This site became the new ClinicalTrials.gov on June 19th. Learn more.
Show more
ClinicalTrials.gov Menu IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu IMPORTANT: Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu
Give us feedback

Copanlisib (BAY80-6946) Drug-drug Interaction and Cardiovascular Safety Study in Advanced Solid Tumor Patients

This study is currently recruiting participants.
See Contacts and Locations
Verified May 2017 by Bayer
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT02253420
First received: September 29, 2014
Last updated: May 26, 2017
Last verified: May 2017
  Purpose
In summary, copanlisib is metabolized mainly by the CYP3A4 enzyme, thus a study to evaluate potential DDI (drug-drug interaction) of copanlisib with concomitant CYP3A4 modulators such as Itraconazole (CYP3A4 inhibitor) and Rifampin (CYP3A4 inducer) is necessary. With this regard this study aims to evaluate the effect of Itraconazole or Rifampin on the absorbtion, distribution, metabolization and elimination of Copanlisib (BAY80-6946) . In addition, as parameters of cardiovascular safety , the effect of copanlisib on the heart's ability to pump blood and to rule out copanlisib's potential for causing a specific type of life-threatening arrhythmia, QT/QTc intervals and left ventricular ejection fraction will be evaluated.

Condition Intervention Phase
Medical Oncology Drug: Copanlisib (BAY80-6946) Drug: Itraconazole Drug: Rifampin Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Other
Official Title: An Open-label Non-randomized, Phase 1 Study to Evaluate the Effect of (a) Itraconazole or Rifampin on the Pharmacokinetics of a Single Intravenous Dose of Copanlisib and (b) Copanlisib on Cardiovascular Safety in Subjects With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Area under the curve of Copanlisib [AUC (0-168)] [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.33 (arm B)1.5, (arm A), 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
    Area under the curve from dosing to 168 h after dosing

  • Area under the curve of Copanlisib [AUC (0-168)] with Itraconazole [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
    Area under the curve from dosing to 168 h after dosing

  • AUC (0-168) of Copanlisib with Rifampin [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15. ]
    Within cycle 1, at pre-dose and at 10 min, 1, 1.33, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15

  • Area under the curve of Copanlisib (AUC) [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.33 (arm B)1.5 (arm A), 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Area under the curve of Copanlisib (AUC) with Itraconazole [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • AUC of Copanlisib with Rifampin [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.33, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Maximum concentration attained after dosing (Cmax) of Copanlisib [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.33 (arm B)11.5, , 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Maximum concentration attained after dosing (Cmax) of Copanlisib with Itraconazole [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Maximum concentration attained after dosing (Cmax) of Copanlisib with Rifampin [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.33, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Time-matched largest change of QT interval (Frederica's correction) [QTcF] after dosing of Copanlisip [ Time Frame: Baseline and Cycle 1: Day 1 ]
    Continuous 12-Lead electrocardiograms / electrocardiographys (ECGs) will be collected using 12-Lead Digital Holter Recorder


Secondary Outcome Measures:
  • Area under the curve from dosing to last measurement [AUC(0-tlast)] of Copanlisib [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.33 (arm B)1.5 (arm A), 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Area under the curve from dosing to last measurement [AUC(0-tlast)] of Copanlisib with Itraconazole [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1,1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Area under the curve from dosing to last measurement [AUC(0-tlast)] of Copanlisib with Rifampin [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.33, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Time from dosing to attainment of Cmax (tmax) of Copanlisib [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Time from dosing to attainment of Cmax (tmax) of Copanlisib with Itraconazole [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Time from dosing to attainment of Cmax (tmax) of Copanlisib with Rifampin [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.33, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Time from dosing to last measurement (tlast) of Copanlisib [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.33 (arm B)1.5 (arm A), 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Time from dosing to last measurement (tlast) of Copanlisib with Itraconazole [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Time from dosing to last measurement (tlast) of Copanlisib with Rifampin [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.33, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Terminal half-life (t1/2) of Copanlisib [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Terminal half-life (t1/2) of Copanlisib with Itraconazole [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Terminal half-life (t1/2) of Copanlisib with Rifampin [ Time Frame: Within cycle 1, at pre-dose and at 10 min, 1, 1.33, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after start of drug infusion on Days 1 and 15 ]
  • Urine [AE,ur(0-24)] after dosing of Copanlisib [ Time Frame: Within cycle 1, in two sampling intervals from 0-8 and > 8 up to 24 hours after start of drug infusion on Days 1 and 15 ]
    Amount of drug excreted via urine during the collection interval 0 - 24 hours post administration

