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

• Register: ClinicalTrials.gov
• Last refreshed on: 26 November 2012
• Main ID: NCT01208454
• Date of registration: 23/09/2010
• Primary sponsor: National Cancer Institute (NCI)
• Public title: Vorinostat and Isotretinoin in Treating Patients With High-Risk Refractory or Recurrent Neuroblastoma
• Scientific title: Phase I Study of Vorinostat in Combination With 13-Cis-Retinoic Acid in Patients With Refractory/Recurrent Neuroblastoma
• Date of first enrolment: December 2010
• Target sample size: 54
• Recruitment status: Recruiting
• URL: http://clinicaltrials.gov/show/NCT01208454
• Study type: Interventional
• Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Countries of recruitment

Canada, United States

Contacts

• Name: Julie Park
• Affiliation: New Approaches to Neuroblastoma Therapy Consortium

Key inclusion & exclusion criteria

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



Age minimum: N/A
Age maximum: 30 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Disseminated Neuroblastoma

Localized Unresectable Neuroblastoma

Recurrent Neuroblastoma

Regional Neuroblastoma

Stage 4S Neuroblastoma

Intervention(s)

Drug: isotretinoin

Drug: vorinostat

Other: diagnostic laboratory biomarker analysis

Other: pharmacological study

Primary Outcome(s)

Maximum tolerated dose (MTD) of vorinostat, determined according to incidence of DLT graded using NCI CTCAE version 4.0 [Time Frame: 28 days]

Toxicity as assessed by NCI CTCAE v. 4.0 [Time Frame: Up to 2 years]

Secondary Outcome(s)

Best response, assessed using RECIST [Time Frame: Up to 2 years]

Survival [Time Frame: Up to 2 years]

Time-to-failure [Time Frame: Up to 2 years]

Secondary ID(s)

N2008-02

NCI-2011-02522

Source(s) of Monetary Support

Please refer to primary and secondary sponsors