A Phase II Clinical Trial of Induction Chemotherapy Regimen Gemcitabine, Paclitaxel and Oxaliplatin (GemPOx) Followed by a Single Cycle of High Dose Chemotherapy (HDC) and Autologous Hematopoietic Stem Cell Rescue (AuHSCR) for Patients With Recurrent or Progressive Intracranial Germ Cell Tumors
Phase: PHASE2
Conditions: CNS Germ Cell Tumor
Sponsor: Nationwide Children's Hospital

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A PHASE II CLINICAL TRIAL OF INDUCTION CHEMOTHERAPY WITH  
GEMCITABINE, PACLITAXEL AND OXALIPLATIN (GemPOx)  
FOLLOWED BY A SINGLE CYCLE OF MARROW-ABLATIVE CHEMOTHERAPY  
AND AUTOLOGOUS HEMATOPOIETIC PROGENITOR CELL RESCUE (AuHPCR)  
FOR PATIENTS WITH RECURRENT OR PROGRESSIVE  
CENTRAL NERVOUS SYSTEM GERM CELL TUMORS 
 
 
 
 
COORDINATING CENTER 
Nationwide Children’s Hospital 
700 Children’s Dr. 
Columbus, Ohio 43205-2664 
 
PRINCIPAL INVESTIGATOR 
Jonathan Finlay. MB, Ch.B. 
700 Children’s Dr. 
Room ED544 
Columbus, Ohio 43205-2664 
 
 
PROTOCOL VERSION: 1/5/2017 
 
 
 
 
 

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Table of Contents 
 
Section                      
 
 
 
 
 
     
                        Page 
 
Study Committee 
 
 
 
 
 
 
 
 
5 
List of Abbreviations 
 
 
 
 
 
 
 
 
7 
 
1.0    
Abstract and Experimental Schema 
 
 
 
 
 
9, 10 
 
2.0 
Objectives 
 
 
 
 
 
 
 
 
 
2.1 
Primary Objectives 
 
 
 
 
 
 
 
11 
2.2 
Secondary Objectives  
 
 
 
 
 
 
11 
 
3.0  
Background and Rationale 
 
 
 
 
 
 
 
3.1 
Introduction on Intracranial Germ Cell Tumors (ICGCT) 
 
 
 
12 
 
3.2 
Rational for Gemcitabine 
 
 
 
 
 
 
12 
3.3 
Rationale for Paclitaxel   
 
 
                          
            12 
3.4 
Rationale for Oxaliplatin  
 
 
 
 
 
 
13 
3.5 
Rationale for Paclitaxel and Oxaliplatin Combination  
 
 
 
13 
3.6 
Rationale for Gemcitabine and Paclitaxel Combination                     
 
13           
3.7        Rationale for Oxaliplatin and Gemcitabine Combination                   
 
14         
3.8        Rationale for Combining Paclitaxel, Gemcitabine and Oxaliplatin     
 
14 
3.9        Rationale for High Dose Chemotherapy and Autologous Hematopoietic 
 
15 
Stem Cell Rescue 
 
4.0 
Patient Eligibility and Study Entry                                                                  
4.1 
Study Enrollment 
 
 
 
 
 
 
 
16 
4.2 
Patient Status  
 
 
 
 
 
 
 
16 
4.3 
Organ Function Requirements  
 
 
 
 
 
18 
4.4 
Pregnancy/Contraception 
 
 
 
 
 
 
19 
4.5 
Regulatory 
 
 
 
 
 
 
 
 
19 
4.6 
Exclusion Criteria                                                                                
 
19 
 
5.0 
Treatment Plan  
 
 
 
 
 
 
 
 
5.1 
Induction Treatment Plan 
 
 
 
 
              
20 
5.2 
Collection of Peripheral Hematopoietic Stem Cells 
              
 
25 
5.3 
Guidelines for Proceeding to Consolidation High Dose Chemotherapy 
            26 
5.4 
Consolidation High Dose Chemotherapy Plan 
 
 
 
 
27        
5.5        Radiation Therapy 
 
 
 
 
 
 
 
29 
 
6.0 
Supportive Care Guidelines during Induction  
 
 
 
 
 
6.1 
Venous Access   
 
 
 
 
 
 
 
30 
6.2 
Antiemetics 
 
 
 
 
 
 
 
 
30 
6.3 
Use of Hematopoietic Growth Factor (G-CSF) 
 
 
 
 
30 
6.4 
Blood Products  
 
 
 
 
 
 
 
30 
6.5 
Febrile Neutropenia 
 
 
 
 
 
 
 
30 
6.6 
Pneumocystis Carinii Prophylaxis 
 
 
 
 
 
30 

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6.7       Fungal Prophylaxis                                                                              
 
31 
6.8       Nutritional Support                                                                               
 
31 
6.9 
Diabetes Insipidus 
 
 
 
 
 
 
 
31 
 
7.0 
Supportive Care Guidelines during Consolidation  
 
 
 
7.1 
Post-autologous Hematopoietic Re-infusion G-CSF Therapy 
 
 
32 
7.2 
Blood Product Support   
 
 
 
 
 
 
32 
7.3 
Pneumocystis Carinii Prophylaxis 
 
 
 
 
 
32 
7.4 
Viral Prophylaxis 
 
 
 
 
 
 
 
32 
7.5 
Fungal Prophylaxis                                                                              
 
32 
7.6 
Febrile Neutropenia 
 
 
 
 
 
 
 
32 
7.7 
Nutritional Support 
 
 
 
 
 
 
 
32 
7.8 
Nephrotoxic Drugs 
 
 
 
 
 
 
 
33 
7.9 
Corticosteroid Use 
 
 
 
 
 
 
 
33 
 
8.0 
Drug Information 
 
 
 
 
 
 
 
 
8.1 
Carboplatin 
 
 
 
 
 
 
 
 
34 
8.2 
Etoposide 
 
 
 
 
 
 
 
 
35 
8.3 
Gemcitabine 
 
 
 
 
 
 
 
 
38 
8.4 
Granulocyte Colony Stimulating Growth Factor 
 
 
 
 
39 
8.5 
Oxaliplatin 
 
 
 
 
 
 
 
 
41 
8.6 
Paclitaxel 
 
 
 
 
 
 
 
 
43 
8.7 
Thiotepa 
 
 
 
 
 
 
 
 
45 
 
9.0 
Required Observations  
 
 
 
 
 
 
9.1 
Required Observations Before and During Protocol Therapy 
 
 
47 
9.2 
Required Observations Following Completion of Protocol Therapy  
 
48 
 
10.0 
Criteria for Removal from Protocol Therapy and Off Study Criteria  
 
10.1 
Criteria for Removal from Protocol Therapy 
 
 
 
 
49 
10.2 
Off Study Criteria 
 
 
 
 
 
 
 
49 
 
11.0 
Staging and Evaluation Criteria  
 
 
 
 
 
11.1 
Staging and Pre-Treatment Evaluation 
 
 
 
 
 
50 
11.2 
Methodology to Determine Tumor Measurements  
 
 
 
51 
11.3 
Response Criteria 
 
 
 
 
 
 
 
53 
 
 
12.0 
Statistical Consideration  
 
 
 
 
 
 
55 
 
13.0 
Neurosurgical Guidelines 
 
 
 
 
 
 
 
13.1 
Control of Raised Intracranial Pressure  
 
 
 
 
57 
13.2 
Cerebrospinal Fluid Sampling 
 
 
 
 
 
 
57 
13.3 
Direct Tumor Surgery 
 
 
 
 
 
 
 
58 
13.4 
Extent of Surgical Resection 
 
 
 
 
 
 
58 
13.5 
Neurosurgical On-study Requirements 
 
 
 
 
 
59 
 
 

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14.0 
Neuropathology Guidelines 
 
 
 
 
 
 
 
14.1 
Criteria for Diagnosis of Germinoma 
 
 
 
 
 
60 
14.2 
Criteria for Diagnosis of Immature Teratoma 
 
 
 
 
60 
14.3 
Criteria for Diagnosis of Mature Teratoma 
 
 
 
 
60 
14.4 
Criteria for Diagnosis of Teratoma with Malignant Elements 
 
 
61 
14.5 
Criteria for Diagnosis of Endodermal Sinus Tumor (Yolk sac tumor) 
 
61 
 
14.6  
Criteria for Diagnosis of Embryonal Carcinoma 
 
 
 
 
61 
14.7 
Criteria for Diagnosis of Choriocarcinoma 
 
 
 
 
62 
14.8 
Minimal Required Studies 
 
 
 
 
 
 
62 
14.9 
Central Pathology Review Process 
 
 
 
 
 
64 
 
15.0 
Neuroradiology Guidelines 
 
 
 
 
 
 
 
15.1 
MRI scanning  
 
 
 
 
 
 
 
65 
15.2 
Scan Parameters 
 
 
 
 
 
 
 
65 
15.3 
Timing of Radiologic Studies 
 
 
 
 
 
 
66 
15.4 
Centralized Neuroradiology Review 
 
 
 
 
 
67 
 
16.0 
Radiation Therapy Guidelines 
 
 
 
 
 
 
68 
 
17.0 
Data and Safety Monitoring Plan  
 
 
  
17.1 
Study Monitoring  
 
 
 
 
 
 
 
69 
17.2 
Reviews by Protocol Chairs and Co-Chairs 
 
 
 
 
69 
17.3 
Automated Data Delinquency Reporting System  
 
 
 
70 
17.4 
Semi-Annual GemPOx Meeting Minutes  
 
 
 
 
70 
17.5 
Auditing and Subsites 
 
 
 
 
 
 
 
70 
17.6 
Data Safety Monitoring Board Membership (DSMB) 
 
 
 
70 
17.7 
Meetings 
 
 
 
 
 
 
 
 
71 
17.8 
DSMC Decisions and Recommendations  
 
 
 
 
71 
 
 
18.0 
Reporting of Adverse Events and Toxicities/Adverse Event Criteria  
 
71 
18.1  
Routine Toxicity Reporting 
 
 
 
 
 
 
71 
18.2  
Guidelines for Reporting Adverse Drug Reactions for Commercial Agents in an Expedited 
 
Manner  
 
 
 
 
 
 
 
 
72 
 
 
 
 
 
 
 
 
 
18.3 
Adverse Event Reporting Requirements  
 
 
 
 
72 
 
19.0 
References 
 
 
 
 
 
 
 
 
74 
Appendix I: Performance Status Criteria  
 
 
 
 
 
77 
Appendix II: Eligible/Not Eligible Anticonvulsant Drugs 
 
 
 
 
78 
 
Roadmaps 
Figure 1: GemPOx Induction 
 
 
 
 
 
 
 
80 
Figure 2: GemPox Consolidation  
 
 
 
 
 
 
82 
 
  
 

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STUDY COMMITTEE    
 
STUDY CHAIR 
Jonathan Finlay, M.B., Ch.B 
Nationwide Children’s Hospital 
700 Children’s Drive Room ED544 
Columbus, Ohio 43205-2664 
Phone: 614-722-4087 
Fax: 614-722-3369 
Email:jonathan.finlay@nationwidechildrens.org 
 
COMMITTEE MEMBER 
Diana Osorio, M.D. 
Neuroncology 
Nationwide Children’s Hospital 
700 Children’s Drive Room ED 558 
Columbus, Ohio 43205-2664 
Phone: 614-722-3550 
Fax: 614-722-3369 
Email: diana.osorio@nationwidechildrens.org 
 
COMMITTEE MEMBER  
Jeffrey Leonard, M.D. 
Neurosurgery 
Nationwide Children’s Hospital 
700 Children’s Drive 
Columbus, Ohio 43205-2664 
Phone: 614-722-2086 
Fax: 614-722-2041 
Email:jeffrey.leonard@nationwidechildrens.org  
 
COMMITTEE MEMBER  
Jeffery Auletta, M.D. 
Bone Marrow Transplant 
Nationwide Children’s Hospital 
700 Children’s Drive 
Columbus, Ohio 43205-2664 
Phone: 614-722-6883 
Fax: 614-722-3699 
Email: Jeffery.Auletta@nationwidechildrens.org 
 
         COMMITTEE MEMBER 
Daniel Boue, M.D. 
         Neuropathology 
Nationwide Children’s Hospital 
700 Children’s Drive 
Columbus, Ohio 43205-2664 
Phone: 614-722-5310 
Fax: 614-722-2899 
Email:daniel.boue@nationwidechildrens.org         
 
          COMMITTEE MEMBER 
Nicholas Zumberge, M.D. 
Neuroradiology 
Nationwide Children’s Hospital 
700 Children’s Drive 
Columbus, Ohio 43205-2664 
Phone:614-722-2359 
Fax:614-722-2332  
Email:nicholas.zumberge@nationwidechildrens 
.org 
        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       

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COMMITTEE MEMBER 
Abi Clark, PharmD, BCPS 
Clinical Pharmacy Specialist, Hematology/Oncology 
Nationwide Children’s Hospital 
700 Children’s Drive 
Columbus, Ohio 43205 
Office: 614-722-6981 
Fax: 614-722-2488 
Email: abi.clark@nationwidechildrens.org 
 
 
COMMITTEE MEMBER                        
Sharon Gardner, M.D. 
Bone Marrow Transplant 
NYU Langone Medical Center 
160 East 32nd Street, 2nd Floor 
Hassenfeld Children Center 
New York, NY 10016 
Phone: 212-263-8400 
Fax: 212-263-8410 
Email: Sharon.Gardner@nyumc.org 
 
COMMITTEE MEMBER  
Joseph Stanek, M.S. 
Biostatistics 
Nationwide Children’s Hospital  
700 Children’s Drive 
Columbus, Ohio 43205-2664 
Phone : 614-722-3026 
Fax : 614-722-4635 
Email : joseph.stanek@nationwidechildrens.org 
 
 
COMMITTEE MEMBER 
Michele Vaughan, BS, CCRP 
Clinical Research Office Director 
Nationwide Children’s Hospital 
700 Children’s Drive ED542 
Columbus, Ohio 43205-2664 
Phone: 614-722-6146 
Fax: 614-722-4635 
Email:Michele.vaughan@nationwidechildrens.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
AFP  
 
