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

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ClinicalTrials.gov Identifier: NCT00867178
Recruitment Status : Active, not recruiting
First Posted : March 23, 2009
Last Update Posted : March 24, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE March 20, 2009
First Posted Date  ICMJE March 23, 2009
Last Update Posted Date March 24, 2021
Actual Study Start Date  ICMJE February 25, 2009
Actual Primary Completion Date December 30, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 7, 2019)
  • Dose-limiting toxicity of proposed vorinostat [ Time Frame: Up to 21 days ]
    Will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
  • Feasibility in terms of completing 3 courses of induction therapy [ Time Frame: Within 98 days ]
    Simon's two-stage optimal design will be used to assess feasibility.
  • Prognostic value of histopathological classification of pediatric medulloblastoma [ Time Frame: Up to 5 years ]
    Will be assessed by single-nucleotide polymorphism (SNP) analysis and gene expression analysis. 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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 20, 2009)
  • Feasibility of regimen
  • Toxicity of regimen according to NCI CTCAE Version 3.0
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 16, 2018)
  • Response rate of this approach in patients with measurable residual disease (primary site and/or metastatic sites) [ Time Frame: Up to 5 years ]
    Separate exact confidence interval estimates of objective responses following induction therapy will be constructed for patients with medulloblastomas (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 ]
    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 ]
    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 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 20, 2009)
  • Preliminary response rate in patients with measurable residual disease
  • Disease-specific progression-free and overall survival
  • Prognostic values of histopathological classification and biological markers
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vorinostat Combined With Isotretinoin and Chemotherapy in Treating Younger Patients With Embryonal Tumors of the Central Nervous System
Official Title  ICMJE A Feasibility Study of Vorinostat (SAHA) Combined With Isotretinoin and Chemotherapy in Infants With Embryonal Tumors of the Central Nervous System
Brief Summary 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 they work 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, by stopping them from dividing, or by stopping them from spreading. Giving vorinostat with isotretinoin and combination chemotherapy may be an 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.
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 cycles 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 cycles 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 cycles 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Medulloblastoma
  • Pineoblastoma
  • Supratentorial Embryonal Tumor, Not Otherwise Specified
Intervention  ICMJE
  • Radiation: 3-Dimensional Conformal Radiation Therapy
    Undergo conformal radiation therapy
    Other Names:
    • 3-dimensional radiation therapy
    • 3D Conformal
    • 3D CONFORMAL RADIATION THERAPY
    • 3D CRT
    • 3D-CRT
    • Conformal Therapy
    • Radiation Conformal Therapy
    • Radiation, 3D Conformal
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Drug: Cisplatin
    Given IV
    Other Names:
    • Abiplatin
    • Blastolem
    • Briplatin
    • CDDP
    • Cis-diammine-dichloroplatinum
    • Cis-diamminedichloridoplatinum
    • Cis-diamminedichloro Platinum (II)
    • Cis-diamminedichloroplatinum
    • Cis-dichloroammine Platinum (II)
    • Cis-platinous Diamine Dichloride
    • Cis-platinum
    • Cis-platinum II
    • Cis-platinum II Diamine Dichloride
    • Cismaplat
    • Cisplatina
    • Cisplatinum
    • Cisplatyl
    • Citoplatino
    • Citosin
    • Cysplatyna
    • DDP
    • Lederplatin
    • Metaplatin
    • Neoplatin
    • Peyrone''s Chloride
    • Peyrone''s Salt
    • Placis
    • Plastistil
    • Platamine
    • Platiblastin
    • Platiblastin-S
    • Platinex
    • Platinol
    • Platinol- AQ
    • Platinol-AQ
    • Platinol-AQ VHA Plus
    • Platinoxan
    • Platinum
    • Platinum Diamminodichloride
    • Platiran
    • Platistin
    • Platosin
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Carloxan
    • Ciclofosfamida
