Trial record 1 of 1 for:    NCT01014936
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First-in-Man, Dose-escalation Trial of C-met Kinase Inhibitor MSC2156119J in Subjects With Advanced Solid Tumors

This study has been completed.
Sponsor:
Collaborator:
Merck KGaA
Information provided by (Responsible Party):
EMD Serono
ClinicalTrials.gov Identifier:
NCT01014936
First received: November 13, 2009
Last updated: December 16, 2015
Last verified: December 2015
  Purpose

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 to one of two dosing regimens:

  • 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)

Condition Intervention Phase
Patients With Solid Tumors, Either Refractory to Standard Therapy or for Which no Effective Standard Therapy is Available
Drug: MSC2156119J (EMD 1214063)
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Open-label, Non-randomized, Dose-escalation First-in-man Trial to Investigate the c-Met Kinase Inhibitor MSC2156119J Under Three Different Regimens in Subjects With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by EMD Serono:

Primary Outcome Measures:
  • To determine the maximum tolerated dose (MTD) of MSC2156119J for each of two treatment regimens in subjects with advanced solid tumors [ Time Frame: After first cycle of treatment ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To assess the safety profile and tolerability of MSC2156119J [ Time Frame: Scheduled visits throughout each cycle of treatment ] [ Designated as safety issue: Yes ]
  • Maximum observed plasma concentration (Cmax) of MSC2156119J [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
  • Time to reach maximum plasma concentration (Tmax) of MSC2156119J [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
  • Apparent terminal rate constant (λz) of MSC2156119J [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
    Apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal loglinear phase.

  • Apparent terminal half-life ( t1/2) of MSC2156119J [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
    Apparent terminal half-life, calculated by natural log 2 divided by terminal rate constant (λz).

  • Area under the plasma concentration versus time curve from time zero to infinity (AUC0-inf) [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
    AUC0-inf will be calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ terminal elimination rate constant (λz), where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ).

  • Area under the plasma concentration versus time curve from time zero to the last sampling time (AUC0-t) [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
    Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLQ). AUC0-t will be calculated according to the mixed log-linear trapezoidal rule.

  • Area under the plasma concentration versus time curve within one dosing interval (AUC tau) [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
  • Apparent body clearance ( CL/f) of MSC2156119J [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
    Apparent body clearance of the drug from plasma, CL = Dose/AUC0−inf

  • Apparent volume of distribution (Vz/f) of MSC2156119J [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
    Apparent volume of distribution associated to the terminal phase, calculated by Dose divided by (AUC0-inf multiplied by λz)

  • Volume of distribution at steady state (Vss/f) of MSC2156119J [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
    Volume of distribution at steady state was calculated as CL multiplied by MRT

  • Mean residence time (MRT) of MSC2156119J [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
    MRT was calculated as AUMC0−inf/AUC0−inf, where AUMC0−inf is the area under the first moment curve from time zero to infinity following last administration.

  • Renal clearance of MSC2156119J [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
    Renal clearance of drug was calculated as Amount excreted from time 0 to t (Ae0-t) divided by (AUC0-t)

  • Amount excreted into urine (Ae) [ Time Frame: Day 1,3,14, 17 (Cycle 1) Regimen 1,3 ; Day 8 (Cycle 1) Regimen 3; Day 1, 19 (Cycle 1) Regimen 2;Day 1, 14 (Cycle 2) Regimen 1,3; Day 1,19 (Cycle 2) Regimen 2; Day 1 (cycle 3 onwards) regimen 1,2,3; ] [ Designated as safety issue: No ]
  • To explore pharmacodynamic (Pd) markers in blood and tumor tissue [ Time Frame: Scheduled visits throughout each cycle of treatment ] [ Designated as safety issue: No ]
  • To assess the safety profile, anti-tumor effects, and PK/Pd of MSC2156119J in subjects with and without specific c-Met alterations (at the MTD) [ Time Frame: Scheduled visits throughout each cycle of treatment ] [ Designated as safety issue: No ]
  • To explore genes that may be involved in the absorption, distribution, metabolism, and elimination (ADME) of MSC2156119J [ Time Frame: Scheduled visits throughout each cycle of treatment ] [ Designated as safety issue: No ]
  • To assess the anti-tumor effects of MSC2156119J [ Time Frame: Post two cycles of treatment ] [ Designated as safety issue: No ]

