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 : Completed
First Posted : March 23, 2009
Last Update Posted : January 13, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Medulloblastoma Pineoblastoma Supratentorial Embryonal Tumor, Not Otherwise Specified||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||Phase 1|
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.
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.
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 :||Interventional (Clinical Trial)|
|Actual Enrollment :||33 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Feasibility Study of Vorinostat (SAHA) Combined With Isotretinoin and Chemotherapy in Infants With Embryonal Tumors of the Central Nervous System|
|Actual Study Start Date :||February 25, 2009|
|Actual Primary Completion Date :||April 9, 2020|
|Actual Study Completion Date :||December 22, 2021|
Experimental: Treatment (vorinostat, isotretinoin, chemotherapy)
See Detailed Description
Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo conformal radiation therapy
Drug: Etoposide Phosphate
Other Name: Etopophos
Other: Laboratory Biomarker Analysis
Procedure: Peripheral Blood Stem Cell Transplantation
Drug: Vincristine Sulfate
- 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.
- 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.
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|Ages Eligible for Study:||2 Months to 47 Months (Child)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00867178
|United States, California|
|Children's Hospital Los Angeles|
|Los Angeles, California, United States, 90027|
|Lucile Packard Children's Hospital Stanford University|
|Palo Alto, California, United States, 94304|
|United States, District of Columbia|
|Children's National Medical Center|
|Washington, District of Columbia, United States, 20010|
|United States, Illinois|
|Lurie Children's Hospital-Chicago|
|Chicago, Illinois, United States, 60611|
|United States, Maryland|
|National Cancer Institute Pediatric Oncology Branch|
|Bethesda, Maryland, United States, 20892|
|United States, New York|
|Memorial Sloan Kettering Cancer Center|
|New York, New York, United States, 10065|
|United States, North Carolina|
|Duke University Medical Center|
|Durham, North Carolina, United States, 27710|
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center|
|Cincinnati, Ohio, United States, 45229|
|United States, Pennsylvania|
|Children's Hospital of Philadelphia|
|Philadelphia, Pennsylvania, United States, 19104|
|Children's Hospital of Pittsburgh of UPMC|
|Pittsburgh, Pennsylvania, United States, 15224|
|United States, Tennessee|
|Pediatric Brain Tumor Consortium|
|Memphis, Tennessee, United States, 38105|
|Saint Jude Children's Research Hospital|
|Memphis, Tennessee, United States, 38105|
|United States, Texas|
|M D Anderson Cancer Center|
|Houston, Texas, United States, 77030|
|Texas Children's Hospital|
|Houston, Texas, United States, 77030|
|United States, Washington|
|Seattle Children's Hospital|
|Seattle, Washington, United States, 98105|
|Principal Investigator:||Sarah E Leary||Pediatric Brain Tumor Consortium|
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2012-03167 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
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 )
|First Posted:||March 23, 2009 Key Record Dates|
|Last Update Posted:||January 13, 2022|
|Last Verified:||September 2021|
Neoplasms, Germ Cell and Embryonal
Central Nervous System Neoplasms
Neoplasms by Histologic Type
Neuroectodermal Tumors, Primitive
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Nervous System Neoplasms
Neoplasms by Site
Central Nervous System Diseases
Nervous System Diseases