  • Urine [AE,ur(0-24)] after dosing of Copanlisib with Itraconazole [ Time Frame: Within cycle 1, in two sampling intervals from 0-8 and > 8 up to 24 hours after start of drug infusion on Days 1 and 15 ]
    Amount of drug excreted via urine during the collection interval 0 - 24 hours post administration

  • Urine [AE,ur(0-24)] after dosing of Copanlisib with Rifampin [ Time Frame: Within cycle 1, in two sampling intervals from 0-8 and > 8 up to 24 hours after start of drug infusion on Days 1 and 15 ]
    Amount of drug excreted via urine during the collection interval 0 - 24 hours post administration

  • Number of participants with adverse events as a measure of safety and tolerability of Copanlisib [ Time Frame: At approximately 29 months ]
    Safety analysis will be conducted continuously until safety follow-up

  • Effect of Copanlisib on PR intervals [ Time Frame: Cycle 1: Day 1 ]
    Continuous 12-Lead electrocardiograms / electrocardiographys (ECGs) will be collected using 12-Lead Digital Holter Recorder

  • Effect of Copanlisib on QRS intervals [ Time Frame: Cycle 1: Day 1 ]
    Continuous 12-Lead electrocardiograms / electrocardiographys (ECGs) will be collected using 12-Lead Digital Holter Recorder

  • Effect of Copanlisib on ECG waveform morphology [ Time Frame: Cycle 1 Day 1 ]
    Continuous 12-Lead electrocardiograms / electrocardiographys (ECGs) will be collected using 12-Lead Digital Holter Recorder

  • Effect of Copanlisib on left ventricular ejection fraction (LVEF) [ Time Frame: Baseline ,and in the last week of Cycle 1, and in the last 2 weeks of Cycle 2, Cycle 3, Cycle 6 and every third cycle (Cycle 9, Cycle 12, etc.) and end of treatment ]
    MUGA scans


Estimated Enrollment: 58
Actual Study Start Date: October 8, 2014
Estimated Study Completion Date: December 19, 2018
Estimated Primary Completion Date: June 28, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Copanlisib with and without concomitant Itraconazole (Arm A)

To evaluate the effect of Itraconazole on the pharmacokinetics of Copanlisib (BAY80-6946) and safety in patients with advanced solid tumor. Cycle 1 of the study will be conducted in 2 parts: Part 1 and part 2:

  • Part 1 of Cycle 1: 6 patients will be enrolled and will receive 12 mg of copanlisib on Day 1 and Day 15. Itraconazole 200 mg will be administered twice a day on Day 12 and then once daily from Days 13 to 21.
  • Part 2 of Cycle 1: 20 patients will be enrolled and receive copanlisib doses of either 12 mg, 30 mg or 60 mg on Days 1 and 15 with the same dose administered on both days. Copanlisib dose for Part 2 will be based on safety and copanlisib pharmacokinetics in Part 1. Itraconazole 200 mg will be administered twice a day on Day 12 and then once daily from Days 13 to 21.
  • Cycle 2 and subsequent cycles: All patients will receive copanlisib doses of 60 mg on Days 1, 8 and 15.
Drug: Copanlisib (BAY80-6946)

Part 1 of Cycle 1 Cycle 1 Day 1: Single i.v. dose 12mg Cycle 1 Day 15: Single i.v. dose 12 mg Part 2 of Cycle 1 Cycle 1 Day 1: Single i.v. dose TBD (based on Part 1 data) Cycle 1 Day 15: Single i.v. dose TBD (based on part 1 data)

Part 1 & Part 2

Cycle 2 and subsequent cycles:

Day 1: Single i.v. dose of 60mg Day 8: Single i.v. dose of 60mg Day15: Single i.v. dose of 60mg

Drug: Itraconazole
Cycle 1 Day 12: 2 x 200 mg itraconazole oral (two doses, 12 hours apart) Cycle 1 Days 13-21: 200 mg itraconazole oral, once daily in the morning
Experimental: Copanlisib with and without concomitant Rifampin (Arm B)
  • To evaluate the effect of Rifampin on the pharmacokinetics of Copanlisib (BAY 80-6946) and safety in patients with advanced solid tumor in Cycle 1. Approximately 30 subjects will receive 60mg of copanlisib on Cycle 1 Day 1 and Cycle 1 Day 15. Rifampin will be administered once a day from Cycle 1 Day 10 to Day 21. Holter monitoring will be performed on Cycle 1 Day -1 and Cycle 1 Day 1 to evaluate the effect of copanlisib on the QT/QTc assessment.
  • Cycle 2 and subsequent cycles, all patients will receive copanlisib dose of 60 mg on Days 1, 8 and 15. Holter monitoring will be performed on Cycle 3 Day 1 and Cycle 6 Day 1.
Drug: Copanlisib (BAY80-6946)