Alpha-fetoprotein  
 
ALT  
 
Alanine aminotransferase 
 
ANC  
 
Absolute Neutrophil Count 
 
AST  
 
Aspartate transaminase 
 
AUC  
 
Area Under the Curve 
 
AuHPCR  
Autologous Hematopoietic Progenitor Cell Rescue 
 
BSA  
 
Body Surface Area 
 
BUN  
 
Blood Urea Nitrogen 
 
CNS  
 
Central Nervous System 
 
CNS GCT  
Central Nervous System Germ Cell Tumors 
 
CR  
 
Complete Response 
 
CRU                 Complete Response with Unconfirmed Residual 
 
CSA  
 
Canadian Standards Association 
 
DI  
 
Diabetes Insipidus 
 
DSMO   
dimethyl sulfoxide 
 
EFS                 Event-free Survival 
 
FDA  
 
Food and Drug Administration 
 
G-CSF   
Granulocyte-Colony Stimulating Factor 
 
GTS  
 
Growing Teratoma Syndrome 
 
HCGβ   
Beta Human Chorionic Gonadotropin 
 
HDC   
High Dose Chemotherapy 
 
Hgb  
 
Hemoglobin 
 
HPC  
 
Hematopoietic progenitor cells 

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ICP  
 
Intracranial Pressure 
 
IRB 
 
Institutional Review Board 
 
MiRNA   
microRNA 
 
MMGCT  
Mixed Malignant Germ Cell Tumors 
 
NCH   
Nationwide Children's Hospital 
 
OS  
 
Overall Survival  
 
PD  
 
Progressive Disease 
 
Plts  
 
Platelets 
 
PR  
 
Partial Response 
 
PRBC   
Packed Red Blood Cell 
 
RBC  
 
Red Blood Cell 
 
RT  
 
Radiation Therapy 
 
SD  
 
Stable Disease 
 
SR                   Sufficient Response 
 
TMP/SMZ  
Trimethoprim/sulfamethoxazole 
 
TPN  
 
Total Parental Nutrition 
 
TTF  
 
Time to Treatment Failure 
 
ULN  
 
Upper Limit Normal 
 
VGPR              Very Good Partial Response 
 
VP-16   
Etoposide 
 

 
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1.0 
ABSTRACT 
 
Patients with pure germinoma of the central nervous system (CNS) have a high rate of cure, while only 
about two-thirds of patients with CNS non-germinomatous or mixed malignant germ cell tumors (MMGCT) 
are cured following upfront therapy. Even after recurrence, patients with intracranial germinoma have a 
higher likelihood of achieving remission with the known active chemotherapy agents. On the other hand, 
when relapses occur in patients with intracranial MMGCT, it is difficult to cure these patients with commonly 
used salvage chemotherapy regimens and therefore these patients have poor outcomes. To date, the best 
results have been achieved by employing a two-stage approach: initial intensive chemotherapy to achieve 
minimal residual tumor, followed by high-dose chemotherapy (HDC) with autologous hematopoietic 
progenitor cell rescue (AuHPCR). This approach has been reported in two multi-center studies to produce 
no more than 50% cure rates for patients with recurrent CNS germ cell tumors (GCT). A critical component 
of success here is the ability to achieve a state of minimal residual tumor with induction chemotherapy, 
prior to consolidation with HDC. Identifying new drugs and drug combinations to maximize achievement of 
minimal residual, especially in patients with MMGCT is required. A body of preclinical and clinical data in 
recurrent systemic germ cell tumors in adults has provided a strong rationale for evaluating the combination 
of gemcitabine, paclitaxel and oxaliplatin (GemPOx) in a multi-institutional phase II clinical trial for 
progressive or recurrent CNS GCT.  
 
This study includes an induction phase consisting of the GemPOx chemotherapy combination.  Following 
induction, only patients with MMGCT who have achieved a sufficient response to the GemPOx regimen will 
undergo consolidation with a single HDC cycle followed by AuHPCR. The decision to administer irradiation 
following study therapy will be left to the individual investigators.  Patients with intracranial germinoma who 
have achieved a sufficient response will receive further treatment at the discretion of the treating physician. 
The primary aim of this phase II trial is to determine the response rates and the toxicities to the GemPOx 
combination, and the secondary aim is to optimize survival in patients with CNS GCTs, especially in those 
with MMGCT. 

 
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Recurrent/Refractory ICGCT
MMGCT
Induction: GemPOx x 2cycles
RESPONSE ASSESSMENT
PD
CR
<CR
Consolidation: 
HDC+AuHPCR
+/- RT
Induction: GemPOx x 2cycles
SD/PR
CR
2nd look surgery
CR
With 
increasing 
markers
With 
normal 
markers
Off study
2nd look surgery
Confirm GTS* and/or 
CR after surgery
*GTS = Growing Teratoma Syndrome
Recurrent/Refractory ICGCT
MMGCT
Induction: GemPOx x 2cycles
RESPONSE ASSESSMENT
PD
CR
<CR
Consolidation: 
HDC+AuHPCR
+/- RT
Induction: GemPOx x 2cycles
SD/PR
CR
2nd look surgery
CR
With 
increasing 
markers
With 
normal 
markers
Off study
2nd look surgery
Confirm GTS* and/or 
CR after surgery
*GTS = Growing Teratoma Syndrome
Figure 1: EXPERIMENTAL SCHEMA FOR MIXED MAILIGNANT GERM CELL TUMOR 
Germinoma
Induction: GemPox x 2 cycles
Recurrent/Refractory ICGCT
RESPONSE ASSESSMENT
PD
CR
<CR
Off Study
Consolidation: 
HDC+AuHPCR
+/- RT
Continue 
on study
RT
Physician’s 
Discretion
Induction: GemPOx x 2cycles
CR/PR/SD
PD
Off Study
Germinoma
Induction: GemPox x 2 cycles
Recurrent/Refractory ICGCT
RESPONSE ASSESSMENT
PD
CR
<CR
Off Study
Consolidation: 
HDC+AuHPCR
+/- RT
Continue 
on study
RT
Physician’s 
Discretion
Induction: GemPOx x 2cycles
CR/PR/SD
PD
Off Study
Figure 2: EXPERIMENTAL SCHEMA FOR PURE GERMINOMA 
 
CR 
SR
    SR 

 
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2.0    OBJECTIVES 
 
2.1  Primary Objectives 
 
2.1.1     To estimate response rate after at least two and up to four courses of induction chemotherapy with 
GemPOx regimen in patients with recurrent CNS MMGCT.  
 
2.1.2   To estimate the rate of completion of induction chemotherapy and progression to high-dose 
chemotherapy (HDC) with autologous hematopoietic progenitor cell rescue (AuHPCR) 
 
2.1.3  To assess the toxicity of GemPOx regimen in all patients with CNS GCT (pure germinoma and 
MMGCT). 
 
2.2   Secondary Objectives 
 
2.2.1 
To correlate serum and cerebrospinal fluid (CSF) tumor marker (AFP and HCGβ) responses with 
radiographic response after two and/or four GemPOx cycles and also after HDC followed with 
AuHPCR. 
 
2.2.2 
To identify specific exosomal microRNAs in the CSF specific for recurrent CNS GCT at study entry 
and to determine if decrease/disappearance of such CSF MiRNAs correlates with radiographic 
and/or tumor marker documentation of response to induction and consolidation therapies, and 
correlates with event-free survival. 
 
2.2.3  To assess the overall survival (OS) and event-free survival (EFS) of patients treated on the 
 
GemPOx induction regimen followed by the HDC and AuHPCR in patients with progressive 
 
or recurrent CNS GCT. 
 
2.2.4  To determine the feasibility of peripheral hematopoietic stem cell mobilization with GemPOx 
 
induction regimen. 
 
2.2.5     To evaluate the toxicity of HDC and AuHPCR following GemPOx induction. 
 
 

 
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3.0    BACKGROUND AND RATIONALE 
 
3.1    Introduction on CNS Germ Cell Tumors (CNS GCT) 
 
Patients with pure germinoma have a highly favorable prognosis with over an 80-90% cure rate using either 
irradiation alone or reduced dose and volume irradiation with modest chemotherapy.1-14 However, patients 
with MMGCT, despite combined intensive chemotherapy and full dose craniospinal irradiation and focal 
boost, have a much poorer outcome, with reported survival rates ranging between 40 and 70 %.1,10-13, 15 
 
There are very few studies that have addressed the treatment of patients with recurrent CNS germ cell 
tumors (GCT), largely due to the rarity of this disease.16-18 High salvage rates using irradiation and 
chemotherapy are achieved for pure germinomas that were initially treated with chemotherapy alone.16 
However, sustained responses to the commonly used salvage regimens are difficult to achieve when 
relapses occur following combined chemotherapy and radiation therapy.19 The survival of patients who 
experience relapse after both modalities of therapy, or those who do not respond to initial treatment, is very 
poor. Promising results have been published in case series incorporating novel salvage regimens with high 
dose, marrow ablative chemotherapy after achieving minimal residual tumor.20, 21 In order to achieve a state 
of minimal residual tumor prior to a single cycle of myeloablative chemotherapy and AuHSCR, it is 
imperative that new drugs and drug combinations be evaluated that will have the best chance of achieving 
such tumor response.  
 
The combination of gemcitabine, paclitaxel and oxaliplatin has been shown to be effective in recurrent 
systemic GCT arising outside the CNS.  
 
3.2    Rationale for Gemcitabine (Gem)  
 
In a phase II trial conducted at Indiana University, 20 patients with recurrent or progressive systemic GCT 
(13 patients were treated with three prior regimens and 13 patients were platinum refractory) received 
single agent gemcitabine.22  Three (15%) out of 20 patients showed an objective response; including one 
complete response (CR). Three additional patients achieved a minor radiographic or tumor marker 
response. Gemcitabine was well tolerated with only one patient with grade 3 nausea and six patients with 
grade 3 leucopenia. In a phase II German trial of 31 patients with recurrent systemic GCT (22 patients had 
recurrence after HDC with AuHSCR), six patients (19%) responded favorably to gemcitabine alone, 
including two who experienced marker normalization and four who had a 75% decline in tumor markers.23 
 
3.3    Rationale for Paclitaxel (P)  
 
Preclinical studies of paclitaxel have demonstrated cytotoxicity in a non-seminomatous GCT cell line and in 
nude mouse xenografts.24, 25 In a phase II clinical trial conducted at Memorial Sloan-Kettering Cancer 
Center, patients with recurrent and/or progressive testicular GCTs were treated with single agent 
paclitaxel.26  Eight (26%) of 31 patients achieved an overall response. Responses were noted in those who 
had failed to respond to vinblastine, ifosfamide and cisplatin and in men with poor prognostic features, 
including mediastinal primary site and with incomplete responses to prior cisplatin therapy. Similar results 
were seen in a phase II German trial, in which 24 patients with poor prognostic GCTs achieved 25% 
response rate to single agent paclitaxel.27 In addition, five patients (21%) displayed stabilization. The 
median duration of responses to paclitaxel was 8 months.  
 

 
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3.4   Rationale for Oxaliplatin (Ox) 
 
 Oxaliplatin, a third-generation platinum compound, is more effective than cisplatin and exhibits similar and 
greater cytotoxicity in several human tumor cell lines.28 In comparison with cisplatin, oxaliplatin exhibits a 
favorable toxicity profile with a substantially lower rate of nephrotoxicity, ototoxicity and 
myelosuppression.29, 30 In vitro data on non-seminomatous germ cell lines indicate incomplete cross-
resistance between cisplatin and oxaliplatin, providing the rationale for the evaluation of oxaliplatin in 
cisplatin-refractory patients.(31) Additionally, the dose limiting toxicity, maximum - tolerated dose and 
adverse effect profile of oxaliplatin in pediatric patients are similar to those observed in adults.32, 33 The 
Pediatric Brain Tumor Consortium conducted a phase II study of oxaliplatin in 43 children with recurrent 
malignant embryonal brain tumors and reported minimal toxicity and good tolerance to paclitaxel in 
children.34 The German Testicular Cancer Study Group investigated the response of oxaliplatin in 32 
patients with systemic GCT who were refractory to cisplatin or relapsed after HDC plus AuHSCR.  Overall, 
four patients (13%) achieved a partial response (PR) and two patients achieved disease stabilization.35  
 
3.5a   Rationale for Paclitaxel and Oxaliplatin Combination 
 
When paclitaxel was combined with oxaliplatin in the treatment of patients with systemic germ cell tumors 
who had failed cisplatin-based chemotherapy, 6% of the patients had a partial response and 34% of the 
patients had stabilization of their disease.60  
 
The major toxicity with this combination was myelosuppression. Grade II sensory neurotoxicity was seen in 
8/27 patients. No grade III or grade IV neurotoxicity was observed in this clinical trial demonstrating that 
paclitaxel and oxaliplatin combination is feasible and well tolerated.     
 
3.5b   Rationale for Gemcitabine and Paclitaxel Combination  
 
A combination of gemcitabine and paclitaxel was evaluated in a phase II trial for patients with recurrent 
systemic GCT who recurred after receiving three prior regimens, some having undergone HDC plus 
AuHPCR.36 Six (21.4%) of 28 patients responded, including three CRs. Two of the complete responders 
were continuously without disease at 15 and 25 months. Toxicity was primarily marrow suppression but 
was manageable, with only a single case of neutropenic fever. A phase II study was conducted at Indiana 
University of 32 patients with systemic GCT who had progressed after cisplatin combination chemotherapy 
and subsequent HDC with tandem transplantation. 37  Ten (31%) of the 32 patients achieved objective 
responses, of whom six were complete responders; four of these six (12.5%) were continuously disease 
free at 20, 40, 44 and 57 months from the start of the combined gemcitabine and paclitaxel therapy, 
respectively.  
 
3.5c  Rationale for Oxaliplatin and Gemcitabine Combination  
 
The combination of gemcitabine and oxaliplatin yields excellent tolerability and predictable 
pharmacokinetics.38 In a phase II study with a combination of oxaliplatin plus gemcitabine in 35 heavily pre-
treated men with recurrent systemic GCT- three patients attained a CR, two patients attained a marker 
negative PR, and 11 patients attained tumor marker PRs, resulting in an overall response rate of 46%.39 
Major toxicity consisted mainly of myelosuppression.  The combination of oxaliplatin and gemcitabine has 
been evaluated in several other small phase II trials, demonstrating similar outcomes.40, 41  
 

 
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3.5d  Rationale for Combining Paclitaxel, Gemcitabine and Oxaliplatin (GemPOx)  
 
Based on the series of the above consecutive phase II trials, the German group conducted a multi-center 
phase II clinical trial with combination of the gemcitabine, oxaliplatin and paclitaxel in patients who were 
either cisplatin refractory or multiply relapsed systemic GCT after HDC.42 Of 41 patients, 5% achieved CR, 
34% achieved tumor marker negativity, and 12% tumor marker partial responses, resulting in an overall 
response rate of 51%. In five responding patients, a complete tumor resection was feasible after the end of 
chemotherapy, resulting in an overall CR rate of 17%. After a median follow-up of 5 months (range 0-20), 
15% of the patients remained in CR after the gemcitabine, oxaliplatin and paclitaxel chemotherapy with or 
without residual tumor resection, with median response duration of 8 months (1 to 17+). The major toxicities 
were leucopenia (grade 3) in 15%, anemia in 7% and thrombocytopenia in 49% of the patients.  
 
