Volasertib + Decitabine in Patients With Acute Myeloid Leukemia (AML)

Study Overview
=================
Brief Summary
-----------------
Dose Escalation (MTD Finding) Phase: To investigate the maximum tolerated dose (MTD), safety and pharmacokinetics of different volasertib administration schedules in combination with decitabine in previously untreated AML patients >= 65 years of age who are considered ineligible for standard intensive therapy, or patients with relapsed or refractory AML regardless of prior treatment status. MTD Extension Phase: To collect additional data on safety, efficacy and pharmacokinetics of volasertib in combination with decitabine in previously untreated patients with AML >= 65 years of age and considered ineligible for standard intensive therapy.

Official Title
-----------------
An Open Label, Phase I, Dose Escalation Trial to Investigate the Maximum Tolerated Dose, Safety, Pharmacokinetics, and Efficacy of Volasertib in Combination With Decitabine in Patients >= 65 Years With Acute Myeloid Leukemia

Conditions
-----------------
Leukemia, Myeloid, Acute

Intervention / Treatment
-----------------
* Drug: decitabine iv
* Drug: volasertib iv infusion


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Dose Escalation Phase: patients with previously untreated AML, relapsed or refractory AML regardless of prior treatment status. MTD Extension Phase: previously untreated AML (prior treatment for Myelodysplastic Syndrome(MDS) is allowed). Age >= 65 years. Previously untreated patients must be ineligible for receiving standard intensive therapy at the time of enrolment, in the opinion of the investigator and based on documented medical reasons. Histologically or cytologically confirmed AML (except for APL, FAB (French-American-British)subtype M3) according to the World Health Organisation classification. Eastern co-operative oncology group (ECOG) performance score =< 1 at screening. Signed and dated written informed consent by start date of Screening Visit in accordance with Good Clinical Practice and local legislation. Exclusion criteria: MTD Extension Phase: Prior chemotherapy for AML (except for hydroxyurea). Patients can receive treatment with hydroxyurea in order to reduce high White Blood Cells count for no more than 28 days (cumulative); discontinuation of hydroxyurea at least one day prior to the study treatment is required. Please note that any prior therapy for MDS is allowed. Acute promyelocytic leukemia (APL, FAB subtype M3), according to World Health Organisation classification. Hypersensitivity to the trial drugs. Other malignancy currently requiring active therapy (except for hormonal/anti-hormonal treatment, e.g. in prostate or breast cancer). Known clinical central nervous system (CNS) symptoms deemed by the investigator to be related to leukemic CNS involvement. QTcF (QT interval corrected for heart rate by the Fridericia formula) > 470 ms, calculated as the mean value of the triplicates taken at least 2 minutes apart at baseline or QTcF prolongation deemed clinically relevant by the investigator. Baseline Left Ventricular Ejection Fraction of < 45% or below the lower limit of institutional normal range. Aspartate amino transferase (AST) or alanine amino transferase (ALT) > 2.5 x the upper limit of normal (ULN). Patients with elevated liver enzyme(s) due to leukemic involvement are allowed up to = 5 x the ULN. Total bilirubin > 1.5 x ULN. For patients with Gilbert's syndrome or elevation due to hepatic infiltrate, total bilirubin must be <4 x ULN. Creatinine clearance (CLcr) < 30 ml/min (estimated creatinine clearance by the Cockcroft-Gault (C-G) equation. Severe illness or organ dysfunction involving the kidneys, liver or other organ system, including active uncontrolled infection, which in the opinion of the investigator precludes treatment with decitabine or would interfere with the evaluation of the safety of the study treatment. Presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) Classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to study entry. 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. Patients with a systemic fungal, bacterial, viral, or other infection that is not controlled. Contraindications for decitabine treatment according to the manufacturer's prescribing information provided in the Investigator Site File Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception during the trial and for a minimum of 6 months after completion of study treatment. Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second medically acceptable method of contraception during the trial and for a minimum of 6 months after completion of study treatment. Pregnant or breast feeding patients. Treatment with any investigational drug within 2 weeks of administration of first study medication dose or within less than five half -lives of the investigational drug before treatment with the present trial drug, whichever is shorter, and / or persistence of toxicities of prior anti-leukemic therapies which are deemed clinically relevant. Prior treatment with a Plk inhibitor such as volasertib or treatment in a clinical trial using a Plk inhibitory compound.

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: volasertib + decitabine<br>dose escalation and MTD (Maximum Tolerated Dose) Extension (Note: Decitabine is a Backbone Treatment and Volasertib is Investigational Medicinal Product (IMP)) | Drug: decitabine iv<br>* decitabine iv fixed dose<br>Drug: volasertib iv infusion<br>* volasertib iv infusion (Body Surface Area (BSA) based dosing)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 decitabine. 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 decitabine at which the incidence of DLT was ≤17% (i.e. 1/6 patients) during Cycle 1. | 4 weeks | 
| Number of Subjects With Dose Limiting Toxicities (DLT) in Cycle 1 | Number of subjects with Dose Limiting Toxicities (DLT) in Cycle 1 is presented | 4 weeks |