Sorafenib and Cyclophosphamide/Topotecan in Patients With Relapsed and Refractory Neuroblastoma

NCT02298348 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: NANT 2013-02
• Study Type: interventional
• Target: 18
• Locations: 2 countries
• Sites: 12

Brief Summary

This study will combine three drugs: sorafenib, cyclophosphamide and topotecan. Adding sorafenib to cyclophosphamide and topotecan may increase the effectiveness of this combination. The investigators first need to find out the highest dose of sorafenib that can be given safely together with cyclophosphamide and topotecan. This is the first study to test giving these three drugs together and will help determine the highest dose of sorafenib that can safely be given together with cyclophosphamide and topotecan to patients with resistant/relapsed neuroblastoma.

Conditions

Neuroblastoma

Keywords

Neuroblastoma; NANT; Sorafenib; Relapse

Outcome Measures

Primary Outcomes (2)

• The maximum tolerated dose of sorafenib given twice each day when given in combination with cyclophosphamide/topotecan for 5 days

  By dose level (Dose Escalation of Sorafenib Only; The entry dose of sorafenib at 125 mg/m2 /dose is equivalent to 62.5% of the single agent MTD for pediatric solid tumor patients). Two to six evaluable patients will be entered at each of the three dose levels for determination of the maximum tolerated dose. The minimum sample size required to identify the MTD is 4 patients.

  2 years

• The number and types of toxicities of sorafenib when administered in combination with cyclophosphamide and topotecan.

  Patients will be evaluable for inclusion in dose escalation consideration if they have received \>80% of the 70 planned doses of sorafenib, \>= 4 of the 5 planned doses of cyclophosphamide, and \>=4 of the 5 planned doses of topotecan in course 1 AND are followed until Day 35 of the first course of therapy. In addition, patients who experience DLT at any time after the first dose of sorafenib are evaluable for inclusion in dose escalation consideration. Toxicity will be assessed and reported on all patients who begin sorafenib therapy. All toxicities observed will be summarized and graded using the CTCAE criteria, version 4.0 which can be downloaded from the CTEP home page (http://ctep.cancer.gov). The type of toxicities (organ affected or laboratory determination), severity, duration, and reversibility or outcome will be recorded. Toxicities observed during the first course of therapy (day -6 through day 28) will be assessed to define the MTD and guide dose escalation.

  2 years

Study Arms (1)

Sorafenib and Cyclophosphamide/Topotecan

OTHER

Sorafenib and Cyclophosphamide/Topotecan with growth factor support.

Drug: Sorafenib; Drug: Cyclophosphamide; Drug: Topotecan

Interventions

Sorafenib DRUG

Sorafenib -100-200mg/m2/dose (dose escalation), Orally BID continuously Days 1 thru 28 Cyclophosphamide - 250 mg/m2/day IV x 5 days - day 1 thru day 5 Topotecan - 0.75 mg/m2/day IV x 5 days - day 1 thru day 5

Also known as: SORAFENIB TOSYLATE, NEXAVARTM , BAY 54-9085

Sorafenib and Cyclophosphamide/Topotecan

Cyclophosphamide DRUG

250mg/m2/day IV x5 days (Day 1 through Day 5 of each course)

Also known as: Cytoxan

Sorafenib and Cyclophosphamide/Topotecan

Topotecan DRUG

0.75mg/m2.day IV x5 days (Day 1 through Day 5 of each course)

Also known as: SKF-104864,, Hycamtin®

Sorafenib and Cyclophosphamide/Topotecan

Eligibility Criteria

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

You may qualify if:

