Trial Outcomes & Findings for Volasertib in Combination With Azacitidine in Japanese Patients With Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (NCT NCT02201329)

NCT ID: NCT02201329

Last Updated: 2018-07-30

Results Overview

This outcome measure presents number of participants with DLTs in the first cycle for the determination of MTD. DLT was defined as any of the following Adverse Events (AEs) considered to be related to the study drug (Volasertib and/or Azacitidine). 1. Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 drug-related non-haematologic toxicity. 2. Drug-related AEs that led to inability to deliver the full dose of the study drugs (Volasertib and/or Azacitidine) according to the assigned dose level within Cycle 1. 3. Absence of haematological recovery (sustained CTCAE grade ≥3 thrombocytopenia \<50000/mm\^3 and/or neutropenia \<1000/mm\^3) after completing Cycle 1 and lasting at least until Day 57 (from Day 1 of Cycle 1) despite complete marrow blast clearance on Day 29 (\<5% blasts in the bone marrow. 4. Any other drug-related AEs that required treatment delay of ≥4 weeks between the Cycle 1 and Cycle 2 (i.e., Cycle 2 was not started until Day 57 of Cycle 1)).

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

5 participants

Primary outcome timeframe

Up to 57 days.

Results posted on

2018-07-30

Participant Flow

Participant milestones

Participant milestones
Measure	Volasertib 200 mg The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m\^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.
Overall Study STARTED	5
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Volasertib 200 mg The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m\^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.
Overall Study Progressive Dis./Relapse/Clinical Prog.	3
Overall Study Withdrawal by Subject	2

Baseline Characteristics

Volasertib in Combination With Azacitidine in Japanese Patients With Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Volasertib 200 mg n=5 Participants The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m\^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.
Age, Continuous	73.2 Years STANDARD_DEVIATION 4.6 • n=99 Participants
Sex: Female, Male Female	2 Participants n=99 Participants
Sex: Female, Male Male	3 Participants n=99 Participants

PRIMARY outcome

Timeframe: Up to 57 days.

Population: MTD Set: This patient set included all patients in the treated set who were evaluable for MTD determination.

Outcome measures

Outcome measures
Measure	Volasertib 200 mg n=5 Participants The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m\^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.
Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)	2 Participants

PRIMARY outcome

Timeframe: Up to 57 days.

Population: MTD Set: This patient set included all patients in the treated set who were evaluable for MTD determination.

This outcome measure presents MTD of Volasertib in Combination with Azacitidine. The MTD was defined as the highest dose level at which Dose Limiting Toxicities (DLTs) were reported in not more than 1 in 6 evaluable patients during Cycle 1.

Outcome measures

Outcome measures
Measure	Volasertib 200 mg n=5 Participants The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m\^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.
Maximum Tolerated Dose of Volasertib	NA mg On the basis of DLTs, the MTD of Volasertib administered intravenously on Days 1 and 15 in 28-day cycles in combination with Azacitidine was considered to be less than 200 mg.

SECONDARY outcome

Timeframe: Up to 9 months.

Population: Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine.

This outcome measure presents overall Objective Response (CR+PR+mCR). Response to treatment was evaluated according to the International Working Group (IWG) 2006 criteria. Best response was tabulated from all available data, with each patient being classified into one of the categories defined in CR, PR, mCR.

Outcome measures

Outcome measures
Measure	Volasertib 200 mg n=5 Participants The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m\^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.
Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR) Objective Response (OR)	2 Participants
Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR) Complete Remission (CR)	0 Participants
Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR) Partial Remission (PR)	0 Participants
Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR) Marrow Complete Remission (mCR)	2 Participants

SECONDARY outcome

Timeframe: -0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration.

Population: Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine.

This outcome measure presents maximum measured concentration of Volasertib 200 mg in plasma (Cmax).

Outcome measures

Outcome measures
Measure	Volasertib 200 mg n=5 Participants The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m\^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.
Maximum Measured Concentration of the Volasertib 200 mg in Plasma (Cmax)	713 ng/mL Geometric Coefficient of Variation 44.4

SECONDARY outcome

Timeframe: -0.05 hours before drug administration and 0:30 (hours:minutes), 1:00, 1:30, 2:00, 3:00, 4:00, 24:30, 48:30, 96:30, 144:30 and 335:55 after drug administration.

