Phase I Combination of Midostaurin, Bortezomib, and Chemo in Relapsed/Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of bortezomib in combination with
midostaurin and intensive chemotherapy in patients with relapsed/refractory acute myeloid
leukemia (AML).

II. To define the specific toxicities and the dose limiting toxicity (DLT) of midostaurin
and bortezomib in combination with intensive chemotherapy in relapsed/refractory AML.

SECONDARY OBJECTIVES:

I. To determine the rate of complete remission (CR) of midostaurin and bortezomib in
combination with intensive chemotherapy. II. To determine the overall response rate (ORR).
III. To characterize the biological activity of midostaurin and bortezomib to potentially
increase endogenous phosphatase activity and therefore inhibit aberrant tyrosine kinases by
assessing FLT3 and KIT tyrosine kinase activity as well as SHP-1(Anti-Src Homology
Phosphatase-1)phosphatase activity. IV. To correlate the biological activity of midostaurin
and bortezomib to potentially increase endogenous phosphatase activity with clinical
response. V. To conduct pharmacokinetic studies of midostaurin and bortezomib together and
in combination with intensive chemotherapy.

VI. To determine the efficacy of midostaurin and bortezomib in combination with intensive
chemotherapy at the maximum tolerated dose in patients with FLT3 or KIT tyrosine kinase
mutations.

OUTLINE:

This is a dose escalation study of bortezomib. Patients are assigned to 1 of 2 treatment
groups. GROUP I (Dose levels 1-2): Patients receive oral midostaurin twice daily on days
1-14 and bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 28 days for up to 3
courses in the absence of disease progression or unacceptable toxicity. GROUP II (Dose
levels 3-6): Patients receive mitoxantrone hydrochloride IV over 10 minutes, etoposide IV
over 1 hour, and cytarabine IV over 6 hours on days 1-6. Patients also receive oral
midostaurin twice daily on days 8-21 and bortezomib IV on days 8, 11, 15, and 18. Treatment
continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria

- Patients age >18 with relapsed or refractory acute myeloid leukemia by WHO criteria
are eligible for dose levels 1 and 2. Patients age >18 and ≤ 70 with relapsed or
refractory acute myeloid leukemia by WHO criteria are eligible for dose levels 3
through 6. Patients with secondary AML are eligible

- If the patient has co-morbid medical illness, life expectancy attributed to this must
be greater than 6 months

- Eastern Cooperative Oncology Group (ECOG) performance status <2

- Patients must have adequate organ function as defined below:

- total bilirubin <2.0mg/dL or ≤1.5 ULN(institutional upper limit of normal)

- AST(aspartate aminotransferase)(SGOT)/ALT(Alanine aminotransferase) (SGPT) <2.5
X institutional ULN

- creatinine <1.7 mg /dL

- 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. If the patient does not agree, the patient
is not eligible. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately

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

- Patients must have recovered from the toxicity of prior therapy to less than Grade 2

- Patients status post prior hematopoietic stem cell transplantation are eligible

Exclusion criteria

- Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study. Hydroxyurea may be
administered until initiation of treatment on the study

- Patients receiving any other investigational agents or patients that have received
other investigational agents within 14 days of enrollment

- Patients with active central nervous system disease or with granulocytic sarcoma as
sole site of disease

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to midostaurin, bortezomib, mitoxantrone, etoposide
or cytarabine that are not easily managed. Patient has a hypersensitivity to
bortezomib, boron, or mannitol.

- Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements. As infection is a common feature of AML, patients with active infection
are permitted to enroll provided that the infection is under control. Myocardial
infarction within 6 months prior to enrollment or has New York Heart Association
(NYHA) Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension,
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of
acute ischemia or active conduction system abnormalities. Prior to study entry, any
ECG abnormality at screening has to be documented by the investigator as not
medically relevant.

- Ejection fraction <50%

- Patients with serious medical or psychiatric illness likely to interfere with
participation in this clinical study.

- Pregnant women or women who are breastfeeding are excluded from this study.

- Patients with pre-existing Grade 2 or higher neuropathy or other serious neurologic
toxicity that would significantly increase risk of complications from bortezomib
therapy are excluded.

- Patients with a known confirmed diagnosis of HIV infection (due to concern for
increased toxicity with the regimen in combination with HAART) or active viral
hepatitis.

- Patients with any pulmonary infiltrate including those suspected to be of infectious
origin. In particular, patients with resolution of clinical symptoms of pulmonary
infection but with residual pulmonary infiltrates on chest x-ray are not eligible
until pulmonary infiltrates have completely resolved.

- Patients who have had any surgical procedure, excluding central venous catheter
placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1.

- Patients with advanced malignant solid tumors are excluded.

- Patients with known impairment of gastrointestinal (GI) function or GI disease that
may significantly alter the absorption of midostaurin.

- Patients with prior midostaurin treatment are excluded.