3.6  Rationale for HDC and AuHPCR 
 
Alkylating agents have been shown to be active against both CNS and systemic GCTs.19 Thiotepa can 
cross the blood brain barrier extremely efficiently.43 Dose response effects have been suggested for 
carboplatin and etoposide in patients with systemic GCT.45, 46 The combination of carboplatin, etoposide 
and thiotepa has been used to treat malignant brain tumors and the combination has proven to be well 
tolerated.44 
 
Modak et al. has assembled the largest experience with thiotepa-based HDC regimens followed by 
AuHSCR in the treatment of high-risk patients with recurrent CNS GCTs, many of whom had experienced 
multiple prior relapses of disease.20 With a median follow-up of 35 months, seven of the nine patients with 
recurrent germinomas were alive, while four of the 12 MMGCTs patients were alive. Of the eight patients 
who achieved a CR with salvage protocols before consolidation with HDC, five survived without assessable 
disease six to 48 months after HDC. The French Society of Pediatric Oncology (SFOP) reported on 20 
patients with recurrent ICGCT (13 MMGCT, 7 germinomas) who underwent HDC with AuHPCR using a 
conditioning regimen of etoposide and thiotepa; 16 were in first relapse, two in second relapse, two with 
refractory disease and 20 having received carboplatin based chemotherapy as part of their front line 
therapy prior to a recurrence. (21)  Nine patients treated on this study had a complete response and nine 
achieved a partial response and only two patients had progression of their disease. At a median follow-up 
of 29 months, 16 patients were reported alive; 13 were in continuing complete remission (four with 
germinoma and nine with MMGCT).  In a study conducted by the European Group for Blood and Marrow 
Transplantation47 salvage HDC was utilized in 23 patients with extragonadal GCTs including nine patients 
with  CNS GCTs. Twenty-two patients had MMGCT and one had germinoma. Complete responses were 
achieved in 16 of the 23 patients (70%). At a median follow-up of 66 months, 11 patients (48%) were 
reported disease- free of whom three patients (33%) had CNS GCT.  
 
Reports from the two studies (Modak et al.20 and SFOP21) have shown that the survival rate in patients with 
relapsed CNS GCT and especially with MMGCT is improved with the treatment strategy of HDC and 
AuHPCR when these patients are in CR prior to HDC.   
 
 
 
 
 
 

 
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3.7  Rationale For Evaluation of Cerebrospinal Fluid (CSF) exosomal microRNAs (MiRNAs) 
 
More accurate tests to objectively determine the persistence of residual tumor, such as that afforded by 
persistence of specific tumor-related miRNAs are needed to tailor and optimize therapies. Exosomes are 
endosomally-derived membrane vesicles that are released from both healthy and tumor cells, including 
germ cell tumors arising both within the brain and beyond. Packaged within exosomes are microRNAs 
(miRs), some of which are tumor specific oncomiRs that are up-regulated in the presence of certain cancer 
cells; specific cancers have distinct miR profiles. Brain tumor related exosomes, containing their miR cargo, 
eventually reach the CSF, so that changes in the amount of miR burden in the brain is reflected in 
measurements of miRs in the CSF, providing significant and direct information on the presence or absence 
of tumor cells within the brain. Therefore, exosomal miR profiles in the CSF may serve as biomarkers of 
tumor persistence or recurrence or elimination following therapy. 
 
Two groups have independently reported upon miR profiles in CNS germ cell tumors (Terashima et al Br. J. 
Neurosurg. (abstr) 2013), or intra-and extra-CNS GCT (Murray et al, Br. J. Neurosurg. (abstr) 2013) 
showing that miR 371-375 and miR-302a isolated from the CSF of GCT patients are highly up-regulated 
prior to treatment, and decreased following treatment, with specific miRs associated with specific 
germinoma and non-germinomatous histologic sub-types. 
 
We hypothesize that specific CSF miRNA will prove to be accurate markers for tumor presence and 
predictors of response to therapy, with normalization being associated with improved progression-free 
survival in patients under treatment for recurrent central nervous system (CNS) germ cell tumors (GCT). 
The goal of the proposal is to prove this hypothesis within the context of an ongoing prospective multi-
center trial of uniform treatment for patients with recurrent CNS GCT. 

 
Version 1.05.2017 
 
 
 
 
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4.0    PATIENT ELIGIBILITY AND STUDY ENTRY 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be waived. All 
clinical and laboratory data required as 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.  
 
4.1    Study Enrollment 
 
4.1.1 IRB Approval 
 
Protocol must be approved by the treating institution’s Institutional Review Board (IRB) and on file at 
Nationwide Children’s Hospital 
 
4.1.2   Timing 
 
Patients must be enrolled before treatment begins. The date protocol therapy is to start must be no later 
than 42 days from the time of recurrence and within 7 days from enrollment. 
 
 
4.2   Patient Status 
 
4.2.1 
Age 
 
No age limit 
 
4.2.2 
Diagnosis 
 
Histological Diagnosis 
 
CNS GCT including pure germinoma and MMGCT. Patients with histologically proven germinoma and 
MMGCT, including endodermal sinus tumor (yolk sac tumor), embryonal carcinoma, choriocarcinoma and 
mixed germ cell tumor will be eligible for the study. Patients with mature/immature teratoma who have 
tumor marker elevations are eligible on this study. Patient with ONLY mature and/or immature teratoma are 
ineligible in the absence of the tumor marker elevations.  
 
Cytology and Tumor Markers 
  
• Lumbar CSF must be assayed for cytology, alpha fetoprotein (AFP) and beta human chorionic 
gonadotrophin (HCGβ). A quantitative serum determination of AFP and HCGβ should be 
performed at the time of the lumbar CSF assay.  
• For the diagnosis of pure germinoma, HCGβ (serum and CSF) must be < 100 mIU/ml, serum AFP 
must be < 10 IU/l (ng/ml) and < institutional norm and initial CSF AFP< 2 IU/l (ng/ml) and < 
institutional norm with histologically proven diagnosis of germinoma at diagnosis or subsequent 
relapse. 
• For histologically unconfirmed MMGCT, serum and/or CSF tumor markers of HCGβ >100 mIU/ml 
or any elevation of above AFP>10 IU/L (ng/ml) and/or above institutional norm in the serum and 
CSF AFP>2 IU/L (ng/ml) and/or institutional norm. 

 
Version 1.05.2017 
 
 
 
 
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• Patients with no elevations of serum and/or CSF HCGβ and AFP must have histological diagnosis 
of malignant GCT or germinoma. 
 
4.2.3 
Disease Status:  
 
Patient must either have recurrence of CNS GCT or should be refractory to initial therapy. 
 
4.2.4    Disease Evaluation 
 
4.2.4.1 Diagnostic Imaging 
 
a) MRI scans of the brain and spine must be completed within 21 days prior to patient registration. All MRI 
scans should be with and without gadolinium. 
b) All patients who do not have surgery performed must have MRI scans obtained prior to induction. 
c) All patients who have surgery performed must have a cranial MRI pre-operative and post-operative 
(should be done within 72 hours of surgery or within 21 days following surgery).  
d) A MRI of the spine is required within 10 days prior to or at least 10 days after surgery.  
 
4.2.4.2 Tumor Markers 
        
a) Serum HCGβ and AFP levels must be assessed within 7 days prior to registration. 
b) Patient must have lumbar CSF for cytology, protein, AFP and HCGβ within 7 days prior to registration.   
 
4.2.5 
Performance Status 
              
Have a Karnofsky performance status greater than or equal to 50 for patients aged 16 years or older and a 
Lansky performance status greater than or equal to 50 for patients less than 16 years old.  
 
4.2.6 
Life Expectancy:  
 
Must be ≥ 8 weeks. 
 
4.2.7     Prior Therapy 
 
4.2.7.1  Chemotherapy 
 
a) Must not have received cytotoxic chemotherapy within 14 days of entry on to this study.  
b) Patient must not have received any prior marrow-ablative chemotherapy and autologous hematopoietic 
cell transplant.  
c) Patient must have not received gemcitabine, oxaliplatin and/or paclitaxel chemotherapy agents.  
 
4.2.7.2 
Biologic Agent 
               
Must not have received any biological modifier within 14 days of entry on to this study.   
 
 

 
Version 1.05.2017 
 
 
 
 
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4.2.7.3 
Radiation Therapy (RT) 
 
At least 4 weeks for focal RT or ≥ 6 weeks for craniospinal RT must have elapsed prior to study entry. 
 
4.2.7.4 
Surgery 
 
Patient must have recovered from the surgery. 
 
4.2.8 
Concomitant Medications 
 
• Corticosteroid therapy and endocrine replacement therapy (L-thyroxine, testosterone, estrogen, 
DDAVP) are permissible. Any patient already receiving human growth replacement therapy should 
discontinue this prior to commencing chemotherapy, and should not restart until 3 years from 
diagnosis.  
 
• Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and general supportive 
care are to be used as necessary. 
 
• Concomitant use of any enzyme inducing anticonvulsants is not allowed.    
 
4.3        Organ Function Requirements 
4.3.1     Adequate Bone Marrow Function Defined As:  
 
• Absolute neutrophil count (ANC) greater than or equal to 750/mm3 
• Platelets (Plts) greater than or equal to 75,000/mm3  (transfusion independent) 
• Hemoglobin (Hgb) greater than 8.0 g/dL (may have packed red blood cell (PRBC) transfusion) 
 
 
4.3.2 
Adequate Liver Function Defined As: 
 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x institutional upper 
limit of normal for age 
• Total bilirubin ≤ 2 x institutional upper limit of normal for age 
• Liver function test must be obtained within 14 days prior to registration.  
 
4.3.3 
Adequate Renal Function as Defined As: 
 
• Patients must have adequate renal function defined as < 1.5x normal serum creatinine as adjusted 
for age:                          
Age                                                                 Maximum Serum Creatinine (mg/dL)                 
< 5 years                                                                                         0.8  
> 5 and < 10 years                                                                           1.0 
> 10 and < 15 years                                                                         1.2  
> 15 years                                                                                       1.5 

 
Version 1.05.2017 
 
 
 
 
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• Or a calculated or measured creatinine clearance or radioisotope GFR > 70ml/min/1.73m2 obtained 
within 14 days prior to registration. 
               
                          4.4 
Pregnancy/Contraception 
 
Patients who are pregnant or breast-feeding are not eligible. Nursing mothers must agree not to breastfeed 
during therapy. Females of childbearing potential must practice an effective method of birth control while 
participating in this study and for those who have achieved menarche, must have a negative pregnancy test 
prior to study entry. 
 
4.5    Regulatory 
 
4.5.1 
All patients and/or their parents or legal guardians must sign a written informed consent.  
4.5.2 
All institutional and FDA requirements for human studies must be met.  
 
4.6   Exclusion Criteria 
 
4.6.1 
Patients with CNS GCTs who are newly diagnosed are excluded from the study. 
4.6.2 
Patients with the diagnosis of mature or immature teratoma in the absence of tumor marker 
elevations are excluded from the study. 
4.6.3 
Patients who are pregnant or breastfeeding are excluded from the study. 
4.6.4 
Patients who have received previously a high dose chemotherapy regimen and autologous 
transplant are excluded from this study. 
4.6.5 
Patients who have received gemcitabine, oxaliplatin and/or paclitaxel are excluded from this study. 

 
Version 1.05.2017 
 
 
 
 
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5.0    TREATMENT PLAN 
5.1 
Induction Treatment Plan:  
 
• All patients with CNS GCT after enrollment to this study will receive two cycles of induction 
chemotherapy regimen GemPOx. Only patients who have failed to achieve a sufficient response 
(SR) and do not have progression of their disease will receive two additional cycles with a 
maximum of four induction cycles.  
•  A cycle is defined as 14 days unless there is a delay in bone marrow recovery. No more than 28 
days of delay will be allowed when leukapheresis is planned in between induction cycles. 
Leukapheresis is allowed ONLY after two induction cycles. For details on Leukapheresis, see 
section 5.2. For details on delay in beginning a cycle due to prolong myelosuppression, see section 
5.1    
• Each cycle will begin when ANC > 750/mm3 and platelets > 75,000/mm3. Please see section 9.1 for 
additional monitoring that is required prior, during and following each induction cycle.  
• Treatment regimen consists of paclitaxel 170mg/m2 IV over three hours followed by gemcitabine 
800mg/m2 IV  10mg/ m2/min over 1 hour and oxaliplatin 100/m2 IV over 2 hours.   
 
• Further therapy for patients with germinoma who have achieved sufficient response either after 
two or four induction cycles will depend on the discretion of the treating physician. Physician can 
decide to continue the patient on this study to receive the consolidation phase or remove the 
patient from the study and treat him with radiation therapy.   
• Patients with intracranial MMGCT who have achieved sufficient response either after two or four 
induction cycles will proceed on this study to receive the consolidation phase. After four cycles if 
patient has any residual disease (patients with PR or SD), a “second look surgery” will be strongly 
recommended. If CR is achieved following second-look surgery, they would proceed to 
consolidation phase.  
• Patients with an increasing mass in the context of normal serum and CSF tumor markers should 
proceed to second-look surgery in order to evaluate for growing teratoma syndrome (GTS). If the 
patient does have GTS, complete removal of the mass is recommended. Patient can then continue 
therapy on this protocol following the surgery. For details on the diagnosis of GTS please see 
section 14.3. 
• All patients developing PD (after excluding GTS) will be considered off study therapy. 
 
5.1.1 Induction Chemotherapy Administration Guidelines 
 
Patients should have double lumen venous catheter line to receive chemotherapy. Consideration should be 
given to placement of a tunneled leukapheresis-grade catheter to use for chemotherapy administration and 
peripheral hematopoietic stem cell collection.   Institutional standards may take precedence for dilution of 
individual medications, hydration and antiemetics.  The use of magnesium and calcium containing 
hydration solutions to decrease incidence of peripheral neuropathy is not encouraged.  
AGENT 
DOSE 
ROUTE/DURATION 
DAYS 
INTERVAL 
Paclitaxel 
170mg/m2 
IV over 3 hours 
D1 
14 days 
Gemcitabine 
800mg/m2 
IV over 1 hour 
D1 
14 days 
Oxaliplatin 
100mg/m2 
IV over 2 hours  
D1 
14 days 

 
Version 1.05.2017 
 
 
 
 
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Suggested Pre-chemotherapy Hydration: D5 0.45 Normal Saline to run at 125ml/m2/hour until 
chemotherapy ready. 
 
Hour – 30 minutes: Suggested Pre-medications and Antiemetics 
 
Dexamethasone 0.5 mg/kg/dose IV 30 minutes prior to paclitaxel (maximum dose: 50 mg) and continue 
every six hours for 24 hours.  
 
Ranitidine 1 mg/kg IV 30 minutes prior to paclitaxel x one dose (maximum dose: 50 mg). 
 
Diphenhydramine 0.5-1 mg/kg IV 30 minutes prior to paclitaxel x one dose (max dose: 50 mg. 
 
Antiemetics as per the choice of treating physician and institutional standards to be used. 
 
• Hour 0: Paclitaxel 170 mg/m2 in D5W (dose<100mg =150ml; > 100mg=250ml) IV over 3 hours x 1 
dose on day 1 only followed by: 
 
• Hour 3: Gemcitabine 800 mg/m2/dose in 250ml normal saline IV over 1 hour x 1 dose on day 1 
only followed by: 
 
• Hour 4: Oxaliplatin 100 mg/m2 in 250ml D5W IV over 2 hours x 1 dose on day 1 only. 
 
