a collaborative effort of: sarc: trial coordination nci: principal investigators
DESCRIPTION
Phase II Trial of Neoadjuvant Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated High Grade Unresectable Malignant Peripheral Nerve Sheath Tumors. A collaborative effort of: SARC: Trial coordination NCI: Principal investigators SARC institutions Selected NF1 centers - PowerPoint PPT PresentationTRANSCRIPT
Phase II Trial of Neoadjuvant Phase II Trial of Neoadjuvant Chemotherapy in Sporadic and Chemotherapy in Sporadic and
Neurofibromatosis Type 1 Neurofibromatosis Type 1 Associated High Grade Unresectable Associated High Grade Unresectable Malignant Peripheral Nerve Sheath Malignant Peripheral Nerve Sheath
TumorsTumors• A collaborative effort of:A collaborative effort of:
– SARC: Trial coordinationSARC: Trial coordination– NCI: Principal investigatorsNCI: Principal investigators– SARC institutions SARC institutions – Selected NF1 centersSelected NF1 centers
• Funded through a Clinical Trial Funded through a Clinical Trial Award by the US Army DoDAward by the US Army DoD
MPNST Trial ObjectivesMPNST Trial Objectives• Primary objective:Primary objective:
– Response rate (CR/PR, WHO criteria) Response rate (CR/PR, WHO criteria) after 4 cycles of neoadjuvant after 4 cycles of neoadjuvant chemotherapy in NF1 and sporadic MPNSTchemotherapy in NF1 and sporadic MPNST
• Secondary objectives:Secondary objectives:– Response evaluation with Response evaluation with 1818FDG-PET and FDG-PET and volumetric MRIvolumetric MRI
– Correlate response by imaging studies Correlate response by imaging studies with pathologic responsewith pathologic response
– Molecular biology of MPNSTs , tissue Molecular biology of MPNSTs , tissue microarraymicroarray
– Serum proteomics (compared to sera from Serum proteomics (compared to sera from pts with NF1 and plexiform pts with NF1 and plexiform neurofibromas)neurofibromas)
– Epidemiology of MPNSTs in NF1Epidemiology of MPNSTs in NF1
Trial DesignTrial Design• Eligibility:Eligibility: High grade unresectable MPNSTHigh grade unresectable MPNST
MPNSTMPNST
NF1NF1
SporadicSporadic
IE IE x2x2
IA x2IA x2
IA x 2IA x 2
Response Response EvaluationEvaluation
Local Local ControlControl ChemotherapyChemotherapy
IE x2IE x2
PETPET3D MRI3D MRI
SurgerySurgeryXRTXRT
Statistical plan:Statistical plan:Simon optimal two-stage design (0.1 Simon optimal two-stage design (0.1 alpha/beta)alpha/beta)
First stage 17 patients, go to second stage First stage 17 patients, go to second stage if 4+/17 respondif 4+/17 respond
Chemotherapy active in strata if 11+/37 Chemotherapy active in strata if 11+/37 patients respondpatients respond
MRIMRIPETPET
3D MRI3D MRI
Treatment SchemaPatients receiving radiation therapy for local controlCycle 1 2 3 4 5 6 7 8Week 0 3 6 9 12 15 18 21Drugs Ifos
DoxoDxrz
MesnaG-CSF/Neulasta
IfosDoxoDxrz
MesnaG-CSF/Neulasta
IfosEtop
MesnaG-CSF/Neulasta
IfosEtop
MesnaG-CSF/Neulasta
IfosEtop
MesnaG-CSF/Neulasta
IfosEtop
MesnaG-CSF/Neulasta
IfosDoxoDxrz
MesnaG-CSF/Neulasta
IfosDoxoDxrz
MesnaG-CSF/Neulasta
Patients not receiving radiation therapy for local controlCycle 1 2 3 4 5 6 7 8Week 0 3 6 9 12 15 18 21Drugs Ifos
DoxoDxrz
MesnaG-CSF/Neulasta
IfosDoxoDxrz
MesnaG-CSF/Neulasta
IfosEtop
MesnaG-CSF/Neulasta
IfosEtop
MesnaG-CSF/Neulasta
IfosDoxoDxrz
MesnaG-CSF/Neulasta
IfosDoxoDxrz
MesnaG-CSF/Neulasta
IfosEtop
MesnaG-CSF/Neulasta
IfosEtop
MesnaG-CSF/Neulasta
Dxrz =Dexrazoxane 375 mg/m2/dose IV over 15-30 minutes immediately prior to Doxoon days 1, 2Doxo =Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2Ifos =Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5
Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5Mesna =Mesna 360 mg/m2/dose IV, first dose over 60 minutes (with Ifos) and doses 2-8over 15 minutes every 3 hours on days 1, 2, 3, 4, 5 with Ifos. Other standard mesnadosing regimens including oral administration of mesna (360 mg/m2 PO q 3hr supplied asscored 400mg tablets), used at participating institutions, are also permissible.G-CSF = Filgrastim 5µg/ kg/ dose SC daily starting 24-36 hours after last dose ofchemotherapy until post-nadir ANC ≥1,500/µl, or pegfilgrastim (neulastaTM) forpatients weighing ≥ 45 kg: 6 mg SC x 1 dose starting 24 hours after completion ofchemotherapy.
