Phase 1
N=149
First-in-Man, Dose-escalation Trial of C-met Kinase Inhibitor MSC2156119J in Subjects With Advanced Solid Tumors
Patients With Solid Tumors, Either Refractory to Standard Therapy or for Which no Effective Standard Therapy is Available
Bottom Line
View on ClinicalTrials.gov: NCT01014936 ↗Enrolled (actual)
149
Serious AEs
35.6%
Results posted
Apr 2017
Primary outcome: Primary: Number of Subjects With Any Dose Limiting Toxicity (DLT) — 1; 3; 2 subjects
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- MSC2156119J (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- EMD Serono
- Primary completion
- Oct 2015
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Subjects With Any Dose Limiting Toxicity (DLT) |
1; 3; 2 | — |
| PRIMARY Recommended Phase 2 Dose (RP2D) |
500 | — |
| PRIMARY Number of Subjects With Treatment-Related Adverse Events |
14; 23; 39 | — |
| SECONDARY Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death |
41; 45; 59; 14; 17; 22 | — |
| SECONDARY Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1 |
56.62; 70.65; 107.0; 147.0; 193.8; 306.4 | — |
| SECONDARY Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2 |
55.55; 115.5; 134.8; 142.4; 333.7; 5.926 | — |
| SECONDARY Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3 |
246.5; 552.0; 329.9; 433.5; 666.1; 761.0 | — |
| SECONDARY Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1 |
112.6; 204.6; 262.8; 379.3; 697.2; 810.9 | — |
| SECONDARY Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2 |
88.55; 181.4; 178.4; 300.5; 722.4; 8.458 | — |
| SECONDARY Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3 |
741.6; 795.0; 943.1; 1006; 1219; 1805 | — |
| SECONDARY Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1 |
8.000; 10.000; 10.000; 8.000; 8.000; 10.000 | — |
| SECONDARY Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2 |
9.000; 8.000; 9.000; 8.000; 24.000; 10.000 | — |
| SECONDARY Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3 |
8.000; 8.000; 10.000; 10.000; 10.000; 10.000 | — |
| SECONDARY Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1 |
2.125; 8.000; 8.000; 4.000; 8.000; 8.000 | — |
| SECONDARY Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2 |
10.000; 10.000; 8.000; 10.000; 8.000; 8.000 | — |
| SECONDARY Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3 |
10.000; 10.000; 8.000; 3.183; 8.833; 9.075 | — |
| SECONDARY Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 1 |
— | — |
| SECONDARY Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 2 |
— | — |
| SECONDARY Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 3 |
— | — |
| SECONDARY Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 1 |
— | — |
| SECONDARY Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 2 |
— | — |
| SECONDARY Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 3 |
— | — |
| SECONDARY Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1 |
849.4; 1283.0; 1433.5; 2532.7; 3105.5; 5467.9 | — |
| SECONDARY Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 2 |
1771.5; 3665.3; 3794.2; 4659.6; 10818.0; 206.9 | — |
| SECONDARY Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 3 |
4209.3; 3190.8; 5667.3; 4980.9; 10355.6; 13352.6 | — |
| SECONDARY Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 1 |
7532.7; 14113.2; 18334.0; 18409.6; 56102.4; 82253.4 | — |
| SECONDARY Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 2 |
4079.6; 5079.7; 4962.0; 7963.8; 36701.1; 375.2 | — |
| SECONDARY Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time (AUC0-t) After Multiple Dose of MSC2156119J : Regimen 3 |
15694.9; 17498.1; 20210.4; 17107.8; 27716.9; 39730.6 | — |
| SECONDARY Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 1 |
— | — |
| SECONDARY Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 2 |
— | — |
| SECONDARY Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 3 |
— | — |
| SECONDARY Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1 |
848.7; 1283.0; 1731.3; 2454.5; 3090.2; 5462.8 | — |
| SECONDARY Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2 |
1771.5; 3657.3; 3794.2; 4659.6; 10786.4; 206.9 | — |
| SECONDARY Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3 |
4206.5; NA; 5917.9; 7575.8; 11796.4; NA | — |
| SECONDARY Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1 |
2266.7; 4443.1; 5499.6; 8099.6; 13938.4; 18276.5 | — |
| SECONDARY Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2 |
3031.7; 7565.6; 5305.5; 9051.1; 27760.2; 273.7 | — |
| SECONDARY Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3 |
15597.6; 17498.1; 20169.3; 21972.2; 27214.4; 39283.7 | — |
