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

Not Recruiting

Trial ID: NCT01208454,7,29,26500,45600


This phase I trial is studying the side effects and the best dose of vorinostat when given together with isotretinoin to see how well it works in treating patients with high-risk refractory or recurrent neuroblastoma. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Isotretinoin may help vorinostat work better by making tumor cells more sensitive to the drug. Giving vorinostat together with isotretinoin may be an effective treatment for neuroblastoma.

Official Title

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

Stanford Investigator(s)


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

   - 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

   - 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

   - 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

   - 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

   - 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

   - 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

   - 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+

   - 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

   - 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


drug: isotretinoin

other: pharmacological study

drug: Vorinostat

other: laboratory biomarker analysis

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Pediatric Hematology/Oncology

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