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Enzyme Inhibitors

Will receive volasertib combined with idarubicin plus cytarabine in a 3+7 schedule as induction chemotherapy. Volasertib dose will be given on day 4 in a dose escalation schedule over 3 dose levels (140 mg/m2, 170 mg/m2, 200 mg/m2) in successive cohorts.

Non-hematologic toxicity will be determined using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria for adverse events. Hematologic toxicity will be determined by days to absolute neutrophil count (ANC) and platelet recovery.

Addition of single dose of volasertib intravenously (IV) on Day 4 of treatment protocol.

Volasertib

Given IV daily on Days 1-3 of treatment protocol.

Given IV daily as 24-hour continuous infusion on Day 1-7 of treatment protocol.

Joseph Brandwein, MD

This is a Phase I clinical trial to determine the maximum tolerated dose (MTD) of the polo-like kinase-1 inhibitor volasertib which can be safely combined with idarubicin plus cytarabine induction chemotherapy for previously untreated patients with acute myeloid leukemia. (AML).

Main inclusion criteria:

1. AML, any subtype except acute promyelocytic leukemia (APL)
2. At least one of the following features:

   i. Age 18-75 with adverse risk cytogenetics ii. Age 18-75 with antecedent myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD), or therapy-related AML iii. Age 60-75, regardless of risk category
3. No prior therapy for AML other than hydroxyurea
4. Judged by treating physician to be medically fit for induction chemotherapy
5. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2
6. Normal left ventricular ejection fraction

Subjects will receive induction chemotherapy consisting of idarubicin 12 mg/m2 on Days 1-3 plus cytarabine 200 mg/m2 (age 18-59) or 100 mg/m2 (age 60-75) as a continuous IV infusion x 7 days. Volasertib will be administered on day 4 in a dose-escalation schedule, using a standard 3+3 dose escalation design, over 3 dose levels. Once the MTD has been determined, an additional dose expansion cohort will be accrued.

A Study of Volasertib Plus Induction Chemotherapy for Acute Myeloid Leukemia

A Phase I Study of Volasertib Combined With Standard Induction Chemotherapy for Previously Untreated Patients With Acute Myeloid Leukemia (VIAC)

Anonymized data will be made available to Boehringer-Ingelheim.

Non-hematologic toxicities will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Hematologic toxicities will be assessed by determining number of days to neutrophil (ANC) recovery to \>0.5 x10(9)/L or platelet recovery to \>20 x10(9)/L.

DLT is defined as grade 3-4 non-hematologic toxicity (except grade 3 nausea, vomiting, mucositis or creatinine elevation due to tumor lysis syndrome, and grade 3-4 neutropenic infections and electrolyte abnormalities) using CTCAE version 4.0.Hematologic DLT is defined as ANC recovery to \>0.5 x10(9)/L or platelet recovery to \>20 x10(9)/L of \> 42 days.

MTD is defined as maximum dose of volasertib associated with \< 2/6 DLTs at a given dose level.

Complete response (CR) defined as \<5% marrow blasts with ANC \> 1.0 x10(9)/L and platelets \>100 x 10(9)/L, with no extramedullary disease. CRi defined as same, but ANC \<1.0 and/or platelets \<100.

Spots Global Cancer Trial Database for leukemia, megakaryoblastic, acute