Copanlisib, Gemcitabine Hydrochloride, and Cisplatin in Treating Patients with Cholangiocarcinoma That Is Locally Advanced, Metastatic, or Cannot Be Removed by Surgery

Inclusion Criteria

• Patients 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
• Patients 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
• The patient must have radiographic measurable disease per Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) criterion
• 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 measurable
• Subjects must be able to understand and be willing to sign the written informed consent form; a signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure
• All acute toxic effects of any prior treatment have resolved to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) grade 1 or less at the time of signing the informed consent form (ICF) except for alopecia
• Total bilirubin =< 1.5 x the upper limits of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer)
• Alkaline phosphatase limit =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer)
• Serum creatinine =< 1.5 x the ULN and calculated creatinine clearance > 30 ml/min
• Platelet count >= 100,000 /mm^3
• Hemoglobin (Hb) >= 9 g/dL
• Absolute neutrophil count (ANC) >= 1000/mm^3
• Blood transfusion to meet the inclusion criteria will be allowed
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug; post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test
• Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 3 months after the last dose of study drug; the definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate
• Multi-gated acquisition scan (MUGA) or echocardiogram (ECHO) for left ventricular ejection fraction (LVEF) >= 45%
• Subject 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 (> CTCAE grade 2)
• Known history of human immunodeficiency virus (HIV) infection
• Known active hepatitis B or C
• Patients with seizure disorder requiring medication
• Strong inducers of cytochrome P450 3A4 (CYP3A4) are not permitted starting day -14 of cycle 1
• Patients with 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
• Glycosylated hemoglobin (HbA1c) > 8.5% or fasting plasma glucose > 160 mg/dL at screening
• Concurrent diagnosis of pheochromocytoma
• Pregnant or breast-feeding patients; women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment
• Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study
• Proteinuria of CTCAE grade 3 or higher (> 3.5 g/24 h, measured by urine protein: creatinine ratio on a random urine sample)
• Excluded therapies and medications for cancer * Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of study enrollment; subjects must have recovered from the toxic effects of the previous anti-cancer chemotherapy or immunotherapy (with the exception of alopecia); anti-cancer therapy is defined as any agent or combination of agents with clinically proven anti-tumor activity administered by any route with the purpose of affecting the malignancy, either directly or indirectly, including palliative and therapeutic endpoints; however, subjects with prostate cancer who are receiving depot luteinizing hormone-releasing hormone (LHRH) agonist therapy may continue on this treatment * Hormonal therapy during the study or within 2 weeks of first study enrollment * Radiotherapy to target lesions during study or within 4 weeks of first study treatment * An irradiated lesion is considered evaluable only if it has shown enlargement since the completion of last radiation * Bone marrow transplant or stem cell rescue * Bisphosphonate therapy during the first 2 cycles of treatment * Granulocyte colony stimulating factor (G-CSF) and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the principal investigator; however they may not be substituted for a required dose reduction; erythropoietins are not permitted * Investigational drug therapy outside of this trial during or within 4 weeks of first study treatment