Phase I Dose Escalation Trial of Volasertib in Combination With Azacitidine in Patients With MDS or CMML

Myelodysplastic Syndromes Clinical Trial

Official title:

An Open Label Phase I Dose Escalation Trial to Investigate the Maximum Tolerated Dose, Safety, Pharmacokinetics and Efficacy of Intravenous Volasertib in Combination With Subcutaneous Azacitidine in Patients With Previously Untreated High-risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) and Not Candidates for Haematopoetic Stem Cell Transplant

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01957644
• Other study ID #: 1230.33
• Secondary ID: 2013-001290-24
• Status: Terminated
• Phase: Phase 1
• Start date: November 6, 2013
• Est. completion date: December 16, 2016

Study information

• Verified date: September 2018
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To investigate the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of volasertib in combination with azacitidine in patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) and not candidates for hematopoietic stem cell transplant

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 16
• Est. completion date: December 16, 2016
• Est. primary completion date: December 16, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Adult patients with previously untreated, intermediate-2 or high- risk MDS or CMML not eligible for hematopoietic stem cell transplantation (HSCT) based on documented patients characteristics like age, performance status, concomitant diagnoses, and organ dysfunctions

• Further inclusion criteria apply

Exclusion criteria:

• Prior or concomitant therapy for higher risk MDS (for example, but not limited to, hypomethylating agents like azacitidine). Note: Prior treatment with erythropoetin (EPO) is allowed up to > 1 week before treatment with study medication. Patients must have not received MDS therapy since diagnosis of higher-risk MDS. However, previous lenalidomide treatment could have been administered for lower-risk MDS treatment as long as this therapy was discontinued at least > 4 weeks before initiation of the current study treatment.

• Treatment with any investigational drug within 2 weeks before first administration of present trial drug or within less than 5 half lives of the investigational drug before treatment with the present trial drug, whichever is longer.

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

• Corrected QT interval according to Fridericia (QTcF) prolongation > 470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome).The QTcF will be calculated as the mean of the 3 Electrocardiograms (ECGs) taken at screening.

• Total bilirubin > 1.5 x upper limit of normal not related to Gilberts disease, hemolysis, or secondary to MDS.

• Aspartate amino transferase (AST) or alanine amino transferase (ALT) > 2.5 x the upper limit of normal (ULN) Creatinine > 1.5 x ULN

• Active hepatitis B or hepatitis C, or laboratory evidence for a chronic infection (hepatitis test results done in routine diagnostics are acceptable if done within 14 days before first study treatment dose).

• HIV infection (HIV test results in routine diagnostics are acceptable if done within 14 days before first study treatment dose).

• Severe illness or organ dysfunction involving the kidney, liver or other organ system (e.g. active uncontrolled infection , unstable angina pectoris or history of severe congestive heart failure, clinically unstable cardiac disease or pulmonary disease), which in the opinion of the investigator would interfere with the evaluation of the safety of the study treatment

• Further exclusion criteria apply

Related Conditions & MeSH terms

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

Intervention

Drug:
• Azacitidine

• Volasertib

Locations

Country	Name	City	State
France	1230.33.33002 Boehringer Ingelheim Investigational Site	Marseille
France	1230.33.33001 Boehringer Ingelheim Investigational Site	Paris
Germany	1230.33.49011 Boehringer Ingelheim Investigational Site	Berlin
Germany	1230.33.49002 Boehringer Ingelheim Investigational Site	Dresden
Germany	1230.33.49001 Boehringer Ingelheim Investigational Site	Düsseldorf
Germany	1230.33.49005 Boehringer Ingelheim Investigational Site	Frankfurt/Main
Germany	1230.33.49004 Boehringer Ingelheim Investigational Site	Freiburg
Germany	1230.33.49010 Boehringer Ingelheim Investigational Site	Hamburg
Germany	1230.33.49008 Boehringer Ingelheim Investigational Site	Hannover
Germany	1230.33.49012 Boehringer Ingelheim Investigational Site	Kassel
Germany	1230.33.49014 Boehringer Ingelheim Investigational Site	Leipzig
Germany	1230.33.49009 Boehringer Ingelheim Investigational Site	Mannheim
Germany	1230.33.49006 Boehringer Ingelheim Investigational Site	München
Germany	1230.33.49003 Boehringer Ingelheim Investigational Site	Ulm

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

France,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Determination of the Maximum Tolerated Dose (MTD) Based on the Occurrence of Dose-limiting Toxicity (DLT) in Cycle 1	The primary objective of the dose-escalation part of this study was to determine the MTD of volasertib in combination with azacitidine. The MTD was to be identified based on the DLT information collected during the first treatment cycle of each dosing schedule. DLT was defined as a non-haematological drug-related toxicity of Common Terminology Criteria for Adverse Events (CTCAE) grade =3. The MTD corresponded to the highest dose of volasertib and azacitidine at which the incidence of DLT was =17% (i.e. 1/6 patients) during Cycle 1.; The planned dose escalation schedules of Part 2 were not completed because the trial was prematurely discontinued. Hence, a final conclusion of the MTD of volasertib in combination with azacitidine cannot be drawn in this trial.; Number of patients with DLT in cycle 1 in escalation part is presented to determine MTD.	4 weeks
Primary	Number of Participants With Dose Limiting Toxicities (DLT) in Cycle 1	Number of participants with Dose Limiting Toxicities (DLT) in Cycle 1 (escalation part to determine MTD) is presented .	4 weeks
Secondary	Percentage of Patients With Objective Response (OR)	OR was defined as best overall response of complete remission (CR) or partial remission (PR) defined according to the International Working Group (IWG) 2006 criteria.; Complete remission (CR): Bone marrow: <5 % myeloblasts with normal maturation of all cell lines*; Persistent dysplasia will be noted*; Peripheral blood: hemoglobin (Hgb) > 11 Grams Per Decilitre (g/dL); Platelets >100 x 109/L; Neutrophils > 1.0 x 109/L; Blasts 0 % *Dysplastic changes should consider the normal range of dysplastic changes; Partial remission (PR): All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by >50% to pre-treatment but still >5%; Cellularity and morphology not relevant	From randomisation until data cut-off (16Dec2016); up to 159 weeks

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