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Azacitidine

Antimetabolites

Enzyme Inhibitors

Volasertib (d1 - one hour iv.) + Azacitidine 75 mg/m2 once daily on Days 1-7 (7 consecutive days) (28-day cycle)

Volasertib (d 7 - one hour iv.) + Azacitidine 75 mg/m2 once daily on Days 1-7 (7 consecutive days) (28-day cycle)

Volasertib (d 1 and 7 - one hour iv.) + Azacitidine 75 mg/m2 once daily on Days 1-7 (7 consecutive days) (28-day cycle)

Volasertib

Boehringer Ingelheim

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

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

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

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.

Number of participants with Dose Limiting Toxicities (DLT) in Cycle 1 (escalation part to determine MTD) is presented .

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

Patients were intravenously administered escalating dose of volasertib 250 milligram (mg) (Volasertib (BI 6727), solution for infusion) on Day 1+15 (28-day cycle) combined with subcutaneous administration of Azacitidine (powder for reconstitution of an injection suspension) 75 milligram / square meter (mg/m2) once daily on Days 1 to 7 (28- day cycle)

Volasertib 250 mg + Azacitidine (Escalation Cohort)-Part 1

Patients were intravenously administered escalating dose of volasertib 300 mg (Volasertib (BI 6727), solution for infusion) on Day 1+15 (28-day cycle) combined with subcutaneous administration of Azacitidine (powder for reconstitution of an injection suspension) 75 mg/m2 once daily on Days 1 to 7 (28-day cycle)

Volasertib 300 mg + Azacitidine (Escalation Cohort)- Part 1

Patients were intravenously administered volasertib 250 mg (Volasertib (BI 6727), solution for infusion) on Day 1+15 (28-day cycle) combined with subcutaneous administration of Azacitidine (powder for reconstitution of an injection suspension) 75 mg/m2 once daily on Days 1 to 7 (28-day cycle) in the expansion cohort

Volasertib 250 mg + Azacitidine (Expansion Cohort)- Part 1

Patients were intravenously administered escalating dose of volasertib 170 mg/m2 (Volasertib (BI 6727), solution for infusion) on Day 7 combined with subcutaneous administration of Azacitidine (powder for reconstitution of an injection suspension) 75 mg/m2 once daily on Days 1 to 7 (28-day cycle)

Volasertib 170 mg/m2 + Azacitidine (Escalation Cohort)- Part 2

Patients were intravenously administered escalating dose of volasertib 110 mg/m2 (Volasertib (BI 6727), solution for infusion) on Day1 and Day 7 combined with subcutaneous administration of Azacitidine (powder for reconstitution of an injection suspension) 75 mg/m2 once daily on Days 1 to 7 (28-day cycle)

Volasertib 110 mg/m2 + Azacitidine (Escalation Cohort)- Part 2

Total

Age, Continuous

Sex: Female, Male

Treated set (TS): All entered patients receiving ≥1 dose of study medication were included in the TS

The sponsor discontinued the development of volasertib on 25 Nov 2016 and this trial was discontinued on 16 Dec 2016 for non-clinical reasons. The number of patients enrolled in Part 2 of the study was too small for a meaningful analysis.

Boehringer Ingelheim, Call Center

MTD set: The MTD set was used for the first treatment cycle (Cycle 1) analysis and excluded any treated patients that missed any dose of trial medication in Cycle 1 for reasons other than DLT

Determination of the Maximum Tolerated Dose (MTD) Based on the Occurrence of Dose-limiting Toxicity (DLT) in Cycle 1

Number of Participants With Dose Limiting Toxicities (DLT) in Cycle 1

Efficacy set (ES): All the treated patients without any protocol violations related to efficacy

Spots Global Cancer Trial Database for Phase I Dose Escalation Trial of Volasertib in Combination With Azacitidine in Patients With MDS or CMML

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