Clinical trial NCT01453387: MSC2015103B in Solid Tumors
Official title: A Phase I Dose-Escalation First-In-Human Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral MEK Inhibitor MSC2015103B Administered With Two Different Treatment Schedules in Subjects With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Solid Tumor
Keywords: MEK inhibitor
Solid Tumor
Phase I
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
First posted: 2011-10-17
Enrollment: 28
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: The main purpose of this study is to test the experimental drug, MSC2015103B at different dose levels and on different treatment schedules, to see whether it is safe and can be tolerated when given to subjects once a day one day per week over a 21-day period or once a day three times per week over a 21-day period. The investigators would also like to find out how MSC2015103B is broken down by the body.

Additional purposes of the trial are to assess side effects of MSC2015103B and to find out whether MSC2015103B has anti-cancer effects. In addition, the investigators would like to explore pharmacokinetics.


Eligibility criteria: Inclusion Criteria:

* Pathologically confirmed solid tumor preferably, but not exclusively, including pancreatic, thyroid, colorectal, non-small cell lung, endometrial, renal, breast, ovarian carcinoma, or melanoma which is locally advanced or metastatic, and either refractory after standard therapy for the disease or for which no effective standard therapy is available
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) of less than or equal to (\<=) 1
* Has read and understands the informed consent form and is willing and able to give informed consent. Fully understands requirements of and willing to comply with all trial visits and assessments
* Evidence of measurable disease at trial entry as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0.
* Willing to provide archival tissue samples for molecular analysis

Other inclusion criteria as defined in protocol.

Exclusion Criteria

* Bone marrow impairment as evidenced by hemoglobin less than (\<) 9.0 gram per deciliter (g/dL), neutrophil count \< 1.5 x 10\^9 per liter (/L), and/or platelets \<100 x 10\^9/L per liter (/L)
* Renal impairment as evidenced by serum creatinine greater than (\>) 1.5 x upper limit of normal (ULN) and/or calculated creatinine clearance \< 50 milliliter per minute (mL/min) (Cockcroft-Gault formula)
* Liver function and liver cell integrity abnormality as defined by total bilirubin \> 1.5 x ULN, or aspartate aminotransferase/alanine aminotransferase (AST/ALT) \> 2.5 x ULN, for subjects with liver involvement AST/ALT \> 5 x ULN. Subjects with albumin \< 2.5 g/dL are also excluded
* History of central nervous system (CNS) metastases.
* History of difficulty of swallowing, malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the tested product.
* Chronic diarrhea that is \>= Grade 2 in severity
* Clinically significant cardiac conduction abnormalities
* A left ventricular ejection fraction of \< 45%
* A history of stroke or myocardial infarction within the past year
* A history of uveitis and scleritis
* Retinal pathology beyond normal age-related processes
* Evidence of a retinal vein occlusion on fluorescein angiogram or a history of retinal vein occlusion
* Subjects are also excluded if their ophthalmologist finds that their optic disc is at risk for a central retinal vein occlusion
* History of glaucoma
* Subjects requiring daily and/or chronic systemic steroids
* Pregnant or nursing females Other exclusion criteria as defined in protocol.

Primary outcomes:
measure: Number of Subjects Who Experienced Dose-limiting Toxicities (DLT)
timeFrame: Up to Day 21 of Cycle 1
measure: Percentage of Subjects Who Experienced DLT
timeFrame: Up to Day 21 of Cycle 1
Secondary outcomes:
measure: Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation
timeFrame: From the initiation of the trial till the data cut-off date 15 July 2013
measure: Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication
timeFrame: From the initiation of the trial till the data cut-off date 15 July 2013
measure: Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication
timeFrame: From the initiation of the trial till the data cut-off date 15 July 2013
measure: Maximum Plasma Concentration (Cmax)
timeFrame: Schedule 1 : 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Days 1 and 17.
measure: Time to Reach Maximum Plasma Concentration (Tmax)
timeFrame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17.
measure: Apparent Terminal Half Life (T1/2)
timeFrame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17.
measure: Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf])
timeFrame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17.
measure: AUC Versus Time Curve Within One Dosing Interval (AUC0-tau)
timeFrame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1 and Week 3; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1 and 17.
measure: Apparent Oral Clearance of the Drug From Plasma (CL/f)
timeFrame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1.
measure: Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f)
timeFrame: Schedule 1: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, 24.0, 48 or 72, 72 or 96 and 168 hours post-dose during Week 1; Schedule 2: 0, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0, 10.0, and 24.0 hours post-dose on Day 1.
measure: Extracellular Signal-regulated Kinase (ERK) Phosphorylation Levels
timeFrame: Schedule 1: Day 1: Pre-dose; Post-dose: 2, 4, 8, 24 hour; 48 or 72 hour; 48 or 96 hour, 168 hour; Day 15: Pre-dose; Schedule 2: Day 1: Pre-dose; Post-dose: 2, 8, 24, 48, 96 hour; Day 15: Pre-dose; Day 17: Pre-dose; Post-dose: 2, 8, and 24 hour
measure: Percentage of Subjects With Overall Response
timeFrame: Every 6 Weeks until complete response or till data cut-off date 15 July 2013
measure: Percentage of Subjects With Clinical Benefit
timeFrame: Every 6 Weeks until complete response or till data cut-off date 15 July 2013
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
Study officials:
affiliation: Merck Serono, a division of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: