Vorinostat and Isotretinoin in Treating Patients With High-Risk Refractory or Recurrent Neuroblastoma

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of vorinostat pediatric suspension
administered daily 4 times per week orally for two weeks, in combination with twice daily
13-cis-retinoic acid ([cisRA], isotretinoin) orally for 14 days to children with refractory
or recurrent neuroblastoma.

II. To define the toxicities of vorinostat administered in combination with cisRA.

SECONDARY OBJECTIVES:

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 dose-escalation study of vorinostat.

Patients receive isotretinoin orally (PO) twice daily (BID) on days 1-14, PO suspension* of
vorinostat once daily (QD) on days 1-4 of course 1, and capsules of vorinostat PO QD on days
1-4 and 8-11 of course 2 and subsequent courses. Treatment repeats every 28 days for up to
24 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.

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:

- Patients must be =< 21 years of age when registered on study for dose levels -1 to 5
and Expansion Cohort 1; patients age 22-30 years of age at time of study registration
are eligible for Expansion Cohort 2

- Patients must have a diagnosis of neuroblastoma either by histologic verification of
neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased
urinary catecholamines

- Patients must have high-risk neuroblastoma

- Patients must have at least ONE of the following:

- Recurrent/progressive disease at any time; biopsy not required, even if partial
response to intervening therapy

- Refractory disease (i.e. less than a partial response to frontline therapy,
including a minimum of 4 cycles of chemotherapy); no biopsy is required to
document eligibility

- Persistent disease after at least a partial response to frontline therapy (i.e.
patient has had at least a partial response to frontline therapy but still has
residual disease by metaiodobenzylguanidine [MIBG] scan, computed tomography
[CT]/magentic resonance imaging [MRI], or bone marrow aspirates/biopsies);
patients in this category are REQUIRED to have histologic confirmation of viable
neuroblastoma from at least one residual site; tumor seen on routine bone marrow
morphology is sufficient; bone marrow immunocytology alone is not sufficient for
eligibility

- Patients must have at least ONE of the following sites of disease (excluding those
patients entered in the Expansion Cohort) :

- Measurable tumor on MRI or CT scans or X-ray; measurable is defined >= 20 mm in
one dimension; for spiral CT defined as >= 10 mm in one dimension; for patients
with persistent disease, a biopsy of site seen on CT/MRI must have demonstrated
viable neuroblastoma; if the lesion was radiated, then biopsy must be done >= 4
weeks after radiation completed

- MIBG scan with positive uptake at a minimum of one site; for patients with
persistent disease, a biopsy of an MIBG positive site must have demonstrates
viable neuroblastoma; if the lesion was radiated, then biopsy must be done >= 4
weeks after radiation completed

- Bone marrow with tumor cells seen on routine morphology (not by neuron specific
enolase [NSE] staining only) of one bone marrow sample of a bilateral aspirate
and/or biopsy

- Patients entered in the Expansion Cohorts 1 or 2 who have had a prior relapse are
eligible with no measurable or evaluable sites of tumor (i.e. in second complete
response)

- Patients must have a life expectancy of at least 6 weeks and a Lansky (=< 16 years)
or Karnofsky (> 16 years) score of at least 50

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to study enrollment

- Must have received last dose of myelosuppressive chemotherapy at least 3 weeks prior
to start of vorinostat; this includes cytotoxic agents given on a low dose metronomic
regimen

- Must have received last dose of biologic (anti-neoplastic agent) (includes retinoids)
at least 7 days prior to start of vorinostat

- Must have received last dose of monoclonal antibodies at least 7 days or 3
half-lives, whichever is longer, prior to start of vorinostat

- Patients must not have received radiation (small port) for a minimum of two weeks
prior to start of vorinostat; for patients with only one site of measurable or
evaluable disease, radiation must not have been given to that site unless that site
has demonstrated clear progression after radiation

- A minimum of 12 weeks prior to start of vorinostat is required following prior large
field radiation therapy (i.e. total body irradiation, craniospinal, whole abdominal,
total lung, > 50% marrow space), otherwise a minimum of 6 weeks must have elapsed if
other substantial bone marrow (BM) radiation

