Phase I Study of Vorinostat in Combination With 13-Cis-Retinoic Acid in Patients With Refractory/Recurrent Neuroblastoma
I. To determine the maximum-tolerated dose of vorinostat in combination with isotretinoin in
patients with high-risk refractory or recurrent neuroblastoma.
II. To define the toxicities of vorinostat administered in combination with cisRA.
I. To determine the pharmacokinetics of vorinostat given as a pediatric suspension.
II. To describe the relationship of vorinostat pharmacokinetics to the occurrence of
III. To determine the pharmacokinetics of cisRA given in combination with vorinostat.
IV. To describe histone acetylation levels in peripheral blood mononuclear cells after
different doses of vorinostat.
V. To describe, within the context of a Phase I study, the response rate of vorinostat
combined with cisRA in patients with recurrent/refractory neuroblastoma.
VI. To describe the toxicity and response rate of vorinostat at the determined maximal
tolerated dose combined with cisRA in patients ages 22-30 years of age at study entry with
OUTLINE: This is a multicenter, dose-escalation study of vorinostat.
Patients receive oral isotretinoin twice daily on days 1-14, oral suspension* of vorinostat
once daily on days 1-4 of course 1, and oral capsules of vorinostat once daily on days 1-4
and 8-11 of course 2 and subsequent courses. Treatment repeats every 28 days for up to 12
courses in the absence of disease progression or unacceptable toxicity.
EXPANSION COHORT 1 (≤ 21 years of age): Once the maximum-tolerated dose (MTD) has been
determined, patients are treated at that dose level as above.
EXPANSION COHORT 2 (22-30 years of age): Patients receive isotretinoin as above and
vorinostat at the MTD on days 1-3 and 8-10.
Treatment repeats every 28 days for up to 12 courses in the absence of disease progression
or unacceptable toxicity. Patients may undergo peripheral blood mononuclear cells collection
for pharmacokinetics and histone acetylation studies.
After completion of study therapy, patients are followed up periodically.
NOTE: *Patients less than 10 years of age are encouraged to continue to use oral suspension
beyond course 1.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD) of vorinostat, determined according to incidence of DLT graded using NCI CTCAE version 4.0
New Approaches to Neuroblastoma Treatment (NANT)
United States: Food and Drug Administration
|Children's Hospital of Philadelphia||Philadelphia, Pennsylvania 19104|
|Children's Hospital Los Angeles||Los Angeles, California 90027-0700|
|Cincinnati Children's Hospital Medical Center||Cincinnati, Ohio 45229-3039|
|Children's Hospital Boston||Boston, Massachusetts 02115|
|Seattle Children's Hospital||Seattle, Washington 98105|
|Children's Healthcare of Atlanta - Egleston||Atlanta, Georgia 30322|
|Dana-Farber Harvard Cancer Center||Boston, Massachusetts 02115|
|Lucile Packard Children's Hospital Stanford University||Palo Alto, California 94304|
|University of California San Francisco Medical Center-Parnassus||San Francisco, California 94143|
|New Approaches to Neuroblastoma Treatment (NANT)||Los Angeles, California 90027-6016|