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

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT02631590
• Collaborator: Bayer (Industry)
• Enrollment: 24
• Location: 1
• Arm: 1
• Actual Duration (Months): 56
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Biliary Carcinoma; Gall Bladder Carcinoma; Cholangiocarcinoma; Gastrointestinal Tumor	Drug: Cisplatin; Drug: Gemcitabine; Drug: Copanlisib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Copanlisib (BAY 80-6946) in Combination With Gemcitabine and Cisplatin in Advanced Cholangiocarcinoma
• Actual Study Start Date: Jul 5, 2016
• Actual Primary Completion Date: Oct 25, 2019
• Actual Study Completion Date: Mar 5, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Combination Therapy 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; Cisplatin administered once as intravenous (IV) infusion over 60 minutes. Treatment is on Days 1 and 8 every 21 days.; Other Names: Platinol ; Drug: Gemcitabine; Gemcitabine administered as 30-min IV infusion. Treatment is on Days 1 and 8 every 21 days.; Other Names: Gemzar ; Drug: Copanlisib; 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.; Other Names: BAY 80-6946

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [6 months]

   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.)

Secondary Outcome Measures

1. Response Rate [Up to 24 months]

   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.

2. Overall Survival (OS) [Up to 24 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Bayer

Investigators

• Principal Investigator: Richard D. Kim, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 26, 2018

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT02631590
• Other Study ID Numbers: MCC-18435
• First Posted: Dec 16, 2015
• Last Update Posted: Aug 4, 2021
• Last Verified: Aug 1, 2021

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: intra-hepatic biliary system; extra-hepatic biliary system; gall bladder; advanced biliary cancer; unresectable; locally advanced; metastatic disease
• Additional relevant MeSH terms: Carcinoma; Cholangiocarcinoma; Urinary Bladder Neoplasms; Digestive System Neoplasms; Gastrointestinal Neoplasms; Gemcitabine

Study Results

Participant Flow

Arm/Group Title	Combination Therapy
Arm/Group Description	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. Cisplatin: Cisplatin administered once as intravenous (IV) infusion over 60 minutes. Treatment is on Days 1 and 8 every 21 days. Gemcitabine: Gemcitabine administered as 30-min IV infusion. Treatment is on Days 1 and 8 every 21 days. Copanlisib: 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.
Period Title: Overall Study
STARTED	24
COMPLETED	24
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Combination Therapy
Arm/Group Description	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. Cisplatin: Cisplatin administered once as intravenous (IV) infusion over 60 minutes. Treatment is on Days 1 and 8 every 21 days. Gemcitabine: Gemcitabine administered as 30-min IV infusion. Treatment is on Days 1 and 8 every 21 days. Copanlisib: 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.
Overall Participants	24
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 50%
>=65 years	12 50%
Sex: Female, Male (Count of Participants)
Female	15 62.5%
Male	9 37.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 12.5%
Not Hispanic or Latino	21 87.5%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	22 91.7%
More than one race	0 0%
Unknown or Not Reported	1 4.2%
Region of Enrollment (participants) [Number]
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	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.)
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Therapy
Arm/Group Description	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. Cisplatin: Cisplatin administered once as intravenous (IV) infusion over 60 minutes. Treatment is on Days 1 and 8 every 21 days. Gemcitabine: Gemcitabine administered as 30-min IV infusion. Treatment is on Days 1 and 8 every 21 days. Copanlisib: 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.
Measure Participants	24
Median (95% Confidence Interval) [months]	6.2

2. Secondary Outcome

Title	Response Rate
Description	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.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

Number of participants evaluable for response

Arm/Group Title	Combination Therapy
Arm/Group Description	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. Cisplatin: Cisplatin administered once as intravenous (IV) infusion over 60 minutes. Treatment is on Days 1 and 8 every 21 days. Gemcitabine: Gemcitabine administered as 30-min IV infusion. Treatment is on Days 1 and 8 every 21 days. Copanlisib: 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.
Measure Participants	19
Partial Response	31.6 131.7%
Stable Disease	57.9 241.3%

3. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Therapy
Arm/Group Description	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. Cisplatin: Cisplatin administered once as intravenous (IV) infusion over 60 minutes. Treatment is on Days 1 and 8 every 21 days. Gemcitabine: Gemcitabine administered as 30-min IV infusion. Treatment is on Days 1 and 8 every 21 days. Copanlisib: 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.
Measure Participants	24
Median (95% Confidence Interval) [months]	13.7

