Clinical trial NCT00982865: Trial of MSC1936369B in Subjects With Solid Tumors
Official title: A Multicenter, Open Label, Phase I Trial of the MEK Inhibitor MSC1936369B Given Orally to Subjects With Solid Tumours
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Cancer
Keywords: MEK inhibitor
Cancer
Solid tumors
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
Collaborators: name: Merck Serono S.A., Geneva
First posted: 2009-09-23
Enrollment: 182
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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\*10\^9/Liter, platelets \< 100\*10\^9/Liter
* Renal impairment as evidenced by serum creatinine \> 1.5\*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\*ULN, or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \> 2.5\*ULN, for subjects with liver involvement AST/ALT \> 5\*ULN
* INR \> 1.5\*ULN
* Serum calcium \> 1\*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

Primary outcomes:
measure: Number of Subjects Experienced Any Dose-Limiting Toxicity (DLT) Over the First Cycle - Day 1 to 21
timeFrame: Day 1 up to Day 21 of Cycle 1
Secondary outcomes:
measure: Number of Subjects With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Discontinuation
timeFrame: Baseline up to 253 weeks
measure: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Death
timeFrame: Baseline up to 253 weeks
measure: Number of Subjects With Clinical Significant Laboratory Abnormalities and Vital Signs Reported as Treatment Emergent Adverse Events
timeFrame: Baseline up to 253 weeks
measure: Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours (h) post-dose on Cycle 1(C1) Day 1 (D1), Cycle 1 Day 12 (D12) and Cycle 3 (C3) Day 1
measure: Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (Without Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (With Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
measure: Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 3 Once Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 3 Twice Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
measure: Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
measure: Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 2 (Without Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 2 (With Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
measure: Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 3 Once Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 3 Twice Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
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 MSC1936369B: Regimen 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
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 MSC1936369B: : Regimen 2 (Without Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
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 MSC1936369B: Regimen 2 (With Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
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 MSC1936369B: Regimen 3 Once Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
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 MSC1936369B: Regimen 3 Twice Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B : Regimen 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (Without Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (With Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 3 Twice Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 3 Once Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
measure: Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (Without Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (With Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
measure: Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 3 Once Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 3 Twice Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
measure: Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
measure: Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (Without Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (With Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
measure: Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 3 Once Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 3 Twice Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
measure: Apparent Volume of Distribution Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
measure: Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (Without Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (With Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
measure: Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 3 Once Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 3 Twice Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
measure: Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 1
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 12 and Cycle 3 Day 1
measure: Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 2 (Without Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 2 (With Food Effect)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24 hours post-dose on Cycle 1 Day 1 and Day 2
measure: Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 3 Once Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 3 Day 1
measure: Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 3 Twice Daily
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 10 h post-dose on Cycle 1 Day 1 and Day 15; pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8 h post dose on Cycle 3 Day 1
measure: Phosphorylated Extra-Cellular Signal-Regulated Kinase (pERK) Fold Change in Peripheral Blood Monocyte Cells (PBMC) and Tot ERK Fold Change in Peripheral Blood Monocyte Cells (PBMC)
timeFrame: Pre-dose on C1D1, C1D2, C1D5, C1D8; 2, 4, 8 h post-dose on C1D1; pre-dose, 2, 8, 24 h post-dose on C1D12-15; pre-dose, 2, 4 h post-dose on C1D3
measure: Number of Subjects With Clinical Benefit (Complete Response [CR], Partial Response [PR] or Stable Disease [SD}) and Progressive Disease (PD) Based on the Best Overall Response (BOR)
timeFrame: Baseline until disease progression (assessed up to end of treatment [253 weeks])
Other outcomes:
Locations:
city: Westmead
country: Australia
facility: Westmead Hospital
city: Brussels
country: Belgium
facility: Jules Bordet Institute
city: Ghent
country: Belgium
facility: Ghent University Hospital
city: Bordeaux
country: France
facility: Institute Bergonié
city: Paris
country: France
facility: Hôpital Beaujon
city: Paris
country: France
facility: Hopital Saint Louis
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Toulouse
country: France
facility: Institute Claudius Regaud
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute - Antonie van Leeuwenhoek Hospital
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Lebbe C, Italiano A, Houede N, Awada A, Aftimos P, Lesimple T, Dinulescu M, Schellens JHM, Leijen S, Rottey S, Kruse V, Kefford R, Raymond E, Faivre S, Pages C, Gomez-Roca C, Schueler A, Goodstal S, Massimini G, Delord JP. Selective Oral MEK1/2 Inhibitor Pimasertib in Metastatic Melanoma: Antitumor Activity in a Phase I, Dose-Escalation Trial. Target Oncol. 2021 Jan;16(1):47-57. doi: 10.1007/s11523-020-00767-1.
citation: Delord JP, Italiano A, Awada A, Aftimos P, Houede N, Lebbe C, Pages C, Lesimple T, Dinulescu M, Schellens JHM, Leijen S, Rottey S, Kruse V, Kefford R, Faivre S, Gomez-Roca C, Scheuler A, Massimini G, Raymond E. Selective Oral MEK1/2 Inhibitor Pimasertib: A Phase I Trial in Patients with Advanced Solid Tumors. Target Oncol. 2021 Jan;16(1):37-46. doi: 10.1007/s11523-020-00768-0.