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Vorinostat and Bortezomib in Treating Young Patients With Refractory or Recurrent Solid Tumors, Including Central Nervous System Tumors and Lymphoma

Primary Purpose

Childhood Burkitt Lymphoma, Childhood Central Nervous System Choriocarcinoma, Childhood Central Nervous System Germ Cell Tumor

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
vorinostat
bortezomib
pharmacological study
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Childhood Burkitt Lymphoma

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Histologically confirmed solid tumors, including CNS tumors or lymphoma

    • Histological confirmation not required for the following diagnoses

      • Intrinsic brain stem tumors
      • Optic pathway gliomas
      • Pineal tumors and elevations of cerebral spinal fluid or serum tumor markers, including alpha-fetoprotein or beta-human chorionic gonadotropin, allowed
      • Relapsed or refractory disease
  • Must have measurable or evaluable tumor
  • No known curative therapy or therapy proven to prolong survival with an acceptable quality of life
  • Karnofsky performance status (PS) 60-100% for patients > 16 years of age OR Lansky PS60-100% for patients ≤ 16 years of age

    • Neurologic deficits inpatients with CNS tumors must have been relatively stable for a minimum of 1week
    • Patients who are unable to walk because ofparalysis, but who are up in a wheelchair, will be considered ambulatory for thepurpose of assessing the performance score
  • ANC ≥ 1,000/μL
  • Platelet count ≥ 100,000/μL (transfusion independent, defined as not receiving platelet transfusions within the past 7 days)

    • Patients with known bone marrow metastatic disease allowed provided they meet the blood count criteria and are not known to be refractory to platelet transfusion
  • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)

    • Patients with known bone marrow metastatic disease allowed provided they meet the blood count criteria and are not know to be refractory to RBC or platelet transfusion
  • Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age and/or gender as follows:

    • 0.6 mg/dL (1 to < 2 years of age)
    • 0.8 mg/dL (2 to < 6 years of age)
    • 1.0 mg/dL (6 to < 10 years of age)
    • 1.2 mg/dL (10 to < 13 years of age)
    • 1.5 (male) or 1.4 (female) (13 to < 16 years of age)
    • 1.7 (male) or 1.4 (female) ( ≥ 16 years of age)
  • Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 times upper limit ofnormal
  • ALT ≤ 110 U/L
  • Serum albumin ≥ 2 g/dL
  • QTc interval ≤ 450 milliseconds
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Must be able to swallow capsules or liquids
  • Able to comply withthe safety-monitoring requirements of the study, in the opinion of the investigator
  • No peripheral neuropathy ≥ grade 2 within the past 14 days
  • No known hypersensitivity to vorinostat or bortezomib
  • No uncontrolled infection
  • No concurrent enzyme-inducing anticonvulsants
  • Must be recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy
  • More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea)
  • At least 7 days since prior therapy with any of the following:

    • Hematopoietic growth factors
    • Biologic (anti-neoplastic) agent

      • For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
    • Corticosteroids unless on a stable or decreasing dose
  • At least 7 days or 3 half-lives, whichever is longer, since prior monoclonal antibodies
  • At least 2 weeks since prior local palliative radiotherapy (small port)
  • At least 6 months since prior total-body irradiation therapy, craniospinal radiotherapy, or ≥ 50% of pelvis irradiated
  • At least 6 weeks since prior substantial bone marrow radiotherapy
  • At least 3 months since prior stem cell transplantation or rescue and no evidence of active graft-vs-host disease
  • At least 2 weeks since prior and no concurrent valproic acid
  • At least 6 weeks since priorimmunotherapy (e.g., tumor vaccines)
  • No prior vorinostat
  • No other concurrent investigational drugs or other anticancer agents, including chemotherapy, radiotherapy, immunotherapy, or biologic therapy

Sites / Locations

  • Childrens Memorial Hospital
  • Dana-Farber Cancer Institute
  • Columbia University Medical Center
  • Children's Hospital of Pittsburgh of UPMC
  • St. Jude Children's Research Hospital
  • Baylor College of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (vorinostat, bortezomib)

Arm Description

Patients receive oral vorinostat once daily on days 1-5 and 8-12 and bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Maximum-tolerated dose defined as the maximum dose at which fewer than one-third of patients experience DLT according to NCI CTCAE version 3.0
In addition to determination of the MTD, a descriptive summary of all toxicities will be reported.

