Sorafenib in Children and Young Adults With Recurrent or Progressive Low-Grade Astrocytomas
Primary Purpose
neurofibromatosis1 (NF1), Recurrent or Progressive Optic Pathway Gliomas (OPG), Recurrent or Progressive Low-grade Glioma
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sorafenib (Nexavar)
Sponsored by
About this trial
This is an interventional treatment trial for neurofibromatosis1 (NF1) focused on measuring neurofibromatosis1 (NF1), Recurrent or progressive optic pathway gliomas (OPG), Recurrent or progressive low-grade glioma, sorafenib, low-grade astrocytoma
Eligibility Criteria
Inclusion Criteria:
- Age: greater than or equal to 2 years of age
- Patients with neurofibromatosis-1 (NF1) are eligible
- Recurrent/progressive optic pathway gliomas (OPG) by MRI criteria, after standard therapy - histologic confirmation not required OR Histologically confirmed, radiographically recurrent or progressive low-grade glioma (WHO grade I or II) by MRI criteria, after standard therapy.
- Karnofsky performance status (PS) 60-100% (greater than or equal to 16 years of age) OR Lansky PS 60-100% (< 16 years of age)
- Absolute neutrophil count ≥ 1,000/mm³ (unsupported)
- Platelet count ≥ 75,000/mm³ (unsupported)
- Normal PT, PTT, and INR (for patients on prophylactic anticoagulation only)
- Diastolic blood pressure (DBP) ≤ the 95th percentile for age and gender and not currently receiving medication for the treatment of hypertension.
- Adequate pulmonary function, defined as: no evidence of dyspnea at rest, no exercise intolerance, and pulse oximetry > 94% if termination is clinically indicated.
- Not received myelosuppressive chemotherapy or treatment with biologicals or monoclonal antibodies within 4 weeks of enrollment onto this study (6 weeks if prior nitrosurea)
- At least 7 days since the completion of therapy with a hematopoietic growth factor and at least 14 days from the last administration of PEGylated GCSF (Neulasta®)
- If prior radiation therapy, ≥ 6 months must have elapsed since the last fraction for craniospinal therapy and ≥ 3 months for focal radiotherapy including radiosurgery.
- If prior surgery, ≥ 8 weeks must have elapsed since (≥ 4 weeks for minor surgery/procedures including central line placement)
- Steroids are allowed for progressive symptoms but patient must be on a stable or decreasing dose for at least 1 week prior to study entry
- Any neurologic deficits must be stable for ≥ 1 week
Exclusion Criteria:
- Patients with serious concurrent infection or medical illness, including overt hepatic or renal disease, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety.
- Baseline hypertension greater than grade 1.
- Prior treatment with sorafenib
- Other concurrent investigational drugs
- Other concurrent anticancer agents or therapies, including chemotherapy, radiotherapy, immunotherapy, or biologic therapy
- Concurrent therapeutic anticoagulation. Prophylactic anticoagulation (i.e. low dose heparin) of venous or arterial access devices is allowed.
- Concurrent administration of any of cytochrome P450 enzyme-inducing agents, including grapefruit juice and drugs listed under Section 9.7.
- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
- Uncontrolled hypertension Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
- Active clinically serious infection
- Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
- Pulmonary hemorrhage/bleeding event
- Any other hemorrhage/bleeding event
- Serious non-healing wound, ulcer, or bone fracture.
- Evidence or history of unresolved bleeding diathesis or coagulopathy.
- Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.
- Known or suspected allergy to sorafenib.
- Any malabsorption problem.
- Patients with history of any prior CNS bleeding.
- Patients with any non-healed wounds.
Sites / Locations
- New York University Stephen D. Hassenfeld Children's Center for Cancer & Blood Disorders
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Sorafenib (Nexavar)
Arm Description
Sorafenib will be administered orally BID (approximately every 12 hours). Grapefruit juice is not allowed while taking sorafenib. A cycle of therapy is considered to be 28 days and there is no interruption between cycles. Patients may receive up to a total of 12 cycles provided that no off-protocol or off-study criteria are met.
Outcomes
Primary Outcome Measures
Response Rate to Sorafenib
To estimate the objective response rates to sorafenib in children and young adults with low-grade astrocytomas, including optic pathway gliomas.
Objective Response Rates
Determination of tumor response (CR, PR, SD) will be defined based on the comparison of the baseline MRI performed at study entry to the subsequent MRI which demonstrated best response. PR will be defined by a >15% decrease in tumor volume, as measured by 3D volumetric analysis.
