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Prolonged Isotretinoin Therapy in Patients With High Risk Neuroblastoma

Phase 1
30 Years
Open (Enrolling)

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Trial Information

Prolonged Isotretinoin Therapy in Patients With High Risk Neuroblastoma

Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for 15%
of all pediatric cancer related deaths. The majority of patients present with high-risk
disease that is widely metastatic and aggressive. Historically, less than 30% of these
patients achieved long-term disease-free survival and the majority of relapses occurred
within the first 24 months following treatment. Survival rates have modestly improved with
the addition of high-dose chemotherapy and stem cell rescue, radiotherapy, surgery and
biologic therapy, yet 50% of patients still succumb to their disease. Current treatment of
neuroblastoma also carries significant acute toxicities and those patients that are cured
suffer significant long-term treatment-related morbidities. Therefore, children with
high-risk neuroblastoma are in need of novel therapeutic strategies that will improve cure
rates without adding to acute and long-term toxicities.

Retinoids, derivatives of vitamin A, have been repeatedly shown to arrest cell growth of
neuroblastoma cells in vitro by causing differentiation. Clinical trials in relapsed
neuroblastoma patients with bulky tumors failed to show significant responses to retinoid
therapy. Subsequently, however, a sentinel randomized clinical trial demonstrated that
isotretinoin(13-cis-retinoic acid), when given to patients with minimal residual disease
following consolidation chemotherapy, independently improved the overall survival of
patients with high-risk neuroblastoma. The treatment regimen included isotretinoin for 2
weeks followed by a 2 week rest period for 6 treatment cycles. The treatment was very well
tolerated with minimal side effects. The duration of treatment, 6 months, was arbitrarily
chosen and currently many institutions implement prolonged retinoic acid treatment in
patients with relapsed high-risk disease, yet no formal study has been done to statistically
show improved survival with prolonged biotherapy.

To improve the progression-free survival in patients with high-risk neuroblastoma this trial
will prolong therapy with isotretinoin to 24 months, the time window in which most relapses
occur. The treatment is anticipated to be well tolerated with no increase in adverse side
effects based on the benign side effect profile of patients who have received the typical 6
month treatment course. The trial will consist of a single arm of 20 high-risk
neuroblastoma patients who will receive a total of 24 cycles of isotretinoin (2 weeks on
treatment followed by 2 weeks of rest) compared to the historical and current COG study
treatment of 6 cycles. Patients will be accrued over a 3-year period.

The toxicity and tolerability of a prolonged course of isotretinoin biologic therapy will be
closely monitored with a focus on neuropsychologic and bone toxicities, and isotretinoin
drug levels will be measured to determine if there is a correlation between levels and
anti-tumor efficacy or toxicities. This will provide complementary data to support future
national cooperative group trials.

Inclusion Criteria:

- <=30 years of age

- histologic verification of neuroblastoma

- no active measurable disease on CT/MRI

- ultra high risk status by having mixed response, no response or stable disease
following initial treatment or by having recurrent neuroblastoma

- Karnofsky >=50% for patients >16 years and Lansky >=50% for patients <=16 years

- patients must have completed high risk therapy

- organ function as defined in protocol

Exclusion Criteria:

- patients with active measurable disease

- patients who are pregnant or breast-feeding

- concomitant medications stopped as indicated in protocol

- patients with uncontrolled infection

- patients with history of depression or psychotic disorder requiring medication

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression free survival

Outcome Description:

To determine the progression free survival in patients with high risk neuroblastoma who receive a prolonged course of biologic therapy with isotretinoin

Outcome Time Frame:

5 years after treatment completed

Safety Issue:


Principal Investigator

Howard Katzenstein, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Healthcare of Atlanta/Emory University


United States: Food and Drug Administration

Study ID:

Aflac ST1001



Start Date:

March 2011

Completion Date:

March 2019

Related Keywords:

  • Neuroblastoma
  • neuroblastoma
  • isotretinoin
  • Neuroblastoma



Children's Healthcare of Atlanta Atlanta, Georgia  30342