Part 1 of Cycle 1 Cycle 1 Day 1: Single i.v. dose 12mg Cycle 1 Day 15: Single i.v. dose 12 mg Part 2 of Cycle 1 Cycle 1 Day 1: Single i.v. dose TBD (based on Part 1 data) Cycle 1 Day 15: Single i.v. dose TBD (based on part 1 data)

Part 1 & Part 2

Cycle 2 and subsequent cycles:

Day 1: Single i.v. dose of 60mg Day 8: Single i.v. dose of 60mg Day15: Single i.v. dose of 60mg

Drug: Rifampin
Cycle 1 Days 10 - 21: 600mg Rifampin oral, once daily in the morning

Detailed Description:
The PI3K/AKT/mammalian target of rapamycin (mTOR) pathway is one of the prominent pathways that promote cellular survival and constitutively is activated in many types of cancer. Class I PI3K receptor is downstream of most cancer associated tyrosine kinase growth factor receptors. PI3K inhibitors are expected to be effective not only in PI3K pathway-driven tumors but also in combination with other chemotherapy agents. The management of metabolic effects is an issue that must be addressed in the development of anticancer agents targeting the PI3K-Akt-mTOR pathway. Copanlisib (BAY 80-6946) is a novel PI3K inhibitor being developed for the treatment of advanced and refractory malignancies.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female patients ≥ 18 years of age with histological or cytological confirmed advanced solid tumors that have progressed on, or failed to respond to, therapies known to provide clinical benefit may be enrolled after signing informed consent.
  • Normal left ventricular ejection fraction; adequate liver, renal and bone-marrow functions as assessed by laboratory values.
  • Adequate performance status and life expectancy of at least 3 months.

Exclusion Criteria:

  • Solid-tumor patients with central nervous system (CNS) metastases if treatment completed < 3 months before enrollment or lesions unstable or progressing on MRI scans performed within 1 month of enrollment or unstable symptoms of the CNS metastases.
  • Evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF greater than NYHA Class II
  • Active coronary artery disease or myocardial infarction within the 6 months before study entry; any new-onset angina within the 3 months before study entry or unstable angina; cardiac arrhythmia requiring anti-arrhythmic therapy.
  • Prior diagnosis of Type 1 or 2 diabetes mellitus, hyperglycemia (defined as fasting blood or plasma glucose above 125 mg/dL under 2 separate days, corresponding to 6.94 mmol/L) or HbA1c ≥ 7%.
  • Use of systemic including inhaled corticosteroids within the 2 days before the start of study treatment (however, topical steroids are permitted).
  • Known presence of human immunodeficiency virus (HIV) infection or active hepatitis (B or C).
  • Any ongoing medical, psychological or social condition(s) that may interfere with the subject's - participation in the study or with evaluation of the study results.
  • Known or suspected allergy or hypersensitivity to copanlisib and/or to itraconazole or rifampin
  • Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical management).
  • Anticancer chemotherapy, hormone therapy or immunotherapy within the 4 weeks before the first study treatment or scheduled for administration (of the above) during the study
  • History of, or concurrent, interstitial lung disease (ILD) or severely impaired pulmonary function.
  • Medications with drug-drug interaction potential for itraconazole which is to be excluded before the study and during Cycle 1 such as CYP3A4 substrates with a narrow therapeutic window or which have the potential to prolong QTc
  • Ongoing cytomegalovirus infection as confirmed by positive polymerase chain reaction for cytomegalovirus
  • Concomitant medication contraindicated for use with rifampin (including, but not limited to): cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam, levacetylmethadol (levomethadyl), 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitors metabolised by CYP3A4, such as lovastatin and simvastatin, ergot alkaloids metabolised by CYP3A4, such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine), atazanavir, darunavir, fosamprenavir, ritonavir-boosted saquinavir, saquinavir, or tipranavir
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02253420

Contacts
Contact: Bayer Clinical Trials Contact +49 30 300139003 clinical-trials-contact@bayer.com
Contact: For more information for participation into this trial 646-776-7532 (local) 844-229-3710 (Toll free) Bayer@emergingmed.com

Locations
Canada, Alberta
Recruiting
Edmonton, Alberta, Canada, T6G 1Z2
Canada, British Columbia
Completed
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, Ontario
Recruiting
Hamilton, Ontario, Canada, L8V 5C2
Recruiting
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02253420     History of Changes
Other Study ID Numbers: 16270
Study First Received: September 29, 2014
Last Updated: May 26, 2017

Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bayer:
Phase 1
Advanced solid tumor
PI3 Kinase inhibitor
Drug-drug Interaction

Additional relevant MeSH terms:
Itraconazole
Hydroxyitraconazole
Rifampin
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers

ClinicalTrials.gov processed this record on June 23, 2017