Carfilzomib and Hyper-CVAD in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoma

PRIMARY OBJECTIVES:

I. Safety and tolerability of administering carfilzomib in combination with hyper-CVAD
chemotherapy.

II. Recommended dose of carfilzomib in combination with hyper-CVAD chemotherapy for the
future phase II trial.

SECONDARY OBJECTIVES:

I. Rate of remission after 2nd and 4th cycles. II. Incidence of minimal residual disease by
flow cytometry at 4th cycle.

OUTLINE: This is a dose escalation study of carfilzomib.

Patients receive carfilzomib intravenously (IV) over 30 minutes on days 0, 1, 7, and 8.
Patients also receive hyper-CVAD comprising cyclophosphamide IV over 2 hours every 12 hours
for 6 doses beginning on day 1, vincristine sulfate IV on days 4 and 11, doxorubicin
hydrochloride IV over 2-24 hours on day 4, and dexamethasone orally (PO) on days 1-4 and
11-14 (courses 1 and 3) and methotrexate IV over 24 hours on day 1, cytarabine IV over 2
hours every 12 hours for 4 doses starting on day 2, leucovorin calcium IV or PO every 6 hours
beginning 36 hours after the start of methotrexate infusion, and methylprednisolone IV every
12 hours for 6 doses beginning on day 1 (courses 2 and 4). Patients with cluster of
differentiation (CD)20 positive disease also receive rituximab twice daily on days 1 and 11
of courses 1 and 3 and days 1 and 8 of courses 2 and 4. Treatment repeats every 3-4 weeks for
4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days.

Inclusion Criteria:

- Understand and voluntarily sign an informed consent form

- Able to adhere to the study visit schedule and other protocol requirements

- Newly diagnosed acute lymphoblastic leukemia/lymphoma

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (3 if it is directly
disease related and is expected to get better if the acute lymphoblastic
leukemia/lymphoma [ALL] is under control)

- Left ventricular ejection fraction (LVEF) > 40%

- Total bilirubin =< 3 mg/dL

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.5 x
upper limit of normal

- Creatinine clearance (CrCl) >= 45 mL/minute within 7 days prior to enrollment either
measured or calculated using a standard formula (eg, Cockcroft and Gault); in cases
that creatinine clearance cannot be measured accurately, 24 hour urine can be used

- Disease free of other malignancies beside the ALL at the time of the study

- Male subjects must agree to practice contraception

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 50 mIU/mL within 24 hours prior to the initiation
of the study and they must agree to ongoing pregnancy testing and to practice
contraception

Exclusion Criteria:

- Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from signing the informed consent form

- Pregnant or breast feeding females

- Active congestive heart failure (New York Heart Association [NYHA] class III to IV),
symptomatic ischemia, or conduction abnormalities uncontrolled by conventional
intervention

- Unstable angina or myocardial infarction within 6 months prior to enrollment, NYHA
class III or IV heart failure, uncontrolled angina, history of severe coronary artery
disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or
electrocardiographic evidence of acute ischemia or grade 3 conduction system
abnormalities unless subject has a pacemaker

- Uncontrolled hypertension, uncontrolled pulmonary hypertension or uncontrolled
diabetes within 14 days prior to enrollment

- Subjects with pleural effusions requiring thoracentesis or ascites requiring
paracentesis within 14 days prior to enrollment

- Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study

- Use of any other experimental drug or therapy within 14 days of baseline

- Known history of allergy to Captisol®

- Known sero-positive for active viral infection with human immunodeficiency virus
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); patients who are
sero-positive because of hepatitis B virus vaccine are eligible

- Breakpoint cluster region-Abelson positive (BCR-ABL +) patients will be excluded from
the study