Medical Oncology
Conditions
Keywords
Phase 1, Advanced solid tumor, non-Hodgkin's lymphoma, PI3 Kinase inhibitor, Drug-drug Interaction
Brief summary
To evaluate the effect of itraconazole or rifampin on the absorption, distribution, metabolism and elimination of COPANLISIB (BAY80-6946). To evaluate the effect of copanlisib on QT/QTc intervals and left ventricular ejection fraction as parameters of cardiovascular safety.
Interventions
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 60mg (based on Part 1 data) Cycle 1 Day 15: Single i.v. dose 60mg (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
DRUGItraconazole
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
DRUGRifampin
Cycle 1 Days 10 - 21: 600mg Rifampin oral, once daily in the morning
Sponsors
Bayer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients ≥ 18 years of age with histological or cytological confirmed advanced solid tumors or non-Hodgkin's lymphoma 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). * 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC (0-168) | 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. | AUC (0-168): Area under the curve from dosing to 168 h after dosing |
| AUC | 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. | AUC: Area under the curve |
| Cmax | 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. | Cmax: Maximum concentration attained after dosing |
| QTcF | Holter Monitoring performed on Cycle 1 Day -1 (baseline) and Cycle 1 Day 1 (each cycle is 28 days) | QTcF: Time-matched largest change of QT interval (Frederica's correction) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Urine [AE,ur(0-24)] | From 0-8 hours and >8 up to 24 hours after the start of copanlisib infusion on Days 1 and 15 of Cycle 1 | 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 | At approximately 29 months | Safety analysis will be conducted continuously until safety follow-up |
| PR intervals | Holter Monitoring performed on Cycle 1 Day -1 (baseline) and Cycle 1 Day 1 (each cycle is 28 days) | — |
| AUC(0-tlast) | 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. | AUC(0-tlast): Area under the curve from dosing to last measurable concentration |
| ECG waveform morphology | Holter Monitoring performed on Cycle 1 Day -1 (baseline) and Cycle 1 Day 1 (each cycle is 28 days) | — |
| Left ventricular ejection fraction (LVEF) | At baseline, 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 |
| QTcB | Holter Monitoring performed on Cycle 1 Day -1 (baseline) and Cycle 1 Day 1 (each cycle is 28 days) | QTcB: Bazett's corrected QT interval |
| QRS intervals | Holter Monitoring performed on Cycle 1 Day -1 (baseline) and Cycle 1 Day 1 (each cycle is 28 days) | — |
| tmax | 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. | tmax: Time from dosing to attainment of Cmax |
| tlast | 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. | tlast: Time from dosing to last measurable concentration |
| t1/2 | 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. | t1/2: Terminal half-life |
Countries
Canada, United States
Outcome results
None listed