Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the toxicities and tolerability of bortezomib in combination with
standard-relapse AML therapy (idarubicin/cytarabine or etoposide/high-dose cytarabine) in
pediatric and young adult patients with relapsed or primary-refractory or secondary AML.

II. To estimate the complete response rate to the Arm A and Arm B regimens.

SECONDARY OBJECTIVES:

I. To determine whether bortezomib inhibits proteasome activity, NF-kB activity and induces
apoptosis pathway proteins in leukemia myeloblasts. II. To determine the feasibility of
measuring AML stem cells in relapsed and recovering bone marrow.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are stratified
according to anthracycline*-equivalent cumulative exposure (≤ 400 mg/m² vs > 400 mg/m²).
Patients are assigned to 1 of 2 groups.

GROUP I (efficacy phase, patients with ≤ 400 mg/m² anthracycline-equivalent cumulative
exposure - Closed as of 08/01/10): Patients receive idarubicin IV over 15 minutes on days
1-3, low-dose cytarabine IV continuously over days 1-7, and bortezomib IV on days 1, 4, and
8.

GROUP II (dose-finding phase (closed as of 10/10) and efficacy phase, patients with > 400
mg/m² anthracycline*-equivalent cumulative exposure): Patients receive etoposide IV over 1
hour on days 1-5, high-dose cytarabine IV over 1 hour twice daily on days 1-5, and bortezomib
IV on days 1, 4, and 8.

NOTE: * Anthracycline restriction no longer required for group 2 as of 10/02/10.

All patients receive intrathecal cytarabine prior to courses 1 and 2. In both arms, treatment
repeats every 28 days for up to 2 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study therapy, patients are followed periodically for at least 5 years.

Inclusion Criteria:

- Diagnosis of acute myeloid leukemia (AML) according to WHO classification

- At least 5% blasts in the bone marrow

- With or without extramedullary disease

- To be eligible for the dose-finding phase (closed as of 10/10) :

- Relapsed patients must meet the following criteria:

- Must have had a prior diagnosis of AML, but may NOT have inv(16) or t(8;21)
cytogenetics

- May be in first or any subsequent relapse

- If in first relapse, remission duration must be less than one year

- Refractory patients must meet the following criteria:

- Must have had a prior diagnosis of AML

- May have received one or more attempt at remission induction

- Patients with treatment-related AML may be previously treated or untreated for
secondary AML

- To be eligible for the efficacy phase:

- Relapsed patients must meet the following criteria:

- Must have had a prior diagnosis of AML, with no restriction on prior
cytogenetics

- Must be in first relapse

- Must not have received prior reinduction therapy

- Refractory patients must meet the following criteria:

- Must have had a prior diagnosis of AML

- Must not have received more than one attempt at remission induction (which
may consist of up to two therapy courses)

- Patients with treatment-related AML must be previously untreated for secondary
AML

- No juvenile myelomonocytic leukemia or acute promyelocytic leukemia (APL; FAB M3)

- Patients with the following CNS status are eligible only in the absence of neurologic
symptoms suggestive of CNS leukemia, such as cranial nerve palsy:

- CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin
preparation, regardless of the number of WBCs

- CNS 2, defined as presence of < 5/μL WBCs in CSF and cytospin positive for
blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm:

- CNS 2a: < 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts

- CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts

- CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but
negative by Steinherz/Bleyer algorithm

- Patients with CNS3 disease (presence of ≥ 5/μL WBCs in CSF and cytospin positive for
blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS
leukemia) are not eligible

- CNS toxicity ≤ grade 2

- Lansky (patients ≤ 16 years of age) or Karnofsky (patients > 16 years of age)
performance status (PS) 50-100%

- ECOG PS 0-2

- No Down syndrome

- No Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone
marrow failure syndrome

- No evidence of active graft-vs-host disease

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum
creatinine based on age/gender as follows:

- 0.4 mg/dL for patients 1 month to < 6 months of age

- 0.5 mg/dL for patients 6 months to < 1 year of age

- 0.6 mg/dL for patients 1 to < 2 years of age

- 0.8 mg/dL for patients 2 to < 6 years of age

- 1 mg/dL for patients 6 to < 10 years of age

- 1.2 mg/dL for patients 10 to < 13 years of age

- 1.5 mg/dL (male) or 1.4 mg/dL (female) for patients 13 to < 16 years of age

- 1.7 mg/dL (male) or 1.4 mg/dL (female) for patients ≥ 16 years of age

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age

- ALT < 3.0 times ULN for age (unless elevation due to leukemia involvement)

- Shortening fraction ≥ 27% by ECHO OR LVEF ≥ 50% by gated radionuclide

- Normal respiratory rate and pulse oximetry > 94% on room air

- FEV_1 ≥ 80% of predicted

- FVC and DLCO > 50% (corrected for hemoglobin)

- Patients who are unable to perform pulmonary function tests (PFTs) (e.g., because
of young age) will be excluded provided they have a medical history of
significant prior pulmonary events or chronic pulmonary disease (e.g., pneumonia
requiring mechanical ventilation support, pulmonary GVHD, pneumonectomy, or
pulmonary toxin exposure)

- Children with histories of resolved bronchiolitis, resolved viral pneumonias and
well-controlled asthma are eligible, even if they are unable to perform PFTs

- Patients with seizure disorder may be enrolled if on a non-enzyme-inducing
anticonvulsant and if seizures are well-controlled

- No uncontrolled infection

- No known allergy to idarubicin, cytarabine, etoposide, boron, mannitol or bortezomib

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Concurrent radiotherapy allowed for patients who present with a chloroma that is
producing or threatens to produce an irreversible neurologic deficit

- Recovered from all prior chemotherapy, immunotherapy, or radiotherapy

- More than 2 weeks since prior cytotoxic chemotherapy (4 weeks for nitrosoureas),
except for hydroxyurea, which is allowed up to 24 hours prior to first dose of study
drug, and intrathecal chemotherapy, which is allowed immediately up to administration
of study drug

- Prior steroid allowed as clinically indicated for patients with asthma

- Hydrocortisone and methylprednisolone allowed as premedication in patients with a
history of severe allergic reactions

- At least 7 days since prior biologic agents, such as steroids, retinoids, or donor
lymphocyte infusion without conditioning

- At least 2 weeks since prior local palliative radiotherapy (small port)

- At least 8 weeks since prior craniospinal radiotherapy or ≥ 50% radiation of pelvis

- At least 6 weeks since prior other bone marrow radiation

- At least 1 day since prior green tea containing products, any products containing
vitamin C, flavanoids or other antioxidants (e.g., vitamins, herbal supplements), and
foods with high vitamin C content

- No prior radiotherapy to > 25% of lung volume

- No prior total-body irradiation as part of a hematopoietic stem cell conditioning
regimen

- At least 2 months since prior stem cell transplantation

- No concurrent graft-vs-host disease prophylactic medication

- No prior bortezomib or other proteasome inhibitors

- No other concurrent investigational drugs

- More than 4 days since prior growth factors that support platelet or white cell number
or function

- No concurrent enzyme-inducing anticonvulsant medications known to be potent inducers
of the cytochrome P450 system, including phenytoin, carbamazepine, and phenobarbital

- Concurrent benzodiazepines and gabapentin allowed

- No concurrent grapefruit juice with bortezomib

- No other concurrent cancer chemotherapy or immunomodulating agents

- No concurrent corticosteroids as anti-emetic therapy

- Concurrent corticosteroids therapy allowed as treatment or prophylaxis for
anaphylactic reactions, symptoms of cytarabine syndrome, and as treatment for
presumptive bortezomib-induced pulmonary toxicity.