Secondary Outcome Measures
Full Information
NCT ID
NCT01338857
First Posted
April 18, 2011
Last Updated
December 28, 2016
Sponsor
NYU Langone Health
Collaborators
Bayer Healthcare Pharmaceuticals, Inc./Bayer Schering Pharma
1. Study Identification
Unique Protocol Identification Number
NCT01338857
Brief Title
Sorafenib in Children and Young Adults With Recurrent or Progressive Low-Grade Astrocytomas
Official Title
Phase II Study of Sorafenib in Children and Young Adults With Recurrent or Progressive Low-Grade Astrocytomas
Study Type
Interventional
2. Study Status
Record Verification Date
December 2016
Overall Recruitment Status
Terminated
Why Stopped
Sorafenib ineffective for tx of recurrent or progressive PLGA
Study Start Date
April 2011 (undefined)
Primary Completion Date
March 2013 (Actual)
Study Completion Date
March 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
NYU Langone Health
Collaborators
Bayer Healthcare Pharmaceuticals, Inc./Bayer Schering Pharma
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to determine if a drug called sorafenib can shrink LGA tumors (low-grade astrocytomas) in children and adults. Previous research has given us a better understanding of this type of tumor by studying the genetic "make-up" of LGAs. From this research, the investigators found that a drug called sorafenib may stop the growth of tumor cells by blocking some of the molecules needed for cell growth and by blocking blood flow to the tumor. This trial is studying how well sorafenib works in treating patients with LGAs, and how the effects relate to the specific genetic "make-up" of your particular tumor. This testing of your tumor's genetic make-up is optional and requires available tumor tissue for testing. In summary, the aims of this study are: To see if sorafenib can shrink LGAs; how well sorafenib is tolerated in patients with LGAs; and, how the effects of sorafenib relate to the genetic make-up of individual LGAs (Optional Study)
Detailed Description
Novel therapies are urgently needed for children with relapsed LGA who are not surgical candidates and/or have exhausted standard chemotherapy approaches. Although a vast number of "molecular targeted" agents have been developed over the past decade for the treatment of cancer, none have been evaluated for the treatment of LGAs. Recently, genetic alterations resulting in oncogenic BRAF have been identified to be highly prevalent in LGAs, providing a rational target for therapeutic intervention.
The aims of this clinical trial are to estimate the efficacy, as well as safety and tolerability of sorafenib, a RAF and tyrosine kinase receptor inhibitor, in the treatment of pediatric patients with recurrent LGA. Sorafenib targets several pathways that, based on preliminary data from us and others, are likely contributing to the growth of LGAs: oncogenic BRAF, which is present in the majority of grade I LGAs and VEGFR2 and PDGFR, which are well-described mediators of tumor angiogenesis. Since sorafenib inhibits a number of additional kinases whose role in LGA growth has not yet been explored, it is possible that inhibition of pathways other than the primary targets may result in additional anti-tumor effects of sorafenib in LGA. Although the investigators hypothesize that LGAs with oncogenic BRAF should be most sensitive to sorafenib, the additional targets of sorafenib may also result in significant anti-tumor effects in LGAs with wild-type BRAF. Therefore, the investigators propose to evaluate the efficacy of sorafenib in children with LGAs in a translational clinical trial, stratified by BRAF status and tumor grade.
The investigators expect to learn the following from this clinical translational trial:
The anti-tumor activity of sorafenib in pediatric LGAs
The safety and tolerability of sorafenib in pediatric patients with LGAs
The association of molecular target expression, e.g. oncogenic BRAF, with response rates
The investigators will use the results of the clinical translational trial to determine if sorafenib warrants further clinical study in pediatric LGAs. If the investigators find associations between molecular target expression and response, further studies may be limited to or focus on patients whose tumors have specific molecular features, such as oncogenic BRAF. Sorafenib has also shown promise in combination with classic chemotherapy and can be given together with carboplatin, which is one of the most active agents in LGAs. Therefore, possible synergy between sorafenib and traditional chemotherapy used in the treatment of LGAs, such as carboplatin, could be explored in future clinical trials.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
neurofibromatosis1 (NF1), Recurrent or Progressive Optic Pathway Gliomas (OPG), Recurrent or Progressive Low-grade Glioma
Keywords
neurofibromatosis1 (NF1), Recurrent or progressive optic pathway gliomas (OPG), Recurrent or progressive low-grade glioma, sorafenib, low-grade astrocytoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sorafenib (Nexavar)
Arm Type
Experimental
Arm Description
Sorafenib will be administered orally BID (approximately every 12 hours). Grapefruit juice is not allowed while taking sorafenib. A cycle of therapy is considered to be 28 days and there is no interruption between cycles. Patients may receive up to a total of 12 cycles provided that no off-protocol or off-study criteria are met.
Intervention Type
Drug
Intervention Name(s)
Sorafenib (Nexavar)
Intervention Description
Sorafenib (in tablet form) will be administered orally BID (approximately every 12 hours). Grapefruit juice is not allowed while taking sorafenib. A cycle of therapy is considered to be 28 days and there is no interruption between cycles. Patients may receive up to a total of 12 cycles provided that no off-protocol or off-study criteria are met.
Children/adolescents (< 18 years of age, non-NF1): 200 mg/m2/dose PO twice daily (rounded to the nearest 50 mg increment as per Section 4.1) to a maximum of 400 mg PO twice daily
Adults (greater than or equal to 18 years of age, non-NF1): 400 mg PO twice daily
NF1 patients (regardless of age): 80 mg/m2/dose PO twice daily (rounded to the nearest 50 mg increment as per Section 4.1) to a maximum of 150 mg PO twice daily
Primary Outcome Measure Information:
Title
Response Rate to Sorafenib
Description
To estimate the objective response rates to sorafenib in children and young adults with low-grade astrocytomas, including optic pathway gliomas.
Time Frame
one year
Title
Objective Response Rates
Description
Determination of tumor response (CR, PR, SD) will be defined based on the comparison of the baseline MRI performed at study entry to the subsequent MRI which demonstrated best response. PR will be defined by a >15% decrease in tumor volume, as measured by 3D volumetric analysis.
Time Frame
MRIs performed after every 3rd 28-day cycle and off-study
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age: greater than or equal to 2 years of age
Patients with neurofibromatosis-1 (NF1) are eligible
Recurrent/progressive optic pathway gliomas (OPG) by MRI criteria, after standard therapy - histologic confirmation not required OR Histologically confirmed, radiographically recurrent or progressive low-grade glioma (WHO grade I or II) by MRI criteria, after standard therapy.
Karnofsky performance status (PS) 60-100% (greater than or equal to 16 years of age) OR Lansky PS 60-100% (< 16 years of age)
Absolute neutrophil count ≥ 1,000/mm³ (unsupported)
Platelet count ≥ 75,000/mm³ (unsupported)
Normal PT, PTT, and INR (for patients on prophylactic anticoagulation only)
Diastolic blood pressure (DBP) ≤ the 95th percentile for age and gender and not currently receiving medication for the treatment of hypertension.
Adequate pulmonary function, defined as: no evidence of dyspnea at rest, no exercise intolerance, and pulse oximetry > 94% if termination is clinically indicated.
Not received myelosuppressive chemotherapy or treatment with biologicals or monoclonal antibodies within 4 weeks of enrollment onto this study (6 weeks if prior nitrosurea)
At least 7 days since the completion of therapy with a hematopoietic growth factor and at least 14 days from the last administration of PEGylated GCSF (Neulasta®)
If prior radiation therapy, ≥ 6 months must have elapsed since the last fraction for craniospinal therapy and ≥ 3 months for focal radiotherapy including radiosurgery.
If prior surgery, ≥ 8 weeks must have elapsed since (≥ 4 weeks for minor surgery/procedures including central line placement)
Steroids are allowed for progressive symptoms but patient must be on a stable or decreasing dose for at least 1 week prior to study entry
Any neurologic deficits must be stable for ≥ 1 week
Exclusion Criteria:
Patients with serious concurrent infection or medical illness, including overt hepatic or renal disease, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety.
Baseline hypertension greater than grade 1.
Prior treatment with sorafenib
Other concurrent investigational drugs
Other concurrent anticancer agents or therapies, including chemotherapy, radiotherapy, immunotherapy, or biologic therapy
Concurrent therapeutic anticoagulation. Prophylactic anticoagulation (i.e. low dose heparin) of venous or arterial access devices is allowed.
Concurrent administration of any of cytochrome P450 enzyme-inducing agents, including grapefruit juice and drugs listed under Section 9.7.
Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
Uncontrolled hypertension Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
Active clinically serious infection
Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
Pulmonary hemorrhage/bleeding event
Any other hemorrhage/bleeding event
Serious non-healing wound, ulcer, or bone fracture.
Evidence or history of unresolved bleeding diathesis or coagulopathy.
Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.
Known or suspected allergy to sorafenib.
Any malabsorption problem.
Patients with history of any prior CNS bleeding.
Patients with any non-healed wounds.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Matthias A Karajannis, MD
Organizational Affiliation
NYU
Official's Role
Principal Investigator
Facility Information:
Facility Name
New York University Stephen D. Hassenfeld Children's Center for Cancer & Blood Disorders
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
24351969
Citation
Legault G, Kieran MW, Scott RM, Chordas C, Milla SS, Karajannis MA. Recurrent ascites in a patient with low-grade astrocytoma and ventriculo-peritoneal shunt treated with the multikinase inhibitor sorafenib. J Pediatr Hematol Oncol. 2014 Nov;36(8):e533-5. doi: 10.1097/MPH.0000000000000094.
Results Reference
derived
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Sorafenib in Children and Young Adults With Recurrent or Progressive Low-Grade Astrocytomas
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