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Vorinostat and Decitabine in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia
This study is ongoing, but not recruiting participants.
First Received: January 10, 2006   Last Updated: December 1, 2009   History of Changes
Sponsor: Princess Margaret Hospital, Canada
Collaborator: National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00275080
  Purpose

RATIONALE: Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, 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 decitabine may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of vorinostat when given together with decitabine in treating patients with advanced solid tumors or relapsed or refractory non-Hodgkin's lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia.


Condition Intervention Phase
Leukemia
Lymphoma
Unspecified Adult Solid Tumor, Protocol Specific
Drug: decitabine
Drug: vorinostat
Phase I

Study Type: Interventional
Study Design: Treatment
Official Title: A Phase 1 Study of Vorinostat (Suberoylanilide Hydroxamic Acid; SAHA) in Combination With Decitabine in Patients With Advanced Solid Tumors, Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia in Blast Crisis

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose and recommended phase II dose of vorinostat and decitabine by NCI CTCAE version 3.0 at first course of therapy [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Minimal effective dose of vorinostat in combination with decitabine by bone marrow and/or peripheral blood (for leukemia) at baseline and between days 3-10 [ Designated as safety issue: No ]
  • Pharmacokinetics as measured by peripheral blood between days 1-15 [ Designated as safety issue: No ]
  • Antitumor activity as measured by RECIST, NCI-IWG, NCI criteria every 4 weeks of each course for leukemia and every 8 weeks after every 2 courses for solid tumors or NHL [ Designated as safety issue: No ]
  • Methylation status of gene promoter regions and gene expression by bone marrow and/or peripheral blood (for leukemia) at baseline and between days 3-10 [ Designated as safety issue: No ]
  • Altered response of leukemic cells to PPAr and RAR ligands by bone marrow and/or peripheral blood (for leukemia) at baseline and between days 3-8 [ Designated as safety issue: No ]

Estimated Enrollment: 61
Study Start Date: February 2006
Estimated Primary Completion Date: December 2006 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

Primary

  • Establish the maximum tolerated dose and recommended phase II dose of vorinostat in conjunction with decitabine in patients with advanced solid tumors or relapsed or refractory non-Hodgkin's lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia in blast crisis.

Secondary

  • Identify the minimal effective dose of vorinostat in conjunction with decitabine that will lead to DNA demethylation, histone acetylation, and gene reactivation with tolerable toxicity in these patients.
  • Determine the pharmacokinetic profiles of vorinostat and decitabine in these patients.
  • Correlate pharmacokinetic profiles of vorinostat and decitabine with toxicity and biological activity in these patients.
  • Assess the antitumor activity of vorinostat and decitabine in these patients.

OUTLINE: This is a parallel group, multicenter, dose-escalation study of vorinostat. Patients are stratified according to disease (solid tumors or non-Hodgkin's lymphoma [NHL] vs hematological malignancies). Patients receive 1 of 2 dosing regimens.

  • Regimen 1 (sequential dosing): Patients receive oral vorinostat two or three times daily on days 6-21 or days 6-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Regimen 2 (concurrent dosing): Patients receive oral vorinostat two or three times daily on days 1-21, days 1-14 (patients with hematological malignancies only), or two times daily on days 1-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5. Courses repeat every 28 days or 21 days (patients with hematological malignancies only) in the absence of disease progression or unacceptable toxicity.

In both groups, cohorts of 3-6 patients receive escalating doses of vorinostat until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. The dose level just below MTD would be declared the recommended phase II dose (RPTD). Up to 10 patients are treated at the RPTD.

After completion of study treatment, patients are followed at 4 weeks.

PROJECTED ACCRUAL: A total of 61 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of 1 of the following:

    • Confirmed relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia in blast crisis (CML-BC)

      • Patients with acute promyelocytic leukemia who have relapsed while on tretinoin allowed
      • Patients with previously untreated AML who refuse induction chemotherapy allowed
      • Patients who are not candidates for aggressive management (those that have medical conditions that prevent the administration of standard curative chemotherapy or those who require an allogeneic bone marrow transplantation for curative therapy but lack an appropriate donor) are allowed
    • Histologically or cytologically confirmed relapsed or refractory non-Hodgkin's lymphoma (NHL)
    • Histologically confirmed solid tumor that is metastatic or unresectable or for which standard curative or palliative measures do not exist or are no longer effective

