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

Myelodysplastic Syndromes Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02201329
• Other study ID #: 1230.35
• Status: Completed
• Phase: Phase 1
• Start date: August 2014
• Est. completion date: September 2015

Study information

• Verified date: October 2017
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5
• Est. completion date: September 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 80 Years

Eligibility

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)

3. 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

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

5. 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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelomonocytic, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Azacitidine
Azacitidine (subcutaneous)
• Volasertib
Volasertib escalating doses (intravenous)

Locations

Country	Name	City	State
Japan	Boehringer Ingelheim Investigational Site	Aichi, Nagoya
Japan	Boehringer Ingelheim Investigational Site	Gunma, Maebashi
Japan	Boehringer Ingelheim Investigational Site	Nagasaki, Nagasaki
Japan	Boehringer Ingelheim Investigational Site	Tokyo, Sinagawa-ku

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)	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)).	Up to 57 days.
Primary	Maximum Tolerated Dose of Volasertib	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.	Up to 57 days.
Secondary	Overall Objective Response (OR): Complete Remission (CR), Partial Remission (PR), or Marrow CR (mCR)	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.	Up to 9 months.
Secondary	Maximum Measured Concentration of the Volasertib 200 mg in Plasma (Cmax)	This outcome measure presents maximum measured concentration of 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.
Secondary	Area Under the Concentration-Time Curve of Volasertib 200 mg in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-8)	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 (AUC0-8).	-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.

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