Phase 1
N=180
Trial of MSC1936369B in Subjects With Solid Tumors
Solid Tumors · Cancer
Bottom Line
View on ClinicalTrials.gov: NCT00982865 ↗Enrolled (actual)
180
Serious AEs
53.9%
Results posted
Oct 2018
Primary outcome: Primary: Number of Subjects Experienced Any Dose-Limiting Toxicity (DLT) Over the First Cycle - Day 1 to 21 — 2; 6; 0; 6 Subjects
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- MSC1936369B (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Merck KGaA, Darmstadt, Germany
- Primary completion
- Mar 2013
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Subjects Experienced Any Dose-Limiting Toxicity (DLT) Over the First Cycle - Day 1 to 21 |
2; 6; 0; 6 | — |
| SECONDARY Number of Subjects With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Discontinuation |
47; 82; 15; 34; 23; 45 | — |
| SECONDARY Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Leading to Death |
10; 14; 2; 2 | — |
| SECONDARY Number of Subjects With Clinical Significant Laboratory Abnormalities and Vital Signs Reported as Treatment Emergent Adverse Events |
1; 2; 0; 0; 10; 23 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 1 |
2.02; 3.20; 4.21; 6.69; 12.60; 62.32 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (Without Food Effect) |
1.65; 2.87; 4.55; 17.26; 30.90; 39.19 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 2 (With Food Effect) |
321.14; 1158.00; 305.94; 370.70 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 3 Once Daily |
241.27; 402.77; 316.08; 324.80; 473.27; 376.62 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) of MSC1936369B: Regimen 3 Twice Daily |
132.57; 206.46; 263.08; 178.09; 231.12; 190.42 | — |
| SECONDARY Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 1 |
1.500; 0.750; 1.500; 1.500; 1.500; 1.000 | — |
| SECONDARY Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 2 (Without Food Effect) |
1.500; 1.017; 1.500; 1.000; 0.533; 1.500 | — |
| SECONDARY Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 2 (With Food Effect) |
1.600; 1.000; 2.033; 6.000 | — |
| SECONDARY Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 3 Once Daily |
1.033; 1.500; 2.500; 1.492; 2.000; 1.000 | — |
| SECONDARY Time to Reach Maximum Plasma Concentration (Tmax) of MSC1936369B: Regimen 3 Twice Daily |
1.500; 1.000; 0.667; 1.500; 1.500; 1.500 | — |
| SECONDARY 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 |
4.6; 5.2; 18.5; 22.7; 52.7; 213.9 | — |
| SECONDARY 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) |
1.9; 8.2; 6.7; 67.9; 74.4; 188.4 | — |
| SECONDARY 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) |
1509.6; 3286; 1458.3; 5072.9 | — |
| SECONDARY 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 |
1229.3; 1544.9; 1532.4; 1428.8; 1392.3; 1122.5 | — |
| SECONDARY 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 |
407.2; 681.4; 791.1; 589.3; 838.8; 710.3 | — |
| SECONDARY Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B : Regimen 1 |
136.2; 6.2; 55.5; 31.4; 61.3; 234.1 | — |
| SECONDARY Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (Without Food Effect) |
23.4; 23.6; 59.1; 90.3; 218.4; 646.9 | — |
| SECONDARY Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 2 (With Food Effect) |
1580.6; 3344.3; 1495.7; 5633.8 | — |
| SECONDARY Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 3 Twice Daily |
527.6; 742.3; 939.9; 674.1; 1004.2; 978.4 | — |
| SECONDARY Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MSC1936369B: Regimen 3 Once Daily |
1253.1; 1581.4; 1753.9; 1517.1; 1597.0; 1400.3 | — |
| SECONDARY Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 1 |
3.346; 3.405; 4.599; 4.781; 5.389; 5.335 | — |
| SECONDARY Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (Without Food Effect) |
2.594; 5.119; 5.115; 4.187; 3.305; 4.826 | — |
| SECONDARY Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 2 (With Food Effect) |
4.898; 4.452; 4.534; 6.123 | — |
| SECONDARY Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 3 Once Daily |
4.236; 4.097; 5.259; 5.599; 1.780; 2.680 | — |
| SECONDARY Apparent Terminal Half-life (t1/2) of MSC1936369B: Regimen 3 Twice Daily |
2.050; 2.509; 2.814; 2.890; 3.265; 3.210 | — |
| SECONDARY Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 1 |
132.69; 114.26; 59.80; 48.76; 48.69; 40.01 | — |
| SECONDARY Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (Without Food Effect) |
90.76; 64.09; 43.28; 54.85; 76.77; 61.61 | — |
| SECONDARY Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 2 (With Food Effect) |
56.94; 44.85; 60.17; 26.62 | — |
| SECONDARY Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 3 Once Daily |
47.88; 56.91; 48.31; 62.85; 53.36; 75.63 | — |
| SECONDARY Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of MSC1936369B: Regimen 3 Twice Daily |
114.82; 80.83; 83.86; 71.44; 66.89; 94.48 | — |
| SECONDARY Apparent Volume of Distribution Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 1 |
640.60; 561.27; 396.76; 336.32; 378.56; 307.90 | — |
| SECONDARY Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (Without Food Effect) |
339.58; 473.32; 319.40; 331.36; 366.00; 428.99 | — |
| SECONDARY Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 2 (With Food Effect) |
402.4; 288.1; 393.6; 235.2 | — |
| SECONDARY Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 3 Once Daily |
292.61; 336.38; 366.5; 507.7; 137.0; 292.5 | — |
| SECONDARY Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/F) of MSC1936369B: Regimen 3 Twice Daily |
339.51; 292.59; 340.43; 297.9; 315.0; 437.6 | — |
| SECONDARY Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 1 |
81.33; 42.23; 43.45; 26.80; 13.08; 5.31 | — |
| SECONDARY 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) |
55.78; 31.63; 27.25; 15.10; 12.17; 3.29 | — |
| SECONDARY 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) |
2.54; 1.74; 2.21; 9.96 | — |
| SECONDARY Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 3 Once Daily |
1.88; 2.11; 7.95; 4.28; 9.11; 17.56 | — |
| SECONDARY Area Under the Concentration Time Curve Extrapolated From Last Observation to Infinity Given as Percentage of AUC 0-∞ (AUC Extra): Regimen 3 Twice Daily |
16.82; 7.70; 10.90; 11.78; 14.14; 19.19 | — |
| SECONDARY 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) |
4.524; 3.937; 4.121; 3.629; 1.235; 1.305 | — |
| SECONDARY 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) |
0; 0; 0; 1; 0; 4 | — |
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 ( 1.5*upper limit normal (ULN), and/or calculated creatinine clearance 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
Data sourced from ClinicalTrials.gov (NCT00982865). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.