      • Clinically or radiologically documented disease
      • Patients whose only evidence of disease is tumor marker elevation are not eligible
  • Patients with AML, ALL, or CML-BC who have cerebral spinal fluid involvement may be included

    • May be treated with intrathecal cytarabine and/or methotrexate prior to and/or during the study
  • No known brain metastases in patients with solid tumors or NHL

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-2 OR
  • Karnofsky 60-100%
  • Life expectancy > 12 weeks for patients with solid tumors (including non-Hodgkin's lymphoma) and 6 weeks for patients with hematological malignancies
  • Patients with solid tumors (including NHL) must also have normal marrow function as defined below:

    • Leukocytes ≥ 3,000/mm^3
    • Absolute neutrophil count ≥ 1,500/mm^3
    • Platelets ≥ 100,000/mm^3
  • Creatinine ≤ 150 μmol/L OR
  • Creatinine clearance ≥ 60 mL/min
  • Bilirubin normal
  • AST/ALT ≤ 2.5 times upper limit of normal (ULN)
  • Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control or abstinence) prior to study entry and for the duration of study participation
  • Not pregnant or nursing
  • Negative pregnancy test
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or other agents used in study
  • Able to take oral medications
  • Patients who have a clinical or radiological diagnosis of bowel obstruction are ineligible
  • No ongoing or active infection
  • No symptomatic congestive heart failure
  • No unstable angina pectoris
  • No cardiac arrhythmia
  • No psychiatric illness/social situations that would limit compliance with study requirements
  • No other uncontrolled intercurrent illness

PRIOR CONCURRENT THERAPY:

  • No limitation on the number or types of prior therapy
  • At least 3 weeks since prior radiotherapy, chemotherapy (6 weeks for nitrosoureas or mitomycin C), or molecularly targeted agents

    • Exceptions may be made for low-dose, non-myelosuppressive radiotherapy
  • At least 2 weeks since prior valproic acid or any other histone deacetylase inhibitor
  • Must have recovered from prior therapy
  • Patients with hematological malignancies may receive hydroxyurea until 24 hours prior to starting study medications
  • Previous surgery is permitted provided that wound healing has occurred
  • No prior decitabine
  • No other concurrent investigational agents
  • No other concurrent investigational or commercial agents or therapies administered with the intent to treat the patient's malignancy
  • No HIV-positive patients receiving combination antiretroviral therapy
  • No concurrent prophylactic hematopoietic growth factors (e.g. filgrastim [G-CSF], sargramostim [GM-CSF], thrombopoietin, or epoetin alfa)

    • Hematopoietic growth factors colony stimulating factors for the treatment of cytopenia may be permitted at the discretion of the principal investigator
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00275080

Locations
Canada, Ontario
Margaret and Charles Juravinski Cancer Centre
Hamilton, Ontario, Canada, L8V 5C2
McMaster Children's Hospital at Hamilton Health Sciences
Hamilton, Ontario, Canada, L8N 3Z5
Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
Princess Margaret Hospital, Canada
Investigators
Principal Investigator: Karen W. L. Yee, MD Princess Margaret Hospital, Canada
  More Information

Additional Information:
No publications provided

Study ID Numbers: CDR0000456473, PMH-PHL-046, NCI-6869
Study First Received: January 10, 2006
Last Updated: December 1, 2009
ClinicalTrials.gov Identifier: NCT00275080     History of Changes
Health Authority: United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):
unspecified adult solid tumor, protocol specific
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
splenic marginal zone lymphoma
stage III adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III small lymphocytic lymphoma
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma

Additional relevant MeSH terms:
Anticarcinogenic Agents
Anti-Inflammatory Agents
Antimetabolites
Leukemia, Lymphoid
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Leukemia, Myeloid, Acute
Leukemia
Sensory System Agents
Therapeutic Uses
Lymphoma, Large-Cell, Immunoblastic
Anti-Inflammatory Agents, Non-Steroidal
Analgesics
Lymphoma
Neoplasms by Histologic Type
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immunoproliferative Disorders
Immune System Diseases
Hematologic Diseases
Vorinostat
Myeloproliferative Disorders
Enzyme Inhibitors
Leukemia, Myeloid
Decitabine
Protective Agents
Pharmacologic Actions
Lymphatic Diseases
Neoplasms

ClinicalTrials.gov processed this record on February 08, 2010