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

August 26, 2014 updated by: National Cancer Institute (NCI)

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

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.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. 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 OBJECTIVES:

I. 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.

II. 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.

III. 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.

Study Type

Interventional

Enrollment (Actual)

80

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Ontario
      • Hamilton, Ontario, Canada, L8V 5C2
        • Juravinski Cancer Centre at Hamilton Health Sciences
      • Hamilton, Ontario, Canada, L8S 4L8
        • Chedoke-McMaster Hospitals
      • Toronto, Ontario, Canada, M5G 2M9
        • Princess Margaret Hospital Phase 2 Consortium
      • Toronto, Ontario, Canada, M5G 2M9
        • University Health Network-Princess Margaret Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • 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
  • ECOG performance status 0-2
  • 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
  • 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
  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (enzyme inhibitor, chemotherapy)

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.

Given IV
Other Names:
  • DAC
  • 5-aza-dCyd
  • 5AZA
Given orally
Other Names:
  • SAHA
  • Zolinza
  • L-001079038
  • suberoylanilide hydroxamic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum tolerated dose and recommended phase II dose of vorinostat and decitabine
Time Frame: Course 1
Graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Course 1

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Minimal effective dose of vorinostat in combination with decitabine by bone marrow and/or peripheral blood (for leukemia)
Time Frame: Baseline and between days 3-10
Baseline and between days 3-10
Pharmacokinetics of vorinostat in conjunction with decitabine
Time Frame: Days 1-15
Measured by peripheral blood. Performed by high-performance liquid chromatography (HPLC). Estimated by taking the mean concentration one hour after administration per patient on days 1 and 5 and estimating the mean, median and range over all patients.
Days 1-15
Antitumor activity
Time Frame: Every 4 weeks for leukemia and every 8 weeks for solid tumors or NHL
Measured by Response Evaluation Criteria In Solid Tumors (RECIST), NCI-international working group (IWG), and NCI criteria.
Every 4 weeks for leukemia and every 8 weeks for solid tumors or NHL
Methylation status of gene promoter regions and gene expression
Time Frame: Baseline and between days 3-10
Measured by bone marrow and/or peripheral blood.
Baseline and between days 3-10
Altered response of leukemic cells to PPAr and RAR ligands
Time Frame: Baseline and between days 3-8
Collected by bone marrow and/or peripheral blood (for leukemia)
Baseline and between days 3-8

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Karen Yee, Princess Margaret Hospital Phase 2 Consortium

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2006

Primary Completion (Actual)

November 1, 2009

Study Completion (Actual)

August 1, 2014

Study Registration Dates

First Submitted

January 10, 2006

First Submitted That Met QC Criteria

January 10, 2006

First Posted (Estimate)

January 11, 2006

Study Record Updates

Last Update Posted (Estimate)

August 27, 2014

Last Update Submitted That Met QC Criteria

August 26, 2014

Last Verified

June 1, 2014

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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