Volasertib Combined With Induction Chemotherapy in Acute Myeloid Leukemia

This research study is a Phase I clinical trial, which tests the safety of an investigational
drug and also tries to define the appropriate dose of the investigational drug to use for
further studies. "Investigational" means that the drug is being studied.

As part of this research study, the participant will receive Volasertib in combination with
two other chemotherapy drugs, Idarubicin and Cytarabine. The FDA (the U.S. Food and Drug
Administration) has not approved volasertib as a treatment for any disease.

Idarubicin and Cytarabine are chemotherapy agents that are commonly used to treat individuals
diagnosed with AML. Volasertib inhibits proteins called "polo-like kinases," which are
necessary for cell division. Volasertib binds to these proteins and this inhibits the growth
of cancer cells. Volasertib has been used in laboratory studies and those studies suggest
that volasertib may slow down the growth of Cancer. In a previous clinical trial in patients
with the participant type of leukemia where Volasertib was given along with low doses of
Cytarabine, this drug was found to have some clinical activity against AML. In this study,
researchers would like to combine Volasertib with standard chemotherapy (Cytarabine and
Idarubicin) in order to see if it can be given safely with chemotherapy in individuals with
AML.

The primary purpose of this research study is to determine the highest dose that Volasertib
can be given with Idarubicin and Cytarabine without severe or unmanageable side effects. The
dose identified in this study will be used in future research studies.

Inclusion Criteria:

- Participants must have pathologically confirmed, newly diagnosed acute myeloid
leukemia.

- Adults, age 18 years or older at the time of diagnosis, eligible for standard
induction chemotherapy according to their treating physician.

- ECOG performance status 0-2 (Karnofsky ≥60%, see Appendix A)

- Left ventricular ejection fraction > 50% as measured by echocardiogram or MUGA scan

- Must not have received systemic antineoplastic therapy including radiation therapy
within 14 days of the study enrollment, except hydroxyurea or 6-mercaptopurine for the
purposes of cytoreduction as per the treating physician. Patients may also have
received all-trans retinoic acid (ATRA) if there is an early suspicion of acute
promyelocytic leukemia (APL, M3-AML), although if confirmed to have APL these patients
will be excluded from the study.

- Female patients of childbearing age must have negative pregnancy test.

- Participants must have normal organ and marrow function as defined below:

- total bilirubin < 3 times the ULN

- creatinine within normal institutional limits OR

- creatinine clearance ≥30 mL/min/1.73 m2 for participants with creatinine levels
above institutional normal.

- The effects of volasertib (BI 6727) on the developing human fetus are unknown. For
this reason and because other chemotherapeutic agents are known to be teratogenic,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation, and 6 months after completion of therapy. Should
a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately. Men
treated or enrolled on this protocol must also agree to use adequate contraception for
the duration of study participation, and 6 months after completion of therapy.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Patients will be excluded from this study if they are found to harbor "favorable" risk
cytogenetics41 including:

- APL, t(15;17)

- t(8;21)

- inv(16) or t(16;16) A sample to evaluate patient cytogenetics will be sent at the
time of diagnosis per standard clinical care and the absence of these
cytogenetics must be confirmed by Day 8. If the cytogenetic analysis reveals that
the patient harbors favorable risk cytogenetics, or if the cytogenetic results
are not received prior to Day 8, the participant will be removed from the study.

- Patients with acute bilineal/biphenotypic leukemia

- Participants who have had chemotherapy or radiotherapy within 14 days prior to
entering the study, except for hydroxyurea, 6-MP, and ATRA, as noted.

- Participants who are receiving any other investigational agents.

- Chemo-, hormono-, radio- or immunotherapy or therapy with monoclonal antibodies or
small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the
trial drug

- Persistence of clinically relevant therapy related toxicity from previous anti-cancer
therapy

- Prior allogeneic bone marrow or organ transplantation

- Individuals with a history of a different malignancy are ineligible except for the
following circumstances. Individuals with a history of other malignancies are eligible
if they have been disease-free for at least 5 years and are deemed by the investigator
to be at low risk for recurrence of that malignancy. Individuals with the following
cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer
in situ, and basal cell or squamous cell carcinoma of the skin.

- Current clinical central nervous system (CNS) symptoms deemed by the investigator to
be related to leukemic CNS involvement (no lumbar puncture required, clinical
assessment per investigator's judgment is sufficient).

- Prior treatment with volasertib or another polo-like kinase inhibitor

- A diagnosis of active Hepatitis B or C infection. A patient with a prior infection may
participate, so long as the infection is not active at the time of study screening
tests and according to investigator discretion.

- Current or history of ventricular or life-threatening arrhythmias or diagnosis of
long-QT syndrome. Baseline QTc must be 470 msec or less, according to the Friderica
correction method,42 calculated as the mean of 3 ECGs taken at the time of screening.

- Current or history of congestive heart failure New York Heart Association (NYHA) class
3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF <50%, as
measured by MUGA scan or echocardiogram).

- Known hypersensitivity to the trial drugs or other contraindication to standard "7+3"
induction chemotherapy.

- Although not absolute exclusion criteria, several known drug-drug interactions should
be considered during enrollment (see Section 5.5).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because volasertib, along with standard
induction chemotherapy, carries the potential for teratogenic or abortifacient
effects. Because there is an unknown but potential risk for adverse events in nursing
infants secondary to treatment of the mother with volasertib as well as cytarabine and
idarubicin, breastfeeding should be avoided.

- HIV-positive participants on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with volasertib. In addition, these
participants are at increased risk of lethal infections when treated with
marrow-suppressive therapy.

- Patients with psychological, familial, social, or geographic factors that otherwise
preclude them from giving informed consent, following the protocol, or potentially
hamper compliance with study treatment and follow-up.

- Patients who are otherwise felt unable to comply with the protocol, in the opinion of
the investigator.