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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02201329
• Collaborator: (none)
• Enrollment: 5
• Locations: 4
• Arm: 1
• Duration (Months): 13
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To identify the maximum tolerated dose or recommended dose for further development of volasertib in combination with azacitidine in Japanese patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, and evaluate the safety and tolerability, pharmacokinetics and the preliminary efficacy of this combination.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic	Drug: Azacitidine; Drug: Volasertib	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Phase I Trial of Intravenous Volasertib in Combination With Subcutaneous Azacitidine in Japanese Patients With Higher-risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
• Study Start Date: Aug 1, 2014
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A Volasertib escalating doses + azacitidine	Drug: Azacitidine; Azacitidine (subcutaneous); Drug: Volasertib; Volasertib escalating doses (intravenous)

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) [Up to 57 days.]

   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). Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 drug-related non-haematologic toxicity. 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. 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. 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)).

2. Maximum Tolerated Dose of Volasertib [Up to 57 days.]

   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.

Secondary Outcome Measures

1. Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR) [Up to 9 months.]

   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.

2. Maximum Measured Concentration of the Volasertib 200 mg in Plasma (Cmax) [-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.]

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

3. Area Under the Concentration-Time Curve of Volasertib 200 mg in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) [-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.]

   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-∞).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Patients of age >=20 and <=80 years

2. Patients with primary or treatment-related myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), who are not eligible for hematopoietic stem cell transplantation based on the investigator's judgment, that meet one of the following criteria:

• Intermediate-2 and high-risk MDS according to the International Prognostic Scoring System, in the setting of 5-30% bone marrow blasts

• CMML with >= 10% marrow blasts without myeloproliferative disorder (white blood cell count of <13,000/ µL)

1. Patients with no prior azacitidine treatment, or with prior azacitidine treatment that meet one of the following criteria:

• Patients failing to achieve haematological improvement, partial remission, marrow complete remission or complete remission after 3 cycles of azacitidine or progressed at any time after start of azacitidine

• Patients achieved an initial response and subsequently develop disease progression or relapse

1. Eastern Cooperative Oncology Group performance status score 0 or 1 at screening

2. Signed written informed consent consistent with Good Clinical Practice.

Exclusion criteria:

1. Treatment with systemic therapy for MDS, including an investigational drug, within 14 days before the first dose of study treatment, except for lenalidomide within 12 weeks before the first dose of study treatment, or lack of recovery from any acute toxicities pertinent to the prior systemic therapy.

2. Prior treatment with volasertib

3. Contraindications for azacitidine treatment according to the manufacturer's product information

4. Known hypersensitivity to the trial drugs or its excipients

5. Concomitant malignancy currently requiring active therapy (except for hormonal/anti-hormonal treatment, e.g. in prostate or breast cancer)

6. QTcF prolongation >470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome).

7. Total bilirubin >1.5 x upper limit of normal (ULN) not related to Gilbert's syndrome, hemolysis, or secondary to MDS at screening

8. Aspartate amino transferase or alanine amino transferase >2.5 x ULN

9. Serum creatinine >1.5 x ULN at screening

10. Arterial oxygen pressure <60 torr or arterial oxygen saturation <92% (at room air)

11. Active hepatitis B or hepatitis C, or laboratory evidence of hepatitis with positive results of hepatitis B surface antigen and/or hepatitis C antibody.

12. Human immunodeficiency virus infection.

13. Severe illness or organ dysfunction involving the heart, lung, kidney, liver or other organ system, which in the opinion of the investigator would interfere with the evaluation of the safety of the study treatment including; infection requiring active treatment, poorly controlled ventricular/atrial tachyarrhythmia, use of heart pacer, unstable angina pectoris, history of myocardial infarction or severe congestive heart failure, clinically unstable cardiac or pulmonary disease

14. Any significant concurrent psychiatric disorder or social situation that according to the investigator's judgment would compromise patient's safety or compliance, interfere with consent, study participation, or interpretation of study results

15. All male patients and female patients of child bearing potential who are unwilling to use a medically acceptable method of contraception during the trial and at least 6 months after the end of study treatment (i.e. hormonal contraception, intrauterine device, condom with spermicide, etc.). Note: females are considered to be of child bearing potential unless they have been surgically sterilized or are post-menopausal (complete absence of menses for at least 12 months without other medical reasons).

