Trial Outcomes & Findings for Trial of Volasertib With or Without Azacitidine in Patients With Myelodysplastic Syndromes (NCT NCT02721875)

Last Updated: 2018-08-09

Results Overview

DLT was defined as any of the following adverse events (AEs) considered to be related to study drug: 1. Common terminology criteria for adverse events (CTCAE) v4.03 ≥Grade 3 drug related non- haematological toxicity, excluding; ≥Grade 3 untreated nausea, vomiting or diarrhea. Any laboratory abnormality - not considered clinically significant by investigator or resolved spontaneously or could have been recovered with appropriate treatment within 7 days. Grade 3 infection which could be recovered with appropriate treatment within 7 days. Azacitidine injection site reaction or complications related to azacitidine injection. 2. Febrile neutropenia as defined by CTCAE which could not recovered with appropriate treatment within 7 days. 3. Inability to deliver full dose of volasertib according to the assigned dose level within Cycle 1 due to drug-related AEs. 4. Haematological DLTs. 5. Any other drug-related AEs that resulted in the delay of starting new treatment cycle for ≥4 weeks.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

1 participants

Primary outcome timeframe

First treatment cycle, up to 28 days

Results posted on

2018-08-09

Participant Flow

Participant milestones

Participant milestones
Measure	Volasertib Monotherapy Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle	Volasertib + Azacitidine Combination Subject received volasertib with starting dose 170 mg/m2 on day 8 in combination with subcutaneous (s.c.) or intravenous administration of azacitidine 75 mg/m2 once daily for 7 consecutive days (days 1-7), 28-day cycle
Overall Study STARTED	1	0
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Volasertib Monotherapy Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle	Volasertib + Azacitidine Combination Subject received volasertib with starting dose 170 mg/m2 on day 8 in combination with subcutaneous (s.c.) or intravenous administration of azacitidine 75 mg/m2 once daily for 7 consecutive days (days 1-7), 28-day cycle
Overall Study Progressive disease/relapse	1	0

Baseline Characteristics

Trial of Volasertib With or Without Azacitidine in Patients With Myelodysplastic Syndromes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Volasertib Monotherapy n=1 Participants Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle	Volasertib + Azacitidine Combination Subject received volasertib with starting dose 170 mg/m2 on day 8 in combination with subcutaneous (s.c.) or intravenous administration of azacitidine 75 mg/m2 once daily for 7 consecutive days (days 1-7), 28-day cycle	Total n=1 Participants Total of all reporting groups
Age, Continuous	69 Years n=5 Participants	—	69 Years n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	—	0 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	—	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: First treatment cycle, up to 28 days

Population: Treated Set

Outcome measures

Outcome measures
Measure	Volasertib Monotherapy n=1 Participants Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle	Volasertib + Azacitidine Combination Subject received volasertib with starting dose 170 mg/m2 on day 8 in combination with subcutaneous (s.c.) or intravenous administration of azacitidine 75 mg/m2 once daily for 7 consecutive days (days 1-7), 28-day cycle
Number of Patients With Dose Limiting Toxicities (DLT) in the First Cycle	0 Participants	—

PRIMARY outcome

Timeframe: First treatment cycle, up to 28 days

Population: Treated Set

The MTD was defined as the highest dose with less than 35% risk of the true dose limiting toxicities (DLT) rate being above 0.33 for schedule A, and the highest dose with less than 40% risk of the true DLT rate being above 0.33 for schedule B. The phase I dose-finding was to be guided by a Bayesian 2-parameter logistic regression model (BLRM) with overdose control in each schedule separately.

Outcome measures

Outcome measures
Measure	Volasertib Monotherapy n=1 Participants Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle	Volasertib + Azacitidine Combination Subject received volasertib with starting dose 170 mg/m2 on day 8 in combination with subcutaneous (s.c.) or intravenous administration of azacitidine 75 mg/m2 once daily for 7 consecutive days (days 1-7), 28-day cycle
Maximum Tolerated Dose (MTD) of Volasertib	NA Milligram (mg)/ meter square (m2) MTD was not determined for this treatment schedule due to premature discontinuation of the trial	—

SECONDARY outcome

Timeframe: Up to 168 days

Population: Treated Set

Objective response defined as best overall response of complete remission, partial remission or haematological improvement according to the International Working Group 2006 criteria. It is based on Complete remission (CR): Bone marrow: \<=5% myeloblasts with normal maturation of all cell lines, Peripheral blood: Hemoglobin \>=11 Grams Per Decilitre (g/dL), Platelets \>=100 x 109/L, Neutrophils \>=1.0 x 109/L, Blasts 0%. Peripheral blood responses had to last at least 4 weeks to qualify for CR. Partial remission (PR): All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by \>=50% to baseline but still \>5%, Cellularity and morphology not relevant. Peripheral blood responses must last at least 4 weeks to qualify for PR. Haematological improvement (HI): HI was evaluated in patients with abnormal pretreatment values based on Erythroid response, Platelet response, Neutrophil response. Peripheral blood responses had to last at least 8 weeks to qualify for HI.