Adverse Events

Time Frame	All adverse events collected from start of study drug to 4 weeks after end of treatment, 2 years 3 months.
Arm/Group Title	Combination Therapy
Arm/Group Description	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. Cisplatin: Cisplatin administered once as intravenous (IV) infusion over 60 minutes. Treatment is on Days 1 and 8 every 21 days. Gemcitabine: Gemcitabine administered as 30-min IV infusion. Treatment is on Days 1 and 8 every 21 days. Copanlisib: 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.
All Cause Mortality
	Combination Therapy
	Affected / at Risk (%)	# Events
Total	18/24 (75%)
Serious Adverse Events
	Combination Therapy
	Affected / at Risk (%)	# Events
Total	12/24 (50%)
Blood and lymphatic system disorders
Anemia	1/24 (4.2%)	2
Gastrointestinal disorders
Abdominal Pain	2/24 (8.3%)	2
Ascites	2/24 (8.3%)	2
Colitis	1/24 (4.2%)	1
Colonic obstruction	1/24 (4.2%)	1
Dysphagia	1/24 (4.2%)	1
Gastrointestinal disorders -Other	1/24 (4.2%)	1
Nausea	1/24 (4.2%)	2
General disorders
Edema limbs	1/24 (4.2%)	1
Fatigue	1/24 (4.2%)	1
Pain	1/24 (4.2%)	1
Hepatobiliary disorders
Cholecystitis	1/24 (4.2%)	1
Gallbladder obstruction	1/24 (4.2%)	1
Hepatic infection	1/24 (4.2%)	2
Infections and infestations
Infections and Infestations - Other	1/24 (4.2%)	1
Lung infection	1/24 (4.2%)	1
Sepsis	2/24 (8.3%)	2
Urinary tract infection	1/24 (4.2%)	1
Investigations
Blood bilirubin increased	2/24 (8.3%)	2
Platelet count decreased	1/24 (4.2%)	1
Metabolism and nutrition disorders
Anorexia	1/24 (4.2%)	1
Dehydration	1/24 (4.2%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified - Other	1/24 (4.2%)	1
Renal and urinary disorders
Urinary tract obstruction	1/24 (4.2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/24 (4.2%)	1
Vascular disorders
Thromboembolic event	1/24 (4.2%)	2
Other (Not Including Serious) Adverse Events
	Combination Therapy
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Blood and lymphatic system disorders
Anemia	16/24 (66.7%)	56
Cardiac disorders
Sinus tachycardia	4/24 (16.7%)	4
Paroxysmal atrial tachycardia	1/24 (4.2%)	1
Pericarditis	1/24 (4.2%)	1
Sinus bradycardia	1/24 (4.2%)	1
Ear and labyrinth disorders
Tinnitus	3/24 (12.5%)	3
Ear pain	1/24 (4.2%)	1
Eye disorders
Cataract	1/24 (4.2%)	1
Dry eye	1/24 (4.2%)	2
Gastrointestinal disorders
Nausea	12/24 (50%)	22
Diarrhea	11/24 (45.8%)	12
Abdominal Pain	10/24 (41.7%)	13
Constipation	6/24 (25%)	7
Vomiting	6/24 (25%)	13
Gastrointestinal disorders - Other	3/24 (12.5%)	4
Mucositis oral	3/24 (12.5%)	3
Abdominal distension	2/24 (8.3%)	3
Ascites	2/24 (8.3%)	2
Bloating	2/24 (8.3%)	4
Dysphagia	2/24 (8.3%)	3
Colitis	1/24 (4.2%)	1
Colonic obstruction	1/24 (4.2%)	1
Dry mouth	1/24 (4.2%)	1
Gastroesophageal reflux disease	1/24 (4.2%)	1
Pancreatitis	1/24 (4.2%)	1
Stomach pain	1/24 (4.2%)	1
Toothache	1/24 (4.2%)	1
General disorders
Fatigue	17/24 (70.8%)	27
Fever	8/24 (33.3%)	24
Edema limbs	5/24 (20.8%)	6
Chills	4/24 (16.7%)	7
Pain	4/24 (16.7%)	4
Infusion related reaction	3/24 (12.5%)	4
Non-cardiac chest pain	3/24 (12.5%)	6
General disorders and administration site conditions -Other	2/24 (8.3%)	2
Gait disturbance	1/24 (4.2%)	1
Infusion site extravasation	1/24 (4.2%)	1
Malaise	1/24 (4.2%)	1
