The purpose of this trial is to determine the maximum tolerated dose (MTD) and the doselimiting toxicity (DLT) in a population of subjects with malignant solid tumours, and to generate safety, PK and Pd marker information. Anti-tumour effects over…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety
The number and proportion of subjects experiencing at least a Dose-Limiting
Toxicity (DLT) over the first cycle - day 1 to 21 for each regimen separately.
DLT is defined as any of the following toxicities at any dose level and judged
to be possibly or probably related to the trial medication by the investigator
and/or the sponsor:
• Any grade 3 or more non-haematological toxicity excluding:
- Grade 3 asymptomatic increase in liver function tests
(AST, ALT, ALP) reversible within 7 days for subjects without liver
involvement, or grade 4 for subjects with liver
involvement.
- Grade 3 vomiting if it is encountered despite adequate
and optimal therapy (e.g. 5HT3 antagonists and corticosteroids).
- Grade 3 diarrhoea if it is encountered despite adequate
and optimal anti diarrhoea therapy.
• Any grade 4 neutropenia of > 5 days duration or febrile neutropenia lasting
for more than 1 day.
• Grade 4 thrombocytopenia > 1 day or grade 3 with bleeding.
• Any treatment delay > 2 weeks due to drug-related adverse effects.
Secondary outcome
Safety:
- The number and proportion of subjects experiencing treatment-emergent adverse
events (TEAE).
- The number and proportion of subjects experiencing clinically significant
changes in a laboratory parameter and/or vital signs judged to be related to
the trial medication.
Pharmacokinetics:
Plasma and urine PK parameters of MSC1936369B.
Pharmacodynamic:
Values and changes over time in Pd markers in circulating PBMC, circulating
tumour cells, apoptosis markers, blood circulating markers and in some subjects
in tissue samples: apoptosis, phospho-ERK, marker of proliferation.
Anti-Tumour Activity (Efficacy):
The number and proportion of subjects with clinical benefit (defined as
Complete Response (CR), Partial Response (PR) or stable disease (SD)) and
progressive disease based on the best overall response which depends on the
tumour evaluations assessed at the end of each 2 cycles.
Background summary
There is a need for new drugs, new treatment methods in patients with cancer.
With this study we hope to learn more about new treatments with the Mek
inhibitor available.
Study objective
The purpose of this trial is to determine the maximum tolerated dose (MTD) and
the doselimiting toxicity (DLT) in a population of subjects with malignant
solid tumours, and to generate safety, PK and Pd marker information.
Anti-tumour effects over single and multiple cycles of
several administration regimens will be explored.
A 3 + 3 dose-escalation design, based on DLT assessments is used.
Study design
This is a Phase I open-label, dose-escalation trial. Cohorts of 3 subjects with
solid tumours will be sequentially assigned to regimen 1 or regimen 2 and
receive MSC1936369B at escalating dose levels. At each dose level subjects will
receive MSC1936369B orally once daily on:
Days 1 to 5, 8 to 12 and 15 to 19 of a 21-day cycle: Regimen 1 (R1)
Or
Days 1 to 15 of a 21-day cycle: Regimen 2 (R2)
Once MTD is reached in Regimen 2, at least 12 additional melanoma subjects will
receive MSC1936369B for the food effect evaluation.
A third dosing regimen (regimen 3, R3) will be investigated separately after
completion of dose-escalation of R1 and R2. Subjects will be enrolled in
cohorts of 3 subjects and receive MSC1936369B at escalating dose levels. At
each dose level, subjects will receive
MSC1936369B orally once daily continuously. There will be no treatment day
break, unless required due to toxicity or progressive disease.
A BID administration will be investigated based on the results from R2 and R3
and from the ongoing EMR200066-002 trial investigating BID administration.
Intervention
The number of times that certain interventions are done is not specified, this
will depend on how long (number of cycles) the subject in the study continues.
Each cycle lasts 21 days, in which: MUGA scan or echocardiography, ECGs,
CT-scans, tumor biopsy, blood sampling will be done and urine wil be collected.
In cycle 1 also a chest X-ray will be done.
Please also refer to the schedule of assessments at page 74-81 of the protocol.
Additionally the subjects participating in the food effect study of R2 will
receive a specific breakfast at Day 1 of cycle 1 and cycle 2.
Study burden and risks
In non-clinical toxicology studies the adverse effects of MSC1936369B were
mostly vessel and organ mineralization probably due to calcium/phosphorus
metabolism de-regulation (only rodents, more sensitive in rat), gastro
intestinal effects, mainly in dogs (leading to bloody soft stools and weight
loss), decrease in red blood cell parameters, atrophy in lymphoid organs and
cardio vascular effect in dogs (atrioventricular block, hypertension).
Adverse effects that may be expected to occur in human clinical trials include
gastrointestinal toxicities such as, nausea, vomiting, diarrhoea and
mucositis/stomatitis, calcium phosphorus deregulation, lymphopenia and
cardio-vascular manifestations such as hypertension.
Other MEK inhibitors have been tested in subjects. Side effects such as skin
rash, diarrhea, and visual disturbances have been reported in those studies and
have been observed as well in this trial.
Additional adverse events not previously observed in animals may also occur in
humans.
Subjects in this clinical trial of MSC1936369B will be monitored closely for
the development of adverse effects that may result from trial drug
administration.
Overall, MSC1936369B is thought to have an adequate risk/benefit profile for
subjects with malignancies, who have failed standard therapy. Single-agent
MSC1936369B has shown early signs of clinical activity in melanoma with partial
responses according to RECIST 1.0 and
durable stable diseases with tumour shrinkage. In other tumour types, no clear
objective responses have been observed so far, only stable diseases.
Tupolevlaan 41-61
1119 NW Schiphol-Rijk
NL
Tupolevlaan 41-61
1119 NW Schiphol-Rijk
NL
Listed location countries
Age
Inclusion criteria
1. Pathologically-confirmed solid tumour 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 tumour type will be restricted to melanoma.
2. Age 18 years or older.
3. 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.
4. Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For the purposes of this trial, women of childbearing potential is defined as: *All female subjects after puberty unless they are post-menopausal for at least two years, are surgically sterile or are sexually inactive*.
5. Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to, during and four weeks after the last dose trial medication. Adequate contraception is defined as follows: two barrier methods, or one barrier method with a spermicide or intrauterine device.
Exclusion criteria
1. Bone marrow impairment as evidenced by Haemoglobin < 9.0 g/dL, Neutrophil count < 1.0 x 109/l, platelets < 100 x 109/l.
2. Renal impairment as evidenced by serum creatinine > 1.5 x ULN, and/or calculated creatinine clearance < 60 ml/min.
3. Liver function abnormality as defined by total bilirubin > 1.5 x ULN, or AST/ALT > 2.5 x ULN, for subjects with liver involvement AST/ALT > 5 x ULN.
4. INR > 1.5 x ULN
5. Serum calcium > 1 x ULN.
6. History of CNS metastases, unless subject has been previously treated for CNS metastases, is stable by CT scan without evidence of cerebral oedema, and has no requirements for corticosteroids or anticonvulsants.
7. History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the tested product.
8. Eastern Cooperative Oncology Group Performance status (ECOG PS) greater than 1.
9. Known HIV positivity, active hepatitis C, or active hepatitis B.
10. Has received chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anticancer therapy or surgical intervention within 28 Days or 5 half lives for non-cytotoxics (whichever is longer) of Day 1 of trial drug treatment (6 weeks for nitrosureas or mitomycin C).
11. Has received extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation.
12. Has received any investigational agent within 28 days or 5 half lives for non-cytotoxics (whichever is longer) of Day 1.
13. Has history of any other significant medical disease or intervention such as major gastric or small bowel surgery, recent drainage of significant volumes of ascites or pleural effusion or has a psychiatric condition that might impair the subject*s well being or preclude full participation in the trial.
14. Has significant cardiac conduction defects and/or pacemaker
15. Has hypertension uncontrolled by medication
16. Is a pregnant or nursing female.
17. Has retinal degenerative disease (Hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-004665-18-NL |
| ClinicalTrials.gov | NCT00982865 |
| CCMO | NL35213.031.11 |