Study of CX-4945 in Combination With Gemcitabine and Cisplatin for Frontline Treatment of Cholangiocarcinoma

Protein kinase CK2 is a constitutively active serine/threonine kinase with a long history as
a pro-survival, anti-apoptotic kinase. Given the wide spread overexpression of CK2 in
multiple cancers and its role in multiple non-oncogenic processes required to sustain the
cancer phenotype, a selective inhibitor of CK2 is an attractive targeted approach to treating
cancer.

CX-4945 is a tetracyclic, small molecule carboxylate acid salt that exhibits potent and
highly selective inhibition of CK2. Protein kinase CK2 is also known to play an important
role in the DNA damage repair mechanisms of cancer cells, and this study of CX-4945 in
combination with gemcitabine plus cisplatin will determine if inhibition of CK2, in
conjunction with the use of chemotherapy drugs, will result in improved clinical outcomes for
patients with non-resectable cholangiocarcinoma.

Inclusion Criteria:

- Presence of an unresectable hepatobiliary mass or metastatic disease (consistent with
cholangiocarcinoma, as evidenced by histology or cytology (augmented by fluorescence
in situ hybridization (FISH) where appropriate), for which treatment with gemcitabine
plus cisplatin is intended. Intrahepatic and extrahepatic cholangiocarcinoma patients
may be enrolled.

- For patients enrolled in the Dose Escalation Phase, one or more tumors measurable on
radiograph or CT scan, or evaluable disease defined as non-measurable lesions per
RECIST v. 1.1 (e.g., malignant ascites). All patients enrolled to the Randomized Study
Phase must have measurable disease only.

- Laboratory data as specified below:

- Hematology: Absolute neutrophil count (ANC) >1,500 cells/mm3, platelet count
>100,000 cells/ mm.cu. and hemoglobin > 9 g/dL

- Hepatic: bilirubin <1.5 X Upper Limit of Normal (ULN); alkaline phosphatase
(ALP), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 5.0 X
ULN

- Renal: serum creatinine within normal limits (WNL), defined as within 25% of the
institution's stated reference range, or a calculated creatinine clearance >45
mL/min/1.73 m. sq. for patients with abnormal, increased, creatinine levels.

- Coagulation: International Normalized Ratio (INR) < 1.5 times normal, activated
Partial Thromboplastin Time (aPTT) < 1.5 times normal. Patients receiving
therapeutic doses of anticoagulant therapy may be considered eligible for the
trial if INR and aPTT are within the acceptable therapeutic limits for the
institution.

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 1.

Exclusion Criteria:

- A history of prior systemic treatment with gemcitabine or cisplatin. At least six
months must have elapsed if gemcitabine or cisplatin was administered in an adjuvant
treatment setting. Patients enrolled in the Expansion Cohort, Exploratory Cohorts, and
the Randomized Phase must not have received prior systemic chemotherapies, including
chemoradiation therapy for cholangiocarcinoma.

- Seizure disorders requiring anticonvulsant therapy.

- Known brain metastases (unless previously treated and well controlled for a period of
at least 3 months).

- Major surgery other than diagnostic surgery, within 4 weeks prior to the first dose of
test drug, minor surgery including diagnostic surgery within 2 weeks (14 days)
excluding central IV port placements and needle aspirate/core biopsies. Radio
frequency ablation or transcatheter arterial chemoembolization within 6 weeks prior to
the first dose of test drug.

- Treatment with radiation therapy or surgery within one month prior to study entry.

- Treatment with chemotherapy or investigational drugs within 21 days prior to the
screening visit. Acute toxicities from prior therapy must have resolved to Grade ≤ 1
above baseline.

- Patients with a history of another malignancy within 3 years of the baseline visit.
(Patients with cutaneous carcinomas or in-situ carcinomas will be considered for study
entry on a case-by-case basis).

- Concurrent severe or uncontrolled medical disease (i.e., systemic infection, diabetes,
hypertension, coronary artery disease, congestive heart failure).

- Active symptomatic fungal, bacterial and/or viral infection including active HIV or
viral (A, B or C) hepatitis which would not permit the patient to be managed according
to the protocol.

- Difficulty with swallowing or an active malabsorption syndrome.

- Chronic diarrhea (excess of 2-3 stools/day above normal frequency).

- Gastrointestinal diseases including ulcerative colitis, Crohn's disease, or
hemorrhagic coloproctitis.

- History of gastric or small bowel surgery involving any extent of gastric or small
bowel resection.

- Clinically significant bleeding event within the last 3 months, unrelated to trauma,
or underlying condition that would be expected to result in a bleeding diathesis.