• Hour 6: Resume hydration with D5 0.45 Normal Saline to run at 125 ml/m2/hour until discharge.  
  
Antiemetics at any time are permissible during treatment and should be given as per the institutional policy. 
Replacement of serum electrolytes may be undertaken at any time during treatment.  
 
*Note: During oxaliplatin infusion patients can experience the feeling of difficulty swallowing, shortness of 
breath, shortness of breath, jaw spasm, abnormal tongue sensation and feeling of chest pressure. This has 
been reported rarely (<5%). It generally starts within hours of oxaliplatin infusion and often occurs upon 
exposure to cold. Avoiding exposure to cold helps to prevent this adverse reaction. Future oxaliplatin 
infusions may be given over a longer time frame to help reduce the incidence.  
 
The following are the safety tips that should be advised to each patient receiving this treatment: 
 
While receiving treatment with oxaliplatin advice:  
 
• Cover the skin, mouth and nose if he/she must go outside in cold temperatures and do not breathe 
deeply when exposed to cold air.  
• Do not drink cold drinks or use ice cubes in drinks during and at least for two days following 
oxaliplatin administration.  
• Do not put ice or ice packs on his/her body during and at least for two days following oxaliplatin 
administration.  
• Cover self with a blanket while she/he is receiving oxaliplatin infusion.  
• Do not take things from the freezer or refrigerator without wearing gloves.  

 
Version 1.05.2017 
 
 
 
 
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• Drink fluids warm or at room temperature and always drink through a straw.  
• Do not use ice chips if she/he has nausea or a sore mouth.    
 
5.1.2 Duration of Induction Treatment:  
 
• Patients will continue treatment every 2 weeks until at least 2 cycles have been administered.  
• Only, patients who have failed to achieve a sufficient response and do not have progression of 
their disease will receive two additional cycles with a total of four induction cycles.   
• Patient is taken off protocol therapy if patient develops tumor progression at any time during the 
induction phase.     
                 
5.1.3 
DOSE MODIFICATIONS DURING INDUCTION CHEMOTHERAPY 
 
• Grades I and 2 toxicities should be managed symptomatically, if possible, and treated without 
reduction in the chemotherapy doses. If toxicities are greater than Grade 2, treatment should be 
withheld (except for anemia or neuropathy or as specifically indicated below) until recovery to 
Grade I (or baseline, if baseline was > Grade I).  
 
• Dose modifications for the next cycle and additional cycles are based on day 15 complete blood 
count with differential and toxicity work sheet unless the patient develops cytopenia associated 
infection or bleeding during the prior cycle (see below) or requires hospital admission at which time 
a toxicity assessment should be undertaken and complete blood count obtained.    
  
5.1.3.1   Myelosuppression: 
 
To begin each cycle of induction therapy the following criteria must be met: ANC > 750/mm3 and platelets > 
75,000/mm3. In the event a patient does not meet the criteria for re-treatment, then a maximum of 14 days 
delay is allowed. After a 14-day delay the study PI should be contacted. If the patient has a delay for 7 days 
in beginning the next cycle due to low blood counts then Filgrastim (G-CSF) (5 mcg/kg/day Subcutaneously 
or IV) should be administered 24 hours after the chemotherapy for subsequent cycles. G-CSF should be 
continued until ANC is >1000/mm3 and discontinued at least 48 hours prior to initiation of the next cycle. If 
there is a delay in beginning the next cycle for more than 7 days due to delay in the bone marrow recovery 
despite the administration G-CSF, the doses of oxaliplatin, gemcitabine and paclitaxel should be reduced 
by 25% for all subsequent cycles.   
 
5.1.3.2 Hepatotoxicity:   
 
If the ALT levels are > 10x upper limit of normal (ULN) and/ or total bilirubin is > 2mg/dl before the second 
cycle of treatment, delay start of chemotherapy for 7-14 days. If the liver function has not returned to 
normal, (after a 14-day delay) the study PI should be contacted.  
 

 
Version 1.05.2017 
 
 
 
 
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5.1.3.3    Nephrotoxicity:  
 
If there is an indication of worsening renal function after any course of treatment, a creatinine clearance or 
GFR should be determined. If creatinine clearance is <70 ml/min/1.73m2, delay start of chemotherapy for 7 
days and re-check the creatinine clearance. If the kidney function has not returned to normal (after a 14-
day delay) the study PI should be contacted.  
 
5.1.3.4    Stomatitis:  
 
If Grade 3 and 4 stomatitis occurs, hold chemotherapy until recovery to Grade <1. 
 
5.1.3.5   Paclitaxel Hypersensitivity reactions:  
 
Treatment shall be discontinued for Grade 4 hypersensitivity reactions. There are no dose 
reductions for Paclitaxel hypersensitivity reactions. 
 
Hypersensitivity Treatment Guidelines: 
 
Grade 1: 
 
• Consider decreasing the rate of paclitaxel infusion until recovery from the symptoms; closely 
monitor patient. 
• Resume paclitaxel at the planned initial rate after symptoms resolve on that day of treatment. 
 
Grade 2: 
 
• Interrupt paclitaxel infusion immediately. 
• Give diphenhydramine with or without hydrocortisone; monitor patient until symptoms resolve. 
• Resume infusion after recovery of symptoms; depending on the physician’s assessment of the 
patient, infusion should be resumed at a slower rate, then increased incrementally to the initial 
planned rate. 
• Depending on the intensity of the reaction observed, additional oral or IV pre-medication with an 
antihistamine should also be given for subsequent cycles of treatment, and the rate of paclitaxel 
infusion should be decreased initially and then increased back to the recommended rate gradually 
depending on the physician’s assessment of the patient. 
 
Grade 3: 
 
• Immediately discontinue paclitaxel infusion. 
• Give diphenhydramine with or without hydrocortisone and or epinephrine as needed; monitor 
patient until resolution of symptoms.  
• Resume infusion after recovery of symptoms on that day of treatment; depending on the 
physician’s assessment of the patient, infusion should be resumed at a slower rate, then increased 
incrementally to the initial planned rate. 

 
Version 1.05.2017 
 
 
 
 
-24 - 
• Depending on the intensity of the reaction observed, additional oral or IV premedication with an 
antihistamine should also be given for subsequent induction treatment cycles. The rate of infusion 
should be decreased initially and then increased back to the recommended one hour if symptoms 
have resolved. 
 
Grade 4: 
 
• Infusion should be DISCONTINUED. Patient is taken off protocol therapy.  
 
5.1.3.6  Peripheral Neuropathy: 
 
Neuropathic symptoms and signs: Patients may be treated if they have grade 2 neuropathy but dose delay 
will be at the physician’s discretion and dose reduction should not be undertaken.  For grade 3 or greater 
neuropathy, all drugs must be held until resolution to grade 2, at which time the patient should have a 25% 
reduction in doses of oxaliplatin and paclitaxel. Dose modification will NOT be undertaken for transient 
neuropathic symptoms during the cycle that have resolved by day one of the subsequent cycle. 
 
 
OXALIPLATIN DOSE MODIFICATIONS FOR NON-CTC NEUROLOGICAL TOXICITY 
 
       Toxicity 
               Duration of toxicity 
Persistent1 
1-7 days 
>7days 
Between Cycles 
Paresthsias/dysesthesias 
 
Grade 1: 
Paresthesias/dysesthesias2 of 
short duration that resolves and 
do not interfere with function.  
No change 
No change 
No change 
Grade 2: 
Paresthesias/dysesthesias2 
interfering with function, but not 
ADL   
No change 
No change 
25% dose reduction 
Grade 3: 
Paresthesias/dysesthesias2 with 
pain or with functional 
impairment that also interfere 
with ADL   
1st time: 25% dose 
reduction 
 
2nd time: 50% dose 
reduction 
1st time: 25% dose 
reduction 
 
2nd time: 50% dose 
reduction 
Stop infusion 
Grade 4: Persistent 
Paresthesias/dysesthesias that 
are disabling or life threatening 
Stop infusion. Patient 
is taken off protocol 
therapy.  
 
Stop infusion. Patient 
is taken off protocol 
therapy.  
 
Stop infusion. 
Patient is taken off 
protocol therapy.  
 
Pharyngolaryngeal 
Dysthesias 
(Investigator discretion used for 
grading):  
 
Grade 0 = none  
Grade 1 = mild 
No change 
Increase duration of 
infusion to 6 hours 
Increase duration of 
infusion to 6 hours 

 
Version 1.05.2017 
 
 
 
 
-25 - 
Grade 2 = moderate  
• Stop oxaliplatin infusion. 
• Administer benzodiazepine and give patient reassurance. 
• At the discretion of the investigator, the infusion can be 
restarted at 1/3 the original rate of infusion. 
Grade 3 = severe 
1 = Not resolved by the beginning of the next cycle. 
2 = May be cold induced. 
ADL = Activities of daily living 
 
5.2    Collection of Peripheral Hematopoietic Progenitor Cells (HPCs) 
5.2.1   Insertion of indwelling venous access catheter: 
In children without an appropriate double-lumen leukapheresis-grade catheter in place, leukapheresis may 
be accomplished through a percutaneously placed temporary leukapheresis-grade catheter, which is then 
removed following completion of the leukapheresis. 
5.2.2     Priming with G-CSF: 
If the decision is made to harvest peripheral HPC prior to initiation of chemotherapy, then for three days 
prior to undergoing peripheral HPC leukapheresis, patients will receive G-CSF at a dose of 10-16 mcg/kg 
given as a daily subcutaneous injection, or 16 mcg/kg per day given as twice-daily intravenous injections. 
G-CSF will be discontinued following the last day of leukapheresis. 
 
5.2.3   Timing for Leukapheresis: 
 
Collection of peripheral HPC should be planned ONLY after patients have received two induction cycles. 
Peripheral HPC can be collected after completing second induction cycle or before beginning third or fourth 
induction chemotherapy cycles.  
 
It is best harvested upon recovery from the induction chemotherapy. As soon as the absolute neutrophil 
count (ANC) is observed to be rising, the G-CSF dosage is increased to 10-16 mcg/kg per day as 
subcutaneous injections. G-CSF will be discontinued following the last day of leukapheresis.   
 
5.2.4 Leukapheresis: 
 
Leukapheresis (for the collection of peripheral blood hematopoietic progenitor cells) will be performed using 
a continuous flow cell separator according to the procedure manual with adaptations for small children as 
outlined below. In children without an appropriate double-lumen leukapheresis-grade catheter in place, this 
may be accomplished through a percutaneously placed temporary leukapheresis-grade catheter, which is 
then removed following completion of the leukapheresis. 
 
For patients primed with G-CSF alone, leukapheresis will begin following the fourth day of G-CSF. 
Following each leukapheresis, the cells will be cryopreserved as described in Section 5.2.5.  
 

 
Version 1.05.2017 
 
 
 
 
-26 - 
Prior to freezing, an aliquot of each collection will be analyzed for cell count and immunophenotype. The 
target for the leukapheresis will be 5 x 106 CD34+ cells/Kg, with the goal of infusing no less than 2 x 106 
CD34+ cells/Kg and no more than 10 x 106 CD34+ cells/kg. 
 
For very small patients, the leukapheresis procedure established for adults will be modified.  During the 
procedure, a set volume of blood is contained in the tubing and apparatus.  For larger children and adults, 
this represents less than 10% of their total blood volume and is usually well tolerated. However, in very 
small children, the extracorporeal blood volume may be >10% of their total blood volume and this may 
cause clinically significant hypovolemia.  For patients for whom the extracorporeal blood volume is >10% of 
their total blood volume, the machine will be primed with irradiated packed red blood cells (PRBC). 
 
5.2.5 Peripheral HPC Processing: 
 
Peripheral HPCs should be processed, frozen and stored in a Hematopoietic Cell Cryopreservation 
Laboratory per using standard institutional procedures. 
 
5.3 Guidelines for Proceeding to Consolidation with High Dose Chemotherapy (HDC) 
 
Following recovery from the final cycle of induction chemotherapy, the patient will undergo an extent of 
disease evaluation (see section 9.1). 
 
 
• Following completion of induction chemotherapy, if there is no evidence of obvious residual tumor, 
both on imaging studies and by serum and CSF tumor markers, on extent of disease evaluation, 
patients will proceed directly to the consolidation HDC. 
 
• Following the extent of disease evaluation upon completion of induction chemotherapy, if there is 
radiographic evidence of residual tumor on extent of disease evaluation, then a “second-look” 
surgical procedure should be performed.  After second–look surgery all patients will undergo 
repeat extent of disease evaluation. Following the extent of disease evaluation and recovery from 
the surgery, all patients with CR/CRU/VGPR/PR/SD will proceed to consolidation HDC.  
 
• Following completion of induction chemotherapy, if there is radiographic evidence of residual tumor 
on extent of disease evaluation, which cannot be grossly resected, then the patient will proceed 
directly to consolidation HDC.  
 
• If there is evidence of tumor progression at any time during the induction chemotherapy or at the 
extent of disease evaluation following the completion of induction chemotherapy, either by imaging 
or tumor marker evaluation in the serum or CSF, then the patient is considered to have failed the 
protocol and will discontinue further study-prescribed treatment.   
 
 
 
 
 
 
 
 
 
 

 
Version 1.05.2017 
 
 
 
 
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5.4    Consolidation HDC Treatment Plan 
 
 
Following completion of the post-induction extent of disease and organ function evaluations, (see section 
9.1), patients will undergo consolidation HDC not later than four weeks from the end of the last induction 
cycle. The treatment is as follows: 
 
5.4.1   Days -8, -7 and –6: 
 
Carboplatin will be infused intravenously over four hours daily for three days beginning day -8.  The daily 
dose of Carboplatin will be derived from the creatinine clearance or GFR result measured prior to each 
dose of Carboplatin.  The dose is calculated using the Calvert formula.  This formula was derived to give 
the same systematic exposure (AUC) to carboplatin for patients with varying renal function.  Total body 
carboplatin clearance is the sum of the non-renal clearance plus renal clearance. 
 
For the most part, the non-renal clearance is related to body weight.  The renal clearance is directly 
proportional to the raw creatinine clearance (NOT adjusted to 1.73 m2).  The dose equals the AUC times 
total body clearance. 
 
 
Dose (mg) 
= desired AUC (mg/ml/min) x body clearance 
 
 
 
Dose (mg) 
= AUC x (renal clearance + non-renal clearance) 
 
Patients < 10 years of age: 
 
Daily dose 
= AUC x (raw creatinine clearance + (body wt. x 0.36) 
 
Patients 10 years of age or greater: 
 
Daily dose 
= AUC x (raw creatinine clearance + 25) 
 
For a dose of 500 mg/m2 with normal renal function, the desired AUC is approximately 7 mg/ml/min. 
 
