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Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid, or SAHA) in Combination With Cytosine Arabinoside (Ara-C) and Etoposide for Patients With Relapsed and/or Refractory Acute Leukemias, Myelodysplasias and Myeloproliferative Disorders


Phase 1
18 Years
N/A
Not Enrolling
Both
Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Basophilic Leukemia, Adult Acute Eosinophilic Leukemia, 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 Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), 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 Acute Promyelocytic Leukemia (M3), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Blastic Phase Chronic Myelogenous Leukemia, Chronic Eosinophilic Leukemia, Chronic Myelomonocytic Leukemia, Chronic Neutrophilic Leukemia, de Novo Myelodysplastic Syndromes, Essential Thrombocythemia, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Polycythemia Vera, Previously Treated Myelodysplastic Syndromes, Primary Myelofibrosis, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes

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Trial Information

Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid, or SAHA) in Combination With Cytosine Arabinoside (Ara-C) and Etoposide for Patients With Relapsed and/or Refractory Acute Leukemias, Myelodysplasias and Myeloproliferative Disorders


OBJECTIVES:

I. Determine the feasibility, tolerability, and toxicities, in terms of the maximum
tolerated dose (MTD), of the sequential combination of vorinostat (SAHA) followed by
cytarabine and etoposide in patients with relapsed and/or refractory acute leukemia or
transforming myelodysplastic syndromes or myeloproliferative disorders.

II. Determine whether the addition of SAHA to cytarabine and etoposide chemotherapy improves
outcome, in terms of complete response rate, duration of response, and overall survival, in
these patients.

III. Determine the effects of SAHA on induction of tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL)-death receptors DR4 and DR5 and other pro-apoptotic
mediators in patient-derived cancer cells (leukemia blast cells) and somatic cells (buccal
mucosa cells, using pre-SAHA and on SAHA treatment samples).

IV. Determine the ability of SAHA to block leukemia blast cells in the G1 phase of the cell
cycle (leukemia blast cells, using pre-SAHA and on SAHA treatment samples).

V. Determine the effects of SAHA on the expression of P-glycoprotein/MDR1/ABCB1, and the
breast cancer resistance protein (BCRP/ABCG2), using functional and mRNA/protein assays for
these transporters (leukemia blast cells, using pre-SAHA and on SAHA treatment samples).

OUTLINE: This is a dose-escalation study of vorinostat (SAHA).

Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine intravenously
(IV) over 3 hours twice daily and etoposide IV over 1 hour once daily on days 11-14.
Treatment repeats approximately every 6-7 weeks for up to 3 courses in the absence of
disease progression or unacceptable toxicity.

Patients who achieve complete response after 1 course of therapy may receive 1 or 2 more
courses of therapy. Patients who achieve partial response after 1 course of therapy may
receive 1 more course of therapy. Cohorts of 3-6 patients receive escalating doses of SAHA
until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose
preceding that at which 1 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once
the MTD is determined, an additional 10 patients are treated at that dose. Blood, buccal
cells, and bone marrow samples are collected prior to and during treatment. Samples are used
for pharmacokinetic and pharmacodynamic studies, protein expression studies, and gene
expression profiling. After completion of study treatment, patients are followed within 30
days.


Inclusion Criteria:



- Histologically or cytologically confirmed diagnosis of 1 of the following:

- Relapsed or refractory acute myeloid leukemia (AML)

- Patients with acute promyelocytic leukemia t(15;17) must have failed prior
tretinoin and arsenic trioxide-containing regimen

- Must be refractory to both agents with absence of durable hematologic
response OR relapsed after a complete response duration of < 6 months

- Relapsed or refractory acute lymphoblastic leukemia

- Chronic myelogenous leukemia in accelerated or blastic phase

- Must be refractory to treatment with imatinib mesylate or dasatinib

- Disease progression despite continued treatment with imatinib mesylate
or dasatinib

- Patients in accelerated or blastic phase are eligible if unable to tolerate
imatinib mesylate provided their disease has progressed on dasatinib or if
unable to tolerate dasatinib

