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Trial of MSC1936369B in Subjects With Solid Tumors

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00982865
First Posted: September 23, 2009
Last Update Posted: February 14, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Merck Serono S.A., Geneva
Information provided by (Responsible Party):
Merck KGaA
  Purpose
This is a first in man trial with a primary objective being the determination of the Maximum Tolerated dose (MTD) and the dose-limiting toxicity (DLT) in several regimens of MEK inhibitor MSC1936369B administered orally once a day, in subjects with malignant solid tumors to see how safe is treatment with MSC1936369B.

Condition Intervention Phase
Solid Tumors Cancer Drug: MSC1936369B Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Open Label, Phase I Trial of the MEK Inhibitor MSC1936369B Given Orally to Subjects With Solid Tumours

Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Number of subjects experienced at least a Dose-Limiting Toxicity (DLT) over the first cycle - Day 1 to 21 [ Time Frame: 21 days ]
    DLT was defined using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 (CTCAE), as any of the following toxicities at any dose level and judged to be possibly or probably related to the trial medication by the investigator and/or the sponsor: any Grade 3 or more non-haematological toxicity excluding: Grade 3 asymptomatic increase in liver function tests reversible within 7 days for subjects without liver involvement, or Grade 4 for subjects with liver involvement. Grade 3 vomiting if it is encountered despite adequate and optimal therapy (e.g. 5HT3 antagonists and corticosteroids). Grade 3 diarrhoea if it is encountered despite adequate and optimal anti diarrhoea therapy. Any Grade 4 neutropenia of > 5 days duration or febrile neutropenia lasting for more than 1 day. Grade 4 thrombocytopenia > 1 day or Grade 3 with bleeding. Any treatment delay > 2 weeks due to drug-related adverse effects.


Secondary Outcome Measures:
  • Number of subjects experienced treatment-emergent adverse events (TEAE), serious TEAEs, TEAEs leading to discontinuation and TEAEs leading to death [ Time Frame: From the first dose of study drug administration up to 30+/-3 days after the last dose of study drug administration ]
  • Number of subjects experienced clinically significant changes in laboratory parameters and/or vital signs judged to be related to the trial medication [ Time Frame: From the date of randomization up to end of the treatment , assessed up to 5.4 years ]
  • Maximum observed plasma concentration of pimasertib [ Time Frame: Cycle1:Reg1,2,3:Day1(Cycle 2,3),Day12(reg1);Day15(reg 2,3):Pre-dose,0.5,1,1.5,2, 2.5,4,6,8hours post-dose.Day 2:Pre-dose;Day3,8:Pre-dose,1 and 4 hours post-dose;Cycle 2 Day1:12hours post-dose;Day 2:Pre-dose(reg2 FE cohort);Cycle4+,Reg 1,2,3:Day1:Pre-dose ]
  • Time to reach maximum plasma concentration of pimasertib [ Time Frame: Cycle1:Reg1,2,3:Day1(Cycle 2,3),Day12(reg1);Day15(reg 2,3):Pre-dose,0.5,1,1.5,2, 2.5,4,6,8hours post-dose.Day 2:Pre-dose;Day3,8:Pre-dose,1 and 4 hours post-dose;Cycle 2 Day1:12hours post-dose;Day 2:Pre-dose(reg2 FE cohort);Cycle4+,Reg 1,2,3:Day1:Pre-dose ]
  • 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 pimasertib [ Time Frame: Cycle1:Reg1,2,3:Day1(Cycle 2,3),Day12(reg1);Day15(reg 2,3):Pre-dose,0.5,1,1.5,2, 2.5,4,6,8hours post-dose.Day 2:Pre-dose;Day3,8:Pre-dose,1 and 4 hours post-dose;Cycle 2 Day1:12hours post-dose;Day 2:Pre-dose(reg2 FE cohort);Cycle4+,Reg 1,2,3:Day1:Pre-dose ]
  • Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of pimasertib [ Time Frame: Cycle1:Reg1,2,3:Day1(Cycle 2,3),Day12(reg1);Day15(reg 2,3):Pre-dose,0.5,1,1.5,2, 2.5,4,6,8hours post-dose.Day 2:Pre-dose;Day3,8:Pre-dose,1 and 4 hours post-dose;Cycle 2 Day1:12hours post-dose;Day 2:Pre-dose(reg2 FE cohort);Cycle4+,Reg 1,2,3:Day1:Pre-dose ]
  • Apparent terminal half life of pimasertib [ Time Frame: Cycle1:Reg1,2,3:Day1(Cycle 2,3),Day12(reg1);Day15(reg 2,3):Pre-dose,0.5,1,1.5,2, 2.5,4,6,8hours post-dose.Day 2:Pre-dose;Day3,8:Pre-dose,1 and 4 hours post-dose;Cycle 2 Day1:12hours post-dose;Day 2:Pre-dose(reg2 FE cohort);Cycle4+,Reg 1,2,3:Day1:Pre-dose ]