Enrollment: 149
Study Start Date: November 2009
Study Completion Date: October 2015
Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Regimen 1
MSC2156119J every day for 14 days, followed by seven days with no treatment (21-day cycle).
Drug: MSC2156119J (EMD 1214063)
Cohorts of patients with c-Met alterations will be added at the MTD level in each regimen
Experimental: Regime 2
MSC2156119J three times per week (e.g., Days 1, 3, and 5) for three weeks (21-day cycle).
Drug: MSC2156119J (EMD 1214063)
Cohorts of patients with c-Met alterations will be added at the MTD level in each regimen
Experimental: Regimen 3
MSC2156119J every day for 3 weeks (21-day cycle)
Drug: MSC2156119J (EMD 1214063)
Cohorts of patients with c-Met alterations will be added at the MTD level in each regimen

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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
  2. Histologically or cytologically confirmed solid tumor, either refractory to standard therapy or for which no effective standard therapy is available
  3. Measurable or evaluable disease, as defined by RECIST 1.0
  4. Estimated life expectancy greater than (>) three months
  5. Men or women aged greater than or equal to (>=) 18 years
  6. 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.
  7. 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.
  8. ECOG performance status of 0 to 2
  9. Adequate hematological function:

    • Hemoglobin >= 9.0 g/dL
    • Neutrophils > 1.5 x 109/L
    • Platelets >= 75 x 109/L
  10. Adequate liver function:

    • Total bilirubin less than or equal to (<=) 1.5 x ULN (upper limit to normal)
    • AST/ ALT ≤ 2.5 x ULN

    For subjects with liver metastases:

    • Total bilirubin ≤ 1.5 x ULN
    • AST/ ALT ≤ 5 x ULN
  11. Adequate renal function:

    • Serum creatinine < 1.5 x ULN, and/or
    • Calculated creatinine clearance > 60 mL/min
  12. Resolution of all acute chemotherapy, radiotherapy or surgery-related AEs to Grade <= 2, except for alopecia
  13. Recovery from any surgical intervention
  14. Subjects enrolling after the MTD has been determined must present specific c Met alterations (mutation, overexpression, amplification

Exclusion Criteria:

  1. Received chemotherapy, immunotherapy, hormonal therapy (except subjects with prostate cancer), biologic therapy, or any other investigational agent or anticancer therapy within 28 days (or five half-lives for non-cytotoxics, whichever is shorter), of Day 1 of trial treatment (six weeks for nitrosureas or mitomycin C)
  2. Received extensive prior radiotherapy on more than 30% of bone marrow
  3. Symptomatic primary tumors or metastasis of brain and/or central nervous system, uncontrolled with antiepileptics and requiring high doses of steroids
  4. Known HIV positivity, active hepatitis C, or active hepatitis B
  5. Medical history of liver fibrosis/ cirrhosis
  6. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such
  7. Medical history of difficulty swallowing, malabsorption or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the tested product
  8. Medical history of surgery within six weeks prior to enrollment
  9. Impaired cardiac function (left ventricular ejection fraction < 45% defined by echocardiograph, serious arrhythmia, unstable angina pectoris, congestive heart failure NYHA III and IV, myocardial infarction within the last 12 months prior to trial entry; signs of pericardial effusion)
  10. Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mm Hg)
  11. Peripheral neuropathy Grade >= 2
  12. 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
  13. Women who are pregnant or nursing
  14. Known drug abuse or alcohol abuse
  15. Participation in another clinical trial within the past 28 days
  16. Requires concurrent treatment with a non-permitted drug
  17. Known hypersensitivity to any of the trial treatment ingredients
  18. Legal incapacity or limited legal capacity
  19. Any other reason that, in the opinion of the principal investigator, precludes the subject from participating in the trial
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01014936

Locations
United States, Texas
M.D. Anderson Cancer Center
Houston, Texas, United States
Sponsors and Collaborators
EMD Serono
Merck KGaA
Investigators
Study Director: Medical Responsible EMD Serono, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany
  More Information

Responsible Party: EMD Serono
ClinicalTrials.gov Identifier: NCT01014936     History of Changes
Other Study ID Numbers: EMR200095_001 
Study First Received: November 13, 2009
Last Updated: December 16, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by EMD Serono:
Phase 1
advanced solid tumors
refractory to standard therapy

ClinicalTrials.gov processed this record on August 25, 2016