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Swog c9710: phase iii randomized study of concurrent tretinoin and chemotherapy with or without a single course of arsenic trioxide (as2o3) as initial consolidation therapy followed by intermittent versus continuous tretinoin maintenance therapy for pat
COG-ACNS0334: A Phase III Randomized Trial for the Treatment of Newly Diagnosed Supratentorial PNET and
High Risk Medulloblastoma in Children < 36 Months Old with Intensive Induction Chemotherapy with Methotrexate
Followed by Consolidation with Stem Cell Rescue vs. the Same Therapy Without Methotrexate
Eligibility Reviewed and Verified By
______________________ MD/DO Date_________
_______________________ RN Date____________
Consent Version Dated___________
Important note: The eligibility criteria listed below are interpreted literally and cannot be waived (per COG policy
posted 5/11/01). All clinical and laboratory data required for determining eligibility of a patient enrolled on this trial
must be available in the patient’s medical research record which will serve as the source document for verification at
the time of audit.
Patients must be enrolled before treatment begins. The date protocol therapy is projected to start must be within 31 days of definitive surgery and no later than five calendar days after the date of study enrollment.
Randomization will take place at the time a patient is entered On Study via RDE. Patients will be assigned to either Regimen A “Induction without Methotrexate” or Regimen B “Induction with Methotrexate”. Randomization will be stratified according to 1) M0 medulloblastoma with ≥ 1.5 cm2 residual tumor < 36 months, 2) M1 medulloblastoma (positive lumbar CSF cytology) < 36 months, 3) M2, or M3, or M4 medulloblastoma < 36 months, 4) Supratentorial PNET (any M-stage) < 36 months, 5) M0 medulloblastoma < 8 months without residual disease or with < 1.5cm2 radiographic measurable residual tumor, 6) Anaplastic M0 medulloblastoma < 36 months without residual disease or with < 1.5 cm2 radiographic measurable residual, and 7) Classic M0 (non-desmoplastic) medulloblastoma < 36 months with < 1.5 cm2 radiographic measurable residual tumor.
Children less than 36 months (3 years) of age at time of definitive surgery who have high risk Medulloblastoma will be eligible for study entry. High risk Medulloblastoma is defined by any of the following: > 1.5 cm2 residual disease for any Medulloblastoma histology, or lumbar CSF cytology positive for tumor cells by analysis of fluid collected either before definitive surgery or at
least 10 days after definitive surgery unless contraindicated, or
MRI evidence of M2 or M3 metastatic disease, or M4 disease. (See Appendix III for M-Staging System). Children less than 36 months (3 years) of age at the time of definitive surgery with supratentorial PNET (any M-Stage) will be eligible for study entry. Children less than 8 months of age at the time of definitive surgery with or without measurable radiographic residual tumor with M0 stage Medulloblastoma will be eligible for study entry. Patients with anaplastic medulloblastoma are eligible regardless of M-stage or residual tumor. Patients with M0 classic, non-desmoplastic medulloblastoma (R1) with radiographically measurable residual disease < 1.5 cm2 are eligible.
Cranial MRI (with and without gadolinium) must be done pre-operatively. Post-operatively, Cranial MRI (with and
without gadolinium) must be done, preferably within 48 hours of surgery. Entire spinal MRI must be obtained either
pre-operatively (with gadolinium) or post-operatively (2 weeks following surgery) prior to study enrollment (with and
. Patients with MRI evidence of spinal disease are eligible for this study.
Evaluation of lumbar CSF cytology (cytospin preparation for microscopic evaluation) must be performed either pre-operatively or at least 10 days after definitive surgery unless contraindicated.
Patients must have a life expectancy of > 8 weeks.
Patient must have received no prior radiation therapy or chemotherapy other than corticosteroids. Corticosteroids are allowable for all patients. See Section 14.6
Neurocognitive Testing - Access to neurocognitive testing is required for participation in this study. Institutions
who wish to participate in this study will be required to designate a nurse (outpatient clinic nurse, nurse
practitioner, clinical nurse specialist) who will be responsible for administering the quality-of-life battery,
collation of results of this battery and data submission.
