Copanlisib (BAY 80-6946) in Combination With Gemcitabine and Cisplatin in Advanced Cholangiocarcinoma

Inclusion Criteria:

- Must have histologically or cytologically documented carcinoma primary to the intra-
or extra-hepatic biliary system or gall bladder with clinical and/or radiologic
evidence of unresectable, locally advanced or metastatic disease. Patients with
ampullary carcinoma are not eligible.

- Must not have received any systemic chemotherapy for advanced biliary cancer.

- Patients who received adjuvant chemotherapy plus or minus radiation and had evidence
of disease recurrence within 6 months of completion of the adjuvant treatment are not
eligible. If patients received adjuvant treatment and had disease recurrence after 6
months, patients will be eligible.

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

- Must have radiographic measurable disease.

- Life expectancy of at least 12 weeks (3 months).

- For patients who have received prior radiation, cryotherapy, radiofrequency ablation,
therasphere, ethanol injection, transarterial chemoembolization (TACE) or photodynamic
therapy, the following criteria must be met: 28 days have elapsed since that therapy;
Lesions that have not been treated with local therapy must be present and measureable.

- Adequate bone marrow, liver and liver function.

- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of study drug. Men and women of childbearing
potential must agree to use adequate contraception beginning at the signing of the
Informed Consent Form (ICF) until at least 3 months after the last dose of study drug.

- Must be able to swallow and retain oral medication.

- Availability of archival tumor tissue for biomarkers analysis (minimum of 10 unstained
slides are optional). Specimen from primary site will be allowed.

Exclusion Criteria:

- Previous or concurrent cancer within 3 years prior to treatment start except for
curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial
bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades
lamina propria)].

- Congestive heart failure > New York Heart Association (NYHA) class 2.

- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
months).

- Myocardial infarction less than 6 months before study enrollment

- Uncontrolled hypertension (blood pressure ≥ 150/90 mmHg despite optimal medical
management).

- Arterial or venous thrombotic or embolic events such as cerebrovascular accident
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism
within the 6 months before enrollment.

- Non-healing wound, ulcer, or bone fracture.

- Active clinically serious infections (> Common Terminology Criteria for Adverse Events
(CTCAE) grade 2).

- Known history of human immunodeficiency virus (HIV) infection.

- Known active Hepatitis B or C.

- A seizure disorder requiring medication.

- Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE
Grade 3 within 4 weeks of start of study enrollment.

- Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results.

- Known hypersensitivity to any of the test drugs, test drug classes, or excipients in
the formulation.

- History or concurrent condition of interstitial lung disease of any grade or severely
impaired pulmonary function.

- Unresolved toxicity higher than CTCAE grade 1 attributed to any prior
therapy/procedure excluding alopecia.

- HbA1c >8.5% or fasting plasma glucose > 160 mg/dL at screening.

- Concurrent diagnosis of pheochromocytoma.

- Women who are pregnant or breast feeding.

- Any illness or medical conditions that are unstable or could jeopardize the safety of
the patient and his/her compliance in the study.