Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Objectives

Primary

1. 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

1. 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.
2. Determine the pharmacokinetic profiles of vorinostat and decitabine in these patients.
3. Correlate pharmacokinetic profiles of vorinostat and decitabine with toxicity and biological activity in these patients.
4. Assess the antitumor activity of vorinostat and decitabine in these patients.

Entry 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

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

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/mm³
  • Absolute neutrophil count ≥ 1,500/mm³
  • Platelets ≥ 100,000/mm³
• 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

Expected Enrollment

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

Outcomes

Maximum tolerated dose and recommended phase II dose of vorinostat and decitabine by NCI CTCAE version 3.0 at first course of therapy

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
Pharmacokinetics as measured by peripheral blood between days 1-15
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
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
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

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.

Stathis A, Hotte SJ, Chen EX, et al.: Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas. Clin Cancer Res 17 (6): 1582-90, 2011.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Princess Margaret Hospital

Karen Yee, MD, Principal investigator		Ph: 416-946-4495 Email: karen.yee@uhn.on.ca

Registry Information
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
Trial Start Date		2006-02-15
Trial Completion Date		2006-12-17 (estimated)
Registered in ClinicalTrials.gov		NCT00275080
Date Submitted to PDQ		2005-10-18
Information Last Verified		2008-11-30
NCI Grant/Contract Number		CM17107

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