A Cancer Research UK Phase I/IIa Trial of an Oral Notch Inhibitor (MK-0752) in Combination With Gemcitabine in Patients With Stage IV Pancreatic Cancer
- To determine the recommended phase II dose of MK0752 in combination with gemcitabine
hydrochloride in patients with unresectable stage IV pancreatic cancer. (Phase I)
- To determine the safety and tolerability of this regimen in these patients. (Phase II)
- To assess survival at 6 months. (Phase II)
- To evaluate tumor response in patients treated with this regimen.
- To determine the time to disease progression and 1-year survival.
- To determine the percentage of change in CA19-9 levels.
- To assess target inhibition of MK0752 in plasma.
- To explore the feasibility of measuring MK0752 levels in tumor tissue.
- To establish relationships between measures of tumor expression of molecular target and
objective tumor response.
- To determine the potential for noninvasive imaging using fludeoxyglucose F 18 positron
emission tomography/computed tomography scans as a marker of response to MK0752.
- To determine the pharmacokinetic profile of MK0752 in plasma when administered with and
without gemcitabine hydrochloride.
OUTLINE: This is a multicenter, phase I, dose-escalation study of MK0752 and gemcitabine
hydrochloride followed by an open-label, phase II study.
Patients receive gemcitabine hydrochloride IV on days 1, 8, and 15. Patients receive oral
MK0752 on days -14, -7, 1, 8, 15, and 22 in course 1 only and on days 1, 8, 15, and 22
beginning in course 2 and for all subsequent courses. Treatment with MK0752 and gemcitabine
hydrochloride repeats every 28 days* for 6 courses in the absence of disease progression or
unacceptable toxicity. Patients also undergo fludeoxyglucose F 18 PET/CT scans at baseline
and during study to measure changes in tumor uptake.
NOTE: *The first course is 42 days.
Patients undergo biopsy of tumor at baseline and on day -7. Tumor samples are analyzed to
determine Notch pathway inhibition via IHC and qualitative RT-PCR analysis and for MK0752
concentrations. Hair follicle (from the head) samples are collected at baseline and on day
-7 to determine Notch pathway inhibition via RT-PCR. Blood samples are collected
periodically to determine changes in CA 19-9 levels and MK0752 concentrations.
After completion of study treatment, patients are followed for 28 days and then every 2
months for 1 year. Patients will then be followed up as part of their normal clinic visits
for up to one year after the last patient was treated on the study.
Peer Reviewed and Funded or Endorsed by Cancer Research UK
Allocation: Non-Randomized, Masking: Open Label, Primary Purpose: Treatment
Maximum-tolerated dose of MK0752 in combination with gemcitabine hydrochloride OR the single agent recommended Phase II dose in combination with either 800 mg/m² or 1000 mg/m² as agreed by DDO and clinicians
Duncan Jodrell, MD
Cambridge University Hospitals NHS Foundation Trust
United Kingdom: Medicines and Healthcare Products Regulatory Agency