Secondary Outcome Measures

Disease response assessed according to RECIST criteria
Will be reported descriptively.

Full Information

First Posted
October 10, 2009
Last Updated
July 1, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00994500
Brief Title
Vorinostat and Bortezomib in Treating Young Patients With Refractory or Recurrent Solid Tumors, Including Central Nervous System Tumors and Lymphoma
Official Title
A Phase I Study of Vorinostat and Bortezomib in Children With Refractory or Recurrent Solid Tumors, Including CNS Tumors and Lymphomas
Study Type
Interventional

2. Study Status

Record Verification Date
July 2013
Overall Recruitment Status
Completed
Study Start Date
August 2009 (undefined)
Primary Completion Date
July 2011 (Actual)
Study Completion Date
undefined (undefined)

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 bortezomib in treating young patients with refractory or recurrent solid tumors, including CNS tumors and lymphoma. Vorinostat and bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum-tolerated dose and/or recommended phase II dose of vorinostat in combination with bortezomib in pediatric patients with refractory or recurrent solid tumors, including central nervous system tumors and lymphoma. II. To define and describe the toxicities of this regimen in these patients. III. To characterize the pharmacokinetics of this regimen in these patients. SECONDARY OBJECTIVES: I. To preliminarily define the antitumor activity of this regimen within the confines of a phase I study. II. To assess the biologic activity of bortezomib by measuring NF-κB activity in peripheral blood mononuclear cells (PBMC). III. To assess the biologic activity of bortezomib by measuring endoplasmic reticulum stress response using the GRP78 molecular chaperone marker in PBMC. OUTLINE: This is a multicenter, dose-escalation study of vorinostat. Patients receive oral vorinostat once daily on days 1-5 and 8-12 and bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and during course 1 of study for further analysis. After completion of study therapy, patients are followed up within 30 days.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Childhood Burkitt Lymphoma, Childhood Central Nervous System Choriocarcinoma, Childhood Central Nervous System Germ Cell Tumor, Childhood Central Nervous System Germinoma, Childhood Central Nervous System Mixed Germ Cell Tumor, Childhood Central Nervous System Teratoma, Childhood Central Nervous System Yolk Sac Tumor, Childhood Choroid Plexus Tumor, Childhood Craniopharyngioma, Childhood Diffuse Large Cell Lymphoma, Childhood Immunoblastic Large Cell Lymphoma, Childhood Medulloepithelioma, Childhood Meningioma, Childhood Mixed Glioma, Childhood Nasal Type Extranodal NK/T-cell Lymphoma, Childhood Oligodendroglioma, Recurrent Childhood Anaplastic Large Cell Lymphoma, Recurrent Childhood Brain Stem Glioma, Recurrent Childhood Central Nervous System Embryonal Tumor, Recurrent Childhood Cerebellar Astrocytoma, Recurrent Childhood Cerebral Astrocytoma, Recurrent Childhood Ependymoma, Recurrent Childhood Grade III Lymphomatoid Granulomatosis, Recurrent Childhood Large Cell Lymphoma, Recurrent Childhood Lymphoblastic Lymphoma, Recurrent Childhood Malignant Germ Cell Tumor, Recurrent Childhood Medulloblastoma, Recurrent Childhood Pineoblastoma, Recurrent Childhood Small Noncleaved Cell Lymphoma, Recurrent Childhood Subependymal Giant Cell Astrocytoma, Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor, Recurrent Childhood Visual Pathway and Hypothalamic Glioma, Recurrent Childhood Visual Pathway Glioma, Recurrent/Refractory Childhood Hodgkin Lymphoma, Unspecified Childhood Solid Tumor, Protocol Specific

