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

Study Overview
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Brief Summary
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The purpose of this study is to see if an experimental drug, called copanlisib is effective and safe in treating adult participants with cholangiocarcinoma, when used in combination with gemcitabine and cisplatin.

Official Title
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Phase II Study of Copanlisib (BAY 80-6946) in Combination With Gemcitabine and Cisplatin in Advanced Cholangiocarcinoma

Conditions
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Biliary Carcinoma, Gall Bladder Carcinoma, Cholangiocarcinoma, Gastrointestinal Tumor

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Gemcitabine
* Drug: Copanlisib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination Therapy<br>Treatment Plan: Cisplatin (25 mg/m^2 ) + Gemcitabine (1000 mg/m^2) + copanlisib (60 mg) on days 1 and 8 with day 15 off to be administered on an every 21-days schedule. | Drug: Cisplatin<br>* Cisplatin administered once as intravenous (IV) infusion over 60 minutes. Treatment is on Days 1 and 8 every 21 days.<br>* Other names: Platinol;Drug: Gemcitabine<br>* Gemcitabine administered as 30-min IV infusion. Treatment is on Days 1 and 8 every 21 days.<br>* Other names: Gemzar;Drug: Copanlisib<br>* Experimental Drug: Copanlisib administered as an IV over 60-minutes beginning 1 hour after completing gemcitabine infusion. Treatment is on Days 1 and 8 every 21 days.<br>* Other names: BAY 80-6946;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS at six months. Response and progression will be evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). PFS will be calculated from study entry to documented disease progression, death from any cause, or date of last follow-up, whichever comes first. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression.) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Complete Response + Partial Response according to RECIST 1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | Up to 24 months | 
| Overall Survival (OS) | The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intra-hepatic biliary system, extra-hepatic biliary system, gall bladder, advanced biliary cancer, unresectable, locally advanced, metastatic disease