Clinical trial NCT00867178: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Medulloblastoma
Pineoblastoma
Supratentorial Embryonal Tumor, Not Otherwise Specified
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2009-03-23
Enrollment: 33
Sex: ALL
Minimum age (years): 2
Maximum age (years): 47
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Dose-limiting toxicity of proposed vorinostat
timeFrame: Up to 21 days
measure: Feasibility in terms of completing 3 courses of induction therapy
timeFrame: Within 98 days
measure: Prognostic value of histopathological classification of pediatric medulloblastoma
timeFrame: Up to 5 years
Secondary outcomes:
measure: Response rate of this approach in patients with measurable residual disease (primary site and/or metastatic sites)
timeFrame: Up to 5 years
measure: Progression-free survival (PFS)
timeFrame: Up to 5 years
measure: Overall survival (OS)
timeFrame: Up to 5 years
measure: Predictive values of biological markers in CSF, plasma and urine in the context of a feasibility study
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Bethesda
country: United States
facility: National Cancer Institute Pediatric Oncology Branch
state: Maryland
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Memphis
country: United States
facility: Pediatric Brain Tumor Consortium
state: Tennessee
city: Memphis
country: United States
facility: Saint Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: Pediatric Brain Tumor Consortium
name: Sarah E Leary
role: PRINCIPAL_INVESTIGATOR
References: