Phase I Dose Escalation Trial of MEK1/2 Inhibitor MSC1936369B Combined With Temsirolimus in Subjects With Advanced Solid Tumors
1. Subjects with histologically or cytologically confirmed solid tumors, either
refractory to standard therapy or for which no effective standard therapy is
2. Measurable or evaluable disease at baseline by RECIST 1.0.
3. Age ≥ 18 years.
4. Subject has read and understands the informed consent form and is willing and able to
give informed consent.
5. Performance Status score of ≤ 1 according to the Eastern Cooperative Oncology Group
6. Women of childbearing potential must have a negative blood pregnancy test at the
7. 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 screening, during the trial and for 3 months
after the last dose of trial medication.
Additional inclusion criteria also apply.
1. The subject has previously been treated with an mTOR inhibitor or a MEK inhibitor and
taken off treatment due to drug-related adverse events.
2. The subject has received any of the following:
- Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, any
investigational agent or any other anti-cancer therapy within 28 days (6 weeks
for nitrosoureas or mitomycin C) of Day 1 of trial treatment; non-cytotoxic
chemotherapy or investigational agent with limited potential for delayed
toxicity is permitted if terminated at least 5 halflives prior to Day 1 of trial
- Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior
bone marrow/stem cell transplantation.
3. The subject has not recovered from toxicity due to prior therapy to baseline or
Common Terminology Criteria for Adverse Events (CTCAE v4.0) of Grade 1 or less
4. The subject has poor organ or marrow function
5. History of CNS metastases or primary CNS tumor, unless subject has been previously
treated for these conditions, is asymptomatic and has had no requirement for
anticonvulsants or high dose corticosteroids for a minimum of 2 weeks prior to entry
into the trial.
6. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months of Day 1 of trial drug treatment.
7. Recent major surgery or trauma (within the last 28 days), unhealing/open wounds,
diabetic ulcers, recent drainage of significant volume of ascites or pleural
8. History of congestive heart failure, unstable angina, myocardial infarction,
symptomatic cardiac conduction abnormality, pacemaker, or other clinically
significant cardiac disease or history of a stroke within 3 months prior to entering
9. Baseline corrected QT interval on screening electrocardiogram (ECG) (QTc) ≥ 460 ms or
left ventricular ejection fraction (LVEF) < 40% on screening echocardiogram.
10. Other uncontrolled intercurrent diseases
11. Retinal degenerative disease (hereditary retinal degeneration or age-related macular
degeneration), history of uveitis or history of retinal vein occlusion, or medically
relevant abnormal ophthalmology assessments at screening.
12. Known or suspected allergy to MSC1936369B, temsirolimus, other rapamycins (sirolimus,
everolimus, etc.), their excipients, or any agent given in the course of this trial.
13. Immunization with attenuated live vaccines within one week of trial entry (examples
of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio,
14. Concomitant use of any medications or substances that are strong inhibitors or
inducers of CYP3A enzyme, including, but not limited to, phenytoin, carbamazepine,
barbiturates, azoles, rifampin, phenobarbital, or St. John's Wort.
15. Pregnant or lactating female.
16. Legal incapacity or limited legal capacity.
Additional exclusion criteria also apply.