Outcome measures

Outcome measures
Measure	Volasertib Monotherapy n=1 Participants Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle	Volasertib + Azacitidine Combination Subject received volasertib with starting dose 170 mg/m2 on day 8 in combination with subcutaneous (s.c.) or intravenous administration of azacitidine 75 mg/m2 once daily for 7 consecutive days (days 1-7), 28-day cycle
Objective Response Defined as Best Overall Response of Complete Remission, Partial Remission or Haematological Improvement According to the International Working Group 2006 Criteria Yes	0 Participants	—
Objective Response Defined as Best Overall Response of Complete Remission, Partial Remission or Haematological Improvement According to the International Working Group 2006 Criteria No	1 Participants	—

SECONDARY outcome

Timeframe: Pharmacokinetic (PK) samples were taken at 5 minutes before drug administration and 0:30, 1:00, 2:00, 3:00, 4:00, 24:00, 167:55, 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after drug administration

Population: All evaluable patients were to be included in the PK analysis. Patients who were considered as not evaluable were to be listed with their individual plasma concentrations and individual PK parameters; however, they were not to be included in descriptive statistics for plasma concentrations.

Area under the plasma concentration-time curve over the time interval from zero to the last measured time point tz of volasertib (AUC0-tz) (for monotherapy).

Outcome measures

Outcome measures
Measure	Volasertib Monotherapy n=1 Participants Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle	Volasertib + Azacitidine Combination Subject received volasertib with starting dose 170 mg/m2 on day 8 in combination with subcutaneous (s.c.) or intravenous administration of azacitidine 75 mg/m2 once daily for 7 consecutive days (days 1-7), 28-day cycle
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Measured Time Point tz of Volasertib (AUC0-tz) (for Monotherapy) Cycle 1 - Day 1	2480 Nanogram(ng)*hour(h)/milliliter(mL)	—
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to the Last Measured Time Point tz of Volasertib (AUC0-tz) (for Monotherapy) Cycle 1 - Day 8	5460 Nanogram(ng)*hour(h)/milliliter(mL)	—

SECONDARY outcome

Timeframe: PK samples were taken at 5 minutes before drug administration and 0:30, 1:00, 2:00, 3:00, 4:00, 24:00, 167:55, 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after drug administration

Population: All evaluable patients were to be included in the Pharmacokinetic (PK) analysis. Patients who were considered as not evaluable were to be listed with their individual plasma concentrations and individual PK parameters; however, they were not to be included in descriptive statistics for plasma concentrations.

Maximum measured plasma concentration of volasertib (Cmax) (for monotherapy).

Outcome measures

Outcome measures
Measure	Volasertib Monotherapy n=1 Participants Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle	Volasertib + Azacitidine Combination Subject received volasertib with starting dose 170 mg/m2 on day 8 in combination with subcutaneous (s.c.) or intravenous administration of azacitidine 75 mg/m2 once daily for 7 consecutive days (days 1-7), 28-day cycle
Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy) Cycle 1 - Day 1	467 Nanogram(ng)*/milliliter(mL)	—
Maximum Measured Plasma Concentration of Volasertib (Cmax) (for Monotherapy) Cycle 1 - Day 8	553 Nanogram(ng)*/milliliter(mL)	—

SECONDARY outcome

Timeframe: PK samples were to be taken at 5 minutes before drug administration (167:55) and 168:30, 169:00, 169:30, 170:00, 171:00, 172:00, 192:00, 336:00, 504:00, 672:00 hours after first drug administration of Azacitidine

Population: Due to premature discontinuation of the trial no patient is recruited for combination therapy.

Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity of volasertib (AUC0-∞) (for combination).

Outcome measures

Outcome data not reported

SECONDARY outcome

Population: Due to premature discontinuation of the trial no patient is recruited for combination therapy.

Maximum measured plasma concentration of volasertib (Cmax) (for combination).

Outcome measures

Outcome data not reported

Adverse Events

Volasertib Monotherapy

Serious events: 1 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Volasertib Monotherapy n=1 participants at risk Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle
Gastrointestinal disorders Lower gastrointestinal haemorrhage	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days

Other adverse events

Other adverse events
Measure	Volasertib Monotherapy n=1 participants at risk Subject received volasertib with starting dose of 110 mg/meter square (m2) in solution for intravenous infusion (350 milligram (mg)/175 milliliter (mL) vial (2.0 mg/mL)), on day 1 + 8, 28-day cycle
Infections and infestations Herpes simplex	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Infections and infestations Injection site infection	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Infections and infestations Pneumonia	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Gastrointestinal disorders Oral lichen planus	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Gastrointestinal disorders Small intestine ulcer	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Gastrointestinal disorders Stomatitis	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
General disorders Infusion site extravasation	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Eye disorders Cataract	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Gastrointestinal disorders Dental caries	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Investigations Weight decreased	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Musculoskeletal and connective tissue disorders Pain in extremity	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Renal and urinary disorders Hypertonic bladder	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Reproductive system and breast disorders Benign prostatic hyperplasia	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Skin and subcutaneous tissue disorders Haemorrhage subcutaneous	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Skin and subcutaneous tissue disorders Petechiae	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Skin and subcutaneous tissue disorders Purpura	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days
Vascular disorders Haematoma	100.0% 1/1 • From first drug administration until 30 days after the last dose of study medication, up to 94 days

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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