Fenretinide in Treating Children With Recurrent or Resistant Neuroblastoma

A Phase II Study of Fenretinide (NSC# 374551, IND# 40294) in Children With Recurrent/Resistant High Risk Neuroblastoma

This phase II trial is studying how well fenretinide works in treating children with recurrent or resistant neuroblastoma. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

Study Overview

• Status: Completed
• Conditions: Recurrent Neuroblastoma
• Intervention / Treatment: Drug: fenretinide; Other: pharmacological study

Detailed Description

OBJECTIVES:

Determine the response rate in pediatric patients with recurrent or resistant high-risk neuroblastoma treated with fenretinide.

Determine the toxic effects of this drug in these patients. Determine the proportion of patients with disease detected only by bone marrow immunocytology, who clear all evidence of disease during treatment with this drug.

Determine minimal residual disease response by marrow and meta-iodobenzylguanidine (MIBG) I 123 scan in patients treated with this drug.

OUTLINE: Patients are stratified according to presence of measurable disease on CT scan/MRI (yes vs no). A third stratum of patients with tumor cells in bone marrow by immunocytology only is enrolled but is not evaluated for response.

Patients receive oral fenretinide 3 times daily (or 2 times daily if over 18 years of age) on days 1-7. Treatment repeats every 3 weeks for up to 30 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum III who fail to achieve a complete response after 8 courses of therapy are removed from study.

Patients are followed monthly until blood counts and visual acuity are stable or normalized and then every 6 months for 2 years and annually for 3 years.

PROJECTED ACCRUAL: A total of 70 patients (25 each for strata I and II, 20 for stratum III) will be accrued for this study within 1-2 years.

• Study Type: Interventional
• Enrollment (Anticipated): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Arcadia, California, United States, 91006-3776
      • Children's Oncology Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of recurrent or resistant/refractory high-risk neuroblastoma by one or both of the following:

  • Histological confirmation
  • Demonstration of tumor cells in bone marrow with increased urinary catecholamines

• Stratum I:

  • At least 1 unidimensionally measurable lesion*

    • At least 20 mm by MRI and/or CT scan OR at least 10 mm by spiral CT scan

• Stratum II: Meets one or both of the following criteria:

  • At least 1 site with positive uptake on meta-iodobenzylguanidine (MIBG) I 123 scan
  • Tumor in bilateral bone marrow aspirate/biopsy by routine morphology (no NSE staining only)

• Stratum III:

  • At least 5 tumor cells/10^6 mononuclear cells in the bone marrow by immunocytology only (on 2 successive bone marrows performed from 1 day to 4 weeks apart)
• Patients in first response (i.e., patients with persistent tumor at end of frontline therapy, but who have never had disease relapse or progression) must have histological* or morphological (by bone marrow) confirmation** of viable tumor on CT scan, MRI, or MIBG scan after completion of myeloablative therapy (for strata I and II)
• No catecholamine elevation only
• Performance status - 0-2
• At least 2 months
• Hemoglobin greater than 7.5 g/dL (transfusion allowed)
• Bilirubin no greater than 1.5 times normal
• SGPT and SGOT less than 2.5 times normal
• Creatinine normal for age
• No hematuria or proteinuria greater than 1+ on urinalysis
• Calcium less than 11.6 mg/dL
• Triglycerides less than 300 mg/dL
• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception
• No seizure disorders unless on anticonvulsants and well controlled
• No skin toxicity greater than grade 1
• Must be able to consume entire intact study capsule in the dosage prescribed for body surface area
• Recovered from prior immunotherapy
• At least 7 days since prior anticancer biologic therapy
• At least 2 days since prior growth factors
• Prior autologous stem cell transplantation allowed
• No prior allogeneic stem cell transplantation
• No concurrent immunomodulating agents
• At least 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered
• No concurrent anticancer chemotherapy
• No concurrent steroids
• Recovered from prior radiotherapy
• At least 4 weeks since prior radiotherapy to target lesion
• Prior radiotherapy to non target lesions allowed
• No concurrent radiotherapy to sole measurable lesion for symptom relief
• Concurrent palliative radiotherapy to non target or localized painful lesions allowed
• Prior tretinoin or isotretinoin allowed
• At least 2 weeks since other prior retinoids
• No prior fenretinide
• No concurrent supplemental oral or IV vitamin A, ascorbic acid, or vitamin E (except if contained in routine total parenteral nutrition [TPN] vitamin supplements)
• No concurrent drugs suspected of causing pseudotumor cerebri (e.g., tetracycline, nalidixic acid, nitrofurantoin, phenytoin, sulfonamides, lithium, amiodarone, or vitamin A [except as part of routine TPN supplements])
• No other concurrent anticancer agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (fenretinide); Patients receive oral fenretinide 3 times daily (or 2 times daily if over 18 years of age) on days 1-7. Treatment repeats every 3 weeks for up to 30 courses in the absence of disease progression or unacceptable toxicity.	Drug: fenretinide; Given orally; Other: pharmacological study; Optional correlative studies

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate	A responder is defined to be a patient who achieves a best overall response of complete response (CR), very good partial response (VGPR) or partial response (PR).	Up to 8 courses of therapy
Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0	Assessed via a descriptive tabulation of the toxicity rates, overall and by stratum.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of fenretinide	Assessed via descriptive analysis of the steady state levels of fenretinide overall and by stratum	At baseline and during courses 1, 2, and 5
Plasma retinol levels	Assessed via descriptive analysis of the plasma retinol levels overall and by stratum.	At baseline and during courses 1, 2, and 5
Minimal residual disease (MRD) (Stratum 3)	Assessed by descriptive calculation of the proportion of responders.	Up to 5 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Judith Villablanca, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start: May 1, 2003
• Primary Completion (Actual): March 1, 2006

Study Registration Dates

• First Submitted: January 27, 2003
• First Submitted That Met QC Criteria: January 27, 2003
• First Posted (Estimate): January 28, 2003

Study Record Updates

• Last Update Posted (Estimate): October 8, 2013
• Last Update Submitted That Met QC Criteria: October 7, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Recurrence; Neuroblastoma; Physiological Effects of Drugs; Antineoplastic Agents; Protective Agents; Anticarcinogenic Agents; Fenretinide
• Other Study ID Numbers: NCI-2012-01802 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA098543 (U.S. NIH Grant/Contract); COG-ADVL0024; COG-A0996; CDR0000269408; COG-ANBL0321; ADVL0024 (Other Identifier: Children's Oncology Group); ANBL0321 (Other Identifier: CTEP)