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Phase II Trial of Vorinostat (Suberoylanilide Hydroxamic Acid or SAHA; Zolinza™) in Combination With Gemtuzumab Ozogamicin (Mylotarg™) as Induction and Post-Remission Therapy in Older Patients With Previously Untreated Non-M3 Acute Myeloid Leukemia


Phase 2
60 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), Untreated Adult Acute Myeloid Leukemia

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Trial Information

Phase II Trial of Vorinostat (Suberoylanilide Hydroxamic Acid or SAHA; Zolinza™) in Combination With Gemtuzumab Ozogamicin (Mylotarg™) as Induction and Post-Remission Therapy in Older Patients With Previously Untreated Non-M3 Acute Myeloid Leukemia


PRIMARY OBJECTIVES:

I. To determine the CR/CRi rate after treatment with vorinostat plus GO. (Good risk group)
II. To determine the 30-day survival after treatment with vorinostat plus GO. (Poor risk
group)

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of regimen-associated toxicities, along with
30-day survival after start of treatment with vorinostat plus GO. (Good risk group) II. To
determine the CR/CRi rate after treatment with vorinostat plus GO, and estimate the
frequency and severity of regimen-associated toxicities. (Poor risk group) III. To
investigate the relapse-free survival of patients who achieve CR/CRi and receive maintenance
therapy on this study.

IV. To define cellular factors associated with clinical response to GO/vorinostat and
determine the mechanisms underlying the synergistic effect between GO and vorinostat on
primary AML cells (in vitro correlative and mechanistic studies).

OUTLINE:

REMISSION INDUCTION THERAPY: Patients receive oral vorinostat once daily on days 1-9 and
gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 15-22 days for up to
3 courses.

CONSOLIDATION THERAPY: Beginning within 60 days after the completion of remission induction
therapy, patients receive oral vorinostat once daily on days 1-9 and gemtuzumab ozogamicin
IV over 2 hours on day 8.

MAINTENANCE THERAPY: Patients receive oral vorinostat once daily on days 1-14. Treatment
repeats every 28 days for 4 courses.

All treatment continues in the absence of disease progression or unacceptable toxicity.

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


Inclusion Criteria:



- Morphological diagnosis of AML other then acute promyelocytic leukemia (FAB M3)
according to WHO diagnostic criteria; diagnosis of AML must be based on bone marrow
or peripheral blood studies obtained within 28 days prior to study registration or
start of hydroxyurea (for patients presenting with WBC >= 10,000/uL), and no
potentially anti-leukemic therapy (with the exception of hydroxyurea) must have been
given between AML diagnosis and study registration; a bone marrow biopsy is not
routinely required but should be obtained if the aspirate is dilute, hypocellular, or
inaspirable; outside bone marrows performed within the stipulated time period are
acceptable as long as the slides are reviewed at a study institution

- Cytogenetic analysis on bone marrow or peripheral blood specimen is available; based
on the result from the first interim analysis, patients stratified into the good-risk
group are only eligible if their AML has favorable cytogenetics (core-binding factor
AML) or has a normal karyotype; patients stratified into the poor-risk group are
eligible independent of the cytogenetic analysis

- Pretreatment bone marrow and peripheral blood specimens for correlative studies are
available; if bone marrow was performed at an outside facility, submission of
peripheral blood only is acceptable as long as the peripheral blast count is >
5,000/uL and > 50% of total WBC

- Patients with a history of antecedent MDS are eligible, if prior treatment did not
include intensive chemotherapy; patients may have received hematopoietic growth
factors, thalidomide/lenalidomide, 5-azacytidine/decitabine, arsenic trioxide, signal
transduction inhibitors, or low dose cytarabine (< 100 mg/m2/day) for treatment of
MDS; patients must be off prior therapy for MDS at least 30 days prior to study
registration, and all non-hematologic toxicities must have resolved to < grade 2

- ECOG/WHO/Zubrod performance status of 0-3

- Bilirubin =< 2.5 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 14 days prior to registration)

- SGOT (AST) and SPGT (ALT) =< 1.5 x IULN unless elevation is thought to be due to
hepatic infiltration by AML (assessed within 14 days prior to registration)

- Serum creatinine =< 1.5 x IULN (assessed within 14 days prior to registration)

- Left ventricular ejection fraction >= 40% and no clinical evidence of congestive
heart failure (assessed within 28 days prior to registration, e.g. by MUGA scan or
echocardiography)

- Men of reproductive potential must use an effective contraceptive method throughout
the study and for a period of at least 3 months after the study

- Women must be postmenopausal; a postmenopausal woman is defined as a woman who has
experienced amenorrhea > 12 consecutive months or a woman on hormone replacement
therapy with documented FSH level > 35 mIU/mL (women of childbearing potential must
have a pregnancy test within 28 days prior to registration, and must use an adequate
method of contraception to avoid pregnancy throughout the study and for a period of
at least 3 months after the study)

- Provide signed written informed consent

- Willingness to undergo bone marrow examination on day 8 of first induction cycle

- WBC < 10,000/uL (patients with WBC >= 10,000/uL must undergo cytoreduction with
hydroxyurea prior to enrollment and will not be enrolled if the WBC remains >=
10,000/uL (of note, patients with symptoms/signs of hyperleukocytosis or WBC >
100,000/uL can be treated with leukapheresis prior to enrollment)

Exclusion Criteria:

- 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; there should be no plan to begin therapy for the prior
malignancy at the time of study registration; prior treatment with AML induction-type
chemotherapy is not allowed (note 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; concurrent
hormonal therapy is allowed)

- Myeloid blast crisis of chronic myelogenous leukemia (CML)

- Prior systemic chemotherapy for AML with the exception of hydroxyurea

- Prior treatment with AML induction-type chemotherapy, GO, HDAC inhibitors, or high
dose chemotherapy with hematopoietic stem cell support

- Treatment with HDAC inhibitors during the last 3 years prior to registration,
including the use of valproic acid for seizure activity or other purposes

- Known hypersensitivity to hydroxyurea, GO, or vorinostat

- 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)

- Prior positive test for the human immunodeficiency virus (HIV)

- Breastfeeding

- 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)

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Probability of achieving CR or CRi with induction therapy (Good-risk group)

Outcome Time Frame:

After completion of induction therapy

Safety Issue:

No

Principal Investigator

Roland Walter

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Institutional Review Board

Study ID:

2200.00

NCT ID:

NCT00673153

Start Date:

March 2008

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)
  • Untreated 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

Barbara Ann Karmanos Cancer Institute Detroit, Michigan  48201
Stanford University Stanford, California  94305
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Seattle, Washington  98109
Wake Forest University Health Sciences Winston-Salem, North Carolina  27157