A Dose Escalation Trial of Wee1 Inhibitor MK1775

This is a dose-escalation trial to determine the maximum tolerated dose of MK-1775 when
administered with gemcitabine and radiation, in patients with unresectable pancreatic
cancer. Dose-escalation will be managed by the TITE-CRM algorithm (see below), with the goal
of establishing the target dose, as per the table below. In the clinical studies so far in
which MK-1775 was combined with 800-1000 mg/m2 of gemcitabine, the MTD for a single dose of
MK-1775 was 200 mg. For a 5-dose regimen given bid, the MTD was 50/50/25/25/25 mg, which
would not be anticipated to inhibit pCDC2, which is the target for Wee1 (27). As doses
above 100 mg are required to inhibit pCDC2 in >50% of patients, and, based on our
pre-clinical data, we would like to inhibit for up to at least 30 hours after the
gemcitabine, we would wish to explore a 2 dose regimen (day 1 and day 2), and propose a
starting level of 125 mg. Merck is now evaluating MK-1775 at 175 mg QD x 2 doses with
gemcitabine (1000 mg/m2). A total of 8 patients have completed treatment. They have observed
1/8 DLT of Gr 4 neutropenia or thrombocytopenia, so this will likely be the recommended
phase II dose. Dose confirmation is ongoing. Therefore, our goal would be to reach 175 mg
(day 1,2 and 8,9) with full dose gemcitabine, although we would anticipate pCDC2 inhibition
might be achieved at lower doses (see Sections 10 and 11 for biomarker assessment).

Inclusion Criteria:

- Patients must have pathologically confirmed adenocarcinoma of the pancreas.

- Patients will have unresectable disease as assessed at our weekly Multidisciplinary
Pancreatic Tumor Conference.

=Patients must have a Zubrod performance status of < 2.

- Patients must have adequate organ function defined as follows: absolute neutrophil
count of ≥ 1500/mm3, platelets ≥ 100,000/mm3, serum creatinine ≤ 2 mg/dl, total
bilirubin ≤ 3, (with relief of biliary obstruction if present (PTC tube or
endobiliary stent)) and AST < 5 times the upper limit of normal.

- Patients must be free of any other serious uncontrolled concomitant systemic
disorders or psychiatric condition that would interfere with the safe delivery of
protocol therapy.

- Patients of reproductive potential must agree to use an effective contraceptive
method during participation in this trial and for 6 months after the trial.

- Patients must be aware of the investigational nature of the therapy and provide
written informed consent.

- Patients must be at least 18 years old

- Patient has had prescription or non-prescription drugs or other products known to be
metabolized by CYP3A4, or to inhibit or induce CYP3A4, that cannot be discontinued
prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the
last dose of study medication. Medications of particular concern are the following
inhibitors of CYP3A4: azole antifungals (ketoconazole itraconazole, fluconazole and
voriconazole), macrolide antibiotics (erythromycin, clarithromycin), cimetidine,
aprepitant, HIV protease inhibitors, nefazodone and the following inducers of CYP3A4:
phenytoin, barbiturates and rifampicin. Substrates of CYP3A4 include statins
(lovastatin, simvastatin), midazolam, terfenadine, astemizole, and cisapride. Refer
to Appendix A for a list of commonly used moderate and potent CYP3A4 modifiers. For
other concomitant medications not on this list and known to significantly influence
CYP3A4, the Investigator and SPONSOR will determine if it should be discontinued.

Exclusion Criteria:

- Patients must have no history of previous chemotherapy for pancreatic cancer or
abdominal radiation therapy.

- Patients must not have used any investigational agent in the month before enrollment
into the study.

- No prior therapy for pancreatic cancer