16. Pregnant or nursing female patients

17. Known or suspected active alcohol or drug abuse

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Boehringer Ingelheim Investigational Site	Aichi, Nagoya		Japan
2	Boehringer Ingelheim Investigational Site	Gunma, Maebashi		Japan
3	Boehringer Ingelheim Investigational Site	Nagasaki, Nagasaki		Japan
4	Boehringer Ingelheim Investigational Site	Tokyo, Sinagawa-ku		Japan

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02201329
• Other Study ID Numbers: 1230.35
• First Posted: Jul 28, 2014
• Last Update Posted: Jul 30, 2018
• Last Verified: Oct 1, 2017

• Additional relevant MeSH terms: Leukemia; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Syndrome; Azacitidine

Study Results

Participant Flow

Arm/Group Title	Volasertib 200 mg
Arm/Group Description	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.
Period Title: Overall Study
STARTED	5
COMPLETED	0
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Volasertib 200 mg
Arm/Group Description	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 Participants	5
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	73.2 (4.6)
Sex: Female, Male (Count of Participants)
Female	2 40%
Male	3 60%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)
Description	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). Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 drug-related non-haematologic toxicity. 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. 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. 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)).
Time Frame	Up to 57 days.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Volasertib 200 mg
Arm/Group Description	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.
Measure Participants	5
Number [Participants]	2 40%

2. Primary Outcome

Title	Maximum Tolerated Dose of Volasertib
Description	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.
Time Frame	Up to 57 days.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Volasertib 200 mg
Arm/Group Description	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.
Measure Participants	5
Number [mg]	NA

3. Secondary Outcome

Title	Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR)
Description	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.
Time Frame	Up to 9 months.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Volasertib 200 mg
Arm/Group Description	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.
Measure Participants	5
Objective Response (OR)	2 40%
Complete Remission (CR)	0 0%
Partial Remission (PR)	0 0%
Marrow Complete Remission (mCR)	2 40%

4. Secondary Outcome

Title	Maximum Measured Concentration of the Volasertib 200 mg in Plasma (Cmax)
Description	This outcome measure presents maximum measured concentration of Volasertib 200 mg in plasma (Cmax).
Time Frame	-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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Volasertib 200 mg
Arm/Group Description	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.
Measure Participants	5
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	713 (44.4)

5. Secondary Outcome

Title	Area Under the Concentration-Time Curve of Volasertib 200 mg in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Description	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-∞).
Time Frame	-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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Volasertib 200 mg
Arm/Group Description	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.
Measure Participants	5
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	4190 (25.4)

Adverse Events

Time Frame	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.
Arm/Group Title	Volasertib 200 mg
Arm/Group Description	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.
All Cause Mortality
	Volasertib 200 mg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Volasertib 200 mg
	Affected / at Risk (%)	# Events
Total	2/5 (40%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation	1/5 (20%)
Febrile neutropenia	1/5 (20%)
Immune system disorders
Hypersensitivity	1/5 (20%)
Infections and infestations
Pneumonia	2/5 (40%)
Pyelonephritis	1/5 (20%)
Metabolism and nutrition disorders
Dehydration	1/5 (20%)
Renal and urinary disorders
Acute kidney injury	1/5 (20%)
Other (Not Including Serious) Adverse Events
	Volasertib 200 mg
	Affected / at Risk (%)	# Events
Total	5/5 (100%)
Blood and lymphatic system disorders
Anaemia	1/5 (20%)
Febrile neutropenia	2/5 (40%)
Neutropenia	1/5 (20%)
Thrombocytopenia	2/5 (40%)
Cardiac disorders
Arrhythmia	1/5 (20%)
Eye disorders
Eyelids pruritus	1/5 (20%)
Gastrointestinal disorders
Constipation	1/5 (20%)
Diarrhoea	2/5 (40%)
Enterocolitis	1/5 (20%)
Stomatitis	1/5 (20%)
Tongue coated	1/5 (20%)
General disorders
Fatigue	1/5 (20%)
Injection site reaction	5/5 (100%)
Oedema peripheral	1/5 (20%)
Peripheral swelling	1/5 (20%)
Pyrexia	2/5 (40%)
Hepatobiliary disorders
Hepatic function abnormal	1/5 (20%)
Immune system disorders
Hypersensitivity	1/5 (20%)
Infections and infestations
Paronychia	1/5 (20%)
Pharyngitis	2/5 (40%)
Injury, poisoning and procedural complications
Contusion	1/5 (20%)
Investigations
Alanine aminotransferase increased	1/5 (20%)
Aspartate aminotransferase increased	1/5 (20%)
Blood alkaline phosphatase increased	1/5 (20%)
Blood creatine phosphokinase increased	1/5 (20%)
Blood creatinine increased	1/5 (20%)
Gamma-glutamyltransferase increased	1/5 (20%)
Haemoglobin decreased	1/5 (20%)
Neutrophil count decreased	1/5 (20%)
Platelet count decreased	1/5 (20%)
Weight decreased	1/5 (20%)
White blood cell count decreased	2/5 (40%)
Metabolism and nutrition disorders
Decreased appetite	1/5 (20%)
Dehydration	1/5 (20%)
Hypokalaemia	1/5 (20%)
Iron overload	1/5 (20%)
Musculoskeletal and connective tissue disorders
Back pain	1/5 (20%)
Muscle spasms	1/5 (20%)
Nervous system disorders
Dysgeusia	1/5 (20%)
Renal and urinary disorders
Renal impairment	1/5 (20%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/5 (20%)
Hypoxia	1/5 (20%)
Skin and subcutaneous tissue disorders
Drug eruption	1/5 (20%)
Dry skin	1/5 (20%)
Purpura	1/5 (20%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.