MSC2015103B in Solid Tumors

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: MSC2015103B
* Drug: MSC2015103B


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 - MSC2015103B (Schedule 1)<br> | Drug: MSC2015103B<br>* Schedule 1: MSC2015103B will be administered orally once weekly on Days 1, 8, and 15 of a 21-day cycle until MTD establishment. Starting dose will be 150 microgram (mcg), which will be escalated to 200 mcg, 300 mcg, 450 mcg, 650 mcg, 1000 mcg and 1500 mcg subsequently.<br>|
| Experimental: Part 1 - MSC2015103B (Schedule 2)<br> | Drug: MSC2015103B<br>* Schedule 2: MSC2015103B will be administered orally thrice weekly on Days 1, 3, 5, 8, 10, 12, 15, 17 and 19 of a 21-day cycle until MTD was established. Starting dose will be 150 mcg, and will be escalated to 200 mcg subsequently.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Experienced Dose-limiting Toxicities (DLT) | DLT was evaluated using the National cancer institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. DLT was defined as any of the following AEs occurring during Cycle 1 that are not related to progressive disease (PD) at any dose level: Any Grade 3 or more non-hematological toxicity excluding: Grade 3 diarrhea or associated electrolyte abnormalities that were controlled with adequate and optimal therapies, Grade 3 liver function abnormalities which resolved within 7 days, vomiting. Grade 4 neutropenia of greater than (>) 5 days duration or Grade 3 febrile neutropenia, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, any severe or life threatening AE or any AE or abnormality which impairs daily normal physiological functions, any treatment delay for 2 weeks or more due to adverse effects not related to PD. All events judged to be related by the Investigator to PD were excluded from the DLT definition. | Up to Day 21 of Cycle 1 | 
| Percentage of Subjects Who Experienced DLT | DLT was evaluated using the National cancer institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. DLT was defined as any of the following AEs occurring during Cycle 1 that are not related to PD at any dose level: Any Grade 3 or more non-hematological toxicity excluding: Grade 3 diarrhea or associated electrolyte abnormalities that were controlled with adequate and optimal therapies, Grade 3 liver function abnormalities which resolved within 7 days, vomiting. Grade 4 neutropenia of greater than (>) 5 days duration or Grade 3 febrile neutropenia, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, any severe or life threatening AE or any AE or abnormality which impairs daily normal physiological functions, any treatment delay for 2 weeks or more due to adverse effects not related to PD. All events judged to be related by the Investigator to PD were excluded from the DLT definition. | Up to Day 21 of Cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation | An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. SAE (Serious adverse event) is defined as any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition.. TEAEs are events between first dose of study drug up to the cut-off date (15 July 2013) and were absent before treatment or that worsened relative to pretreatment state. | From the initiation of the trial till the data cut-off date 15 July 2013 | 
| Percentage of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Abnormal laboratory findings and other abnormal investigational findings which were associated with clinical signs and symptoms, lead to treatment discontinuation, or considered medically important by the investigator were reported as AEs. | From the initiation of the trial till the data cut-off date 15 July 2013 | 
| Number of Subjects Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication | Abnormal laboratory findings and other abnormal investigational findings which were associated with clinical signs and symptoms, lead to treatment discontinuation, or considered medically important by the investigator were reported as AEs. | From the initiation of the trial till the data cut-off date 15 July 2013 | 
| Maximum Plasma Concentration (Cmax) |  | 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. | 
| Time to Reach Maximum Plasma Concentration (Tmax) |  | 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. | 
| Apparent Terminal Half Life (T1/2) | The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. | 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. | 
| Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUC[0-inf]) | The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. | 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. | 
| AUC Versus Time Curve Within One Dosing Interval (AUC0-tau) |  | 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. | 
| Apparent Oral Clearance of the Drug From Plasma (CL/f) | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/f was influenced by the fraction absorbed. | 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. | 
| Apparent Volume of Distribution Associated to the Terminal Phase (Vz/f) | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. | 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. | 
| Extracellular Signal-regulated Kinase (ERK) Phosphorylation Levels | ERK phosphorylation levels were to be assessed in peripheral blood mononuclear cells (PBMC) during the dose escalation | 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 | 
| Percentage of Subjects With Overall Response | Overall response was to be confirmed by complete response (CR) or partial response (PR) using response evaluation criteria in solid tumours Version 1.0 (RECIST) during treatment. CR: The disappearance of all target and non-target lesions and normalization of tumor marker level; PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline. | Every 6 Weeks until complete response or till data cut-off date 15 July 2013 | 
| Percentage of Subjects With Clinical Benefit | Clinical benefit was to be confirmed by CR, PR or stable disease (SD) lasting at least 6 weeks (using RECIST v1.0) during treatment. CR: The disappearance of all target and non-target lesions and normalization of tumor marker level; PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started. | Every 6 Weeks until complete response or till data cut-off date 15 July 2013 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEK inhibitor, Solid Tumor, Phase I