Fenretinide Lym-X-Sorb + Ketoconazole + Vincristine for Recurrent or Resistant Neuroblastoma

NCT02163356 | Terminated Phase 1 DMC

• 1 other identifier: SPOC-2013-001
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 4

Brief Summary

Currently there is no known effective treatment for recurrent or resistant neuroblastoma. Fenretinide is an anticancer agent that may work differently than standard chemotherapy. It may cause the buildup of wax-like substances in cancer cells called ceramides. In laboratory studies, it was found that if too much ceramide builds up in the neuroblastoma cells, they die. Fenretinide has been given by mouth as a capsule to many people, including children. When Fenretinide is given in capsules, very little of the drug is absorbed through the intestines into the body. This means patients have to take many capsules of fenretinide by mouth several times a day. In this study, a new oral preparation of fenretinide (called 4-HPR/LXS oral powder) is being tested to see if more fenretinide can be absorbed into the body. 4-HPR/LXS oral powder has been tested previously in a limited number of both children and adult cancer patients. Ketoconazole, commonly used to treat fungus infections, can increase fenretinide levels in the body by interfering with the body's ability to break down fenretinide. Ketoconazole will be given at the same time as the fenretinide powder. There is preclinical data that shows that combining fenretinide and vincristine prolonged survival in animal models, therefore, it is hoped that giving the vincristine with fenretinide will work better against the neuroblastoma that either drug given alone. About 70 children with neuroblastoma have been treated with various versions of the fenretinide powder to date, including about a dozen children that also took the fenretinide powder with ketoconazole, and no toxicities have occurred that limited the dosage and no serious or unexpected side effects occurred. However, vincristine has never been given with fenretinide or fenretinide plus ketoconazole before. Vincristine has been been given before with ketoconazole to both children and adults with neuroblastomas and other cancers.

Conditions

Recurrent Neuroblastoma; Neuroblastoma

Keywords

neuroblastoma; recurrent; resistant

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose

  To determine maximum dose of vincristine when given in combination with 4-HPR/LXS and ketoconazole. Subjects will be enrolled in a standard 3 + 3 design and will receive set doses of HPR/LXS and ketoconazole. Vincristine will be escalated with each dose level up to 1.5 mg/m2. If toxicity occurs due to vincristine, the dose level will be expanded or dose decreased to the previous level as appropriate. If toxicity occurs due to ketoconazole, the dose level will be expanded and the ketoconazole dose decreased to 3 mg/kg/day

  after each subject has completed 1 cycle of therapy (a cycle is 21 days)

• Side effect profile of drug combination

  The side effect profile of the combination therapy will be compared to known single agent side effects looking for new unique drug interactions.

  after each subject receives the drug combination (a cycle is expected to be 21 days)

• Assess plasma pharmacokinetics of fenretinide

  included analysis of metabolites (4-MPR and 4-oxo-HPR) and related plasma sphingolipids

  On day 1 (hour 0, 2, 4, 6), day 7 (hour 0, 2, 4, 6) and day 9 (after 3 pm) for course 1. For courses 2 and 6, day 1 (hour 0, 4 and 6), and day 7 (hour 0, 4, and 6)

Secondary Outcomes (1)

• Disease response

  every 42 days while on therapy

Study Arms (1)

Primary therapy

EXPERIMENTAL

Fenretinide/LXS oral powder 1500 mg/m2/day for 7 days plus ketoconazole 6 mg/kg/day for 7 days plus single dose vincristine (dose escalating) given on day 3. Starting dose of vincristine is 0.75 mg/m2/dose. Followed by 14 days of rest.

Drug: Fenretinide/LXS Oral Powder; Drug: Ketoconazole; Drug: Vincristine

Interventions

Fenretinide/LXS Oral Powder DRUG

Oral Powder

Also known as: 4-HPR, Fenretinide/Lym-X-Sorb, 4-HPR/LXS

Primary therapy

Ketoconazole DRUG

Oral Tablet

Also known as: Nizoral

Primary therapy

Vincristine DRUG

IV

Also known as: Oncovin, Vincristine Sulfate

Primary therapy

Eligibility Criteria

• Age: Up to 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Diagnosed with neuroblastoma either by histological verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines
• Patients must have high-risk neuroblastoma with at least ONE of the following:
• Recurrent/progressive disease at any time
• Refractory disease (i.e. less than a partial response to frontline therapy)
• 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 MIBG, CT/MRI, or bone marrow)
• Patients must have at least ONE of the following sites of disease:
• Measurable tumor on MRI or CT scan or X-ray
• MIBG scan with positive uptake at minimum of one site
• Bone marrow with tumor cells seen on routine morphology
• Patients with a history of complete surgical resection of CNS lesions are eligible if there is no evidence of CNS lesions (MRI or CT required) at study entry evaluation and if other entry criteria are met
• Patients must have a performance status of 0, 1 or 2 (Appendix I). Patients who are unable to walk because of paralysis or tumor pain, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have a life expectancy of greater than or equal to 8 weeks
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
• Must not have received myelosuppressive chemotherapy and/or biologics within 3 weeks of entry onto this study (4 weeks if prior nitrosourea)
• Patients must not have received radiation for a minimum of two weeks prior

You may not qualify if:

• Patients with CNS parenchymal or meningeal-based lesions that are present at study entry evaluation are NOT eligible
• Pregnancy or breast feeding. Due to the potential teratogenic effects of retinoids, pregnant women are NOT eligible. Breast milk feeding by study patient is NOT allowed
• Patients with history of organ and allogeneic stem cell transplantation
• Patients with a known history of allergy to soy products
• Patients with a known history of a severe allergy or sensitivity to wheat gluten
• Patients requiring anti-arrhythmia cardiac medications are NOT eligible
• Prior therapy with fenretinide, or fenretinide + ketoconazole, if DLT's were experienced
• A known history of intolerance to ketoconazole
• A known history of intolerance to vincristine
• Patients on other essential medications for which an interaction with ketoconazole can be expected and for which dose reductions to other essential medications cannot be made in a manner adequate to ensure patient safety
• Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
• Active hepatitis
• Baseline cardiac QTc interval \> 450 msecs

Sponsors & Collaborators

• South Plains Oncology Consortium: lead
• The Evan Foundation: collaborator

Study Sites (4)

The University of Chicago Medicine Comer Children's

Chicago, Illinois, 60637, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75235, United States

Location

Cook Children's Hospital

Fort Worth, Texas, 76104, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Neuroblastoma; Recurrence

Interventions

Fenretinide; Ketoconazole; Vincristine

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Pigments, Biological; Biological Factors; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Study Officials

• Tanya Watt, MD

  University of Texas Southwestern Medical Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 27, 2014
• First Posted: June 13, 2014
• Study Start: May 1, 2014
• Primary Completion: May 1, 2018
• Study Completion: May 1, 2018
• Last Updated: March 31, 2022

Record last verified: 2022-03

Locations

US (4)