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
Overview
- Phase
- Phase 1
- Intervention
- MSC2015103B
- Conditions
- Advanced Solid Tumor
- Sponsor
- EMD Serono
- Enrollment
- 28
- Locations
- 3
- Primary Endpoint
- Number of Subjects Who Experienced Dose-limiting Toxicities (DLT)
- Status
- Terminated
- Last Updated
- 8 years ago
Overview
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.
Investigators
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.
- •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
Exclusion Criteria
- Not provided
Arms & Interventions
Part 1 - MSC2015103B (Schedule 1)
Intervention: MSC2015103B
Part 1 - MSC2015103B (Schedule 2)
Intervention: MSC2015103B
Outcomes
Primary Outcomes
Number of Subjects Who Experienced Dose-limiting Toxicities (DLT)
Time Frame: Up to Day 21 of Cycle 1
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.
Percentage of Subjects Who Experienced DLT
Time Frame: Up to Day 21 of Cycle 1
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.
Secondary Outcomes
- Percentage of Subjects With Overall Response(Every 6 Weeks until complete response or till data cut-off date 15 July 2013)
- Percentage of Subjects Who Experienced Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation(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.)
- Apparent Terminal Half Life (T1/2)(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])(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)(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)(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(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 Who Experienced Clinically Significant Lab Abnormality Judged to be Related to the Trial Medication(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(From the initiation of the trial till the data cut-off date 15 July 2013)
- 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.)
- Percentage of Subjects With Clinical Benefit(Every 6 Weeks until complete response or till data cut-off date 15 July 2013)