- AML arising in the setting of underlying myelodysplastic syndromes (MDS) and/or
myeloproliferative disorders (MPD)

- Secondary or therapy-related AML

- No active CNS leukemia

- Leukostasis OR leukemic blast count > 50,000/mm³ allowed provided patient is treated
with emergency leukapheresis or hydroxyurea to reduce leukemic blast count to <
30,000/mm³

- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN

- Creatinine ≤ 2.0 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No history of cytarabine-related neurotoxicity

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to vorinostat (SAHA) or other agents used in the study

- No other uncontrolled illness, including, but not limited to, any of the following:

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would preclude compliance with
study requirements

- Infection allowed provided patient is receiving active treatment

- No HIV positivity

- See Disease Characteristics

- Recovered from prior therapy

- Persistent alopecia, fingernail discoloration, or hematologic abnormalities
(primarily related to underlying disease) > 4 weeks after last course of
chemotherapy or radiotherapy does not exclude patient

- At least 2 weeks since prior valproic acid or any other histone deacetylase inhibitor

- No more than 3 prior courses of induction/reinduction chemotherapy, including
induction and consolidation therapy or induction therapy after any bone marrow
transplantation or similar procedure

- Prior low-dose azacitidine, growth factors, cytokines, thalidomide, interferon,
or imatinib mesylate for treatment of preceding MDS/MPD do not count as prior
induction/reinduction therapy

- At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas [e.g.,
carmustine] or mitomycin C) or radiotherapy

- At least 24 hours since prior hydroxyurea

- At least 2 weeks since prior imatinib mesylate, hematopoietic growth factors, and
biological agents

- At least 4 weeks since prior autologous stem cell transplantation

- Prior allogeneic stem cell transplantation allowed if all of the following criteria
are met:

- At least 90 days since prior transplant

- No evidence of graft-vs-host disease

- At least 2 weeks since prior immunosuppressive therapy

- No other concurrent anticancer agents or therapies

- No other concurrent investigational agents

- Concurrent hydroxyurea or leukapheresis allowed on days 1-10 of study treatment to
control rising leukemic blasts (blasts > 30,000/mm³) or leukostasis

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum tolerated dose (MTD) of vorinostat (SAHA) in combination with cytarabine and etoposide

Outcome Description:

Based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Outcome Time Frame:

Course 1

Safety Issue:

Yes

Principal Investigator

Douglas Ross

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Maryland Greenebaum Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00088

NCT ID:

NCT00357305

Start Date:

May 2006

Completion Date:

Related Keywords:

  • Accelerated Phase Chronic Myelogenous Leukemia
  • Adult Acute Basophilic Leukemia
  • Adult Acute Eosinophilic Leukemia
  • 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 Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • 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 Acute Promyelocytic Leukemia (M3)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
  • Blastic Phase Chronic Myelogenous Leukemia
  • Chronic Eosinophilic Leukemia
  • Chronic Myelomonocytic Leukemia
  • Chronic Neutrophilic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Essential Thrombocythemia
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • Polycythemia Vera
  • Previously Treated Myelodysplastic Syndromes
  • Primary Myelofibrosis
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Secondary Acute Myeloid Leukemia
  • Secondary Myelodysplastic Syndromes
  • Congenital Abnormalities
  • Primary Myelofibrosis
  • Blast Crisis
  • Neoplasms
  • Leukemia
  • Leukemia, Basophilic, Acute
  • Leukemia, Eosinophilic, Acute
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myeloid, Accelerated Phase
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic
  • Leukemia, Neutrophilic, Chronic
  • Leukemia, Promyelocytic, Acute
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Polycythemia
  • Polycythemia Vera
  • Thrombocythemia, Essential
  • Hypereosinophilic Syndrome
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
  • Thrombocytosis
  • Myelodysplastic-Myeloproliferative Diseases

Name

Location

University of PittsburghPittsburgh, Pennsylvania  15261
University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201