Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. 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. This clinical trial is studying the side effects of giving vorinostat and isotretinoin together with combination chemotherapy and to see how well it works in treating young patients who have undergone surgery for embryonal tumors of the central nervous system

Further Study Information

PRIMARY OBJECTIVES:

I. To investigate the feasibility of administering 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 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 CSF, plasma, urine tumor material in the context of a feasibility study.

OUTLINE: This is a multicenter study.

Induction therapy: Patients receive oral vorinostat once daily and oral isotretinoin twice daily on days 1-4; vincristine sulfate 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. 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 oral vorinostat once daily on days 1, 3, 5, 6, 8, 10, 12, and oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Tumor tissue and peripheral blood mononuclear cells are collected at baseline for gene expression analysis (by SNP array and tissue microarray) and protein and signaling pathway expression via IHC and FISH.

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

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 ATRT) or supratentorial PNET including pineoblastomas

• Patient must be a suitable candidate, by institutional standards for stem cell apheresis

• Patient must have adequate pre-trial tumor material available for use in the biology studies

• 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)

• Serum creatinine =< 1.5 times upper limit of institutional normal for age or GFR >= 70 ml/min/1.73m^2 or estimated GFR (Schwartz bedside) that is > 99ml/min/1.73m^2

• Bilirubin < 1.5 times upper limit of normal for age

• SGPT (ALT) =< 1.5 times institutional upper limit of normal for age

• Signed informed consent according to institutional guidelines must be obtained

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 are excluded

• 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

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Sarah Leary

Principal Investigator

U.S.A.
District of Columbia
	Washington
	Children's National Medical Center
		Roger J. Packer	Ph: 202-884-2120
		Roger J. Packer	Principal Investigator
Pennsylvania
	Philadelphia
	Children's Hospital of Philadelphia
		Peter C. Phillips	Ph: 215-590-2107
		Peter C. Phillips	Principal Investigator
Tennessee
	Memphis
	Pediatric Brain Tumor Consortium
		Sarah Leary	Ph: 206-987-2106
		Sarah Leary	Principal Investigator
	St. Jude Children's Research Hospital
		Larry E. Kun	Ph: 901-595-3565
		Larry E. Kun	Principal Investigator
Washington
	Seattle
	Children's Hospital and Regional Medical Center - Seattle
		Sarah Leary	Ph: 206-987-2106
		Sarah Leary	Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00867178
Information obtained from ClinicalTrials.gov on January 13, 2013

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