At the designated time points, the institutional nurse will
also be responsible for providing the primary caregiver with the appropriate Ages and Stages Questionnaire (ASQ) and
assisting with the coordination of the WeeFIMS phone survey. Institutional nurses must contact one of the study
Study Nurse Researchers are: Tania Shiminski-Maher (718) 920-6668 or firstname.lastname@example.org and Melissa Martin
(404) 785-5589 or email@example.com. Once the ASQ is completed it should be faxed by the institution to Nancy Lyon, R.N., P.N.P, Project Coordinator at Children’s Hospital of Buffalo, NY (CHOB) at phone: (716) 888-1325, Cell: (716) 574-9146, Pager: (716) 643-1152, Fax: (716) 888-1315, e-mail: NLyon@kaleidahealth.org or nancy_lyon@MSN.com and provide patients name and pertinent information. The WeeFIM interview will then be arranged and administered by Ms. Lyon.
Organ Function Requirements: Adequate renal function defined as:
Creatinine clearance (12-24 hour urine collection) or radioisotope GFR ≥ 60 ml/min/1.73m2
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and
SGOT (AST) and SGPT (ALT) < 2 x upper limit of normal (ULN) for age.
Adequate cardiac function defined as:
Shortening fraction of ≥ 27% by echocardiogram, or
Ejection fraction of ≥ 47% by radionuclide angiogram.
Adequate pulmonary function defined as:
no evidence of dyspnea at rest and a pulse oximetry > 94% on room air.
Adequate Bone Marrow Function defined as:
Peripheral absolute neutrophil count (ANC) > 1000/μL
Platelet Count > 100,000/μL (transfusion independent)
Hemoglobin greater than 8 gm/dL (may have received RBC transfusions)
___10. Concomitant Medications Restrictions
Hold trimethoprim/sulfamethoxazole (Bactrim) on the day of HDMTX infusion and continue to hold until the
methotrexate level is less than 0.1 micromolar (1 x 10-7 M).
Avoid probenecid, penicillins, cephalosporins, aspirin, proton pump inhibitors and NSAIDS on the day of
methotrexate and continue until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M) as renal excretion of methotrexate is inhibited by these agents.
Avoid IV contrast media, urinary acidifiers, phenytoin, and fosphenytoin on the day of methotrexate and until the
methotrexate level is less than 0.1 micromolar (1 x 10-7 M).
Concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and carbamazepine) should be
avoided. See Appendix VI.
Clinically significant drug interactions have been reported when using vincristine with strong CYP450 3A4
inhibitors and inducers. Selected strong inhibitors of cytochrome P450 3A4 include azole antifungals, such as fluconazole, voriconazole, itraconazole, ketoconazole, and strong inducers include drugs such as rifampin, phenytoin, phenobarbitol, carbamazepine, and St. John’s wort. The use of these drugs should be avoided with vincristine.
The clinical outcome and significance of CYP450 interactions with cyclophosphamide and etoposide are less
clear. CYP450 3A4 stimulators or inhibitors should be avoided or used with great caution. Aprepitant also interacts with CYP3A4 and should be used with caution with etoposide or vincristine chemotherapy.
Additional inducers or inhibitors of CYP450 enzymes can be found at http://medicine.iupui.edu/clinpharm/ddis/.
Required Clinical, Laboratory and Disease Evaluations
Physical, Neurologic Exam5 Height, Weight, BSA, Head Circumference
MRI of Brain with and without Gadolinium 1
MRI of Spine 2
CSF Cytological Evaluation of Lumbar Fluid
Bone Scan, Bone Marrow Aspirate/Biopsy 3
OAE or Audiogram or Brainstem evoked potential
Echo or MUGA
12-24 hour Creatinine Clearance or Radioisotope GFR
CBC, Diff., Platelet Count
Sodium, Potassium, BUN, Serum Creatinine, Calcium, Phosphorus, Magnesium, AST, ALT, Total Bili
Endocrine Evaluation (See Section 20.0)
Lansky Play Performance Scale (Appendix II)
Required Pathology and Biology Specimens (Section 15 and 16) 4
1. Cranial MRI (with and without gadolinium) must be done pre-operatively. Post-operatively, Cranial MRI (with and
without gadolinium) must be done, preferably with 48 hours of surgery.
2. Entire spinal MRI must be obtained either pre-operatively (with gadolinium) or post-operatively prior to study
enrollment (with and without gadolinium).
3. Obtain if clinically indicated 4. Specimens must be submitted within 3 working days after study enrollment 5. Obtain as indicated, however only the prior to study entry, end of Induction, end of Consolidation, after second look
surgery and relapse exams will be reported.
Patients will receive a total of 6 cycles of chemotherapy- three cycles of induction therapy followed by three cycles of
consolidation therapy. The three induction cycles each include Cyclophosphamide, Etoposide, Vincristine, Cisplatin +/-
Methotrexate. During these first three cycles, sufficient peripheral blood stem cells will be harvested after each cycle of
induction to provide support of the subsequent three consolidation cycles. If a CR has not been achieved after the three cycles
of induction, second look surgery is strongly recommended, then consolidation. If CR is achieved, then patients proceed to
consolidation directly after completion of the 3 induction cycles. Each of three consolidation cycles consists of Carboplatin and
Thiotepa followed by stem cell rescue. After completion of the third consolidation cycle, radiation therapy may or may not be
administered at the discretion of the patient’s treating physician and patient’s family. Radiation is not specified as part of this
protocol nor does its use after protocol completion exclude patients from participation. See Section 18.0 for Recommended
Radiation Therapy Guidelines. Optional Studies
Patients who consent to participate on ALTE07C1 will be assessed at three times points: at 9 months (± 3 months) post cancer
diagnosis; at 30 months (± 3 months) post diagnosis, and again at 60 months (± 3 months) post diagnosis. Age appropriate tests
will be used and will include measures of broad cognitive functioning (IQ) and specific areas of neuropsychological
functioning, emotional-behavioral functioning, and quality of life. Total testing time should be approximately 1 hour at each
PATHOLOGY REVIEW REQUIREMENTS:
Mandatory Submission of Tissue for Pathology Review All pathology must be rapidly centrally reviewed with confirmation of Medulloblastoma or CNS PNET.
specimens must be submitted no later than 3 working days after study enrollment (See Section 15.0 regarding required
specimens and shipping information):
Representative paraffin embedded tissue blocks
If blocks are unavailable, submit the following:
Two (2) H&E stained slide of each representative lesion and Seven (7) unstained positively charged slides from a representative block of the tumor
Mandatory Submission of Tissue for Biology Submission of tissue for biology is mandatory as part of this protocol and must be submitted no later than 3 working
days after enrollment on ACNS0334.
The following specimens must be submitted (See Section 16.0 regarding specimens and
Formalin fixed tissue block or ten (10) unstained positively charged slides Peripheral blood specimens prior to starting therapy: 3ml in a purple top (EDTA) tube and 3 ml in a green top
It is highly recommended snap frozen tissue (a minimum of > 0.5 cm2 is preferred) be submitted when available. As a companion to the clinical hypotheses being tested in this study, the molecular genetic analysis of all patients with suspected AT/RT will be performed. All tumor specimens with loss of INI1 by immunohistochemistry will be screened for a mutation in the INI1 rhabdoid tumor suppressor geneaccording to established protocols. The results will be compared with the pathology review, and with patient outcome. If tissue is positive for INI1 or if histology is consistent with AT/RT then the patient will be removed from protocol therapy. (Rationale: This protocol attempts to eliminate AT/RT patients from this protocol and redirect them to the AT/RT appropriate treatment and specific protocol ACNS0333 when available).
Keil Urogynecology 4500 E. 9th Ave. Ste. 420 Denver, CO 80220 Urodynamic Appointment: _________________________ Special Instructions: 1. Please come to our office with a full bladder. 2. If you have had a knee replacement, have mitral valve prolapse, or must take antibiotics prior to any dental or medical procedure, please take these antibiotics prior to your testing. Please notif
CURRICULUM VITAE Rajesh Kumar Goel EDUCATION Bachelor of Pharmacy (Amravati University, Amravati, (M.S.) India, 1993). Master of Pharmacy in Pharmacology (Panjab University, Chandigarh, India,1995). Ph.D. in Pharmacology (Panjab University, Chandigarh, India, 2004). APPOINTMENTS Associate Professor and Head, Department of Pharmaceutical Sciences and Drug Research