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A Feasibility Study of SAHA Combined With Isotretinoin and Chemotherapy in Infants With Embryonal Tumors of the Central Nervous System


N/A
2 Months
48 Months
Open (Enrolling)
Both
Untreated Childhood Medulloblastoma, Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor

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Trial Information

A Feasibility Study of SAHA Combined With Isotretinoin and Chemotherapy in Infants With Embryonal Tumors of the Central Nervous System


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.


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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Safety and feasibility of administering Vorinostat (SAHA) and Isotretinoin for three days prior and concomitant with cisplatin based chemotherapy over three courses of induction chemotherapy

Outcome Time Frame:

Up to 5 years

Safety Issue:

Yes

Principal Investigator

Sarah Leary

Investigator Role:

Principal Investigator

Investigator Affiliation:

Pediatric Brain Tumor Consortium

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-03167

NCT ID:

NCT00867178

Start Date:

March 2009

Completion Date:

Related Keywords:

  • Untreated Childhood Medulloblastoma
  • Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor
  • Medulloblastoma
  • Carcinoma, Embryonal
  • Central Nervous System Neoplasms
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive

Name

Location

Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Children's National Medical CenterWashington, District of Columbia  20010-2970
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Seattle Children's HospitalSeattle, Washington  98105
Pediatric Brain Tumor ConsortiumMemphis, Tennessee  38105