Caveats: 
• The raw creatinine clearance must be used or the patient will be overdosed by a factor of 
1.73/BSA. (Up to 3.5 times 0.5m2).  Two people should check the dose and it should be compared 
to the dose calculated by BSA. 
• The dose derived from the calculation is the total dose in milligrams, not the dose per m2. 
DAY 
DRUGS 
DOSE  
ROUTE/DURATION 
D -8 to -6 
Carboplatin 
500 mg/m2 or calculated by Calvert 
formula (the smaller value of the two will 
be utilized) 
IV over 4 hours 
D -5 to -3 
Thiotepa 
300mg/m2 or 10mg/Kg (if <36 mos old) 
IV over 3 hours 
Etoposide 
250mg/m2 or 8.3mg/Kg (if < 36 mos old) 
IV over 3 hours 
D -2 to -1 
None 
None 
None 
D 0 
Autologous Hematopoietic Progenitor Cell Rescue 

 
Version 1.05.2017 
 
 
 
 
-28 - 
• Patients with supra-normal creatinine clearance will not get a higher dose than that calculated at a 
dose of 500 mg/m2 or 16.7 mg/kg for children < 3 years of age.  The dose of Carboplatin will be 
calculated using both the Calvert formula and surface area (500 mg/m2 or 16.7 mg/kg) and the 
lower of the two will be used. 
• While hyperhydration is not required with carboplatin administration, patients should be assured at 
least maintenance fluid intake, either intravenously or orally, with replacement of emesis losses, to 
avoid dehydration and possible acute renal insufficiency. 
 
5.4.2 
Days -5, -4 and –3: 
 
Thiotepa 300 mg/m² or 10 mg/kg ( if patient age <36 months) should be infused intravenously over three 
hours to start approximately 24 hours after completion of the last dose of Carboplatin and will be repeated 
daily for three days at approximately 24 hour intervals. 
 
Thiotepa diluted to <1 mg/ml is stable for 8 hrs or less depending on final concentration. Concentrations >1 
mg/ml are stable for 24 hrs at room temperature. This may be significant if a diluted thiotepa dose is made 
early in the day and not administered until late in the afternoon. 
 
Etoposide (VP-16) 250 mg/m² or 8.3 mg/kg (if patient age < 36 months)) should be infused intravenously 
over three hours in 0.9% normal saline (NS) to start immediately upon completion of the Thiotepa infusion 
each day. The duration of the etoposide may be extended in the event that hypotension develops at the 
faster infusion rate. The infusion time is rounded up to the nearest 30-minute period. The final 
concentration is not to exceed 0.6 mg/ml. If etoposide is concentrated to more than 0.5 mg/ml it is stable for 
8 hrs or less, depending on the final concentration (i.e. 0.6 mg/ml = 8 hrs, 1 mg/ml = 2 hrs stability). 
 
5.4.3    Therapy Scheme: 
 
Day -8:  Carboplatin, as calculated from AUC of 7 approx. hour 0 
Day -7:  Carboplatin, as calculated from AUC of 7 approx. hour 24 
Day -6:  Carboplatin, as calculated from AUC of 7 approx. hour 48 
                  
Day -5: Thiotepa 300mg/m² or 10 mg/Kg (if age < 36 mos) approx. hour 72 
Day -5:  Etoposide 250mg/m² or 8.3 mg/Kg (if age < 36 mos) approx. hour 75 
Day -4: Thiotepa 300mg/m² or 10mg/Kg (if age <36 mos) approx. hour 96 
 
 
Day -4: Etoposide 250mg/m² or 8.3 mg/Kg (if age < 36 mos) approx. hour 99 
 
 
Day -3: Thiotepa 300mg/m² or 10mg/Kg (if age < 36 mos) approx. hour 120 
Day -3: Etoposide 250mg/m² or 8.3 mg/Kg (if age <36 mos) approx. hour123 
Day -2: Rest 
Day -1: Rest 
Day  0: Re-infusion of peripheral HPCs approx. hour 200 
 
5.4.4   Peripheral HPC Re-infusion Day 0: 
 
Peripheral HPCs will be thawed and re-infused approximately 72 hours following completion of the last 
dose of chemotherapy. Patients should be adequately hydrated prior to the HPC re-infusion. 
 
The previously cryopreserved peripheral HPCs should be rapidly thawed in a 37oC water bath and re-

 
Version 1.05.2017 
 
 
 
 
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infused through a central venous catheter.  If the dose of dimethylsulfoxide (DMSO) exceeds 1 gm/kg/day 
then consideration should be given to infusing the peripheral HPCs in two aliquots over two days.  
             
 
5.4.5 Post-HPC Re-infusion Hematopoietic Growth Factor (G-CSF) Therapy: 
 
Beginning day +1 post-HPC reinfusion, patients should receive G-CSF at a dose of 5 mcg/kg IV or 
subcutaneously once daily until the ANC is>1,000/mm3 for three consecutive days or as per the treating 
physician’s preference.  If the ANC is not >500/mm3 by Day +21 post-HPC re-infusion, then the dose of G-
CSF should be doubled. Additional autologous HPCs, if available, may also be infused at this time. 
 
5.5 Radiation Therapy  
 
Radiation therapy can be given after the recovery from the consolidation phase in patients with intracranial 
germinoma or MMGCT. Patient with ONLY germinoma can receive radiation therapy after induction therapy 
without undergoing the consolidation phase. The volume and the field of radiation therapy will be 
determined by the treating physician.  
 

 
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6.0    SUPPORTIVE CARE GUIDELINES DURING INDUCTION  
 
6.1   Venous Access  
 
Patients should have double lumen venous catheter line to receive chemotherapy. Consideration should be 
given to placement of a tunneled pheresis catheter to use for chemotherapy administration and peripheral 
HPC collection. During leukapheresis, in the absence of an appropriate double-lumen leukapheresis-grade 
catheter in place, a percutaneously placed temporary leukapheresis-grade catheter should be placed, 
which should be removed following completion of the leukapheresis procedure. 
 
6.2   Antiemetics 
 
Appropriate antiemetics should be administered prophylactically and as needed during chemotherapy. 
Corticosteroid use as an antiemetic should be avoided, if possible. 
 
6.3 Use of Hematopoietic Growth Factor (G-CSF)  
 
Routine use of G-CSF during induction is not recommended on this protocol. However, if the patient has a 
delay for 7-14 days in beginning the next cycle due to low blood counts then G-CSF should be 
administered (for details see section 5.1.3.1). Also, G-CSF is administered during induction cycle when 
leukapheresis is planned for peripheral hematopoietic stem cell harvest (for details see section 5.2). 
Additionally, G-CSF can be administered to patients with severe life threatening infections associated with 
neutropenia, at the discretion of the treating physician.  
 
If G-CSF is administered during induction cycle, it should be noted on the study case report forms.  
 
6.4 Blood Products 
 
PRBCs should be given for symptomatic anemia or Hgb < 8 gm/dL. Platelets should be transfused for 
platelets <20,000-30,000 at any time. All blood products should be irradiated and leukoreduced. Blood 
products should be irradiated following the current Food & Drug Administration (FDA) guidelines found at: 
http://www.fda.gov/cber/gdlns/gamma.html. Investigators in Canadian institutions need to follow the 
Canadian Standards Association (CSA) standards for Blood and Blood Components CAN/CSA-Z902-04 
issued in March 2004 and available at http://www.shopcsa.ca. 
 
6.5  Febrile Neutropenia 
 
Febrile neutropenia should be managed according to the local institutional guidelines. Measures may 
include laboratory testing, blood and urine cultures, and institution of broad-spectrum antibiotics.  
 
6.6 Pneumocystis Jiroveci (Carinii) Prophylaxis 
 
Patients who receive chemotherapy should be started on trimethoprim/sulfamethoxazole (TMP/SMZ) at 
5mg/kg/day dosed 2-3x/week or per primary care institution protocol for Pneumocystis jiroveci (carinii) 
prophylaxis. TMP/SMZ administration can be ceased 4-6 months after therapy has been discontinued. 
Patients with TMP/SMZ allergy should be considered for treatment with dapsone or pentamidine 
(intravenously or inhaled). 

 
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6.7   Fungal prophylaxis 
 
Appropriate antifungal prophylaxis therapy should begin upon starting protocol chemotherapy.   
 
6.8   Nutritional Support 
 
Any patient with greater than 10% weight loss from the baseline should begin nutritional supplementation. 
Nutritional support can be provided by enteric feeding or parenteral hyperalimentation. Use of appetite 
stimulants is also recommended.  
 
6.9 Diabetes Insipidus 
 
Tumors in the suprasellar or pineal areas may present with central diabetes insipidus (DI). Alternatively, 
patients may develop DI after neurosurgical intervention.48 Central DI is defined as the inability to release 
vasopressin from the posterior pituitary in order to reabsorb free water at the renal collecting duct. DI 
manifests as, and is diagnosed by hyperosmolality (>300 mOsm/L) with simultaneous hyposthenuria (<300 
mOsm/L). Patients will exhibit polyuria and nocturia, with a 24-hour urine output above 100 mL/kg/d. Those 
with an intact thirst mechanism will increase their fluid intake to maintain a normal serum osmolality. Those 
with an absent thirst mechanism (adipsia) may present with hypernatremia and severe dehydration. 
Diagnosis can be suspected by fasting the patient overnight and obtaining both first-void morning urine for 
specific gravity and osmolality along with a simultaneous blood specimen for sodium and serum osmolality. 
Inconclusive cases may require a water deprivation test, which should be performed in a Pediatric Clinical 
Research Center.  
 
Treatment of DI requires chronic management with DDAVP, which can be administered in subcutaneous (4 
μg/ml), intranasal (10 μg/0.1 ml), and tablet (100 μg, 200 μg) forms. This is best performed in conjunction 
with a pediatric endocrinologist. 
 
During the entire treatment on this protocol, it is essential that fluid intake and output be carefully monitored 
in patients with DI. Placement of a Foley catheter is sometimes necessary for accurate measurement of 
urine output. In order to prevent renal dysfunction, a steady and increased urine output should be achieved 
by an appropriate DDAVP dosing schedule. This can be established in conjunction with a pediatric 
endocrinologist.  
  

 
Version 1.05.2017 
 
 
 
 
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7.0   SUPPORTIVE CARE GUIDELINES DURING CONSOLIDATION    
 
7.1    Post-Autologous HSC Re-infusion G-CSF Therapy 
 
For details see Section 5.4.5. 
 
7.2    Blood Product Support           
 
For details see Section 6.4. 
 
7.3    Pneumocystis jiroveci (Carini) Prophylaxis 
 
All patients should receive the fixed combination of trimethoprim (5mg/Kg/day) and sulfamethoxazole 
(25mg/Kg/day) in divided doses from day -12 to day -3, either orally (if tolerated) or intravenously as 
prophylaxis for Pneumocystis carinii pneumonia.  This should restart between day +50 and +70 when the 
platelet count is greater than 100,000/mm3 and maintained for approx. 6 months  at a dose of trimethoprim 
5 mg/Kg/day and sulfamethoxazole 25 mg/Kg/day on 2 or 3 consecutive weekdays each week.  Patients 
with a history of allergy to sulfonamides, or who’s peripheral blood counts decline with exposure to 
TMP/SMZ or whose counts have not recovered by day +50 to +70, should receive pentamidine 4 mg/Kg IV 
per dose (maximum 300 mg); several regimens for this exist: one employs 4 doses intravenously given 
within a two week period or by inhalation for 5 doses within a two week period, and then once every 2 to 4 
weeks intravenously or by inhalation, commencing on day +28.  The dose of aerosolized pentamidine is 
300 mg per dose for all patients > 5 years of age. 
 
7.4    Viral Prophylaxis  
 
Patients with clinical or serologic history of herpes simplex virus or varicella-zoster virus infections should 
receive intravenous acyclovir 250 mg/m2 IV every 8 hours, starting from Day +1 until discharge from the 
hospital.  After discharge, patients should receive oral acyclovir 250 to 400 mg/m2 orally three times daily 
until day +30. 
 
7.5    Fungal Prophylaxis 
 
 
Appropriate antifungal agents should be used throughout consolidation, such as fluconazole, clotrimazole 
troches 10 mg  three times daily or nystatin 5 mL swish and swallow 3 to 4 times daily, until mucositis 
resolves and ANC is greater than 500/mm3. 
 
7.6   Febrile Neutropenia 
 
Fever of greater than 38°C, in association with an ANC less than 500/mm3, must prompt immediate 
drawing of all appropriate cultures and initiation of broad-spectrum antibiotics.  Failure of febrile episodes to 
resolve on antibiotics should prompt consideration for institution of a broad-spectrum antifungal therapy. 
 
7.7    Nutritional Support 
 
All patients will most likely require total parenteral nutrition (TPN) during consolidation.  This should be 
initiated as soon as the patient's oral intake declines and usually concomitant with initiation of the 
cytoreductive chemotherapy and no later than day +1 following AuHPCR. As soon as the oropharyngeal 
mucositis resolves, TPN should be tapered and discontinued as rapidly as is metabolically feasible, and 

 
Version 1.05.2017 
 
 
 
 
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oral intake should be encouraged.  Any subsequent need for hyperalimentation in the post-AuHPCR period 
is optimally achieved via the enteral route, either with nasogastric or gastrostomy feeds rather than with 
TPN, since the latter is associated with a higher risk of catheter-related infections and with the development 
of subsequent hepatic dysfunction. 
 
7.8    Nephrotoxic Drugs 
 
Patients being treated on this protocol will receive nephrotoxic chemotherapeutic agents and may develop 
compromised renal function.  Therefore, it is important to bear in mind that aminoglycoside antibiotics, 
amphotericin B and certain other antibiotics are inherently nephrotoxic.  Careful monitoring of renal 
function, by noting serum blood urea nitrogen (BUN), creatinine, electrolytes, and creatinine clearance 
should be undertaken when using these agents.  Abnormal renal function requires modifications of 
antibiotic doses and dose intervals, which can be most rationally determined by monitoring peak and trough 
antibiotic levels in the blood. 
 
7.9    Corticosteroid Use 
 
Patients requiring ongoing corticosteroids (not at replacement doses), usually dexamethasone, because of 
mass effect and edema from residual tumor, must be weaned off of corticosteroids prior to initiation of 
Consolidation Phase chemotherapy.  Corticosteroids not only render patients more susceptible to sepsis 
but can also mask the early signs of symptoms of sepsis.  It is particularly important to be vigilant in 
monitoring such patients for the slightest suggestion of developing infection. These patients should have 
daily surveillance blood cultures drawn during the period of neutropenia. Corticosteroids at replacement 
doses will be allowed during the consolidation phase. Patients who have recently discontinued 
corticosteroids should be administered stress dose corticosteroids if/when readmitted with febrile 
neutropenia. 
 
