Neoplasms
Conditions
Brief summary
The primary objective of the present study is to investigate the influence of co-administration of itraconazole and volasertib on the pharmacokinetic profile of volasertib without co-administration of itraconazole. Secondary objectives are to investigate safety, tolerability and preliminary therapeutic effects following intravenous administration of volasertib.
Interventions
DRUGitraconazole
capsules
DRUGvolasertib
Solution for infusion
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Patients with histologically or cytologically confirmed diagnosis of advanced, non resectable and / or metastatic solid tumour, for whom conventional treatment has failed, or for whom no therapy of proven efficacy exists, or who are not amenable to established forms of treatment based on the investigator's assessment 2. Male or female 3. Age =\>18 and =\<70 years 4. Eastern Cooperative Oncology Group (ECOG) performance score =\< 2 5. Recovery from Common Terminology Criteria for Adverse Events (CTCAE) Grade \>= 2 therapy-related toxicities from previous chemo-, hormone-, immuno-, or radiotherapy (except alopecia)
Exclusion criteria
1. Serious concomitant non-oncological disease considered by the investigator to be incompatible with the protocol 2. Active infectious disease 3. Viral hepatitis, HIV infection 4. Clinical evidence of active brain metastasis or leptomeningeal disease during the past 6 months 5. Second malignancy currently requiring active therapy (except for hormonal / antihormonal treatment e.g. in prostate or breast cancer) 6. Absolute neutrophil count less than 1,500/mm3 7. Platelet count less than 100,000/mm3 8. Total bilirubin greater than 1.5 mg/dL (\> 26 µmol/L, SI unit equivalent) 9. Aspartate amino transferase (AST) and / or alanine amino transferase (ALT) greater than 2.5 times the upper limit of normal (if related to liver metastases greater than five times the upper limit of normal) 10. Serum creatinine greater than 2x upper limit of normal (ULN) 11. QTcF prolongation \> 470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome).The QTcF will be calculated as the mean of the 3 ECGs taken at screening 12. Female patients with childbearing potential and unwilling to use a medically acceptable method of contraception during the trial and for at least six months after end of active therapy. Woman of childbearing potential (premenopausal female) is defined as the female who is not surgically sterilised by hysterectomy or bilateral tubal ligation or post-menopausal for at least 12 months. 13. Treatment with other investigational drugs or participation in another clinical trial within the past four weeks prior to start of therapy or concomitantly with this trial 14. Chemo-, radio- immuno-, or molecular-targeted cancer-therapy within the past four weeks prior to start of therapy or concomitantly with this trial. This restriction does not apply to steroids, bisphosphonates hormonal / antihormonal treatment (e.g. in prostate or breast cancer). 15. Alcohol abuse more than an average 3 units of alcoholic beverages per day or more than 21 units per week (1 unit equals 0.5 pint \[285 mL\] of beer or lager, 1 glass \[125 mL\] of wine, 25 mL shot of 40% spirit) or drug abuse 16. Life expectancy less than 12 weeks 17. Potent CYP 3A4 and P-glycoprotein inhibitors other than the study drug or inducers between one week prior to first drug administration or expected treatment with a respective drug until the last PK sample is collected 1. Strong CYP 3A4 inhibitors: atazanavir, clarithromycin, indinavir, itraconazole (other then study drug), ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin 2. CYP 3A4 inducers: carbamazepine, rifampicin 3. P-gp inhibitors: cyclosporine, erythromycin, itraconazole (other then study drug), ketoconazole, quinidine, phenobarbital salt with quinidine, ritonavir, valspodar, verapamil 4. P-gp inducers: hypericum perforatum, rifampicin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Quantifiable Drug Plasma Concentration After Dose Administration (AUC0-tz) of Volasertib and Its Metabolite CD 10899 | 30 minutes before volasertib administration and 1 hour (h), 1.75h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 72h, 168h, 336h, 504 h after volasertib administration on Day 1 of Cycle 1 (Volasertib+ Itraconazole) and of Cycle 2 (Volasertib). | Area under the plasma concentration-time curve over the time interval from zero to the last quantifiable drug plasma concentration after dose administration (AUC0-tz) of volasertib and its metabolite CD 10899 is reported. |
| Maximum Measured Concentration of Volasertib and Its Metabolite CD 10899 in Plasma (Cmax) | 30 minutes before volasertib administration and 1 hour (h), 1.75h, 4h, 6h, 8h, 12h, 24, 36h, 48h, 72h, 168h, 336h, 504 h after volasertib administration on Day 1 of Cycle 1 (Volasertib+ Itraconazole) and of Cycle 2 (Volasertib). | Maximum measured concentration of the analyte (volasertib and its metabolite CD 10899) in plasma (Cmax) is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve Over the Time Interval From 0 to Infinity (AUC0-∞) of Volasertib and Its Metabolite CD 10899 | 30 minutes before volasertib administration and 1 hour (h), 1.75h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 72h, 168h, 336h, 504 h after volasertib administration on Day 1 of Cycle 1 (Volasertib+ Itraconazole) and of Cycle 2 (Volasertib). | Area under the plasma concentration-time curve over the time interval from 0 to infinity (AUC0-∞) of volasertib and its metabolite CD 10899 is reported. |
Countries
Hungary
Participant flow
Recruitment details
This trial was an uncontrolled, open-label, sequential Drug-drug interaction (DDI) trial of volasertib and itraconazole in patients with advanced, non-resectable and/or metastatic solid tumours, for whom conventional treatment had failed or if they were not amenable to established treatment options.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Volasertib + Itraconazole Then Volasertib Patients were administered from Day-3 to Day 15 of Cycle 1 (cycle duration=21 days) once daily two capsules of 100 milligram (mg) of itraconazole (Orungal®) (total daily dose=200 mg) orally. On Day 1 of Cycle 1 patients were also administered intravenously a single dose of 300 mg of solution for infusion of volasertib as a 2 hour (h) infusion. In case of unexpected toxicity the dose of volasertib was to be reduced to 250 mg or 200 mg.
