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

Primary Purpose

Medulloblastoma, Pineoblastoma, Supratentorial Embryonal Tumor, Not Otherwise Specified

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
3-Dimensional Conformal Radiation Therapy
Carboplatin
Cisplatin
Cyclophosphamide
Etoposide Phosphate
Isotretinoin
Laboratory Biomarker Analysis
Peripheral Blood Stem Cell Transplantation
Thiotepa
Vincristine Sulfate
Vorinostat
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Medulloblastoma

Eligibility Criteria

2 Months - 47 Months (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Hospital Los Angeles
  • Lucile Packard Children's Hospital Stanford University
  • Children's National Medical Center
  • Lurie Children's Hospital-Chicago
  • National Cancer Institute Pediatric Oncology Branch
  • Memorial Sloan Kettering Cancer Center
  • Duke University Medical Center
  • Cincinnati Children's Hospital Medical Center
  • Children's Hospital of Philadelphia
  • Children's Hospital of Pittsburgh of UPMC
  • Pediatric Brain Tumor Consortium
  • Saint Jude Children's Research Hospital
  • M D Anderson Cancer Center
  • Texas Children's Hospital
  • Seattle Children's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (vorinostat, isotretinoin, chemotherapy)

Arm Description

See Detailed Description

Outcomes

Primary Outcome Measures

Dose-limiting toxicity of proposed vorinostat
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
Simon's two-stage optimal design will be used to assess feasibility.
Prognostic value of histopathological classification of pediatric medulloblastoma
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.

Secondary Outcome Measures

Response rate of this approach in patients with measurable residual disease (primary site and/or metastatic sites)
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)
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)
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
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.

Full Information

First Posted
March 20, 2009
Last Updated
January 12, 2022
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00867178
Brief Title
Vorinostat Combined With Isotretinoin and Chemotherapy in Treating Younger Patients With Embryonal Tumors of the Central Nervous System
Official Title
A Feasibility Study of Vorinostat (SAHA) Combined With Isotretinoin and Chemotherapy in Infants With Embryonal Tumors of the Central Nervous System
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
February 25, 2009 (Actual)
Primary Completion Date
April 9, 2020 (Actual)
Study Completion Date
December 22, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Medulloblastoma, Pineoblastoma, Supratentorial Embryonal Tumor, Not Otherwise Specified

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Treatment (vorinostat, isotretinoin, chemotherapy)
Arm Type
Experimental
Arm Description
See Detailed Description
Intervention Type
Radiation
Intervention Name(s)
3-Dimensional Conformal Radiation Therapy
Other Intervention Name(s)
3-dimensional radiation therapy, 3D Conformal, 3D CONFORMAL RADIATION THERAPY, 3D CRT, 3D-CRT, Conformal Therapy, Radiation Conformal Therapy, Radiation, 3D Conformal
Intervention Description
Undergo conformal radiation therapy
Intervention Type
Drug
Intervention Name(s)
Carboplatin
Other Intervention Name(s)
Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cisplatin
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Etoposide Phosphate
Other Intervention Name(s)
Etopophos
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Isotretinoin
Other Intervention Name(s)
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
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Procedure
Intervention Name(s)
Peripheral Blood Stem Cell Transplantation
Other Intervention Name(s)
PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, PERIPHERAL BLOOD STEM CELL TRANSPLANT, Peripheral Stem Cell Support, Peripheral Stem Cell Transplant, Peripheral Stem Cell Transplantation
Intervention Description
Undergo PBSC
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Vincristine Sulfate
Other Intervention Name(s)
Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfate
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Vorinostat
Other Intervention Name(s)
L-001079038, MSK-390, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic Acid, Zolinza
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Dose-limiting toxicity of proposed vorinostat
Description
Will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Time Frame
Up to 21 days
Title
Feasibility in terms of completing 3 courses of induction therapy
Description
Simon's two-stage optimal design will be used to assess feasibility.
Time Frame
Within 98 days
Title
Prognostic value of histopathological classification of pediatric medulloblastoma
Description
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.
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
Response rate of this approach in patients with measurable residual disease (primary site and/or metastatic sites)
Description
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.
Time Frame
Up to 5 years
Title
Progression-free survival (PFS)
Description
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.
Time Frame
Up to 5 years
Title
Overall survival (OS)
Description
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.
Time Frame
Up to 5 years
Title
Predictive values of biological markers in CSF, plasma and urine in the context of a feasibility study
Description
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.
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Months
Maximum Age & Unit of Time
47 Months
Accepts Healthy Volunteers
No
Eligibility 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sarah E Leary
Organizational Affiliation
Pediatric Brain Tumor Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Lucile Packard Children's Hospital Stanford University
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Lurie Children's Hospital-Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
National Cancer Institute Pediatric Oncology Branch
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
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
Pediatric Brain Tumor Consortium
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
Saint Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States

12. IPD Sharing Statement

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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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