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

Information source: New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Neuroblastoma

Intervention: Sorafenib (Drug); Cyclophosphamide (Drug); Topotecan (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: New Approaches to Neuroblastoma Therapy Consortium

Official(s) and/or principal investigator(s):
Josephine HaDuong, MD, Study Chair, Affiliation: Children's Hospital Los Angeles

Overall contact:
Araz Marachelian, MD, Phone: 323-361-5687, Email: amarachelian@chla.usc.edu

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.

Clinical Details

Official title: NANT N2013-02 A Phase I Study of Sorafenib and Cyclophosphamide/Topotecan in Patients With Relapsed and Refractory Neuroblastoma

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

Primary outcome:

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

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

Detailed description: This study will combine three drugs: sorafenib, cyclophosphamide and topotecan. This study involves the use of an experimental drug, called sorafenib. Sorafenib blocks the function of a protein that is important in the growth of cancer cells. This drug has been tested by itself (as a single-agent) in children with relapsed solid tumors, including patients with neuroblastoma. In the laboratory, sorafenib appears to make neuroblastoma tumors smaller, and in addition can help immune cells to be more active in attacking tumors and blocks other harmful immune cells from promoting tumor growth and function. Sorafenib also helps to block tumor cells from developing blood vessels used to "feed" to tumor. Sorafenib is an FDA-approved drug currently widely used for adults with specific types of liver and kidney cancer. Cyclophosphamide and topotecan are both FDA-approved chemotherapy drugs. These drugs are approved for the treatment of certain adult cancers, but have also been used to treat children with cancer. These drugs have been used in combination in many people with neuroblastoma. In some neuroblastoma patients, this combination has reduced the amount of tumor burden. 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.

Eligibility

Minimum age: N/A. Maximum age: 30 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- 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:

MIBG avid. For patients with persistent disease only: If a patient has only 1 or 2 MIBG

avid lesions OR a Curie Score of 1 - 2, then biopsy confirmation of neuroblastoma and/or

ganglioneuroblastoma in at least one site present at time of enrollment (either bone marrow, bone and/or soft tissue) is required to be obtained at any time point prior to enrollment and at least 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.

- FDG-PET avid (only if tumor known to be MIBG non-avid). These patients must have had

a biopsy confirming neuroblastoma and/or ganglioneuroblastoma in at least one FDG-PET avid site present at the time of enrollment done prior to enrollment and at least two weeks subsequent to the most recent prior therapy.

- Non-avid lesion (both MIBG and FDG-PET non-avid). These patients must have had a

biopsy confirming neuroblastoma and/or ganglioneuroblastoma in at least one non-avid lesion present at the time of enrollment done prior to enrollment and at least two weeks subsequent to the most recent prior therapy.

- Patients must have a life expectancy of at least 8 weeks and a Lansky (< 16 years

age) or Karnofsky (> 16 years age) score of at least 50

- Patients must have fully recovered from the acute toxic effects of all previous

chemotherapy, immunotherapy, or radiotherapy prior to study enrollment.

- Patients must not have received the therapies indicated below for the specified time

period prior to the first day of administration of protocol therapy on this study:

- Myelosuppressive chemotherapy: Last dose was given at least 14 days before the start

date for protocol therapy.

- Biologic (anti-neoplastic agent including retinoids): Last dose given at least 7 days

prior to the start date for protocol therapy.

- Monoclonal antibodies: Last dose of any monoclonal antibodies must have received at

least 7 days or 3 half-lives, whichever is longer, prior to the start date for protocol therapy. Please refer to table posted at www. nant. org for definition of half-lives for specific monoclonal antibodies.

- Patients must not have received radiation for a minimum of two weeks prior to study

enrollment.

- Patients are eligible 12 weeks after date of autologous hematopoietic stem cell

infusion following myeloablative therapy (timed from first day of this protocol therapy).

- Patients are not eligible post allogeneic stem cell transplant.

- Patients who have received an autologous hematopoietic stem cell infusion to support

non-myeloablative therapy (such as 131I-MIBG) are eligible at any time as long as they meet the other criteria for eligibility.

- A minimum of 6 weeks must have elapsed after 131I-MIBG therapy prior to start of

protocol therapy.

- Patients who have received prior treatment with cyclophosphamide and topotecan are

eligible if they did not have tumor relapse/progression while receiving this combination.

- Patients who have received prior treatment with sorafenib are eligible, as long as

the sorafenib was not given in combination with cyclosphosphamide and/or topotecan. Patients with tumor relapse/progression while on sorafinib or having dose modifications or experiencing toxicity that required sorafenib to be discontinued are also ineligible to participate in this study.

- Growth factors that support platelet or white cell number or function must not have

been administered within 7 days of blood draw documenting hematopoietic function (ANC, Platelets) eligibility. .

