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

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 criteria:

  • 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 required
    • 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) therapy
• At least 7 days or 3 half-lives, whichever is longer, since prior monoclonal antibodies

• 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 radiotherapy
  • 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