| SECONDARY Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 1 |
— | — |
| SECONDARY Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 2 |
— | — |
| SECONDARY Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 3 |
— | — |
| SECONDARY Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 1 |
— | — |
| SECONDARY Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 2 |
— | — |
| SECONDARY Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 3 |
— | — |
| SECONDARY Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 1 |
— | — |
| SECONDARY Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 2 |
— | — |
| SECONDARY Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 3 |
— | — |
| SECONDARY Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 1 |
— | — |
| SECONDARY Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 2 |
— | — |
| SECONDARY Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 3 |
— | — |
| SECONDARY Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 1 |
— | — |
| SECONDARY Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 2 |
— | — |
| SECONDARY Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 3 |
— | — |
| SECONDARY Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 |
-12.94; -31.43; 5.00; 3.53; 28.10; -10.00 | — |
| SECONDARY Fold Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2 |
1.05; 1.09; 1.12; NA; 1.29; 1.23 | — |
| SECONDARY Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS) |
3; 5; 1; 9; 7; 12 | — |
| SECONDARY Relative Percentage Change In Sum of Longest Diameter (SOLD) of Target Lesions to Post-Baseline Nadir |
25.67; 16.19; 18.87 | — |
| SECONDARY Number of Subjects With Best Overall Response (BOR) |
0; 0; 0; 0; 0; 2 | — |
| SECONDARY Progression-free Survival (PFS) |
1.4; 1.3; 1.4 | — |
Summary
This is a an open-label, dose-escalation, first-in-man (FIM) study designed to explore MSC2156119J, in subjects with advanced solid tumors who have not responded to previous therapies or for whom no other therapies are available.
Subjects will be assigned one of the dosing regimens:
* Regimen 1: MSC2156119J once daily for 14 days, followed by 7 days with no treatment (21-day cycle)
* Regimen 2: MSC2156119J three times per week (e.g., Days 1, 3, and 5) for three weeks (21-day cycle)
* Regimen 3: MSC2156119J every day for three weeks (21-day cycle)
Eligibility Criteria
Inclusion Criteria
- Subject should read and fully understand the requirements of the trial, be willing to comply with all trial visits and assessments, and be willing and able to give informed consent
- Histologically or cytologically confirmed solid tumor, either refractory to standard therapy or for which no effective standard therapy is available
- Measurable or evaluable disease, as defined by RECIST 1.0
- Estimated life expectancy greater than (>) three months
- Men or women aged greater than or equal to (>=) 18 years
- Women of childbearing potential must have a negative blood pregnancy test at the Screening Visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are post-menopausal for at least 12 months, are surgically sterile, or are sexually inactive.
- Subjects and their partners must be willing to avoid pregnancy during the trial and until three months after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator, such as a two-barrier method or one-barrier method with spermicide or intrauterine device. This requirement begins two weeks before receiving the first trial treatment and ends one month after receiving the last treatment.
- ECOG performance status of 0 to 2
- Adequate hematological function:
- Hemoglobin >= 9.0 g/dL
- Neutrophils > 1.5 x 109/L
- Platelets >= 75 x 109/L
- Adequate liver function:
- Total bilirubin less than or equal to ( 60 mL/min
- Resolution of all acute chemotherapy, radiotherapy or surgery-related AEs to Grade = 2
- Medical history of any other significant medical disease, major surgery, or psychiatric condition that might impair the subject's well being or preclude full participation in the trial
- Women who are pregnant or nursing
- Known drug abuse or alcohol abuse
- Participation in another clinical trial within the past 28 days
- Requires concurrent treatment with a non-permitted drug
- Known hypersensitivity to any of the trial treatment ingredients
- Legal incapacity or limited legal capacity
- Any other reason that, in the opinion of the principal investigator, precludes the subject from participating in the trial
Data sourced from ClinicalTrials.gov (NCT01014936). 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.