Vorinostat and Temozolomide in Treating Young Patients With Relapsed or Refractory Primary Brain Tumors or Spinal Cord Tumors

Recurrent Childhood Ependymoma Clinical Trial

Official title:

A Phase I Study of SAHA and Temozolomide in Children With Relapsed or Refractory Primary Brain or Spinal Cord Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01076530
• Other study ID #: NCI-2011-02011
• Secondary ID: ADVL0819CDR00006
• Status: Completed
• Phase: Phase 1
• First received: February 25, 2010
• Last updated: May 1, 2013
• Start date: February 2010

Study information

• Verified date: May 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This phase I trial is studying the side effects and best dose of vorinostat when given together with temozolomide in treating young patients with relapsed or refractory primary brain tumors or spinal cord tumors. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may help temozolomide work better by making tumor cells more sensitive to the drug.

Description:

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose and/or recommended phase II dose of vorinostat in combination with temozolomide in pediatric patients with relapsed or refractory primary CNS tumors.

II. To define and describe the toxicities 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 characterize the pharmacokinetic parameters of vorinostat in these patients.

III. To determine whether acetylated histones in peripheral blood mononuclear cells can be identified as a surrogate marker of the biologic effect of vorinostat at various treatment doses.

IV. To assess the feasibility of collecting and analyzing serum DNA for methylation of the MGMT promoter and describe the relationship between promoter methylation and clinical responses within the confines of this phase I study.

OUTLINE: This is a multicenter, dose-escalation study of vorinostat.

Patients receive oral vorinostat and oral temozolomide once daily on days 1-5. Courses repeat every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.

Patients may undergo blood sample collection periodically for pharmacokinetic and correlative laboratory studies by western blotting and MGMT promoter methylation assays.

After completion of study therapy, patients are followed up for 30 days.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 21 Years

Eligibility

Inclusion Criteria:

• Histologically confirmed CNS malignancy at original diagnosis or relapse

• Histologic confirmation not required for patients with intrinsic brain stem tumors, optic pathway gliomas, or pineal tumors provided CSF or serum tumor markers, including alpha-fetoprotein orbeta-HCG, are elevated

• Recurrent or refractory spinal cord tumors allowed

• Measurable or evaluable disease

• No known curative therapy or therapy proven to prolong survival with an acceptable quality of life

• Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) OR Lansky PS 50-100% (for patients = 16 years of age)

• Neurological deficits must have been relatively stable for = 1 week before study entry

• Patients unable to walk due to paralysis, but who are up in a wheelchair, are considered ambulatory for the purpose of assessing performance status

• ANC = 1,000/µL

• Platelet count = 100,000/µL (transfusion independent, defined as no platelet transfusion within the past 7 days)

• Hemoglobin = 8.0 g/dL (RBC transfusions allowed)

• Creatinine clearance or radioisotope GFR = 70mL/min OR maximum serum creatinine based on age and/or gender as follows:

• 0.6 mg/dL (1 year of age)

• 0.8 mg/dL (2 to 5 years of age)

• 1.0 mg/dL (6 to 9 years of age)

• 1.2 mg/dL (10 to 12 years of age)

• 1.5 mg/dL (males) or 1.4 mg/dL (females) (13 to 15 years of age)

• 1.7 mg/dL (males) or 1.4 mg/dL (females) (= 16 years of age)

• Bilirubin = 1.5 times upper limit of normal

• ALT = 110 U/L

• Serum albumin = 2 g/dL

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Able to swallow capsules or liquid

• Seizure disorder allowed provided it is well controlled with nonenzyme-inducing anticonvulsants

• No pre-existing QTc = 450 msec

• No uncontrolled infection

• No patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of study

• Fully recovered from prior chemotherapy, immunotherapy, or radiotherapy

• More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea)

• At least 7 days since prior hematopoietic growth factors

• At least 7 days since prior biologic agent (antineoplastic agent)

• At least 7 days or 3 half-lives, whichever is longer, since prior monoclonal antibodies

• More than 2 weeks since prior local palliative radiotherapy (small port)

• At least 6 months since prior total-body radiotherapy (TBI), craniospinal radiotherapy, or radiotherapy to = 50% of the pelvis

• At least 6 weeks since other prior substantial bone marrow radiotherapy

• At least 3 months since prior stem cell transplantation or rescue (without TBI)

• No evidence of active graft-vs-host disease

• At least 2 weeks since prior valproic acid

• No prior vorinostat

• Prior temozolomide allowed provided there was no progressive disease during or within 1 month after completion of treatment

• Concurrent corticosteroids allowed provided patient has been on a stable or decreasing dose for = 7 days before study entry

• No other concurrent investigational drugs

• No other concurrent anticancer agents, including chemotherapy, radiotherapy, immunotherapy, or biologic therapy

• No concurrent enzyme-inducing anticonvulsants

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Astrocytoma
• Childhood Atypical Teratoid/Rhabdoid Tumor
• Childhood Central Nervous System Choriocarcinoma
• Childhood Central Nervous System Embryonal 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 Ependymoblastoma
• Childhood Grade I Meningioma
• Childhood Grade II Meningioma
• Childhood Grade III Meningioma
• Childhood High-grade Cerebellar Astrocytoma
• Childhood High-grade Cerebral Astrocytoma
• Childhood Infratentorial Ependymoma
• Childhood Low-grade Cerebellar Astrocytoma
• Childhood Low-grade Cerebral Astrocytoma
• Childhood Medulloepithelioma
• Childhood Mixed Glioma
• Childhood Oligodendroglioma
• Childhood Supratentorial Ependymoma
• Choriocarcinoma
• Choroid Plexus Neoplasms
• Craniopharyngioma
• Ependymoma
• Extra-adrenal Paraganglioma
• Glioma
• Medulloblastoma
• Meningioma
• Neoplasms
• Neoplasms, Germ Cell and Embryonal
• Neuroectodermal Tumors
• Neuroectodermal Tumors, Primitive
• Oligodendroglioma
• Optic Nerve Glioma
• Paraganglioma
• 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 Medulloblastoma
• Recurrent Childhood Pineoblastoma
• Recurrent Childhood Spinal Cord Neoplasm
• Recurrent Childhood Subependymal Giant Cell Astrocytoma
• Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor
• Recurrent Childhood Visual Pathway and Hypothalamic Glioma
• Rhabdoid Tumor
• Spinal Cord Neoplasms

Intervention

Drug:
• vorinostat

• temozolomide

Other:
• diagnostic laboratory biomarker analysis

• pharmacological study

Locations

Country	Name	City	State
Canada	Hospital Sainte-Justine	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Childrens Memorial Hospital	Chicago	Illinois
United States	Baylor College of Medicine	Houston	Texas
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota
United States	Oregon Health and Science University	Portland	Oregon
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose defined as the maximum dose at which fewer than one-third of patients experience DLT using NCI CTCAE version 4.0	In addition to determination of the MTD, a descriptive summary of all toxicities will be reported.	28 days	Yes
Primary	Pharmacokinetic parameters of vorinostat in combination with temozolomide	The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).	Pre-dose, 15 and 30 minutes, 1, 2, 4, 6, 8, and 24 hours	No
Secondary	Response assessed according to RECIST criteria	Will be reported descriptively.	Up to 30 days	No