    
 

 
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8.0  DRUG INFORMATION 
 
8.1 Carboplatin  (Paraplatin®, Cis-diamine (1,1-cyclobutane-dicarboxylato)-platinum)   
NSC #241240 
 
8.1.1 
Description and Mechanism of Action: 
 
The mechanism of action of carboplatin would appear to be similar to that of cisplatin. It binds to replicating 
DNA causing single strand breaks and interstrand cross-links with DNA. Data suggests that other factors 
also contribute to cytotoxicity. The α t½ is 1.1 to 2 hours and the β t½ is 2.6 to 5.9 hours. Carboplatin is not 
protein bound. The major route of elimination of carboplatin is renal excretion. Patients with creatinine 
clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine within 12 hours and 
71% of the dose within 24 hours. In patients with creatinine clearances below 60 mL/min the total body and 
renal clearances of carboplatin decrease as the creatinine clearance decreases. Carboplatin dosages will 
require adjustment dependent on the glomerular filtration rate. 
 
8.1.2    Drug storage, stability and reconstitution:  
 
Carboplatin is available in 50 mg, 150 mg, 450 mg and 600 mg vials.  
 
Aqueous Solution: Carboplatin aqueous solution is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous 
solution of carboplatin in multidose vials. Unopened vials of carboplatin aqueous solution are stable to the 
date indicated on the package when stored at 25° C (77° F); excursions permitted from 15°-30° C (59°-86° 
F). Protect from light. Carboplatin aqueous solution multidose vials maintain microbial, chemical, and 
physical stability for up to 14 days at 25º C following multiple needle entries.  
 
Powder for Injection: Carboplatin powder for injection is a sterile lyophilized white powder in single dose 
vials containing equal parts by weight of carboplatin and mannitol. Unopened vials of carboplatin are stable 
to the date indicated on the package when stored at 15°-30° C (59°-86° F). Protect from light. 
 
Reconstitute lyophilized powder to concentration of 10 mg/ml with sterile water for injection, 5% Dextrose, 
Normal Saline or use premixed 10mg/ml aqueous solution. May further dilute in dextrose or saline 
containing solutions to a final concentration as low as 0.5 mg/ml and infuse over 60 minutes. Carboplatin 
solutions, when prepared as directed are stable for 8 hours at room temperature.  May use institutional and 
clean room standards for stability.  Aluminum can react with carboplatin, causing precipitate formation and 
potency loss. Do not use needles or IV administration sets containing aluminum parts that may come in 
contact with carboplatin for the preparation or administration of the drug. 
 
8.1.3   Supplier: Commercially available from various manufacturers. See package insert for more detailed 
information. 
 
 
 
 
 
 
 

 
Version 1.05.2017 
 
 
 
 
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8.1.4 
Toxicity 
 
 
Common 
Happens to 21-100 
children out of every 
100  
 
Occasional 
Happens to 5-20 
children out of every 
100 
 
Rare 
Happens to <5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting 
 
Hypersensitivity² 
reactions 
(anaphylaxis, 
bronchospasm, 
hypotension), 
constipation, diarrhea 
Metallic taste, rash, 
mucositis 
 
Prompt: 
Within 2-3 weeks 
Myelosuppression1 
(anemia, neutropenia, 
leucopenia, 
thrombocytopenia) 
Electrolyte  
abnormalities  (↓ Na, 
K Ca Mg) 
↑LFTs (alkaline 
phosphatase, 
AST/SGOT, bilirubin), 
abdominal pain, 
nephrotoxicity (↓GFR, 
↑ Cr and Bun) 
 
Delayed: 
Any time later during 
therapy, excluding 
the above conditions 
 
ototoxicity (ringing in  
the ears and hearing 
loss) 
 
Alopecia, temporary 
loss of vision to light 
and colors, peripheral 
neuropathy (with mild 
parethesias, 
diminished sense of 
vibration, light touch, 
pinprick and joint 
position) 
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary leukemia 
 
                
               1 Thrombocytopenia is more severe and can be dose limiting. 
               2 Hypersensitivity reactions are seen more frequently with repeated courses of therapy   
 
     (after 6 cycles in adults). 
 
 
8.2     Etoposide  (VePesid®, Etopophos®,VP-16) NSC #141540 
 
8.2.1    Description and Mechanism of Action:   
 
A semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase II and DNA which 
results in single and double strand DNA breaks. Its main effect appears to be in the S and G2 phase of the 
cell cycle. The initial t½ is 1.5 hours and the mean terminal half-life is 4 to 11 hours. It is primarily excreted 
in the urine. In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. 

 
Version 1.05.2017 
 
 
 
 
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The mean renal clearance of etoposide is 7 to 10 mL/min/m² or about 35% of the total body clearance over 
a dose range of 80 to 600 mg/m². Etoposide, therefore, is cleared by both renal and non-renal processes, 
i.e., metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not 
known. Biliary excretion appears to be a minor route of etoposide elimination. Metabolism accounts for 
most of the non-renal clearance of etoposide.  
 
Etoposide phosphate is a water-soluble ester of etoposide, which is rapidly and completely converted to 
etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that etoposide phosphate is 
bioequivalent to etoposide when it is administered in molar equivalent doses. 
 
The maximum plasma concentration and area under the concentration time curve (AUC) exhibit a high 
degree of patient variability. Etoposide is highly bound to plasma proteins (~94%), primarily serum albumin. 
Pharmacodynamic studies have shown that etoposide systemic exposure is related to toxicity. Preliminary 
data suggests that systemic exposure for unbound etoposide correlates better than total (bound and 
unbound) etoposide. There is poor diffusion into the CSF < 5%.  
 
8.2.2    Drug storage, stability and reconstitution:  
 
Etoposide for injection is available in sterile multiple dose vials. The pH of the clear, nearly colorless to 
yellow liquid is 3 to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30mg benzyl alcohol, 80 mg 
modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial 
headspace contains nitrogen. Unopened vials of Etoposide are stable until expiration date on package at 
room temperature (25°C). Etoposide phosphate for injection is available for intravenous infusion as a sterile 
lyophilized powder in single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 
32.7 mg sodium citrate USP, and 300 mg dextran 40. Etoposide phosphate must be stored under 
refrigeration 2°-8°C (36°- 46°F). Unopened vials of etoposide phosphate are stable until the expiration date 
on the package.  
 
Reconstitute with NS or D5W to achieve a final concentration of 0.2 - 0.4 mg/ml. If solutions are prepared 
with concentrations above 0.4-mg/ml precipitations may occur. 
 
Stability is based on dilution. Vials diluted with NS or D5W as recommended (concentration of 0.2 and 0.4 
mg/ml) are stable for 48 hours. Discard if precipitate is noted. 
 
8.2.3    Supplier:  
 
Commercially available. See package insert for more detailed information. 
 

 
Version 1.05.2017 
 
 
 
 
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8.2.4   Toxicity 
 
 
Common 
Happens to 21-100 
children out of 
every 100  
 
Occasional 
Happens to 5-20 
children out of every 
100 
 
Rare 
Happens to <5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting 
 
Anorexia, hypotension 
during 
infusion 
 
Transient hypotension during 
infusion; anaphylaxis (chills, 
fever, tachycardia, dyspnea, 
bronchospasm, hypotension) 
Prompt: 
Within 2-3 weeks 
Myelosuppression 
(anemia, 
leukopenia), 
alopecia 
Thrombocytopenia, 
diarrhea, abdominal 
pain, asthenia, 
malaise, rashes and 
urticaria 
 
Peripheral neuropathy, mucositis, 
hepatotoxicity, chest pain, 
thrombophlebitis, congestive 
heart failure, Stevens-Johnson 
Syndrome, exfoliative dermatitis 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
 
 
Dystonia, ovarian failure, 
amenorrhea, anovulatory cycles, 
hypomenorrhea, onycholysis of 
nails 
Late: 
Any time after 
completion of treatment 
 
 
Secondary malignancy 
(preleukemic or leukemic 
syndromes) 
Unknown frequency 
and timing 
Fetal toxicities and teratogenic effects of etoposide have been noted in animals. 
 

 
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8.3    Gemcitabine   (Gemzar®, NSC# 613327) 
 
8.3.1 Description and Mechanism of Action:  
 
Gemcitabine (2’-deoxy-2’,2’-difluorocytidine monohydrochloride), an analog of cytosine arabinoside (Ara-C) 
is a novel pyrimidine anti-metabolite. The mechanism of action of gemcitabine has been well characterized. 
It can be deaminated to difluorodeoxycytidine deaminase or converted to dFdCMP by deoxycytidine kinase. 
Difluorodeoxyuridine is inactive, while dFdCMP is further metabolized to dFdCDP and dFdCTP, which, 
when incorporated into DNA, results in chain termination. In comparison to Ara-C incorporation into DNA, 
dFdCTP is less readily excised from DNA by DNA exonuclease. Thus, dFdCTP accumulates intracellularly 
to a greater degree than Ara-C. This may account, in part, for its different spectrum of preclinical and 
clinical activities. In addition, gemcitabine inhibits ribonucleotide reductase, an enzyme that produces 
deoxynucleotides that are required for DNA synthesis. Gemcitabine activity has been demonstrated in 
breast, ovarian, bladder, esophageal, and lung carcinoma. 
 
8.3.2    Drug storage, stability and reconstitution: 
 
Gemcitabine is supplied as a lyophilized powder in sterile vials containing 200mg or 1.0gm of gemcitabine 
as the hydrochloride salt (expressed as the free base), mannitol, and sodium acetate. The lyophilized 
product should be stored below 30 degree C. No degradation of the drug product in the dry state (vials) has 
been observed after six months at 40 degrees C with 75% relative humidity or after three years at room 
temperature.  
 
To reconstitute, add 5ml of 0.9% sodium chloride to the 200mg vial or 25ml of 0.9% sodium chloride to the 
1.0gram vial. These dilutions each yield a gemcitabine concentration of 38 mg/ml. An appropriate amount 
of drug will be prepared with normal saline and administered as a continuous infusion for 30 minutes. Once 
the drug has been reconstituted, it should be stored at room temperature and used within 24 hours. Do not 
refrigerate solutions of reconstituted gemcitabine as crystallization may occur. Store at room temperature 
20-25 degree C (68-77 degrees F). 
 
Normal saline is the only diluent approved for intravenous administration. Do not use other diluents. It 
should be noted that the pH of the undiluted solution is around 3. There may be some local irritation due to 
the low pH (pain at the injection site). Gemcitabine is not a vesicant; extravasation should be handled 
according to local hospital policy concerning extravasation of drugs. 
 
Supplier: Commercially available. See package insert for more detailed information. 
 
 
 
 
 
 
 
 
 
 
 

 
Version 1.05.2017 
 
 
 
 
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8.3.4    Toxicity: 
 
Common 
Happens to 21-100 
children out of every 
100 
 
Occasional 
Happens to 5-20 
children out of every 
100 
 
Rare 
Happens to <5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, 
fever, phlebitis, 
edema, flu-like 
symptoms, rash (L), 
mild diarrhea or 
constipation 
Somnolence (L), 
dyspnea 
Hypotension, hemolytic 
uremic syndrome 
Prompt: 
Within 2-3 weeks 
Myelosuppression, 
liver function 
abnormalities, 
proteinuria, hematuria 
Mucositis, weakness 
(L) 
Renal dysfunction, confusion, 
seizure (L), coma (L), 
pulmonary edema-
noncardiogenic, possibly fatal 
Delayed: 
Any time later during 
therapy, excluding 
the above conditions 
 
Alopecia, 
paresthesias, itching 
 
Late: 
Any time after 
completion of 
treatment 
 
 
 
(L) Toxicity may also occur later 
 
8.4    Granulocyte Colony Stimulating Growth Factor (r-metHuG-CSF, G-CSF, Filgrastim, Neupogen®) 
NSC #614629 
 
8.4.1 
Description and Mechanism of Action:  
 
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by recombinant DNA 
technology. Filgrastim is a 175 amino acid protein with a molecular weight of 18,800 daltons manufactured 
by recombinant DNA technology utilizing E coli bacteria into which has been inserted the human 
granulocyte colony stimulating factor gene. It differs from the natural protein in that the N- amino acid is 
methionine and the protein is not glycosylated.  
 
G-CSF is a lineage specific colony-stimulating factor, which regulates the production of neutrophils within 
the bone marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-cell 
functional activation (including enhanced phagocytic ability, priming of the cellular metabolism associated 
with respiratory burst, antibody dependent killing, and the increased expression of some functions 
associated with cell surface antigens). 
 
The elimination half-life is similar for subcutaneous and intravenous administration, approximately 3.5 
hours. The time to peak concentration when administered subcutaneously is 2 to 8 hours. 
  

 
Version 1.05.2017 
 
 
 
 
-40 - 
8.4.2 
Drug Storage, Stability and Reconstitution:  
 
Supplied as a clear solution in 300 mcg/ml 1 ml or 1.6 ml vials and prefilled syringes containing 300 
mcg/0.5mL or 480 mcg/0.8mL. Vials are preservative free single use vials. Discard unused portions of open 
vials. Store refrigerated at 2-8º C (36-46ºF). Prior to injection, filgrastim may be allowed to reach room 
temperature for a maximum of 24 hours. Avoid freezing and temperatures > 30ºC. 
 
For IV use, dilute in D5W only to concentrations >15 mcg/ml. At concentrations between 5 and 15 mcg/ml, 
human serum albumin should be added to make a final albumin concentration of 0.2% (2 mg/ml) in order to 
minimize the adsorption of filgrastim to infusion containers and equipment. Dilutions of 5 mcg/ml or less are 
not recommended. Diluted filgrastim should be stored at 2-8º C (36-46ºF) and used within 24 hours. Do not 
shake. 
 
8.4.3 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
8.4.4    Toxicity: 
 
 
Common 
Happens to 21-100 
children out of every 
100  
 
Occasional 
Happens to 5-20 
children out of every 
100 
 
Rare 
Happens to <5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
 
Local irritation at the 
injection site, 
headache 
 
Allergic reactions  
 
Prompt: 
Within 2-3 weeks 
Mild to moderate 
medullary bone pain, 
 
Increased alkaline 
phosphatase, lactate 
dehydrogenase and 
uric acid, 
thrombocytopenia 
 
Splenomegaly,  
exacerbation of pre-existing 
skin rashes, 
sickle cell crises in patients 
with SCD, 
excessive leukocytosis 
 
 
Delayed: 
Any time later during 
therapy, excluding 
the above conditions 
 
 
Cutaneous vasculitis, ARDS 
 
Late: 
Any time after 
completion of 
treatment 
 
 
 
 
 
 

 
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8.5    Oxaliplatin (Eloxatin®, SR9669) NSC # 266046, IND # 57004 
 
8.5.1 
Description and Mechanism of Action:   
 
Oxaliplatin is a third generation platinum agent characterized by a DACH (1,2 diaminocyclohexane) ligand. 
Once infused, oxaliplatin undergoes biotransformation into active metabolites. The oxalate ligand in the 
parent compound is replaced by either Cl- or HCO3 - ions to yield dichloro-DACH platin, monochloro-DACH 
platin, and diaquo-DACH platin. Studies on the mechanism of action of oxaliplatin, although not completely 
elucidated, show that the aqua-derivatives resulting from the biotransformation of oxaliplatin interact with 
DNA to form both inter- and intra-strand cross links, resulting in the disruption of DNA synthesis leading to 
cytotoxic and antitumor effects. Oxaliplatin does not undergo cytochrome-P450 metabolism in the liver. 
Renal clearance accounts for approximately 50% of total oxaliplatin clearance. Pharmacokinetic data in 
children is pending. In adults the approximate half-lives are: t½α = 0.28 hrs, t½β = 16.3 hrs, t½γ = 273 hrs. 
 