- Patients are eligible 6 weeks after date of autologous stem cell infusion following
myeloablative therapy (timed from start of vorinostat); patients are eligible 6 weeks
after date of allogeneic stem cell transplant if without evidence of active graft
versus host disease; patients receiving an autologous stem cell infusion to support
non-myeloablative therapy are eligible at any time as long as they meet the
hematologic and other organ function criteria for eligibility

- A minimum of 6 weeks must have elapsed after 131I-MIBG therapy (timed from start of
vorinostat)

- All cytokines or hematopoietic growth factors must be discontinued a minimum of 7
days prior to enrollment on this protocol

- Patients must not be receiving any other anti-cancer agents or radiotherapy at the
time of study entry or while on study

- Patients must not be receiving other investigational medications (covered under
another investigational new drug [IND]) within 30 days of study entry or while on
study

- Since valproic acid has histone deacetylase (HDAC) inhibitory activity, patients must
not have received valproic acid within 30 days of study entry

- Prolongation of the corrected QT (QTc) interval has been rarely observed in adults
receiving vorinostat; patients must not be receiving azole anti-fungal therapy at the
time of study entry or while on protocol therapy; additional agents known to prolong
the QTc interval should be avoided unless therapeutic alternative medications are not
available

- Patients must not be receiving pentamidine therapy for Pneumocystis pneumonia (PCP)
prophylaxis at the time of study entry or while on protocol therapy

- No hematopoietic growth factors within 7 days of enrollment on this protocol

- Patients must not be receiving enzyme-inducing anti-convulsant therapy

- Hemoglobin >= 8 g/dL (transfusion allowed)

- Absolute neutrophil count (ANC) >= 750/uL for patients without marrow metastases at
study enrollment; ANC >= 500/uL for patients with marrow metastases at study
enrollment

- Platelet count >= 50,000/ul, transfusion independent (no platelet transfusions within
1 week)

- Patients with known bone marrow metastatic disease will be eligible for study as long
as they meet hematologic function criteria; patients with marrow disease are not
evaluable for hematologic toxicity; if dose limiting hematologic toxicity occurs in
two patients, then all subsequent patients enrolled must be evaluable for hematologic
toxicity, therefore patients with marrow metastases will be ineligible

- 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)

- Patient must have a urinalysis with no more than 1+ hematuria and/or no more than 1+
proteinuria

- Total bilirubin =< 1.5 x upper limit of normal for age

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and
serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST}) < 3
x upper limit of normal (note that for ALT, the upper limit of normal for all sites
is defined as 45 U/L)

- Alkaline phosphatase =< 2.5 times upper limit of normal

- Normal ejection fraction (>= 55%) documented by either echocardiogram or radionuclide
multi gated acquisition scan (MUGA) evaluation OR normal fractional shortening (>=
27%) documented by echocardiogram

- Corrected QT (QTc) interval =< 450 msec

- Serum triglyceride =< 300 mg/dL

- Serum calcium < grade 2

- All post-menarchal females must have a negative beta-human chorionic gonadotropin
(HCG); males and females of reproductive age and childbearing potential must use
effective contraception for the duration of their participation

- Patients with other ongoing serious medical issues must be approved by the study
chair prior to registration

- Patient and/or parent must have the ability to understand and the willingness to sign
a written informed consent document

Exclusion Criteria:

- Pregnancy, breast feeding, or unwillingness to use effective contraception during the
study; women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation; should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately

- Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study

- Patients with disease of any major organ system that would compromise their ability
to withstand therapy

- Patients with an active or uncontrolled infection; patients on prolonged antifungal
therapy are still eligible if they are culture and biopsy negative in suspected
radiographic lesions and meet other organ function criteria

- Patients receiving enzyme-inducing anti-convulsants, pentamidine or azole anti-fungal
therapy

- Prior treatment with vorinostat combined with cisRA is not allowed; prior therapy
with either vorinostat or cis-retinoic acid single agent or combined with alternative
agents is allowed

- Patients with a paraben allergy cannot take cisRA preparations containing this
compound (i.e., Accutane, Sotret) but are eligible if they can take an alternate
preparation without paraben