Clinical trial NCT01014936: First-in-Man, Dose-escalation Trial of C-met Kinase Inhibitor MSC2156119J in Subjects With Advanced Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Patients With Solid Tumors, Either Refractory to Standard Therapy or for Which no Effective Standard Therapy is Available
Keywords: Phase 1
advanced solid tumors
refractory to standard therapy
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2009-11-17
Enrollment: 149
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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:

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

Primary outcomes:
measure: Number of Subjects With Any Dose Limiting Toxicity (DLT)
timeFrame: Day 1, 3, 8, 14, 17 of Cycle 1 (for Regimen 1 and 3); Day 1, 3, 8, 15, 19 of Cycle 1 (for Regimen 2)
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: Cycle 1 (Day 1 to Day 21)
measure: Number of Subjects With Treatment-Related Adverse Events
timeFrame: Baseline up to 158.01 weeks
Secondary outcomes:
measure: Number of Subjects With Treatment-Emergent AEs (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death
timeFrame: Baseline up to 158.01 weeks
measure: Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Observed Maximum Plasma Concentration (Cmax) After Single Dose of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
measure: Observed Maximum Plasma Concentration (Cmax) After Multiple Dose of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48, 49.32 hours post-dose on Day 1 Cycle 1
measure: Time To Reach Maximum Plasma Concentration (Tmax) After Single Dose of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
measure: Time To Reach Maximum Plasma Concentration (Tmax) After Multiple Dose of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Terminal Half-life ( t1/2) After Single Dose Of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
measure: Apparent Terminal Half-life (t1/2) After Multiple Dose Of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t) After First Dose of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: 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
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: 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
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: 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
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: 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
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
measure: 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
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) After Single Dose Of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48 hours post-dose on Day 1 Cycle 1
measure: Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Single Dose of MSC2156119: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48 hours post-dose on Day 19 Cycle 1
measure: Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau) After Multiple Dose of MSC2156119: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Body Clearance (CL/f) After First Dose of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Volume of Distribution (Vz/f) After First Dose of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
measure: Apparent Volume of Distribution (Vz/f) After Multiple Dose of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Terminal Rate Constant (λz) After Single Dose of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 1 Cycle 1
measure: Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 1
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 2
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 19 Cycle 1
measure: Apparent Terminal Rate Constant (λz) After Multiple Dose of MSC2156119J: Regimen 3
timeFrame: pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10, 24 hours post-dose on Day 14 Cycle 1
measure: Absolute Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2
timeFrame: Baseline, Day 1 Cycle 2
measure: Fold Change From Baseline in Cytoplasm and Membrane H-Score at Day 1 Cycle 2
timeFrame: Baseline, Day 1 Cycle 2
measure: Number of Subjects With Monovalent Antagonist Antibody to Receptor MET (MetMAb) Score (MMS)
timeFrame: Day 1 Cycle 2
measure: Relative Percentage Change In Sum of Longest Diameter (SOLD) of Target Lesions to Post-Baseline Nadir
timeFrame: Baseline, On Treatment (up to 153.3 weeks)
measure: Number of Subjects With Best Overall Response (BOR)
timeFrame: Baseline up to 153.3 weeks
measure: Progression-free Survival (PFS)
timeFrame: Baseline up to 153.3 weeks
Other outcomes:
Locations:
city: Houston
country: United States
facility: M.D. Anderson Cancer Center
state: Texas
Study officials:
affiliation: EMD Serono, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Falchook GS, Kurzrock R, Amin HM, Xiong W, Fu S, Piha-Paul SA, Janku F, Eskandari G, Catenacci DV, Klevesath M, Bruns R, Stammberger U, Johne A, Bladt F, Friese-Hamim M, Girard P, El Bawab S, Hong DS. First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors. Clin Cancer Res. 2020 Mar 15;26(6):1237-1246. doi: 10.1158/1078-0432.CCR-19-2860. Epub 2019 Dec 10.
citation: Xiong W, Hietala SF, Nyberg J, Papasouliotis O, Johne A, Berghoff K, Goteti K, Dong J, Girard P, Venkatakrishnan K, Strotmann R. Exposure-response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations. Cancer Chemother Pharmacol. 2022 Jul;90(1):53-69. doi: 10.1007/s00280-022-04441-3. Epub 2022 Jun 30.