Trial of Volasertib With or Without Azacitidine in Patients With Myelodysplastic Syndromes

An Open Label, Phase I Trial of Intravenous Administration of Volasertib as Monotherapy and in Combination With Azacitidine in Patients With Myelodysplastic Syndrome After Hypomethylating Agents Treatment Failure

The objectives of this trial are to evaluate the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics and preliminary efficacy of volasertib in two dosing schedules of intravenous volasertib as monotherapy or in combination with azacitidine in patients with myelodysplastic syndrome (MDS) after hypomethylating agents (HMA) treatment failure.

Inclusion criteria:

• Patients 18 years and older with diagnosis of WHO classification-defined primary or treatment-related myeloid neoplasms classified as follows:
• Refractory anaemia with excess blasts (RAEB)-1 (5%-9% marrow blasts) or
• RAEB-2 (10%-19% marrow blasts or 5% - 19% peripheral blast) or
• Chronic Myelomonocytic Leukaemia (CMML) (5%-19% blasts) with white blood cell (WBC) count <13000/mm3 or
• Acute Myeloid Leukaemia (AML) (20%-29% marrow blasts, i.e., RAEB-t according to French-American-British [FAB] classification) with WBC count <10000/mm3
• Patients classified as intermediate, high or very high-risk according to Revised - International Prognostic Scoring System (IPSS-R) at the time of enrolment
• Patients who have received a maximum of 24 cycles of frontline HMA treatment prior to enrolment.
• Patients must have received a minimum prior dosing schedule of either:
• Azacitidine 75 mg/m2 x 5 days per cycle or 50 mg/m2 x 7 days per cycle, or
• Decitabine 20 mg/m2 x 5 days per cycle, or
• SGI-110 60 mg/m2 x 5 days per cycle
• Patients must meet either one of the following criteria:
• Progressive disease (PD, according to 2006 International Working Group (IWG) criteria) at any time after initiation of the prior HMA treatment, or
• Relapse after initial complete (CR) or partial remission (PR) or haematological improvement (HI) (according to 2006 IWG criteria); or
• Failure to achieve complete or partial remission or HI (according to 2006 IWG) with no evidence of progression (i.e., Stable Disease [SD]) after at least six cycles of prior azacitidine treatment or at least four cycles of other prior HMA treatment.
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 at screening
• Signed written informed consent consistent with International Conference of Harmonization Good Clinical Practice (ICH-GCP) and local legislation

Exclusion criteria:

• Prior systemic therapy (including investigational drugs) for MDS, CMML or AML within 14 days before treatment with study medication.
• Patients requiring intervention for white blood cell count control with hydroxyurea, chemotherapy, or leukapheresis.
• Prior exposure to more than one line of HMA based treatment.
• Prior exposure to volasertib or other polo-kinase inhibitors
• Patients who were unable to tolerate prior HMA treatment
• Patients with history of hematopoietic stem cell transplant (HSCT)
• Known hypersensitivity to the trial drugs or its excipients
• Second malignancy currently requiring active therapy (except for hormonal/anti-hormonal treatment, e.g., in prostate or breast cancer).
• QTcF value >470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome).