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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00994500
First received: October 10, 2009
Last updated: July 1, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
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
Drug: vorinostat
Drug: bortezomib
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Vorinostat and Bortezomib in Children With Refractory or Recurrent Solid Tumors, Including CNS Tumors and Lymphomas

Resource links provided by NLM:


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

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 [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    Will be reported descriptively.


Enrollment: 20
Study Start Date: August 2009
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (vorinostat, bortezomib)
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.
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00994500

Locations
United States, Illinois
Childrens Memorial Hospital
Chicago, Illinois, United States, 60614
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15224
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
Sponsors and Collaborators
Investigators
Principal Investigator: Jodi Muscal COG Phase I Consortium
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00994500     History of Changes
Other Study ID Numbers: NCI-2011-01980, ADVL0916, CDR0000656719, COG-ADVL0916, U01CA097452
Study First Received: October 10, 2009
Last Updated: July 1, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Astrocytoma
Burkitt Lymphoma
Choriocarcinoma
Craniopharyngioma
Adamantinoma
Endodermal Sinus Tumor
Ependymoma
Glioma
Hodgkin Disease
Lymphoma
Lymphoma, Non-Hodgkin
Lymphomatoid Granulomatosis
Medulloblastoma
Meningioma
Neoplasms, Germ Cell and Embryonal
Neurologic Manifestations
Nervous System Neoplasms
Oligodendroglioma
Teratoma
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Large-Cell, Immunoblastic
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lymphoma, T-Cell
Central Nervous System Neoplasms
Choroid Plexus Neoplasms
Pinealoma
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Lymphoma, Large-Cell, Anaplastic
Germinoma

ClinicalTrials.gov processed this record on April 15, 2014