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

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Untreated Childhood Medulloblastoma; Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor

Intervention: 3-Dimensional Conformal Radiation Therapy (Radiation); Cisplatin (Drug); Cyclophosphamide (Drug); Isotretinoin (Drug); Laboratory Biomarker Analysis (Other); Peripheral Blood Stem Cell Transplantation (Procedure); Thiotepa (Drug); Vincristine Sulfate (Drug); Vorinostat (Drug)

Phase: N/A

Status: Active, not recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Sarah Leary, Principal Investigator, Affiliation: Pediatric Brain Tumor Consortium

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 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.

Clinical Details

Official title: A Feasibility Study of Vorinostat (SAHA) Combined With Isotretinoin and Chemotherapy in Infants With Embryonal Tumors of the Central Nervous System

Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

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

Feasibility in terms of completing 3 courses of induction therapy

Prognostic value of histopathological classification of pediatric medulloblastoma by single-nucleotide polymorphism (SNP) analysis and gene expression analysis

Secondary outcome:

Overall survival (OS)

Predictive values of biological markers in CSF, plasma and urine in the context of a feasibility study

Progression-free survival (PFS)

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

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 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 up every 3 months for 2 years and then every 6 months for 3 years.

Eligibility

Minimum age: 2 Months. Maximum age: 47 Months. Gender(s): Both.

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

- 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)

- Bilirubin < 1. 5 times upper limit of normal for age

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 1. 5

times institutional upper limit of normal for age

- Serum creatinine =< 1. 5 times upper limit of institutional normal for age or

glomerular filtration rate (GFR) >= 70 ml/min/1. 73m^2 or estimated GFR (Schwartz bedside) that is > 99 ml/min/1. 73m^2

- 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 likely 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

Locations and Contacts

Children's Hospital Los Angeles, Los Angeles, California 90027, United States

Lucile Packard Children's Hospital Stanford University, Palo Alto, California 94304, United States

Children's National Medical Center, Washington, District of Columbia 20010, United States

Lurie Children's Hospital-Chicago, Chicago, Illinois 60611, United States

National Cancer Institute Pediatric Oncology Branch, Bethesda, Maryland 20892, United States

Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States

Duke University Medical Center, Durham, North Carolina 27710, United States

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, United States

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States

Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, United States

St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States

M D Anderson Cancer Center, Houston, Texas 77030, United States

Texas Children's Hospital, Houston, Texas 77030, United States

Seattle Children's Hospital, Seattle, Washington 98105, United States

Additional Information

Starting date: February 2009
Last updated: June 3, 2015

Page last updated: August 23, 2015

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