Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin in Treating Older Patients With Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. Determine the vorinostat dose with the most favorable efficacy and toxicity when combined
with azacitidine and GO.

SECONDARY OBJECTIVES:

I. Describe the complete response (CR)/ CR with inadequate recovery (Cri) rate after a total
of 6 cycles of therapy.

II. Describe the disease-free survival of patients that achieve CR/CRi. III. Determine
whether acute myeloid leukemia (AML) characteristics associated with preclinical GO efficacy
predict for clinical benefit, and assess whether differentiation-inducing agents modulate
these characteristics and lower the apoptotic threshold for calicheamicin-gamma1-induced
cytotoxicity (in vitro correlative and mechanistic studies).

OUTLINE: This is phase I, dose-escalation study of vorinostat followed by a phase II study.

Patients receive vorinostat orally (PO) on days 1-9, azacitidine subcutaneously (SC) or
intravenously (IV) over 10-40 minutes on days 1-7, and gemtuzumab ozogamicin IV over 2 hours
on day 8. Treatment repeats every 21 days for up to 12 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 3 years.

Inclusion Criteria:

Prior morphological diagnosis of AML other then acute promyelocytic leukemia according to
the 2001 World Health Organization (WHO) diagnostic criteria; patients with biphenotypic
AML are eligible Requiring first salvage chemotherapy for persistent or relapsing disease,
as defined by standard criteria, after at least one course of conventional chemotherapy,
e.g. with "7+3" A bone marrow biopsy is not routinely required, but should be obtained if
the aspirate is dilute, hypocellular, or inaspirable; outside bone marrow examinations
performed within the stipulated time period are acceptable as long as the slides are
reviewed at the study institution Flow cytometric analysis of the bone marrow aspirate
should be performed according to institutional practice guidelines Duration of CR1 < 12
months (or primary resistant disease) Patients with prior autologous or allogeneic
hematopoietic cell transplantation (HCT) are eligible if relapse occurs 6-12 months
post-transplant Eastern Cooperative Oncology Group (ECOG)/WHO/Zubrod performance status of
0-3, assessed within 14 days prior to registration Must be off any active therapy for AML
with the exception of hydroxyurea for at least 14 days prior to study registration, and
all grade 3 and 4 non-hematological toxicities must have resolved Willingness to
discontinue taking any medications that are generally accepted to have a risk causing
Torsades de Pointes during the study Bilirubin =< 1.5 x Institutional Upper Limit of
Normal (IULN) unless elevation is thought to be due to hepatic infiltration by AML,
Gilbert's syndrome, or hemolysis (assessed within 7 days prior to registration Serum
glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum
glutamic pyruvate transaminase (SPGT) (alanine aminotransferase [ALT]) =< 1.5 x IULN
unless elevation is thought to be due to hepatic infiltration by AML (assessed within 7
days prior to registration) Serum creatinine =< 1.5 x IULN (assessed within 7 days prior
to registration) No clinical or radiographical evidence of heart failure White blood cell
count (WBC) < 25,000/uL, assessed within 3 days prior to registration; patients with WBC
>= 25,000/uL must undergo cytoreduction with hydroxyurea prior to enrollment and will not
be treated if the WBC remains >= 25,000/ uL despite hydroxyurea treatment Patients with
symptoms/signs of hyperleukocytosis or WBC > 100,000/uL can be treated with leukapheresis
prior to enrollment Collection of bone marrow and peripheral blood specimens for
correlative studies prior to study treatment is highly recommended; submission of
peripheral blood only is acceptable as long as the peripheral blast count is > 5,000/uL
and blast count > 50% of total WBC 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; 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 the willingness to sign a written
informed consent document; the consent can be obtained from a legally authorized
representative if the patient is unable to provide informed consent

Exclusion Criteria:

Patients in remission or with second or later relapse

Diagnosis of another malignancy, unless the patient was diagnosed at least 2 years earlier
and has been disease-free for at least 6 months following the completion of curative
intent therapy with the following exceptions:

- Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical
intraepithelial neoplasia, regardless of the disease-free duration, are eligible for
this study if definitive treatment for the condition has been completed

- Patients with organ-confined prostate cancer with no evidence of recurrent or
progressive disease based on prostate-specific antigen (PSA) values are also eligible
for this study if hormonal therapy has been initiated or a radical prostatectomy has
been performed Refractory/relapsing blast crisis of chronic myelogenous leukemia
(CML) Prior anti-AML treatment with GO, histone deacetylase (HDAC) inhibitor
(including the use of valproic acid for control of seizure activity or other
purposes), or demethylating agent Known hypersensitivity to GO, vorinostat,
azacitidine, or mannitol Clinical evidence suggestive of central nervous system (CNS)
involvement with leukemia unless a lumbar puncture confirms the absence of leukemic
blasts in the cerebrospinal fluid (CSF) Human immunodeficiency virus (HIV)-positive
patients are excluded if their cluster of differentiation (CD)4 count is below 200
cells/uL or if they have active acquired immune deficiency syndrome (AIDS)-related
complications, as these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy Pregnancy; women of child-bearing potential
must undergo pregnancy test within 7 days prior to registration; breastfeeding should
be discontinued if the mother is treated with vorinostat, azacitidine, and GO
Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment) Patients may not be receiving any
other investigational agents