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Phase I Study of Vorinostat in Combination With 13-Cis-Retinoic Acid in Patients With Refractory/Recurrent Neuroblastoma

Phase 1
30 Years
Open (Enrolling)
Disseminated Neuroblastoma, Localized Unresectable Neuroblastoma, Recurrent Neuroblastoma, Regional Neuroblastoma, Stage 4S Neuroblastoma

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Trial Information

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
systemic toxicity.

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
recurrent/refractory neuroblastoma.

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.

Inclusion Criteria:

- Histologically confirmed high-risk neuroblastoma and/or demonstration of tumor cells
in the bone marrow with increased urinary catecholamines meeting 1 of the following

- Recurrent and/or progressive disease at any time

- Biopsy not required

- Refractory disease (i.e., less than a partial response to frontline therapy,
including a minimum of 4 courses of chemotherapy)

- Biopsy not required

- Persistent disease by MIBG scan, CT and MRI scan, or bone marrow
aspirates/biopsies after ≥ partial response to frontline therapy

- Histologic confirmation of viable neuroblastoma from at ≥ 1 residual site

- Tumor seen on routine bone marrow morphology allowed

- Bone marrow immunocytology alone not allowed

- Patients in expansion cohorts 1 and 2 who have had a prior relapse are eligible with
no measurable or evaluable sites of tumor (i.e., in second complete response)

- Patient must have ≥ 1 of the following disease sites (excluding patients on the
expansion cohort):

- Measurable tumor by MRI, CT scan, or X-ray

- MIBG scan with positive uptake at a minimum of 1 site

- Bone marrow with tumor cells seen on routine morphology of 1 bone marrow sample
of a bilateral aspirate and/or biopsy

- Life expectancy ≥ 6 weeks

- Lansky performance status (PS) 50-100% (patients ≤ 16 years of age) OR Karnofsky PS
50-100% (patients > 16 years of age)

- Hemoglobin ≥ 8 g/dL (transfusion allowed)

- ANC ≥ 750/μL

- ANC ≥ 500/μL for patients with marrow metastases

- Platelet count ≥ 50,000/μL (transfusion independent)

- No platelet transfusions within 1 week

- Serum creatinine based on age as follows:

- 0.8 mg/dL (≤ 5 years of age)

- 1.0 mg/dL (> 5 and ≤ 10 years of age)

- 1.2 mg/dL (> 10 and ≤ 15 years of age)

- 1.5 mg/dL (> 15 years of age)

- Hematuria ≤ 1+ and/or proteinuria ≤ 1+

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT and AST < 3 times ULN

- Alkaline phosphatase ≤ 2.5 times ULN

- Serum triglycerides ≤ 300 mg/dL

- Serum calcium < grade 2

- Negative pregnancy test

- Not pregnant or nursing

- Fertile patients must use effective contraception

- Normal ejection fraction (≥ 55%) by echocardiogram or radionuclide MUGA OR normal
fraction shortening (≥ 27%) by echocardiogram

- QTc interval ≤ 450 msec

- No patients who, in the opinion of the investigator, may not be able to comply with
the safety of study requirements

- No disease of any major organ system that would compromise the patient's ability to
withstand therapy

- No active or uncontrolled infection

- Patients on prolonged antifungal therapy allowed provided culture and biopsy are
negative in suspected radiographic lesions

- No allergic reactions to paraben preparations (i.e., Accutane, Sotret)

- Alternate preparations to paraben allowed

- Fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy

- At least 3 weeks since prior myelosuppressive chemotherapy, including cytotoxic
agents given on a low-dose metronomic regimen

- At least 7 days since prior biologic anti-neoplastic agent (including retinoids)

- At least 7 days or 3 half-lives, whichever is longer, since prior monoclonal

- More than 2 weeks since prior radiotherapy (small-port)

- No prior radiotherapy in patients with 1 site of measurable or evaluable disease
unless that site has demonstrated clear progression after completion of

- At least 12 weeks since prior large-field radiotherapy (i.e., total-body,
craniospinal, whole abdominal, total lung, or > 50% of marrow space irradiation)

- At least 6 weeks since prior substantial bone marrow radiotherapy

- At least 6 weeks since prior:

- Autologous stem cell infusion following myeloablative therapy

- Allogeneic stem cell transplantation without evidence of active
graft-versus-host disease

- At least 6 weeks since prior ^131I-MIBG therapy

- At least 7 days since prior cytokines or hematopoietic growth factors

- More than 30 days since prior and no concurrent valproic acid

- More than 30 days since prior and no other concurrent investigational medications

- No prior vorinostat combined with isotretinoin

- Prior vorinostat or isotretinoin single-agent or combined with alternative
agents allowed

- No other concurrent anti-cancer agents including chemotherapy, radiotherapy,
biologics, or immunomodulating agents

- No concurrent azole anti-fungal therapy

- No concurrent pentamidine therapy for PCP prophylaxis

- No concurrent enzyme-inducing anti-convulsant therapy

Type of Study:


Study Design:

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

Outcome Measure:

Maximum tolerated dose (MTD) of vorinostat, determined according to incidence of DLT graded using NCI CTCAE version 4.0

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Julie Park

Investigator Role:

Principal Investigator

Investigator Affiliation:

New Approaches to Neuroblastoma Treatment (NANT)


United States: Food and Drug Administration

Study ID:




Start Date:

December 2010

Completion Date:

Related Keywords:

  • Disseminated Neuroblastoma
  • Localized Unresectable Neuroblastoma
  • Recurrent Neuroblastoma
  • Regional Neuroblastoma
  • Stage 4S Neuroblastoma
  • Neuroblastoma



Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Children's Hospital BostonBoston, Massachusetts  02115
Seattle Children's HospitalSeattle, Washington  98105
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
Dana-Farber Harvard Cancer CenterBoston, Massachusetts  02115
Lucile Packard Children's Hospital Stanford UniversityPalo Alto, California  94304
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
New Approaches to Neuroblastoma Treatment (NANT)Los Angeles, California  90027-6016