First-in-Man, Dose-escalation Trial of C-met Kinase Inhibitor MSC2156119J in Subjects With Advanced Solid Tumors

Merck KGaA (EMD Serono)

Status and phase: Completed; Phase 1

Conditions: Patients With Solid Tumors, Either Refractory to Standard Therapy or for Which no Effective Standard Therapy is Available

Treatments: Drug: MSC2156119J

Study type: Interventional

Funder types: Industry

Identifiers

NCT01014936

2013-003767-63 (EudraCT Number)

EMR200095_001

Details and patient eligibility

About

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)

Enrollment: 149 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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149 participants in 3 patient groups

MSC2156119J Regimen 1

Experimental group

Description:

Subjects will be administered with micronized or non-micronized MSC2156119J in dose ranging from 30 mg to 400 mg (capsule formulation) once daily for 14 days, followed by 7 days with no treatment (21-day cycle) in Regimen 1.

Treatment:

Drug: MSC2156119J

MSC2156119J Regimen 2

Experimental group

Description:

Subjects will be administered with micronized or non-micronized MSC2156119J in dose ranging from 60 mg to 315 mg (capsule formulation) once daily 3 times per week for 3 weeks (21-day cycle) in Regimen 2.

Treatment:

Drug: MSC2156119J

MSC2156119J Regimen 3

Experimental group

Description:

Subjects will be administered with micronized MSC2156119J in dose ranging from 300 mg to 1400 mg (capsule or tablet formulation) once daily for 21 days (21-day cycle) in Regimen 3.

Treatment:

Drug: MSC2156119J