Vorinostat Combined With Isotretinoin and Chemotherapy in Treating Younger Patients With Embryonal Tumors of the Central Nervous System

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00867178
First received: March 20, 2009
Last updated: July 18, 2014
Last verified: June 2014
  Purpose

This pilot clinical trial studies the side effects and the best way to give vorinostat with isotretinoin and combination chemotherapy and to see how well it works in treating younger patients with embryonal tumors of the central nervous system. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as isotretinoin, vincristine sulfate, cisplatin, cyclophosphamide, and etoposide phosphate, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving vorinostat with isotretinoin and combination chemotherapy may be and effective treatment for embryonal tumors of the central nervous system. A peripheral blood stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. This may allow more chemotherapy to be given so that more tumor cells are killed.


Condition Intervention
Untreated Childhood Medulloblastoma
Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor
Drug: vorinostat
Drug: isotretinoin
Drug: vincristine sulfate
Drug: cisplatin
Drug: cyclophosphamide
Drug: thiotepa
Procedure: peripheral blood stem cell transplantation
Radiation: 3-dimensional conformal radiation therapy
Other: laboratory biomarker analysis

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Feasibility Study of Vorinostat (SAHA) Combined With Isotretinoin and Chemotherapy in Infants With Embryonal Tumors of the Central Nervous System

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Dose-limiting toxicity (DLT) of proposed vorinostat as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 21 days ] [ Designated as safety issue: Yes ]
  • Feasibility in terms of completing 3 courses of induction therapy [ Time Frame: Within 98 days ] [ Designated as safety issue: No ]
    Simon's two-stage optimal design will be used to assess feasibility.

  • Prognostic value of histopathological classification of pediatric medulloblastoma by single-nucleotide polymorphism (SNP) analysis and gene expression analysis [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Loss of heterozygosity (LOH) analysis and copy number analysis (CNA) will be performed using dChip SNP software (or R bioconductor package) for the paired samples. Association of copy number (and LOH) with gene expression data will be explored. Correlation analysis (Pearson or Spearman Correlation, as appropriate) will be used to estimate the strength of association between each SNP and expression signal. The multiplicity issue will be addressed through estimating the False Discovery Rate.


Secondary Outcome Measures:
  • Response rate of this approach in patients with measurable residual disease (primary site and/or metastatic sites) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Separate exact confidence interval estimates of objective responses following induction therapy will be constructed for patients with MBs and PNETs. Cumulative incidence of objective responses as a function of course of therapy will also be provided.

  • Progression-free survival (PFS) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Kaplan-Meier estimates of distributions of PFS will be provided. If sample sizes allow, these Kaplan-Meier estimates will be produced separately for patients with MBs and PNETs.

  • Overall survival (OS) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Kaplan-Meier estimates of distributions of OS will be provided. If sample sizes allow, these Kaplan-Meier estimates will be produced separately for patients with MBs and PNETs.

  • Predictive values of biological markers in CSF, plasma and urine in the context of a feasibility study [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Frequency of the markers of interest present in this cohort will be provided and their associations with disease outcome will be explored. Similarly if sample size constraints make such analyses feasible, the associations between the markers of interest and clinical and demographic variables will be explored in a descriptive fashion.


Estimated Enrollment: 62
Study Start Date: February 2009
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (vorinostat, isotretinoin, chemotherapy)
See Detailed Description
Drug: vorinostat
Given PO
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Drug: isotretinoin
Given PO
Other Names:
  • 13-CRA
  • Amnesteem
  • Cistane
  • Claravis
  • Sotret
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: thiotepa
Given IV
Other Names:
  • Oncotiotepa
  • STEPA
  • TESPA
  • Tespamin
  • TSPA
Procedure: peripheral blood stem cell transplantation
Undergo PBSC
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Radiation: 3-dimensional conformal radiation therapy
Undergo conformal radiation therapy
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To investigate the feasibility of administering vorinostat (SAHA) and isotretinoin for three days prior and concomitant with cisplatin based chemotherapy over three courses of induction chemotherapy.

II. To describe the toxicity of administering vorinostat (SAHA) and isotretinoin for three days prior and concomitant with cisplatin based chemotherapy over three courses of induction chemotherapy.

III. To investigate prognostic values of histopathological classification and biological markers in the context of a feasibility study.

SECONDARY OBJECTIVES:

I. To estimate the preliminary response rate of this approach in patients with measurable residual disease (primary site and/or metastatic sites).

II. To estimate disease specific progression-free and overall survival, in the context of a feasibility study.

III. To explore the predictive values of biological markers in cerebrospinal fluid (CSF), plasma, urine tumor material in the context of a feasibility study.

OUTLINE:

INDUCTION THERAPY: Patients receive vorinostat orally (PO) once daily (QD) and isotretinoin PO twice daily (BID) on days 1-4; vincristine sulfate intravenously (IV) on days 4, 11, and 18; cisplatin IV over 6 hours on day 4; cyclophosphamide IV over 1 hour on days 5-6; and etoposide phosphate IV over 1 hour on days 4-6. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo peripheral blood stem cell (PBSC) harvesting after each course.

CONSOLIDATION THERAPY: Within 6 weeks (10 weeks if patient is re-staged) after completion of induction therapy, patients receive carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1-2. Patients also receive autologous PBSC rescue infusion over 6 hours on day 4. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Beginning 3 weeks later, patients with M0 non-desmoplastic medulloblastoma also undergo conformal radiotherapy* to the tumor bed.