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Treatment (vorinostat, bortezomib)
Arm Type
Experimental
Arm Description
Patients receive oral vorinostat once daily on days 1-5 and 8-12 and bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
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)
bortezomib
Other Intervention Name(s)
LDP 341, MLN341, VELCADE
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Maximum-tolerated dose defined as the maximum dose at which fewer than one-third of patients experience DLT according to NCI CTCAE version 3.0
Description
In addition to determination of the MTD, a descriptive summary of all toxicities will be reported.
Time Frame
21 days
Secondary Outcome Measure Information:
Title
Disease response assessed according to RECIST criteria
Description
Will be reported descriptively.
Time Frame
Up to 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically confirmed solid tumors, including CNS tumors or lymphoma Histological confirmation not required for the following diagnoses Intrinsic brain stem tumors Optic pathway gliomas Pineal tumors and elevations of cerebral spinal fluid or serum tumor markers, including alpha-fetoprotein or beta-human chorionic gonadotropin, allowed Relapsed or refractory disease Must have measurable or evaluable tumor No known curative therapy or therapy proven to prolong survival with an acceptable quality of life Karnofsky performance status (PS) 60-100% for patients > 16 years of age OR Lansky PS60-100% for patients ≤ 16 years of age Neurologic deficits inpatients with CNS tumors must have been relatively stable for a minimum of 1week Patients who are unable to walk because ofparalysis, but who are up in a wheelchair, will be considered ambulatory for thepurpose of assessing the performance score ANC ≥ 1,000/μL Platelet count ≥ 100,000/μL (transfusion independent, defined as not receiving platelet transfusions within the past 7 days) Patients with known bone marrow metastatic disease allowed provided they meet the blood count criteria and are not known to be refractory to platelet transfusion Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions) Patients with known bone marrow metastatic disease allowed provided they meet the blood count criteria and are not know to be refractory to RBC or platelet transfusion Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age and/or gender as follows: 0.6 mg/dL (1 to < 2 years of age) 0.8 mg/dL (2 to < 6 years of age) 1.0 mg/dL (6 to < 10 years of age) 1.2 mg/dL (10 to < 13 years of age) 1.5 (male) or 1.4 (female) (13 to < 16 years of age) 1.7 (male) or 1.4 (female) ( ≥ 16 years of age) Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 times upper limit ofnormal ALT ≤ 110 U/L Serum albumin ≥ 2 g/dL QTc interval ≤ 450 milliseconds Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Must be able to swallow capsules or liquids Able to comply withthe safety-monitoring requirements of the study, in the opinion of the investigator No peripheral neuropathy ≥ grade 2 within the past 14 days No known hypersensitivity to vorinostat or bortezomib No uncontrolled infection No concurrent enzyme-inducing anticonvulsants Must be recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea) At least 7 days since prior therapy with any of the following: Hematopoietic growth factors Biologic (anti-neoplastic) agent For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur Corticosteroids unless on a stable or decreasing dose At least 7 days or 3 half-lives, whichever is longer, since prior monoclonal antibodies At least 2 weeks since prior local palliative radiotherapy (small port) At least 6 months since prior total-body irradiation therapy, craniospinal radiotherapy, or ≥ 50% of pelvis irradiated At least 6 weeks since prior substantial bone marrow radiotherapy At least 3 months since prior stem cell transplantation or rescue and no evidence of active graft-vs-host disease At least 2 weeks since prior and no concurrent valproic acid At least 6 weeks since priorimmunotherapy (e.g., tumor vaccines) No prior vorinostat No other concurrent investigational drugs or other anticancer agents, including chemotherapy, radiotherapy, immunotherapy, or biologic therapy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jodi Muscal
Organizational Affiliation
COG Phase I Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Childrens Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Vorinostat and Bortezomib in Treating Young Patients With Refractory or Recurrent Solid Tumors, Including Central Nervous System Tumors and Lymphoma

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