Hepatobiliary disorders
Gallbladder obstruction	2/24 (8.3%)	2
Cholecystitis	1/24 (4.2%)	1
Immune system disorders
Allergic reaction	1/24 (4.2%)	1
Infections and infestations
Sepsis	3/24 (12.5%)	3
Upper respiratory infection	3/24 (12.5%)	3
Urinary tract infection	3/24 (12.5%)	4
Infections and infestations - Other	2/24 (8.3%)	5
Gallbladder infection	1/24 (4.2%)	1
Hepatic infection	1/24 (4.2%)	1
Injury, poisoning and procedural complications
Fracture	1/24 (4.2%)	2
Injury, poisoning and procedural complications - Other	1/24 (4.2%)	1
Venous injury	1/24 (4.2%)	1
Investigations
Lymphocyte count decreased	18/24 (75%)	66
Platelet count decreased	18/24 (75%)	45
White blood cell decreased	17/24 (70.8%)	72
Neutrophil count decreased	16/24 (66.7%)	62
Lipase increased	11/24 (45.8%)	33
Alanine aminotransferase increased	10/24 (41.7%)	21
Weight loss	6/24 (25%)	15
Aspartate aminotransferase increased	5/24 (20.8%)	15
Serum amylase increased	5/24 (20.8%)	9
Alkaline phosphatase increased	4/24 (16.7%)	8
Creatinine increased	4/24 (16.7%)	5
Blood bilirubin increased	3/24 (12.5%)	6
Activated partial thromboplastin time prolonged	1/24 (4.2%)	1
Blood antidiuretic hormone abnormal	1/24 (4.2%)	1
Investigations - Other	1/24 (4.2%)	1
Urine output decreased	1/24 (4.2%)	1
Metabolism and nutrition disorders
Hyperglycemia	13/24 (54.2%)	43
Anorexia	11/24 (45.8%)	14
Hyponatremia	7/24 (29.2%)	10
Dehydration	6/24 (25%)	6
Hyperkalemia	6/24 (25%)	8
Hypoalbuminemia	3/24 (12.5%)	4
Hypercalcemia	1/24 (4.2%)	1
Hypernatremia	1/24 (4.2%)	1
Hyperuricemia	1/24 (4.2%)	1
Hypokalemia	1/24 (4.2%)	1
Hypomagnesemia	1/24 (4.2%)	1
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	3/24 (12.5%)	3
Pain in extremity	3/24 (12.5%)	3
Back pain	2/24 (8.3%)	2
Neck pain	2/24 (8.3%)	2
Bone pain	1/24 (4.2%)	1
Musculoskeletal and connective tissue disorders - Other	1/24 (4.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified - Other	1/24 (4.2%)	1
Nervous system disorders
Dizziness	4/24 (16.7%)	4
Dysgeusia	2/24 (8.3%)	3
Peripheral sensory neuropathy	2/24 (8.3%)	5
Headache	1/24 (4.2%)	1
Parathesia	1/24 (4.2%)	2
Psychiatric disorders
Anxiety	3/24 (12.5%)	3
Depression	2/24 (8.3%)	2
Insomnia	2/24 (8.3%)	2
Confusion	1/24 (4.2%)	1
Renal and urinary disorders
Acute kidney injury	1/24 (4.2%)	1
Cystitis noninfective	1/24 (4.2%)	1
Hematuria	1/24 (4.2%)	1
Renal and urinary disorders - Other	1/24 (4.2%)	1
Urine discoloration	1/24 (4.2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/24 (12.5%)	4
Cough	2/24 (8.3%)	2
Hypoxia	2/24 (8.3%)	3
Pleural effusion	2/24 (8.3%)	2
Aspiration	1/24 (4.2%)	2
Atelectasis	1/24 (4.2%)	1
Epistaxis	1/24 (4.2%)	1
Hiccups	1/24 (4.2%)	1
Hoarseness	1/24 (4.2%)	1
Nasal congestion	1/24 (4.2%)	1
Pneumonitis	1/24 (4.2%)	2
Postnasal drip	1/24 (4.2%)	2
Productive cough	1/24 (4.2%)	1
Sore throat	1/24 (4.2%)	1
Wheezing	1/24 (4.2%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	6/24 (25%)	15
Pruritus	2/24 (8.3%)	2
Rash acneiform	2/24 (8.3%)	3
Dry skin	1/24 (4.2%)	1
Skin and subcutaneous tissue disorders - Other	1/24 (4.2%)	1
Skin ulceration	1/24 (4.2%)	1
Vascular disorders
Hypertension	15/24 (62.5%)	54
Hypotension	6/24 (25%)	8
Thromboembolic event	4/24 (16.7%)	9
Phlebitis	1/24 (4.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.