Status:
COMPLETED
Vorinostat and Isotretinoin in Treating Patients With High-Risk Refractory or Recurrent Neuroblastoma
Lead Sponsor:
National Cancer Institute (NCI)
Conditions:
Localized Unresectable Neuroblastoma
Recurrent Neuroblastoma
Eligibility:
All Genders
Up to 30 years
Phase:
PHASE1
Brief Summary
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 recurre...
Detailed Description
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-ci...
Eligibility Criteria
Inclusion
- 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:
- 8 mg/dL (=\< 5 years of age)
- 0 mg/dL (\> 5 and =\< 10 years of age)
- 2 mg/dL (\> 10 and =\< 15 years of age)
- 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
- 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
Key Trial Info
Start Date :
December 1 2010
Trial Type :
INTERVENTIONAL
Allocation :
ACTUAL
End Date :
Estimated Enrollment :
29 Patients enrolled
Trial Details
Trial ID
NCT01208454
Start Date
December 1 2010
Last Update
November 24 2015
Active Locations (13)
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1
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
2
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, United States, 94304
3
UCSF Medical Center-Parnassus
San Francisco, California, United States, 94143
4
Children's Hospital Colorado
Aurora, Colorado, United States, 80045