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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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Pancreatic Cancer

Thank you

Trial Information

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

Inclusion Criteria


- Histologically or cytologically confirmed ductal adenocarcinoma of the pancreas

- Stage IV, unresectable disease

- Assessable disease by endoscopic ultrasound or CT guidance

- Tissue that is assessed by the Investigator as being accessible to biopsy

- No known brain metastases

- Patients with stable symptoms within the past 4 weeks, on a stable dose of
steroids, and able to give informed consent are eligible


- WHO performance status 0-1

- Life expectancy ≥ 12 weeks

- Hemoglobin ≥ 9.0 g/dL

- Absolute neutrophil count ≥ 1.5 x 10^9/L

- Platelet count ≥ 100 x 10^9/L

- Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT ≤ 2.5 times ULN (≤ 5 times ULN if due to liver metastases)

- PT ≤ 1.5 times ULN

- Creatinine clearance ≥ 50 mL/min (uncorrected)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use two forms of highly effective contraception (females) 4
weeks prior to, during, and for 6 months after completion of study therapy or 1 form
of highly effective contraception (males) during and for 6 months after completion of
study therapy

- Written (signed and dated) informed consent and capable of cooperating with treatment
and follow-up

- No nonmalignant systemic disease, including active uncontrolled infection, that
confers a high medical risk to the patient

- No known serologically positive HIV or hepatitis B or C infection

- No other concurrent malignancies except adequately treated cone-biopsied carcinoma in
situ of the uterine cervix, basal or squamous cell carcinoma of the skin, or cancer
survivors who have undergone potentially curative therapy for a prior malignancy,
have no evidence of that disease ≥ 5 years, and are deemed at negligible risk for

- No concurrent congestive heart failure

- No prior history of cardiac disease (New York Heart Association class III-IV
disease), cardiac ischemia, or cardiac arrhythmia

- No other condition that, in the investigator's opinion, would not make the patient a
good recommendation for the clinical trial


- See Disease Characteristics

- Recovered from prior treatments

- No prior chemotherapy for advanced disease

- Adjuvant chemotherapy allowed provided it is completed > 6 months prior to study
treatment. If adjuvant gemcitabine was given, the patient must have tolerated a
dose of at least 800mg/m^2

- No major thoracic or abdominal surgery from which the patient has not yet recovered

- No concurrent participation or planned participation in another interventional
clinical study

- Concurrent participation in an observational study allowed

- No concurrent warfarin

- Low molecular weight heparin allowed

- No concurrent radiotherapy (except palliative for bone pain), endocrine therapy, or

- No other concurrent anticancer therapy or investigational drugs

Type of Study:


Study Design:

Allocation: Non-Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Safety Issue:


Principal Investigator

Duncan Jodrell, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cambridge University Hospitals NHS Foundation Trust


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

April 2010

Completion Date:

Related Keywords:

  • Pancreatic Cancer
  • stage IV pancreatic cancer
  • duct cell adenocarcinoma of the pancreas
  • Pancreatic Neoplasms