8.5.2   Drug storage, stability and reconstitution:  
 
Supplied as freeze-dried powder for intravenous infusion in vials containing 50 mg or 100 mg of oxaliplatin. 
The powder is a white to off-white cake or powder contained in clear glass vials, sealed with an elastomeric 
stopper and aluminum seal with a flip-off cover. The excipient is lactose monohydrate, 450mg and 900mg, 
respectively. Store the intact vials at controlled room temperature (150 - 300 C, not to exceed 300 C).  
 
The freeze-dried powder is stable for 3 years at room temperature and protected from light in the original 
cartons. The freeze-dried powder is reconstituted by adding 10 mL (for the 50 mg vials) or 20 mL (for the 
100 mg vials) of Water for Injection or Dextrose 5% in Water to yield a 5 mg/mL solution. This mixture in the 
original vial is stable for 48 hours under refrigeration (2-8ºC). For administration, the 5 mg/mL reconstituted 
solution must be further diluted with Dextrose 5% in water to a final volume between 250 mL to 500 mL. 
This preparation is stable for 24 hours under refrigeration (2-8ºC) or for 6 hours at room temperature (20-
25ºC). Oxaliplatin concentration of the final dilution should not be less than 0.2 mg/mL. For smaller patients 
in whom volume may be of concern, a final concentration of 0.3-to 0.6 mg/ml oxaliplatin is acceptable. 
However, the dose needs to be mixed immediately prior to administration to ensure stability of oxaliplatin at 
this concentration range. Once the appropriate dose of oxaliplatin is calculated, the drug will be diluted with 
Dextrose 5% in water to a total volume between 250 mL to 500 mL. The infusion should be administered 
over 2 hours.  
 
Oxaliplatin should never be reconstituted or diluted with a sodium chloride solution. Never use 
aluminum-containing needles or intravenous infusion sets to prepare or administer oxaliplatin. 
Never mix oxaliplatin with alkaline drugs, as it is unstable in alkaline conditions. 
 
8.5.3 
Supplier: Commercially available. See package insert for more detailed information. 
 
 
 
 
 
 
 
 
 
 

 
Version 1.05.2017 
 
 
 
 
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8.5.4 
Toxicity : 
 
 
(L) Toxicity may also occur later. 
 
 
 
Common 
Happens to 21-100 
children out of every 
100 
 
Occasional 
Happens to 5-20 
children out of every 
100 
 
Rare 
Happens to <5 children out of every 
100 
 
Immediate: 
Within 1-2 
days of 
receiving 
drug 
 
Headache, rhinitis, 
dyspepsia, taste 
perversion, dizziness, 
hand-foot syndrome, 
flushing, 
rash, insomnia, 
anorexia, 
hypersensitivity, rigors, 
hematuria, dysuria, 
phlebitis 
 
Hiccup, flatulence, dysphasia, 
dyspnea, cough, dehydration, 
tachycardia, drug fever, ataxia, 
pharyngolaryngeal dysesthesia with 
subjective sensations of dysphagia or 
dyspnea with/without laryngospasm or 
bronchospasm, extravasation (rare), 
anaphylaxis, hypertension, chest pain 
   
Prompt: 
Within 2-3 
weeks, 
prior to the 
next course 
 
Nose bleed, weight 
loss, 
mucositis/stomatitis, 
esophagitis, alopecia, 
peripheral edema, 
arthralgia, upper 
respiratory infection, 
pharyngitis, elevated 
serum creatinine, 
hypokalemia 
  
Fatigue, neutropenia, 
thrombocytopenia, anemia, 
infection, transient increase in 
liver function tests, thromboembolism, 
DIC, visual abnormalities exacerbated 
by cold temperatures, elevated AST, 
ALT, Alkaline phosphatase, bilirubin, 
noninfectious otitis, enteritis, ileus and 
GI obstruction, hypocalcemia, 
hypomagnesemia, hyponatremia, 
elevated uric 
acid and acidosis, depression, 
bone pain, urinary retention, 
ocular surface disease, 
extrapyramidal movements, 
pancreatitis 
 
Delayed: 
Any time 
later during 
therapy, 
excluding 
the above 
conditions 
Persistent 
paresthesias of 
mouth/throat and 
extremities 
(may be exacerbated 
by cold 
temperatures) 
 
 
Pulmonary fibrosis, venooclusive 
disease in 
combination regimens 
(hepatomegaly, splenomegaly, 
portal hypertension, 
esophageal varices), renal 
failure, ototoxicity 

 
Version 1.05.2017 
 
 
 
 
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8.6    Paclitaxel (Taxol®, NSC # 125973) 
 
8.6.1 
Description and Mechanism of Action:  
 
Paclitaxel is a diterpene plant product derived via a semi-synthetic process from the bark of the Western 
Yew, Taxus brevifolia. Paclitaxel is an anti-microtubule agent that promotes the assembly of microtubules 
from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the 
inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital 
interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of 
microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.  
 
Paclitaxel is metabolized via the cytochrome P450 isoenzyme CYP2C8 to one major metabolite (6-alpha-
hydroxypaclitaxel), and via the cytochrome P450 isoenzyme CYP3A4 to two minor metabolites (3-para-
hydroxypaclitaxel and 6-alpha, 3"-para-dihydroxypaclitaxel). The terminal half-life ranged from 5.3 to 17.4 
hours, following 1-hour and 6-hour infusions at doses of 15 to 275 mg per square meter of body surface 
area. The elimination of paclitaxel is not completely understood. The mean values for urinary recovery of 
unchanged drug following 1-, 6-, and 24-hour infusions at doses of 15 to 275 mg per square meter of body 
surface area ranged from 1.3% to 12.6% of the dose, indicating extensive nonrenal clearance. High 
concentrations of paclitaxel and its metabolites have been reported in the bile and recovery of paclitaxel in 
the feces accounted for 5% of an administered dose. Total recovery of paclitaxel and metabolites in the 
feces accounted for 56% to 101% of an administered dose. In vitro studies of binding to human serum 
proteins, using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicate that between 89%-98% of 
drug is protein bound. Dosage reduction may be required in hepatic dysfunction. Caution should be 
exercised when administering paclitaxel concomitantly with known substrates or inhibitors of the 
cytochrome P450 isoenzymes CYP2C8 and CYP3A4. 
 
8.6.2 
Drug storage, stability and reconstitution:  
 
Paclitaxel is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose vials. Each mL of 
sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of purified Cremophor® EL* 
(polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. Unopened vials of paclitaxel 
injection are stable until the date indicated on the package when stored between 20°-25° C (68°-77°F), in 
the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon 
refrigeration components in the paclitaxel vial may precipitate, but redisolves upon reaching room 
temperature with little or no agitation. There is no impact on product quality under these circumstances. If 
the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded.                                                
 
Dilute in dextrose or saline solutions to a final concentration between 0.3-1.2 mg/ml (use standard dilution 
volumes of 50, 100, 250, 500, 1000 ml) and infuse over 3 hours using non-PVC containers and 
administration equipment. An inline 0.22 micron filter should be used during administration. The solutions 
are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25°C) and 
room lighting conditions. 
 
Premedicate patients with a corticosteroid, diphenhydramine, and an H2-receptor antagonist 30 minutes 
prior to paclitaxel administration. The paclitaxel is given over a 3-hour infusion. The paclitaxel is diluted to a 
concentration of 1.0 mg/ml in D5W, and should incorporate in-line filtration. The rate of infusion over the 
first 30 minutes will be 25% of the overall infusion rate. 

 
Version 1.05.2017 
 
 
 
 
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8.6.3 
Supplier: Commercially available from various sources. See package insert for more detailed 
information. 
 
8.6.4 
Toxicity 
 
 
Common 
Happens to 21-100 
children out of every 
100  
 
Occasional 
Happens to 5-20 
children out of every 
100 
 
Rare 
Happens to <5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Abnormal ECG, 
asthenia, myalgia, 
arthralgia, nausea, 
flushing, anorexia 
 Diarrhea, vomiting, 
dyspnea, peripheral 
edema, cough, rash, 
hypotension 
Anaphylaxis with dyspnea, 
hypotension, flushing, chest 
pain, and tachycardia, 
angioedema, urticaria, 
hypertension, chills, back 
pain, venous thrombosis, 
chest pain, arrhythmias 
(bradycardia, V tach, 
bigeminy, SVT, atrial fib, AV 
block), MI, injection site 
reaction (erythema, 
tenderness, skin 
discoloration, or swelling at 
the injection site, rarely: 
phlebitis, cellulitis, induration, 
skin exfoliation, necrosis, and 
fibrosis) (L) 
Prompt: 
Within 2-3 weeks 
Alopecia, neutropenia, 
anemia, sensory 
neuropathy, elevated 
SGOT (AST), alkaline 
phosphatase, 
mucositis 
Infections, elevated 
bilirubin, 
thrombocytopenia 
Febrile neutropenia, 
hemorrhage, grand mal 
seizures, syncope, ataxia, 
neuroencephalopathy, 
paralytic ileus, maculopapular 
rash, pruritis, Stevens-
Johnson syndrome, toxic 
epidermal 
necrolysis, conjunctivitis and 
increased lacrimation 
Delayed: 
Any time later during 
therapy, excluding 
the above conditions 
 
 
CHF, interstitial pneumonia, 
lung fibrosis, pulmonary 
embolism, optic nerve and/or 
visual disturbances, ototoxicity 
(hearing loss and tinnitus), 
hepatic necrosis, hepatic 
encephalopathy, nail changes 
(changes in pigmentation or 
discoloration of nail bed) 

 
Version 1.05.2017 
 
 
 
 
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Late: 
Any time after 
completion of 
treatment 
 
 
 
(L) Toxicity may also occur later 
 
8.7  Thiotepa (Tespa, Thiophosphamide, Triethylenethiophosphoramide Tspa, WR-45312) 
 
8.7.1   Description and Mechanism of Action:   
Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and pharmacologically to 
nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of 
ethylenimine radicals, which, like irradiation, disrupt the bonds of DNA. One of the principal bond 
disruptions is initiated by alkylation of guanine at the N-7 position, which severs the linkage between the 
purine base and the sugar and liberates alkylated guanines. Thiotepa is desulfurated by cytochrome P-450 
enzymes such as 2B1 and 2C11, which catalyze the conversion of thiotepa to tepa. Tepa is less toxic than 
thiotepa and has been demonstrated to produce alkali-labile sites in DNA, rather than cross-links. These 
findings indicate that tepa reacts differently from thiotepa and produces monofunctional alkylation of DNA. 
A second metabolite of thiotepa, a mercapturic acid conjugate, is formed via glutathione conjugation. 
Monochloro tepa is the third metabolite found in the urine. Following short intravenous infusion (less than 5 
minutes), peak concentrations of thiotepa were measured within 5 minutes. At steady state, the volume of 
distribution was independent of dose and ranged from 0.3 to 1.6 liters per kilogram (l/kg). Approximately 
4.2% of the original dose is eliminated in the urine within 24 hours as tepa. The elimination half-life of 
thiotepa ranges from 2.3 to 2.4 hours. The half-life of tepa ranged from 3.0 to 21.1 hours in one study. 
 
8.7.2 
Drug storage, stability and reconstitution:  
 
Thiotepa for Injection USP, for single use only, is available in vials containing 15 mg of nonpyrogenic, 
sterile lyophilized powder. Store in a refrigerator at 2° to 8°C (36° to 46°F). PROTECT FROM LIGHT AT 
ALL TIMES. 
 
Guidelines for Administration: Reconstitute thiotepa for injection with 1.5 mL of Sterile Water for Injection 
resulting in a drug concentration of approximately 10 mg/mL. (As per manufacturer’s information: Actual 
content per vial 15.6mg; withdrawable amount 14.7mg/1.4ml; approximate reconstituted concentration: 
10.4mg/ml). When reconstituted with Sterile Water for Injection, solutions of thiotepa should be stored at 
refrigerated temperatures 2° to 8°C (36° to 46°F) and used within 8 hours. The reconstituted solution is 
hypotonic and should be further diluted with Sodium Chloride Injection (0.9% NaCl) prior to use. 
Reconstituted solutions further diluted with Sodium Chloride Injection should be used immediately. In order 
to eliminate haze, filter solutions through a 0.22 micron filter [Polysulfone membrane (Gelman’s Sterile 
Aerodisc®, Single Use) or triton-free mixed ester of cellulose/PVC (Millipore’s MILLEX®- GSFilter Unit)] 
prior to administration. Filtering does not alter solution potency. Reconstituted solutions should be clear. 
Solutions that remain opaque or precipitate after filtration should not be used. When thiotepa is given in 
bone marrow transplant doses, bathe the patient frequently (≥ 2 baths/day) to avoid the contact dermatitis 
and discoloration of the skin that is seen with high dose. 
 
