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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

Primary Purpose

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)

Status
Completed
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
vorinostat
decitabine
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Chedoke-McMaster Hospitals
  • Juravinski Cancer Centre at Hamilton Health Sciences
  • Princess Margaret Hospital Phase 2 Consortium
  • University Health Network-Princess Margaret Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (enzyme inhibitor, chemotherapy)

Arm Description

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.

Outcomes

Primary Outcome Measures

Maximum tolerated dose and recommended phase II dose of vorinostat and decitabine
Graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

Secondary Outcome Measures

Minimal effective dose of vorinostat in combination with decitabine by bone marrow and/or peripheral blood (for leukemia)
Pharmacokinetics of vorinostat in conjunction with decitabine
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.
Antitumor activity
Measured by Response Evaluation Criteria In Solid Tumors (RECIST), NCI-international working group (IWG), and NCI criteria.
Methylation status of gene promoter regions and gene expression
Measured by bone marrow and/or peripheral blood.
Altered response of leukemic cells to PPAr and RAR ligands
Collected by bone marrow and/or peripheral blood (for leukemia)

Full Information

First Posted
January 10, 2006
Last Updated
August 26, 2014
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00275080
Brief 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
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2014
Overall Recruitment Status
Completed
Study Start Date
February 2006 (undefined)
Primary Completion Date
November 2009 (Actual)
Study Completion Date
August 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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), Blastic Phase Chronic Myelogenous Leukemia, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, 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, Secondary Acute Myeloid Leukemia, 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, Stage IV Adult Diffuse Mixed Cell Lymphoma, Stage IV Adult Diffuse Small Cleaved Cell Lymphoma, Stage IV Adult Immunoblastic Large Cell Lymphoma, Stage IV Adult Lymphoblastic Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Small Lymphocytic Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
80 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (enzyme inhibitor, chemotherapy)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
vorinostat
Other Intervention Name(s)
L-001079038, SAHA, suberoylanilide hydroxamic acid, Zolinza
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
decitabine
Other Intervention Name(s)
5-aza-dCyd, 5AZA, DAC
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Maximum tolerated dose and recommended phase II dose of vorinostat and decitabine
Description
Graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Time Frame
Course 1
Secondary Outcome Measure Information:
Title
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
Title
Pharmacokinetics of vorinostat in conjunction with decitabine
Description
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.
Time Frame
Days 1-15
Title
Antitumor activity
Description
Measured by Response Evaluation Criteria In Solid Tumors (RECIST), NCI-international working group (IWG), and NCI criteria.
Time Frame
Every 4 weeks for leukemia and every 8 weeks for solid tumors or NHL
Title
Methylation status of gene promoter regions and gene expression
Description
Measured by bone marrow and/or peripheral blood.
Time Frame
Baseline and between days 3-10
Title
Altered response of leukemic cells to PPAr and RAR ligands
Description
Collected by bone marrow and/or peripheral blood (for leukemia)
Time Frame
Baseline and between days 3-8

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Karen Yee
Organizational Affiliation
Princess Margaret Hospital Phase 2 Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Chedoke-McMaster Hospitals
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8S 4L8
Country
Canada
Facility Name
Juravinski Cancer Centre at Hamilton Health Sciences
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8V 5C2
Country
Canada
Facility Name
Princess Margaret Hospital Phase 2 Consortium
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
University Health Network-Princess Margaret Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada

12. IPD Sharing Statement

Learn more about this trial

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

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