Vorinostat Combined With Isotretinoin and Chemotherapy in Treating Younger Patients With Embryonal Tumors of the Central Nervous System
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.
Untreated Childhood Medulloblastoma
Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor
Drug: vincristine sulfate
Procedure: peripheral blood stem cell transplantation
Radiation: 3-dimensional conformal radiation therapy
Other: laboratory biomarker analysis
|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|
- 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.
- 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 PFS will be provided.
- Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Kaplan-Meier estimates of distributions will be provided.
- 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.
|Study Start Date:||February 2009|
|Estimated Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
Experimental: Treatment (vorinostat, isoretinoin, chemotherapy)
See Detailed Description
Other Names:Drug: isotretinoin
Other Names:Drug: vincristine sulfate
Other Names:Drug: cisplatin
Other Names:Drug: cyclophosphamide
Other Names:Drug: thiotepa
Other Names:Procedure: peripheral blood stem cell transplantation
Other Names:Radiation: 3-dimensional conformal radiation therapy
Undergo conformal radiation therapy
Other Names:Other: laboratory biomarker analysis
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.
OUTLINE: This is a multicenter 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 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 every 3 months for 2 years and then every 6 months for 3 years.
|United States, California|
|Children's Hospital Los Angeles||Recruiting|
|Los Angeles, California, United States, 90027|
|Contact: Girish Dhall 323-361-4629 firstname.lastname@example.org|
|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 email@example.com|
|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 firstname.lastname@example.org|
|Principal Investigator: Lindsay B. Kilburn|
|United States, Illinois|
|Lurie Children's Hospital-Chicago||Recruiting|
|Chicago, Illinois, United States, 60614|
|Contact: Stewart Goldman 312-227-4844 email@example.com|
|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 firstname.lastname@example.org|
|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 email@example.com|
|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 firstname.lastname@example.org|
|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 email@example.com|
|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 firstname.lastname@example.org|
|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 email@example.com|
|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 firstname.lastname@example.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 email@example.com|
|Principal Investigator: Anita Mahajan|
|Texas Children's Hospital||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Murali M. Chintagumpala 832-822-4266 firstname.lastname@example.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 email@example.com|
|Principal Investigator: Sarah E. Leary|
|Principal Investigator:||Sarah Leary||Pediatric Brain Tumor Consortium|