Data Collection on TrialData Collection on TrialPatient registration and Data Patient registration and Data
submissionsubmissionSARC WebsiteSARC Website
Tumor tissue from diagnosis and Tumor tissue from diagnosis and at time of surgery (if at time of surgery (if
applicable):applicable):
Washington Washington University, St. University, St.
Louis, MOLouis, MO
Serum samples for proteomics: Serum samples for proteomics: Pre treatment, pre and post Pre treatment, pre and post
local controllocal control NCI, Pediatric NCI, Pediatric Oncology BranchOncology BranchMRI for central response MRI for central response
evaluation and comparison 3D, evaluation and comparison 3D, 2D, 1D2D, 1D
1818FDG-PET pre treatment and FDG-PET pre treatment and after 4 cycles of chemotherapy after 4 cycles of chemotherapy
(not mandatory)(not mandatory)
Phenotypic analysis for NF1 at Phenotypic analysis for NF1 at baseline(questionnaire)baseline(questionnaire)
NNFF Database NNFF Database Vancouver, CanadaVancouver, Canada
Protocol StatusProtocol Status
• NCI IRB and DoD approval obtainedNCI IRB and DoD approval obtained• Data forms developed by SARCData forms developed by SARC
• Informed consent has to receive Informed consent has to receive institutional and US Army IRB institutional and US Army IRB approval prior to patient entryapproval prior to patient entry– Model informed consent with US Army Model informed consent with US Army requested elements was provided by requested elements was provided by SARCSARC
– SARC and NCI will assist in SARC and NCI will assist in development and review of development and review of institutional informed consentinstitutional informed consent
Site / PI information required by DoD:Site / PI information required by DoD:• PI Assurance formPI Assurance form• Facility Safety PlanFacility Safety Plan• MPA or FWA numberMPA or FWA number• PI most recent GCP trainingPI most recent GCP training
Planned reimbursement to sites:Planned reimbursement to sites:• IRB review/approvalIRB review/approval• $ 3500 / patient entered$ 3500 / patient entered• $ 15 serum sample, $ 400 tumor $ 15 serum sample, $ 400 tumor processing/shipmentprocessing/shipment
• $ 100 CT/MRI, $ 200 PET ($ 100 CT/MRI, $ 200 PET (to ensure to ensure compliance with protocol)compliance with protocol)
DoD Requirements and ReimbursementDoD Requirements and Reimbursement
DoD Funded NF1 DoD Funded NF1 ConsortiumConsortium
Operations Center Award:Operations Center Award:• University of Alabama at BirminghamUniversity of Alabama at BirminghamSite Award recipients:Site Award recipients:• University of Alabama at BirminghamUniversity of Alabama at Birmingham• Children’s Hospital BostonChildren’s Hospital Boston• Children’s Hospital of PhiladelphiaChildren’s Hospital of Philadelphia• Children’s National Medical Center, Children’s National Medical Center, Washington, DCWashington, DC
• Cincinnati Children’s Hospital Medical Cincinnati Children’s Hospital Medical CenterCenter
• National Cancer Institute, Bethesda, MDNational Cancer Institute, Bethesda, MD• University of ChicagoUniversity of Chicago• University of UtahUniversity of Utah• Washington University, St. Louis, MOWashington University, St. Louis, MO