Trial Outcomes & Findings for Investigation of Potential Drug-drug Interaction of Volasertib With Itraconazole in Patients With Various Tumours (NCT NCT01772563)

Last Updated: 2023-09-01

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

28 participants

Primary outcome timeframe

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).

Results posted on

2023-09-01

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.
Cycle 1 STARTED	28
Cycle 1 Treated With 300 mg Volasertib	3
Cycle 1 Treated With 250 mg of Volasertib	25
Cycle 1 COMPLETED	24
Cycle 1 NOT COMPLETED	4
Cycle 2 and Beyond STARTED	24
Cycle 2 and Beyond Treated With 300 mg Volasertib in Cycle 2	1
Cycle 2 and Beyond Treated With 250 mg Volasertib in Cycle 2	21
Cycle 2 and Beyond Treated With 200 mg Volasertib in Cycle 2	1
Cycle 2 and Beyond COMPLETED	1
Cycle 2 and Beyond NOT COMPLETED	23

Reasons for withdrawal

Reasons for withdrawal
Measure	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.
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

Investigation of Potential Drug-drug Interaction of Volasertib With Itraconazole in Patients With Various Tumours

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Volasertib + Itraconazole Then Volasertib n=28 Participants 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.
Age, Continuous	55.6 Years STANDARD_DEVIATION 8.8 • n=5 Participants
Sex: Female, Male Female	18 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	28 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Volasertib+ Itraconazole (Cycle 1) n=21 Participants 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.	Volasertib (Cycle 2) n=21 Participants 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.
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 nanogramhour/milliliter (ngh/mL) Geometric Coefficient of Variation 36.0	7140 nanogramhour/milliliter (ngh/mL) Geometric Coefficient of Variation 55.6
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 nanogramhour/milliliter (ngh/mL) Geometric Coefficient of Variation 63.8	1130 nanogramhour/milliliter (ngh/mL) Geometric Coefficient of Variation 58.0

PRIMARY outcome

Timeframe: 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.

Maximum measured concentration of the analyte (volasertib and its metabolite CD 10899) in plasma (Cmax) is reported.

Outcome measures

Outcome measures
Measure	Volasertib+ Itraconazole (Cycle 1) n=21 Participants 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.	Volasertib (Cycle 2) n=21 Participants 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.
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	7.10 nanogram/milliliter (ng/mL) Geometric Coefficient of Variation 63.4
Maximum Measured Concentration of Volasertib and Its Metabolite CD 10899 in Plasma (Cmax) volasertib	328 nanogram/milliliter (ng/mL) Geometric Coefficient of Variation 46.0	414 nanogram/milliliter (ng/mL) Geometric Coefficient of Variation 53.1

SECONDARY outcome

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.

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.

Outcome measures

Outcome measures
Measure	Volasertib+ Itraconazole (Cycle 1) n=21 Participants 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.	Volasertib (Cycle 2) n=21 Participants 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.
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 nanogramhour/milliliter (ngh/mL) Geometric Coefficient of Variation 38.4	7610 nanogramhour/milliliter (ngh/mL) Geometric Coefficient of Variation 55.5
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 nanogramhour/milliliter (ngh/mL) Geometric Coefficient of Variation 67.1	1310 nanogramhour/milliliter (ngh/mL) Geometric Coefficient of Variation 61.9

Adverse Events

Volasertib + Itraconazole (Cycle 1)

Serious events: 12 serious events

Other events: 21 other events

Deaths: 0 deaths

Monotherapy Volasertib (Cycle>=2)

Serious events: 11 serious events

Other events: 21 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Volasertib + Itraconazole (Cycle 1) n=28 participants at risk 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.	Monotherapy Volasertib (Cycle>=2) n=24 participants at risk This group included all patients who were administered volasertib from Cycle 2 onwards. 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.
Blood and lymphatic system disorders Anaemia	32.1% 9/28 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.	37.5% 9/24 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.
Blood and lymphatic system disorders Leukopenia	25.0% 7/28 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.	33.3% 8/24 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.
Blood and lymphatic system disorders Thrombocytopenia	46.4% 13/28 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.	33.3% 8/24 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.
Gastrointestinal disorders Diarrhoea	3.6% 1/28 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.	8.3% 2/24 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.
Gastrointestinal disorders Vomiting	0.00% 0/28 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.	12.5% 3/24 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.
Infections and infestations Upper respiratory tract infection	0.00% 0/28 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.	12.5% 3/24 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.
Investigations Blood creatine phosphokinase increased	0.00% 0/28 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.	12.5% 3/24 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.
Investigations Blood lactate dehydrogenase increased	3.6% 1/28 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.	20.8% 5/24 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.
Investigations Platelet count increased	0.00% 0/28 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.	16.7% 4/24 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.
Nervous system disorders Headache	3.6% 1/28 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.	8.3% 2/24 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.
Skin and subcutaneous tissue disorders Alopecia	7.1% 2/28 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.	8.3% 2/24 • Volasertib + Itraconazole (Cycle 1) arm: From start of itraconazole administration until 21 days after the administration of volasertib, up to 24 days. Monotherapy Volasertib (Cycle>=2): From start of monotherapy with volasertib (Day 1 of Cycle 2) until 21 days after the last administration of volasertib, up to 2712 days. Treated set (TS): All patients who received at least 1 dose of volasertib. This was the full analysis set; it was mainly used for safety analyses.

Additional Information

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