On Day 1 of Cycle 2 (cycle duration=21 days) patients were administered intravenously a single dose of 300 mg of solution for infusion of volasertib as a 2 hour (h) infusion. In case of unexpected toxicity the dose of volasertib was to be reduced to 250 mg or 200 mg.
After Cycle 2 (i.e cycles ≥3): Patients with clinical benefits were administered intravenously on Day 1 of each cycle (cycles ≥3) solution for infusion of volasertib. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Cycle 1 | Dose limiting toxicity | 2 |
| Cycle 1 | Progressive disease | 2 |
| Cycle 2 and Beyond | Progressive disease | 17 |
| Cycle 2 and Beyond | Refused continuing medication | 4 |
| Cycle 2 and Beyond | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Volasertib + Itraconazole Then Volasertib |
|---|---|
| Age, Continuous | 55.6 Years STANDARD_DEVIATION 8.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 1 / 24 |
| other Total, other adverse events | 21 / 28 | 21 / 24 |
| serious Total, serious adverse events | 12 / 28 | 11 / 24 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Quantifiable Drug Plasma Concentration After Dose Administration (AUC0-tz) of Volasertib and Its Metabolite CD 10899
Area under the plasma concentration-time curve over the time interval from zero to the last quantifiable drug plasma concentration after dose administration (AUC0-tz) of volasertib and its metabolite CD 10899 is reported.
Time frame: 30 minutes before volasertib administration and 1 hour (h), 1.75h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 72h, 168h, 336h, 504 h after volasertib administration on Day 1 of Cycle 1 (Volasertib+ Itraconazole) and of Cycle 2 (Volasertib).
Population: Primary pharmacokinetic set (pPKS) 250 mg: All patients in the treated set (TS) who were treated with volasertib 250 mg in Cycle 1 and Cycle 2 and who provided complete pharmacokinetic (PK) measures without important protocol violations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Volasertib+ Itraconazole (Cycle 1) | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Quantifiable Drug Plasma Concentration After Dose Administration (AUC0-tz) of Volasertib and Its Metabolite CD 10899 | volasertib | 6690 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 36 |
| Volasertib+ Itraconazole (Cycle 1) | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Quantifiable Drug Plasma Concentration After Dose Administration (AUC0-tz) of Volasertib and Its Metabolite CD 10899 | CD 10899 | 855 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 63.8 |
| Volasertib (Cycle 2) | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Quantifiable Drug Plasma Concentration After Dose Administration (AUC0-tz) of Volasertib and Its Metabolite CD 10899 | volasertib | 7140 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 55.6 |
| Volasertib (Cycle 2) | Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Quantifiable Drug Plasma Concentration After Dose Administration (AUC0-tz) of Volasertib and Its Metabolite CD 10899 | CD 10899 | 1130 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 58 |
Comparison: Statistical analysis of Volasertib:~AUC0-tz was log-transformed prior to fitting an analysis of variance (ANOVA) model. This model included effects for 'treatment' and 'subject'. 90% confidence intervals (CIs) were computed, then back-transformed to the original scale to give the point estimator and interval estimates for the geometric mean ratio (GMR).90% CI: [82.07, 106.81]
Comparison: Statistical analysis of CD 10899:~AUC0-tz was log-transformed prior to fitting an analysis of variance (ANOVA) model. This model included effects for 'treatment' and 'subject'. 90% confidence intervals (CIs) were computed, then back-transformed to the original scale to give the point estimator and interval estimates for the geometric mean ratio (GMR).90% CI: [67.83, 84.632]
Primary
Maximum Measured Concentration of Volasertib and Its Metabolite CD 10899 in Plasma (Cmax)
Maximum measured concentration of the analyte (volasertib and its metabolite CD 10899) in plasma (Cmax) is reported.
