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

This is an interventional treatment trial for Localized Unresectable Neuroblastoma Read More

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