- Patients must not be receiving any other anti-cancer agents or radiotherapy at the

time of study entry or while on study.

- Patients must not be receiving other investigational medications (covered under

another IND) while on study.

- Treatment with clinically significant enzyme inducers, such as the enzyme-inducing

antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin, rifapentine or St. John's wort within 14 days prior to the first dose of sorafenib and during protocol therapy must not be used as these may interfere with sorafenib metabolism. Non-enzyme inducing anticonvulsants (Keppra, etc.) can be used after discussion with study chair.

- Patients must not be receiving active anti-coagulation therapy at the time of study

entry (or while on study).

- Patients with cardiac arrhythmias must not be receiving anti-arrhythmic medication at

time of study entry (or while on study).

- Patients must not be receiving anti-hypertensive medications at time of study entry.

- ANC: 1000/ul (no short acting hematopoietic growth factors within 7 7 days of blood

draw documenting eligibility and no long-acting hematopoietic growth factors within 14 days of blood draw documenting eligibility)

- Platelet count: 100,000/ul and transfusion independent (no platelet transfusions

within 7 days of blood draw documenting eligibility)

- Patients with known bone marrow metastatic disease will be eligible for study as long

as they meet hematologic function criteria above.

- Hematuria ≤ 1+ on urinalysis

- Age-adjusted serum creatinine 1. 5 x normal for age/gender

- Total bilirubin 1. 5 x normal for age, AND

- SGPT (ALT) ≤ 135 U/L and SGOT (AST) ≤ 3X ULN. (for the purpose of this study, the

upper limit of normal [ULN] for SGPT [ALT] is 45 U/L).

- Serum albumin > 2. 5 g/dl

- Patient must have blood pressure ≤ 95th percentile for age, height, and gender

- Patients may not be on medical therapy for hypertension at time of enrollment.

- Patient must have a QT/QTc interval ≤ 450 msec.

- INR and aPTT < 1. 2 times upper limit of normal for age.

- No history of bleeding diathesis.

- Amylase and Lipase < 1. 5 x normal for age.

- Patients with other ongoing serious medical issues must be approved by the study

chair prior to registration. Exclusion Criteria:

- 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)

Locations and Contacts

Araz Marachelian, MD, Phone: 323-361-5687, Email: amarachelian@chla.usc.edu

Children's Hospital Los Angeles, Los Angeles, California 90027-0700, United States; Not yet recruiting
Araz Marachelian, MD, Phone: 323-361-5687, Email: amarachelian@chla.usc.edu

Lucille Salter Packer Children's Hospital, Stanford University, Palo Alto, California 94305, United States; Recruiting
Claire - Twist, MD, Phone: 650-723-5535, Email: claire.twist@stanford.edu

UCSF Comprehensive Cancer Center, San Francisco, California 94143, United States; Not yet recruiting
Katherine K. Matthay, MD, Phone: 415-476-3831

Children Hospital of Colorado, Aurora, Colorado 80045, United States; Not yet recruiting
Margaret Macy, MD, Phone: 720-777-8856, Email: Margaret.macy@childrenscolorado.org

Children's Healthcare of Atlanta, Atlanta, Georgia 30322, United States; Recruiting
Kelly Goldsmith, MD, Phone: 404-785-0853, Email: kgoldsm@emory.edu

University of Chicago, Comer Children's Hospital, Chicago, Illinois 60637, United States; Recruiting
Susan L. Cohn, MD, Phone: 773-702-2571, Email: Scohn@peds.bsd.uchicago.edu

Childrens Hospital Boston, Dana-Farber Cancer Institute., Boston, Massachusetts 02115, United States; Recruiting
Suzanne - Shusterman, MD, Phone: 617-632-3725, Email: suzanne_shusterman@dfci.harvard.edu

C.S Mott Children's Hospital, Ann Arbor, Michigan 48109, United States; Recruiting
Gregory Yanik, MD, Phone: 734-936-8785, Email: gyanik@umich.edu

Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States; Not yet recruiting
Stephen Roberts, MD, Phone: 212-639-4034, Email: robertss@mskcc.org

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, United States; Recruiting
Brian Weiss, MD, Phone: 513-636-9863, Email: brian.weiss@chmcc.org

Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Not yet recruiting
Meredith Irwin, MD, Phone: 416-813-7654, Email: meredith.irwin@sickkids.ca

Cook Children's Healthcare System, Fort Worth, Texas 76104, United States; Recruiting
Meaghan Granger, MD, Phone: 682-885-4007

Children's Hospital and Regional Medical Center - Seattle, Seattle, Washington 98105, United States; Not yet recruiting
Julie R. Park, MD, Phone: 206-987-1947, Email: Julie.park@seattlechildrens.org

Additional Information

Starting date: April 2015
Last updated: August 14, 2015

Page last updated: August 23, 2015

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