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A Phase 1/2 Study of Vorinostat (Zolinza®) in Combination With Gemtuzumab Ozogamicin (Mylotarg®) and Azacitidine (Vidaza®) in Patients 50 Years of Age and Older With Relapsed/Refractory Non-APL Acute Myeloid Leukemia (AML)


Phase 1/Phase 2
50 Years
N/A
Not Enrolling
Both
Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Recurrent Adult Acute Myeloid Leukemia

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Trial Information

A Phase 1/2 Study of Vorinostat (Zolinza®) in Combination With Gemtuzumab Ozogamicin (Mylotarg®) and Azacitidine (Vidaza®) in Patients 50 Years of Age and Older With Relapsed/Refractory Non-APL Acute Myeloid Leukemia (AML)


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose-limiting toxicity and maximum tolerated dose of vorinostat (Phase I)

Outcome Time Frame:

42 days

Safety Issue:

Yes

Principal Investigator

Roland Walter

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-01147

NCT ID:

NCT00895934

Start Date:

May 2009

Completion Date:

Related Keywords:

  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Recurrent Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic

Name

Location

University of Washington Medical Center Seattle, Washington  98195-6043
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Seattle, Washington  98109
Harrison Bremerton Hematology and Oncology Bremerton, Washington  98310
Stanford University Hospitals and Clinics Stanford, California  94305