• Patients must be \< 30 years of age when registered on study.
• 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 according to COG risk classification at the time of study enrollment. Patients who were initially considered low or intermediate risk, but then reclassified as high risk are also eligible.
• Patients must have at least ONE of the following:
• Recurrent/progressive disease at any time prior to study enrollment - regardless of response to frontline therapy.
• Refractory disease: persistent sites of disease after achieving a best overall response of no response to front line therapy after a minimum of 4 cycles of induction therapy AND patient has never had recurrent/progressive disease.
• Persistent disease: persistent sites of disease after achieving a best overall response of partial response to frontline therapy after a minimum of 4 cycles of induction therapy AND patient has never had recurrent/progressive disease.
• Patients must have at least ONE of the following (lesions may have received prior radiation therapy as long as they meet the other criteria listed below):
• At least one MIBG avid bone site or diffuse MIBG uptake.
• For recurrent/progressive or refractory disease, a biopsy is not required regardless of number of MIBG avid lesions
• For persistent disease, if patient has only 1 or 2 MIBG avid lesions OR a Curie core of 1 - 2, then biopsy confirmation of neuroblastoma and/or ganglioneuroma in at least one site present at the time of enrollment (bone marrow, bone or soft tissue) is required to be obtained at any time point prior to enrollment and two weeks subsequent to most recent prior therapy. If a patient has 3 or more MIBG avid lesions OR a Curie Score of ≥ 3 then no biopsy is required for eligibility.
• Any amount of neuroblastoma tumor cells in the bone marrow based on routine morphology (with or without immunocytochemistry) in at least one sample from bilateral aspirates and biopsies.
• At least one soft tissue site that meets criteria for a TARGET lesion defined by:
• Size: Lesion can be accurately measured in at least one dimension with a longest diameter ≥ 10mm, or for lymph nodes ≥ 15mm short axis. Lesions meeting size criteria will be considered measurable.
• In addition to size, a site needs to meet one of the following criteria:

You may not qualify if:

• Subjects with calculated BSA \< 0.40 m2 are not eligible for study participation as Sorafenib dosing for this study cannot accommodate subjects of this size utilizing commercially available drug formulation.
• Pregnancy: Serum B-HCG must be negative in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events.
• Patients who have an active or uncontrolled infection are excluded. 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 with prior allogeneic transplant are not eligible.Patients with a documented history of cerebrovascular accidents and/or TIA within the past 6 months are not eligible.
• Patients with a history of intracranial hemorrhage are not eligible.
• Patients with a history of venous or arterial thrombosis personally or in a first degree relative before the age of 40 years are not eligible unless the thrombotic event was associated with a central line.
• Patient with prolonged QT/QTc (defined as QTc interval \> 450 msec) are not eligible.
• Patient declines participation in NANT 04-05. (Neuroblastoma Biology Study)

Sponsors & Collaborators

• University of Michigan: collaborator
• New Approaches to Neuroblastoma Therapy Consortium: lead
• University of California, San Francisco: collaborator
• Children's Hospital Los Angeles: collaborator
• Lucile Packard Children's Hospital: collaborator
• Children's Hospital Medical Center, Cincinnati: collaborator
• Seattle Children's Hospital: collaborator
• Dana-Farber Cancer Institute: collaborator
• The Hospital for Sick Children: collaborator
• Children's Healthcare of Atlanta: collaborator
• University of Chicago: collaborator
• Cook Children's Health Care System: collaborator
• Children's Hospital Colorado: collaborator

Study Sites (12)

Children's Hospital Los Angeles

Los Angeles, California, 90027-0700, United States

Location

UCSF Comprehensive Cancer Center

San Francisco, California, 94143, United States

Location

Children Hospital of Colorado

Aurora, Colorado, 80045, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

University of Chicago, Comer Children's Hospital

Chicago, Illinois, 60637, United States

Location

Childrens Hospital Boston, Dana-Farber Cancer Institute.

Boston, Massachusetts, 02115, United States

Location

C.S Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

Cook Children's Healthcare System

Fort Worth, Texas, 76104, United States

Location

Children's Hospital and Regional Medical Center - Seattle

Seattle, Washington, 98105, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

MeSH Terms

Conditions

Neuroblastoma; Recurrence

Interventions

Sorafenib; Cyclophosphamide; Topotecan

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)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Camptothecin; Alkaloids

Study Design

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

Study Record Dates

• First Submitted: August 26, 2014
• First Posted: November 21, 2014
• Study Start: October 8, 2015
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: March 23, 2026

Record last verified: 2026-03

Locations

US (11); CA (1)