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AzTrials

Accelerated Phase Chronic Myelogenous LeukemiaPhase 1NCT00357305

Vorinostat, Cytarabine, and Etoposide in Treating Patients With Relapsed and/or Refractory Acute Leukemia or Myelodysplastic Syndromes or Myeloproliferative Disorders

A Phase 1 study testing vorinostat, cytarabine and etoposide in people with Accelerated Phase Chronic Myelogenous Leukemia and Adult Acute Basophilic Leukemia, run by National Cancer Institute (NCI) at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This phase I trial is studying the side effects and best dose of vorinostat when given together with cytarabine and etoposide in treating patients with relapsed or refractory acute leukemia or myelodysplastic syndromes or myeloproliferative disorders. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
vorinostat, cytarabine and etoposide
Could I receive a placebo?
No, everyone receives an active treatment
How many people
25 participants
Where
2 sitesUnited States
Study dates
May 2006to Nov 2011
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 46Show fewer
  • 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

Who cannot join

None listed.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • University of Maryland Greenebaum Cancer Center

    Baltimore, Maryland, 21201-1595

  • University of Pittsburgh

    Pittsburgh, Pennsylvania, 15232

Other trials in United States

About this study

Official title: 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

This phase I trial is studying the side effects and best dose of vorinostat when given together with cytarabine and etoposide in treating patients with relapsed or refractory acute leukemia or myelodysplastic syndromes or myeloproliferative disorders. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with cytarabine and etoposide may kill more cancer cells.

Read the detailed description

OBJECTIVES:

  1. 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).

  1. 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.

Being tested
vorinostat, cytarabine, etoposide, pharmacological study, laboratory biomarker analysis
Medical subject headings
Leukemia, Myeloid, Accelerated Phase, Leukemia, Basophilic, Acute, Leukemia, Eosinophilic, Acute, Leukemia, Megakaryoblastic, Acute, Leukemia, Monocytic, Acute, Leukemia, Myeloid, Acute, Congenital Abnormalities, Leukemia, Myelomonocytic, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • vorinostatDrug

    Also called L-001079038, SAHA, suberoylanilide hydroxamic acid, Zolinza

    Given orally

  • cytarabineDrug

    Also called ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U

    Given IV

  • etoposideDrug

    Also called EPEG, VP-16, VP-16-213

    Given IV

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

  • laboratory biomarker analysisOther

    Correlative studies

Study groups in NCT00357305
Study groupRoleWhat they receive
Treatment (enzyme inhibitor, chemotherapy)ExperimentalPatients receive oral SAHA two or three times daily on days 1-7 and cytarabine 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.
Receives: Drug: vorinostat; Drug: cytarabine; Drug: etoposide; Other: pharmacological study; Other: laboratory biomarker analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

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

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

    Measured: Course 1

Secondary outcomes (8)

  1. Response rate

    Measured using a bone marrow aspirate and/or biopsy. 90% confidence interval will be calculated

    Measured: Baseline, day 4-7 of course 1, and after each course

  2. Progression-free survival

    Estimated using the Kaplan-Meir method.

    Measured: At 30 days after completion of study treatment and continued follow up visits

  3. Disease-specific survival

    Estimated using the Kaplan-Meir method.

    Measured: At 30 days after completion of study treatment and continued follow up visits

  4. One-year survival

    Estimated using the Kaplan-Meir method.

    Measured: At 1 year

  5. Overall survival

    Measured from time of enrollment onto this study to the time of death. Estimated using the Kaplan-Meir method.

    Measured: At 30 days after completion of study treatment and continued follow up visits

  6. Degree of upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptors and proteins associated with apoptosis

    Performed by the Rnase protection assay.

    Measured: Baseline and days 4-7 of course 1

  7. Alterations in cell cycle phase

    Patient-derived bone marrow or peripheral blood mononuclear cells will be evaluated for cell cycle phase distribution, using the hypotonic propidium-iodide method and flow cytometry.

    Measured: Baseline and days 4-7 of course 1

  8. Expression of MDR proteins at MTD of SAHA

    Using quantitative, real-time polymerase chain reaction (PCR) methods with product detected using specific hybridization probes.

    Measured: Baseline and days 4-7 of course 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jul 2006 (estimated)
  2. Study startMay 2006
  3. Primary completionNov 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
25 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00357305
Sponsor's protocol ID
NCI-2009-00088
Other IDs
GCC 0447, NCI-6829, CDR0000487484
Status last verified
May 2013
First submitted
26 Jul 2006
Last updated
3 May 2013
Results posted
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing vorinostat, cytarabine and etoposide in people with Accelerated Phase Chronic Myelogenous Leukemia and Adult Acute Basophilic Leukemia, run by National Cancer Institute (NCI) at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 46 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 May 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose (MTD) of vorinostat (SAHA) in combination with cytarabine and etoposide (time frame: Course 1). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00357305.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 May 2013.

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