Other Outcome Measures:
  • Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of pimasertib [ Time Frame: Cycle1:Reg1,2,3:Day1(Cycle 2,3),Day12(reg1);Day15(reg 2,3):Pre-dose,0.5,1,1.5,2, 2.5,4,6,8hours post-dose.Day 2:Pre-dose;Day3,8:Pre-dose,1 and 4 hours post-dose;Cycle 2 Day1:12hours post-dose;Day 2:Pre-dose(reg2 FE cohort);Cycle4+,Reg 1,2,3:Day1:Pre-dose ]
  • Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of pimasertib [ Time Frame: Cycle1:Reg1,2,3:Day1(Cycle 2,3),Day12(reg1);Day15(reg 2,3):Pre-dose,0.5,1,1.5,2, 2.5,4,6,8hours post-dose.Day 2:Pre-dose;Day3,8:Pre-dose,1 and 4 hours post-dose;Cycle 2 Day1:12hours post-dose;Day 2:Pre-dose(reg2 FE cohort);Cycle4+,Reg 1,2,3:Day1:Pre-dose ]
  • Values and changes over time in PD markers in circulating PBMC, circulating tumor cells, apoptosis markers, blood circulating markers and in some subjects in tissue samples: apoptosis, phospho-ERK, marker of proliferation. [ Time Frame: From the date of randomization up to 5.4 years ]
  • Number and proportion of subjects with clinical benefit (Complete Response, Partial Response or stable disease) and progressive disease based on the best overall response which depends on the tumor evaluations assessed at the end of each 2 cycles. [ Time Frame: From the date of randomization up to 5.4 years ]

Enrollment: 180
Actual Study Start Date: December 2007
Study Completion Date: April 2016
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MSC1936369B Regimen 1
Orally once daily on Days 1 to 5, 8 to 12 and 15 to 19 of a 21-day cycle.
Drug: MSC1936369B
MSC1936369B will be administered to subjects at a dose of 1 to 120 milligram (mg) at escalating dose levels once daily up to 2 cycles (Each cycle of 21 days) and if the subject will be treated beyond 2 cycles the treatment continues until progressive disease or intolerable toxicity or investigator/subject decision.
Other Name: Pimasertib
Experimental: MSC1936369B Regimen 2 and Regimen 2 Food Effect

Orally once a day on Days 1 to 15 of a 21-day cycle.

Orally once a day from Day 1 to 21.