Time frame: 30 minutes before volasertib administration and 1 hour (h), 1.75h, 4h, 6h, 8h, 12h, 24, 36h, 48h, 72h, 168h, 336h, 504 h after volasertib administration on Day 1 of Cycle 1 (Volasertib+ Itraconazole) and of Cycle 2 (Volasertib).
Population: Primary pharmacokinetic set (pPKS) 250 mg: All patients in the treated set (TS) who were treated with volasertib 250 mg in Cycle 1 and Cycle 2 and who provided complete pharmacokinetic set (PK) measures without important protocol violations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Volasertib+ Itraconazole (Cycle 1) | Maximum Measured Concentration of Volasertib and Its Metabolite CD 10899 in Plasma (Cmax) | volasertib | 328 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 46 |
| Volasertib+ Itraconazole (Cycle 1) | Maximum Measured Concentration of Volasertib and Its Metabolite CD 10899 in Plasma (Cmax) | CD 10899 | 4.51 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 78.4 |
| Volasertib (Cycle 2) | Maximum Measured Concentration of Volasertib and Its Metabolite CD 10899 in Plasma (Cmax) | volasertib | 414 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 53.1 |
| Volasertib (Cycle 2) | Maximum Measured Concentration of Volasertib and Its Metabolite CD 10899 in Plasma (Cmax) | CD 10899 | 7.10 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 63.4 |
Comparison: Statistical analysis of volasertib:~Cmax was log-transformed prior to fitting an analysis of variance (ANOVA) model. This model included effects for 'treatment' and 'subject'. 90% confidence intervals (CIs) were computed, then back-transformed to the original scale to give the point estimator and interval estimates for the geometric mean ratio (GMR).90% CI: [64.896, 97.137]
Comparison: Statistical analysis of CD 10899:~Cmax was log-transformed prior to fitting an analysis of variance (ANOVA) model. This model included effects for 'treatment' and 'subject'. 90% confidence intervals (CIs) were computed, then back-transformed to the original scale to give the point estimator and interval estimates for the geometric mean ratio (GMR).90% CI: [55.372, 72.775]
Secondary
Area Under the Plasma Concentration-time Curve Over the Time Interval From 0 to Infinity (AUC0-∞) of Volasertib and Its Metabolite CD 10899
Area under the plasma concentration-time curve over the time interval from 0 to infinity (AUC0-∞) of volasertib and its metabolite CD 10899 is reported.
Time frame: 30 minutes before volasertib administration and 1 hour (h), 1.75h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 72h, 168h, 336h, 504 h after volasertib administration on Day 1 of Cycle 1 (Volasertib+ Itraconazole) and of Cycle 2 (Volasertib).
Population: Primary pharmacokinetic set (pPKS) 250 mg: All patients in the Treated Set (TS) who were treated with volasertib 250 mg in Cycle 1 and Cycle 2 and who provided complete pharmacokinetic (PK) measures without important protocol violations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Volasertib+ Itraconazole (Cycle 1) | Area Under the Plasma Concentration-time Curve Over the Time Interval From 0 to Infinity (AUC0-∞) of Volasertib and Its Metabolite CD 10899 | volasertib | 7360 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 38.4 |
| Volasertib+ Itraconazole (Cycle 1) | Area Under the Plasma Concentration-time Curve Over the Time Interval From 0 to Infinity (AUC0-∞) of Volasertib and Its Metabolite CD 10899 | CD 10899 | 1020 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 67.1 |
| Volasertib (Cycle 2) | Area Under the Plasma Concentration-time Curve Over the Time Interval From 0 to Infinity (AUC0-∞) of Volasertib and Its Metabolite CD 10899 | volasertib | 7610 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 55.5 |
| Volasertib (Cycle 2) | Area Under the Plasma Concentration-time Curve Over the Time Interval From 0 to Infinity (AUC0-∞) of Volasertib and Its Metabolite CD 10899 | CD 10899 | 1310 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 61.9 |
Comparison: Statistical analysis of volasertib:~AUC0-∞ was log-transformed prior to fitting an analysis of variance (ANOVA) model. This model included effects for 'treatment' and 'subject'. 90% confidence intervals (CIs) were computed, then back-transformed to the original scale to give the point estimator and interval estimates for the geometric mean ratio (GMR).90% CI: [87.09, 109.94]
Comparison: Statistical analysis of CD 10899:~AUC0-∞ was log-transformed prior to fitting an analysis of variance (ANOVA) model. This model included effects for 'treatment' and 'subject'. 90% confidence intervals (CIs) were computed, then back-transformed to the original scale to give the point estimator and interval estimates for the geometric mean ratio (GMR).90% CI: [69.001, 86.871]