NOTE: *Patients with supratentorial primary tumors or metastatic disease undergo radiotherapy at the discretion of treating physician.

MAINTENANCE THERAPY: Beginning 4 weeks after completion of radiotherapy or immediately after completion of consolidation therapy, patients receive vorinostat PO QD on days 1, 3, 5, 6, 8, 10, 12, and 13 and isotretinoin PO BID on days 1-14. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

  Eligibility

Ages Eligible for Study:   2 Months to 47 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a histologically confirmed, newly-diagnosed medulloblastoma (except for patients with the histology of localized (M0) desmoplastic medulloblastoma or atypical teratoid/rhabdoid tumor [ATRT]) or supratentorial primitive neuroectodermal tumor (PNET) including pineoblastomas
  • Patients must have not received any prior therapy other than surgery and/or steroids
  • Patient must have adequate pre-trial formalin-fixed, paraffin-embedded (FFPE) tumor material available for use in the biology studies and central pathology review; if snap frozen tissue is not available, the study chair must be contacted to discuss eligibility
  • Patient must be a suitable candidate, by institutional standards for stem cell apheresis
  • Lansky performance score (LPS for =< 16 years of age) >= 30 assessed within two weeks prior to registration
  • No prior therapy except surgery and/or corticosteroids alone
  • Absolute neutrophil count (ANC) >= 1000/ul (unsupported)
  • Platelets >= 100,000/ul (unsupported)
  • Hemoglobin >= 8 g/dL (may be supported)
  • Bilirubin < 1.5 times upper limit of normal for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 1.5 times institutional upper limit of normal for age
  • Serum creatinine =< 1.5 times upper limit of institutional normal for age or glomerular filtration rate (GFR) >= 70 ml/min/1.73m^2 or estimated GFR (Schwartz bedside) that is > 99 ml/min/1.73m^2
  • Parents/legal guardians must have the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines

Exclusion Criteria:

  • Patients with diagnosis of atypical teratoid/rhabdoid tumor (ATRT by histology, immunohistochemistry and/or molecular analysis) and desmoplastic M0 medulloblastoma will be excluded from the study
  • Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that would compromise the patient's ability to tolerate protocol therapy or would likely interfere with the study procedures or results
  • Patients receiving any other anticancer or investigational drug therapy are excluded; patients having taken valproic acid within 2 weeks prior to initiation of treatment are excluded
  • Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy
  • Patients with a parabens allergy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00867178

Locations
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Girish Dhall    323-361-4629    gdhall@chla.usc.edu   
Principal Investigator: Girish Dhall         
Lucile Packard Children's Hospital Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Paul G. Fisher    650-721-5889    pfisher@stanford.edu   
Principal Investigator: Paul G. Fisher         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Lindsay B. Kilburn    202-476-3854    lkilburn@cnmc.org   
Principal Investigator: Lindsay B. Kilburn         
United States, Illinois
Lurie Children's Hospital-Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Stewart Goldman    312-227-4844    sgoldman@luriechildrens.org   
Principal Investigator: Stewart Goldman         
United States, Maryland
National Cancer Institute Pediatric Oncology Branch Recruiting
Bethesda, Maryland, United States, 20892
Contact: Katherine E. Warren    301-435-4683    warrenk@mail.nih.gov   
Principal Investigator: Katherine E. Warren         
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Ira J. Dunkel    212-639-2153    dunkeli@mskcc.org   
Principal Investigator: Ira J. Dunkel         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Sridharan Gururangan    919-684-3506    gurur002@mc.duke.edu   
Principal Investigator: Sridharan Gururangan         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Maryam Fouladi    513-803-0721    maryam.fouladi@cchmc.org   
Principal Investigator: Maryam Fouladi         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Peter C. Phillips    215-590-2107    phillipsp@email.chop.edu   
Principal Investigator: Peter C. Phillips         
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Ian F. Pollack    412-692-5881    ian.pollack@chp.edu   
Principal Investigator: Ian F. Pollack         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Alberto Broniscer    901-595-4925    alberto.broniscer@stjude.org   
Principal Investigator: Alberto Broniscer         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Anita Mahajan    713-563-2350    amahajan@mdanderson.org   
Principal Investigator: Anita Mahajan         
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Murali M. Chintagumpala    832-822-4266    mxchinta@txch.org   
Principal Investigator: Murali M. Chintagumpala         
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Contact: Sarah E. Leary    206-987-2106    sarah.leary@seattlechildrens.org   
Principal Investigator: Sarah E. Leary         
Sponsors and Collaborators
Investigators
Principal Investigator: Sarah Leary Pediatric Brain Tumor Consortium
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00867178     History of Changes
Other Study ID Numbers: NCI-2012-03167, NCI-2012-03167, PBTC-026, PBTC-026, U01CA081457
Study First Received: March 20, 2009
Last Updated: July 18, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Medulloblastoma
Central Nervous System Neoplasms
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Glioma
Neoplasms, Neuroepithelial
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Vorinostat
Cisplatin
Cyclophosphamide
Thiotepa
Vincristine
Isotretinoin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents

ClinicalTrials.gov processed this record on August 28, 2014