    • Ciclofosfamide
    • Cicloxal
    • Clafen
    • Claphene
    • CP monohydrate
    • CTX
    • CYCLO-cell
    • Cycloblastin
    • Cycloblastine
    • Cyclophospham
    • Cyclophosphamid monohydrate
    • Cyclophosphamide Monohydrate
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
  • Drug: Etoposide Phosphate
    Given IV
    Other Name: Etopophos
  • Drug: Isotretinoin
    Given PO
    Other Names:
    • 13-cis retinoic acid
    • 13-cis-Retinoate
    • 13-cis-Retinoic Acid
    • 13-cis-Vitamin A Acid
    • 13-cRA
    • Absorica
    • Accure
    • Accutane
    • Amnesteem
    • cis-Retinoic Acid
    • Cistane
    • Claravis
    • Isotretinoinum
    • Isotrex
    • Isotrexin
    • Myorisan
    • Neovitamin A
    • Neovitamin A Acid
    • Oratane
    • Retinoicacid-13-cis
    • Ro 4-3780
    • Ro-4-3780
    • Roaccutan
    • Roaccutane
    • Roacutan
    • Sotret
    • ZENATANE
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Procedure: Peripheral Blood Stem Cell Transplantation
    Undergo PBSC
    Other Names:
    • PBPC transplantation
    • PBSCT
    • Peripheral Blood Progenitor Cell Transplantation
    • Peripheral Stem Cell Support
    • Peripheral Stem Cell Transplant
    • Peripheral Stem Cell Transplantation
  • Drug: Thiotepa
    Given IV
    Other Names:
    • 1,1'',1''''-Phosphinothioylidynetrisaziridine
    • Girostan
    • N,N'', N''''-Triethylenethiophosphoramide
    • Oncotiotepa
    • STEPA
    • Tepadina
    • TESPA
    • Tespamin
    • Tespamine
    • Thio-Tepa
    • Thiofosfamide
    • Thiofozil
    • Thiophosphamide
    • Thiophosphoramide
    • Thiotef
    • Tifosyl
    • TIO TEF
    • Tio-tef
    • Triethylene Thiophosphoramide
    • Triethylenethiophosphoramide
    • Tris(1-aziridinyl)phosphine sulfide
    • TSPA
    • WR 45312
  • Drug: Vincristine Sulfate
    Given IV
    Other Names:
    • Kyocristine
    • Leurocristine Sulfate
    • Leurocristine, sulfate
    • Oncovin
    • Vincasar
    • Vincosid
    • Vincrex
    • Vincristine, sulfate
  • Drug: Vorinostat
    Given PO
    Other Names:
    • L-001079038
    • MSK-390
    • SAHA
    • Suberanilohydroxamic Acid
    • Suberoylanilide Hydroxamic Acid
    • Zolinza
Study Arms  ICMJE Experimental: Treatment (vorinostat, isotretinoin, chemotherapy)
See Detailed Description
Interventions:
  • Radiation: 3-Dimensional Conformal Radiation Therapy
  • Drug: Carboplatin
  • Drug: Cisplatin
  • Drug: Cyclophosphamide
  • Drug: Etoposide Phosphate
  • Drug: Isotretinoin
  • Other: Laboratory Biomarker Analysis
  • Procedure: Peripheral Blood Stem Cell Transplantation
  • Drug: Thiotepa
  • Drug: Vincristine Sulfate
  • Drug: Vorinostat
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 7, 2019)		 33
Original Estimated Enrollment  ICMJE
 (submitted: March 20, 2009)		 62
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date December 30, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • Absolute neutrophil count (ANC) >= 1000/ul (unsupported) (within 14 days of registration and within 7 days of the start of treatment)
  • Platelets >= 100,000/ul (unsupported) (within 14 days of registration and within 7 days of the start of treatment)
  • Hemoglobin >= 8 g/dL (may be supported) (within 14 days of registration and within 7 days of the start of treatment)
  • Bilirubin < 1.5 times upper limit of normal for age (within 14 days of registration and within 7 days of the start of treatment)
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 1.5 times institutional upper limit of normal for age (within 14 days of registration and within 7 days of the start of treatment)
  • Serum creatinine =< 1.5 times upper limit of institutional normal for age or glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or estimated GFR (Schwartz bedside) that is > 99 ml/min/1.73 m^2 (within 14 days of registration and within 7 days of the start of treatment)
  • 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 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Months to 47 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00867178
Other Study ID Numbers  ICMJE NCI-2012-03167
NCI-2012-03167 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PBTC-026
PBTC-026 ( Other Identifier: Pediatric Brain Tumor Consortium )
PBTC-026 ( Other Identifier: CTEP )
U01CA081457 ( U.S. NIH Grant/Contract )
UM1CA081457 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sarah E Leary Pediatric Brain Tumor Consortium
PRS Account National Cancer Institute (NCI)
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP