib metabolites in plasma, urine, and feces		Day 8-21	No
Primary	Plasma concentration profiles: Plasma concentrations of [14C] pimasertib and its metabolites		Day 8	No
Secondary	Pharmacokinetic (PK) parameters: Cmax, tmax, ?z, t1/2, CL, CL/f, Vz, VC, Vz/f for unlabeled pimasertib and IV single tracer dose of [14C] pimasertib		Day 1	No
Secondary	PK parameters: Cmax, tmax, AUC0-t, AUC0-8, Ae0-t, ?z, t1/2, CL/f, Vz/f of total radioactivity following single dose pimasertib spiked with [14C] pimasertib		Day 8	No
Secondary	Pimasertib plasma protein binding		Day 8	No
Secondary	Total radioactivity ratio blood/plasma		Day 8	No
Secondary	Anti-tumor activity defined as CR, PR, or SD and PD based on the Investigator tumor evaluations performed every 2 cycles in accordance with Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1)		Cycle 3, 5, 7 and thereafter every alternate cycle up to 4 weeks after last study dose	No
Secondary	Number of subjects with treatment emergent adverse events (TEAEs)		Baseline up to 4 weeks after last study dose	No