Population: Treated Set (TS): This patient set included all patients who were dispensed study medication and were documented to have taken at least one dose of either Volasertib or Azacitidine.

This outcome measure presents area under the concentration-time curve of Volasertib 200 mg + Azacitidine 75 mg/m\^2 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞).

Outcome measures

Outcome measures
Measure	Volasertib 200 mg n=5 Participants The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m\^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.
Area Under the Concentration-Time Curve of Volasertib 200 mg in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)	4190 ng*h/mL Geometric Coefficient of Variation 25.4

Adverse Events

Volasertib 200 mg

Serious events: 2 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Volasertib 200 mg n=5 participants at risk The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m\^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.
Blood and lymphatic system disorders Disseminated intravascular coagulation	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Blood and lymphatic system disorders Febrile neutropenia	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Immune system disorders Hypersensitivity	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Infections and infestations Pneumonia	40.0% 2/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Infections and infestations Pyelonephritis	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Metabolism and nutrition disorders Dehydration	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Renal and urinary disorders Acute kidney injury	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.

Other adverse events

Other adverse events
Measure	Volasertib 200 mg n=5 participants at risk The patients received Volasertib 200 mg administered by Intravenous Infusion (IV) over 60 minutes on Day 1 and Day 15 of 28-day and Azacitidine 75 mg/m\^2 administered by subcutaneous injection on days 1-7 of 28 day treatment cycle.
Blood and lymphatic system disorders Anaemia	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Blood and lymphatic system disorders Febrile neutropenia	40.0% 2/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Blood and lymphatic system disorders Neutropenia	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Blood and lymphatic system disorders Thrombocytopenia	40.0% 2/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Cardiac disorders Arrhythmia	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Eye disorders Eyelids pruritus	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Gastrointestinal disorders Constipation	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Gastrointestinal disorders Diarrhoea	40.0% 2/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Gastrointestinal disorders Enterocolitis	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Gastrointestinal disorders Stomatitis	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Gastrointestinal disorders Tongue coated	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
General disorders Fatigue	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
General disorders Injection site reaction	100.0% 5/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
General disorders Oedema peripheral	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
General disorders Peripheral swelling	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
General disorders Pyrexia	40.0% 2/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Hepatobiliary disorders Hepatic function abnormal	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Immune system disorders Hypersensitivity	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Infections and infestations Paronychia	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Infections and infestations Pharyngitis	40.0% 2/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Injury, poisoning and procedural complications Contusion	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Investigations Alanine aminotransferase increased	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Investigations Aspartate aminotransferase increased	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Investigations Blood alkaline phosphatase increased	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Investigations Blood creatine phosphokinase increased	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Investigations Blood creatinine increased	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Investigations Gamma-glutamyltransferase increased	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Investigations Haemoglobin decreased	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Investigations Neutrophil count decreased	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Investigations Platelet count decreased	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Investigations Weight decreased	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Investigations White blood cell count decreased	40.0% 2/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Metabolism and nutrition disorders Decreased appetite	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Metabolism and nutrition disorders Dehydration	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Metabolism and nutrition disorders Hypokalaemia	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Metabolism and nutrition disorders Iron overload	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Musculoskeletal and connective tissue disorders Back pain	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Musculoskeletal and connective tissue disorders Muscle spasms	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Nervous system disorders Dysgeusia	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Renal and urinary disorders Renal impairment	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Respiratory, thoracic and mediastinal disorders Dyspnoea	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Respiratory, thoracic and mediastinal disorders Hypoxia	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Skin and subcutaneous tissue disorders Drug eruption	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Skin and subcutaneous tissue disorders Dry skin	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.
Skin and subcutaneous tissue disorders Purpura	20.0% 1/5 • From first drug administration until 30 days after last trial drug administration in the last treatment cycle or the decision of study treatment discontinuation, whichever is later, and was up to 389 days.

Additional Information

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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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