Drug: MSC1936369B
MSC1936369B will be administered to subjects at a dose of 1 to 255 mg at escalating dose levels once daily up to 2 cycles (Each cycle of 21 days) and if the subject will be treated beyond 2 cycles the treatment continues until progressive disease or intolerable toxicity or investigator/subject decision.
Other Name: Pimasertib
Drug: MSC1936369B
Subjects in the regimen 2 food effect cohort will be sequentially assigned in a 1:1 ratio to either the fed/fasted sequence or fasted/fed sequence for Day 1 of Cycle 1 and Cycle 2. Subjects will be administered with MSC1936369B at a dose of 90-150 mg at escalating dose levels once daily up to 2 cycles (Each cycle of 21 days) and if the subject will be treated beyond 2 cycles the treatment continues until progressive disease or intolerable toxicity or investigator/subject decision.
Other Name: Pimasertib
Experimental: MSC1936369B Regimen 3 once daily
Orally once a day from Day 1 to 21.
Drug: MSC1936369B
MSC1936369B will be administered to subjects at a dose of 60 to 90 mg at escalating dose levels once daily up to 2 cycles (Each cycle of 21 days) and if the subject will be treated beyond 2 cycles the treatment continues until progressive disease or intolerable toxicity or investigator/subject decision.
Other Name: Pimasertib
Experimental: MSC1936369B Regimen 3 twice daily
Orally twice a day from either Days 1 to 15 of a 21-day cycle (similar to Regimen 2) or up to Day 21 (similar to Regimen 3).
Drug: MSC1936369B
MSC1936369B will be administered to subjects at a dose of 45 to 75 mg at escalating dose levels once daily up to 2 cycles (Each cycle of 21 days) and if the subject will be treated beyond 2 cycles the treatment continues until progressive disease or intolerable toxicity or investigator/subject decision.
Other Name: Pimasertib

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathologically-confirmed solid tumor which is locally advanced or metastatic, and either refractory after standard therapy for the disease or for which no effective standard therapy is available. In the regimen 3, regimen 2 food-effect, and BID cohorts, the tumor type will be restricted to melanoma.
  • Age greater than or equal to (>=) 18 years
  • Has read and understands the informed consent form and is willing and able to give informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments

Exclusion Criteria:

  • Bone marrow impairment as evidenced by Haemoglobin less than (<) 9.0 gram per deciliter (g/dL), Neutrophil count < 1.0 x 10^9/Liter, platelets < 100 x 10^9/Liter
  • Renal impairment as evidenced by serum creatinine > 1.5 x upper limit normal (ULN), and/or calculated creatinine clearance < 60 milliliter per minute (mL/min)
  • Liver function abnormality as defined by total bilirubin > 1.5 x ULN, or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 x ULN, for subjects with liver involvement AST/ALT > 5 x ULN
  • INR > 1.5 x ULN
  • Serum calcium > 1 x ULN
  • History of central nervous system (CNS) metastases, unless subject has been previously treated for CNS metastases, is stable by computer tomography (CT) scan without evidence of cerebral oedema, and has no requirements for corticosteroids or anticonvulsants
  • History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the tested product
  • Eastern Cooperative Oncology Group Performance status (ECOG PS) greater than (>) 1
  • Known human immunodeficiency virus (HIV) positivity, active hepatitis C, or active hepatitis B
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00982865


Locations
Australia
Westmead Hospital
Westmead, Australia
Belgium
Jules Bordet Institute
Brussels, Belgium, B-1000
Ghent University Hospital
Ghent, Belgium
France
Institute Bergonié
Bordeaux, France
Hôpital Beaujon
Paris, France, 92118
Hopital Saint Louis
Paris, France
Centre Eugène Marquis
Rennes, France
Institute Claudius Regaud
Toulouse, France, 03 31052
Netherlands
Netherlands Cancer Institute - Antonie van Leeuwenhoek Hospital
Amsterdam, Netherlands
Sponsors and Collaborators
Merck KGaA
Merck Serono S.A., Geneva
Investigators
Study Director: Medical Responsible Merck KGaA
  More Information

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT00982865     History of Changes
Other Study ID Numbers: 28062
2007-004665-18 ( EudraCT Number )
First Submitted: September 22, 2009
First Posted: September 23, 2009
Last Update Posted: February 14, 2017
Last Verified: February 2017

Keywords provided by Merck KGaA:
MEK inhibitor
Cancer
Solid tumors