A phase II/III randomized, open-label study to compare the efficacy and safety of intravenous volasertib in combination with subcutaneous cytarabine versus investigator*s choice of anti-leukemic treatment in adult patients with relapsed or refractory acute myeloid leukemia with no established treatment options (POLO-AML 1)

Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in
adults. AML is characterized by uncontrolled growth of immature bone marrow
cells, leading to impaired production of normal blood cells. Symptoms are
caused by the decrease in the number of normal blood cells. Without
therapeutic intervention, the disease progresses and leads to death within
months after initial diagnosis. In the majority of patients with AML who
achieve a complete remission after initial therapy the leukemia will recur
within 3 years after diagnosis. Patients with recurrent or refractory AML have
a worse prognosis, especially if they are not eligible for intensive treatment.
For this group of patients, no established treatment options are available.
Volasertib is an inhibitor of polo-like kinase 1 (PLK1), a target that is
overexpressed in various human cancers. Published preclinical and clinical data
suggest that PLK1 is a potential target for the treatment of AML. Clinical
trials with volasertib have shown that this drug has an acceptable safety
profile. Volasertib in combination with low-dose cytarabine shows preliminary
anti-leukemia activity, suggesting that this therapy is effective in patients
with relapsed/refractory AML. Therefore, this study has been designed to
further test the efficacy of this combination.

To investigate the efficacy, safety, and pharmacokinetics of volasertib in
combination with low-dose cytarabine versus investigator*s choice of
anti-leukemic treatment in patients with relapsed or refractory acute myeloid
leukemia with no established treatment options.

Phase II/III, randomized, active-controlled, open-label, parallel group
comparison.
A total of 450 patients will be randomized in a 1:1 ratio to received treatment
in Arm A or Arm B. An interim analysis will be performed at the end of the
phase II part of the study. The phase II part is completed when 300 patients
have been enrolled and treated for at least 4 cycles or discontinued/dropped
out of the trial. When complete remission (CR, see below) shows statistical
significance, further patients will be enrolled into the phase III of the
study.

Arm A: intravenous volasertib 350 mg every two weeks and subcutaneous low-dose
cytarabine injections twice daily on days 1-10 of a 28-day cycle.

Arm B: investigator choice of the most appropriate anti-leukemic treatment
available in the local market

This study investigates the efficacy and safety of the combination of
volasertib and cytarabine in patients with relapsed/refractory AML who are not
eligible to receive intensive treatment. The expected adverse events are:
neutropenia, leukopenia, thrombocytopenia, anemia, gastro-intestinal disorders,
alopecia. These adverse events can be monitored well and supportive treatment
is available.
Patients will undergo repeated blood samplings for safety and disease
assessment, recording of vital signs, and bone marrow examinations, which would
be performed regardless of participation in this study. However, the frequency
of these procedures may be higher than usual.
Additional blood samplings will be performed for pharmacokinetic analyses. A
single blood draw may be performed for an optional pharmacogenetic test during
the first cycle. The patient may refuse participation in this sampling, but can
continue to participate in the main study. These procedures can lead to local
pain, bruising, irritation, or an infection in rare cases.