8.7.3    Supplier: Commercially available from various manufacturers. See package insert for further 
information. 

 
Version 1.05.2017 
 
 
 
 
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8.7.4 
Toxicity 
 
 
Common 
Happens to 21-100 
children out of every 100  
 
Occasional 
Happens to 5-20 children 
out of every 100 
 
Rare 
Happens to <5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, 
anorexia, fatigue, 
Weakness 
 
Pain at the injection site, 
Dizziness, headache, 
blurred vision, abdominal 
pain, Contact dermatitis, 
rash 
Anaphylaxis, laryngeal 
edema, wheezing, hives 
 
Prompt: 
Within 2-3 weeks 
Myelosuppression; At 
higher doses in 
conditioning regimens for 
BMT: mucositis, 
esophagitis 
 
At higher doses in 
Conditioning regimens for 
BMT: inappropriate 
behavior, confusion, 
somnolence,  increased liver 
transaminases, increased 
bilirubin, hyperpigmentation 
of the skin  
Febrile reaction, 
Conjunctivitis, dysuria, 
urinary retention 
 
Delayed: 
Any time later 
during therapy, 
excluding the 
above conditions 
gonadal 
dysfunction/infertility, 
azoospermia, amenorrhea 
 
 
Alopecia, Secondary 
Malignancy 
 
Unknown 
Frequency 
and Timing: 
Fetal and teratogenic toxicities: Carcinogenic and teratogenic effects of thiotepa have 
been noted in animal models at doses ≤ to those used in humans. It is not known if 
thiotepa is excreted into human breast milk. 
(L) Toxicity may also occur later 
 

 
Version 1.05.2017 
 
 
 
 
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9.0 
REQUIRED OBSERVATIONS 
 
9.1 
Required Observations Before and During Protocol Therapy  
 
Studies 
Baseline 
Prior to 
each cycle 
of 
induction 
End of 
induction 
Prior to 
second look 
surgery 
Following 
second look 
surgery 
Prior to 
starting 
consolidation 
During 
consolidation 
End of 
therapy** 
(Day +42) 
 
Height, weight and 
BSA 
X 
X 
X 
X 
X 
X 
X 
X 
Cranial MRI with 
and without 
gadolinium 
X2 
 
X4 
X 
X2 
X 
 
X 
Spine MRI with 
and without 
gadolinium   
X3 
 
X4 
X 
X3 
X 
 
X 
Lumbar CSF 
cytology and 
tumor markers 
(AFP and HCGβ) 
and MiRNA10 
X 
 
X4 
 
X 
X 
 
X 
Serum tumor 
markers9(AFP and 
HCGβ 
X 
X1 
X4 
X 
X 
X 
 
X 
Serum creatinine, 
BUN, Calcium, 
Phosphate, 
Magnésium, 
Potassium, 
Sodium, Glucose 
X 
X 
X 
X 
 
X 
X5 
X 
AST, ALT, Total 
bilirubin 
X 
X 
X 
 
 
X 
X5 
X 
Other Labs8 
 
 
 
 
 
X 
 
 
 
CBC, differential, 
platelet count 
X 
X1 
X 
X 
 
X 
X5 
X 
Creatinine 
clearance or 
nuclear GFR scan 
 
 
 
 
 
X 
X6 
 
Endocrine 
evaluation7 
X 
 
 
 
X 
 
 
X 
Ophthalmology 
evaluation 
X 
 
 
 
 
 
 
 
Pregnancy test (if 
applicable) 
X 
 
 
 
 
 
 
 
Audiometry 
X 
 
 
 
 
X 
 
X 
Central Pathology 
review  (for details 
see section 14.8.1 
and 14.9) 
X 
 
 
 
X 
 
 
 
1=  Obtain weekly. 
2=  All brain post-operative imaging should be done within 72 hours of surgery. If imaging cannot be obtained at this time, then it 
should be done after 10 days but within 21 days following surgery. 
3=  Either performed pre-operatively or at least 10 days after surgery and preferably performed in two planes. 
4=  Obtain after second and fourth induction course  
5=  Obtain  twice weekly until engraftment. 
6=  Obtain prior to each dose of carboplatin to calculate the Calvert formula. 
7=  Endocrine evaluations for each patient in therapy consist of free T4, TSH, IGF1, IGFBP3, LH (in males, over age10, or in 
females, over age 9), FSH (in males, over age 10, or in females over age 9), Testosterone (in males over age 10), estradiol 
(in females, over age 9), Tanner stage, cortisol 8AM, Na, K, Cl, CO2, BUN, Cr, first morning void specific gravity. If any 
endocrine parameter is abnormal, then referral to a pediatric endocrinologist for further evaluation, dynamic testing, and 
treatment is required. 

 
Version 1.05.2017 
 
 
 
 
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8=  Antibody titers to: cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), human 
immunodeficiency virus (HIV), hepatitis A, B and C viruses.  Also, hepatitis B surface antigen should be tested. 
9=  Serum markers should be obtained around the same time when CSF markers are obtained. If serum markers are obtained 
prior to CSF analysis, then serum markers should be repeated at the time of CSF marker analysis.  
10= MiRNA optional research study 
**=  If Radiation therapy is given following consolidation then end of therapy will be calculated from the completion of the 
radiation therapy.  
 
9.2      Required Observations Following Completion of Protocol Therapy  
 
Studies 
3 
months 
6 
months 
9 
months 
12 
months 
16 
months 
20 
month
s 
24 
months 
30 
months 
36 
months 
 
Annually 
after 3 
years 
 
Height, weight  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cranial MRI with and 
without gadolinium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spine MRI with and without 
gadolinium3   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum tumor markers and 
MiRNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum creatinine, BUN, Ca, 
Magnésium, Potassium, 
Sodium 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
AST, ALT, Total bilirubin 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X X1 
CBC, differential, platelet 
count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Endocrine evaluation2 
 
X 
 
X 
 
 
X 
 
X 
X 
1=   Repeat if abnormal on a monthly basis until stable or normalized after the end of therapy. If normal at the end of therapy 
then repeat only as clinically indicated. 
2=   Endocrine evaluations for each patient in therapy consist of free T4, TSH, IGF1, IGFBP3, LH (in males, over age 10, or in 
females, over age 9), FSH (in males, over age 10, or in females over age 9), Testosterone (in males over age 10), estradiol 
(in females, over age 9), Tanner stage, cortisol 8AM, Na, K, Cl, CO2, BUN, Cr, first morning void specific gravity. If any 
endocrine parameter is abnormal, then referral to a pediatric endocrinologist for further evaluation, dynamic testing, and 
treatment is required. 
3=   If the on-study evaluation is negative, then MRI spine do not need to be repeated thereafter, unless the patient 
demonstrates  radiographic or tumor marker evidence of disease recurrence or progression.  

 
Version 1.05.2017 
 
 
 
 
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10.0   CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY  
 
AND OFF STUDY CRITERIA 
 
10.1   Criteria for Removal from Protocol Therapy 
 
a)  
Progressive disease. 
b)  
Failure to fulfill criteria to proceed to Consolidation (see Section 5.3). 
c)  
Refusal of further protocol therapy by patient/parent/guardian. 
d)  
Completion of protocol therapy. 
e)  
Physician determines it is in patient’s best interest. 
f)  
Grade 4 paclitaxel hypersensitivity toxicity. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for off study (see below). 
Follow-up data will be required unless consent was withdrawn. 
 
10.2  
Off Study Criteria 
 
a)  
Death. 
b)  
Lost to follow-up. 
c)  
Entry into another therapeutic study. 
d)  
Withdrawal of consent for any further data submission. 
e)  
Tenth anniversary of study closure to accrual. 
 

 
Version 1.05.2017 
 
 
 
 
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11.0    STAGING AND EVALUATION CRITERIA 
 
11.1 
Staging and Pre-Treatment Evaluation 
 
11.1.1   Definitions of M (Metastatic) Strata 
  
There are 3 staging stratum: M+, modified M+ and M0. 
 
1.   M+ (disseminated disease):  
• Leptomeningeal or intraventricular metastases visualized on MRI scans of the brain and spine. 
• Clumps of tumor cells on lumbar CSF cytology. 
• Visible tumor studding the walls of the lateral or third ventricles noted during endoscopy or surgery. 
• Primary tumor arising within the parenchyma of the brain, brainstem or spinal cord. 
• Measurable multi-focal tumors arising in both the pineal and suprasellar regions (multiple midline 
tumors). 
• Infiltrative, intra-axial extension on brain MRI > 1 cm beyond enhancing tumor. 
 
2.  Modified M+ (occult multi-focal disease): 
• M0 at diagnosis with a localized pineal region tumor with signs and symptoms of diabetes insipidus 
without measurable disease in the suprasellar region. 
• M0 at diagnosis (either pineal or suprasellar primary), and there is ≥ 65 % volumetric or ≥ 50% 
area reduction from baseline of the presumed uninvolved suprasellar or pineal region site on MRI 
after the completion of chemotherapy (see Section 11.3). 
 
3.   M0 (localized disease): 
 
• None of the above. 
 
11.1.2    Definition of the Primary Tumor Site 
 
Four categories of primary site are recognized: 
• Pineal region 
• Suprasellar region 
• Both pineal and suprasellar regions 
• Other 
 
It may be difficult to determine the primary site in some patients who present with widespread metastases. 
The suggestible upper normal limit of size for the pineal gland is a maximum diameter of 10 mm in one 
dimension and up to 8 mm in the remaining dimensions with a total volume less than 140 mm3. The 
maximal diameter of the infundibulum is 2-3 mm in any single plane. 
 
11.1.3    Assessment of Tumor Markers 
 
The serum markers may be obtained prior to surgery but should be repeated at the time of CSF analysis. 
Lumbar ± ventricular CSF tumor markers may be obtained at the time of surgery or 1-2 weeks after 
surgery. Results of the CSF markers may take 5-7 days. 

 
Version 1.05.2017 
 
 
 
 
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11.1.4 Other Staging Considerations 
 
• Parts of the staging evaluation can be performed before or within 2 weeks following surgery. The 
brain and spine enhanced MRI may be obtained prior to surgery. If the spine MRI is performed 
prior to surgery, than only the brain MRI need be repeated post-op. This should be performed 
within 72 hours of surgery. It is desirable to perform the lumbar puncture either during surgery or 
within the first or second week following surgery, assuming any raised intracranial pressure has 
been controlled with a third ventriculostomy or ventriculo-peritoneal shunt. 
• Although radical resection of the primary CNS germ cell tumor is not recommended, the patient is 
still eligible for this protocol if the tumor is totally resected and there is no other evaluable disease. 
• Although this study is eager to accumulate CSF data from ventricular fluid obtained at the time of 
surgery, only the results of a lumbar CSF analysis will be used for the determination of protocol 
eligibility and staging. There may be the unusual circumstance when the neurosurgeon advises 
against a post-op lumbar puncture. 
 
11.2     Methodology to Determine Tumor Measurement 
 
11.2.1   Response Determination using 3-D Measurements 
 
Three rather than 2-dimensional tumor measurements are preferred for all target lesions. Tumor response 
criteria are determined by changes in all 3 dimensional measurements: width (W), transverse (T), and 
length (L) measurements. 
 
Reports for the follow-up exams should reiterate the measurements obtained at baseline for each target 
lesion. Non-target lesions or newly occurring lesions should also be enumerated in these reports and 
changes in non-target lesions should be described. 
 
3-D measurements can be made using either T1 or T2 weighted images (which ever gives the best 
estimate of tumor size). The longest diameter (W) can be measured in the imaging plane (i.e. axial, coronal 
or sagittal) in which the tumor is best measured, provided the same plane is used in follow up studies. The 
transverse (T) measurement is perpendicular to the width in the selected plane, and the entire length (L) is 
the tumor extent in the plane perpendicular to the selected plane. This latter measurement may be easily 
calculated on the MRI scan by summing the slice position (SP) or table position (TP) of all the images in 
which the tumor is visible and then adding one additional gap thickness. (See drawing below for 
illustration). 
 
 
 
 
 
 
 
 
 
 

 
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GUIDELINES: TUMOR SIZE MEASUREMENT BASED ON CROSS-SECTIONAL IMAGING 
 
• A, B, C, D, & E are contiguous parallel slices 
in the X-Y plane (usually axial) showing the 
tumor  
• W and T are the maximal perpendicular 
diameters on the slice (C in this example) 
showing the largest surface area. 
• Tumor length in the Z-axis (L) (perpendicular 
to X-Y plane) can be obtained either by the [a] 
(difference in table position of the first and last 
slices showing the tumor + one slice 
thickness), or [b] the product of (slice 
thickness + gap) and the number of slices 
showing the tumor. 
 
Only the solid component of cystic/necrotic tumor should be measured. If cysts/necrosis composes the 
majority of the lesion, the lesion may not be “measurable”.  
Leptomeningeal tumor spread is not a target lesion and cannot be measured in a quantitative fashion. 
 
Presence and location of leptomeningeal tumor spread should be noted as well as changes in 
extent/thickness assessed on follow up studies. 
 
11.2.2    Overall Response Assessment 
 
The overall response assessment takes into account response in both target and non-target lesion, and the 
appearance of new lesions, and normalization of markers, where applicable, according to the criteria 
described in the table below. The overall response assessment is shown in the last column, and depends 
on the assessments of target, non-target, marker, and new lesions in the preceding columns. 
 

 
Version 1.05.2017 
 
 
 
 
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Target Lesions Non-Target 
Lesions 
New Lesions Markers 
Normal/Abnormal/Rising 
Overall 
Response 
CR 
CRU 
CR or CRU 
CR or CRU 
PR 
CR or PR 
SD 
Any 
SD 
PD 
Any 
Any 
CR 
CR or CRU 
CR 
Non-PD 
Non-PD 
Non-PD 
Non-PD 
Any 
Non-PD 
Any 
PD 
Any 
No 
No 
No 
No 
No 
No 
No 
Any 
Yes 
Any 
Any 
Yes 
Normal 
Normal 
Normal 
Normal 
Normal 
Abnormal – not rising 
Normal/Abnormal-not rising 
Abnormal-rising 
Any 
Any 
Any 
Any 
CR 
CRU 
CRU 
PR1 
PR1 
PR2 
SD 
PD 
PD 
PD 
PD 
PD 
 1= Partial Response with normal markers 
       2= Partial Response with abnormal (but not rising) markers 
 
The sections that follow discuss the selection and evaluation of each of these types of lesions. 
11.2.3 Selection of Target and Non-Target Lesions 
 
• For most CNS tumors, only one lesion/mass is present and therefore is considered a “target” for 
measurement/follow up to assess for tumor progression/response. 
• If multiple measurable lesions are present, up to 5 should be selected as “target” lesions. Target 
lesions should be selected on the basis of size and suitability for accurate repeated measurements. 
All other lesions will be followed as non-target lesions. 
• The lower size limit of the target lesion(s) should be at least twice the thickness of the slices 
showing the tumor to decrease the partial volume effect (e.g. 8 mm lesion for a 4 mm slice). 
• Any change in size of non-target lesions should be noted, though does not need to be measured. 
 
11.3     Response Criteria 
 
11.3.1    Response Criteria for Target Lesions 
 
1. Response criteria are assessed in 3 dimensions – the product of Length (L) x W (longest perpendicular 
diameter) x T (transverse length). An elliptical model volume (=0.5 L x W x T) is used. 
 
2. To assess response/progression, the ratio is calculated: 
L x W x T (current scan) 
L x W x T (reference scan) 
 
3. Development of new disease or progression in any established lesions is considered progressive 
disease, regardless of response in other lesions – e.g. when multiple lesions show opposite responses, the 
progressive disease takes precedence. 
 
 
 

 
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11.3.2.1 Response Criteria for target lesions: 
 
Complete Response (CR): Disappearance of all target lesions. 
 
Complete Response with Unconfirmed Residual (CRU): Small residual lesion, unclear if scar versus tiny 
resdidual tumor, no greater than 1cm in maximal tumor diameter excluding any area of calcification. 
 
Very Good Partial Response (VGPR): Small residual lesion, representing > 90% decrease in the sum of the 
products of the three perpendicular diameters of all target lesions (up to 5), taking as reference the initial 
baseline measurements. 
 
Partial Response (PR): ≥65% decrease in the sum of the products of the three perpendicular diameters of 
all target lesions (up to 5), taking as reference the initial baseline measurements. 
 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of the three perpendicular 
diameters of all target lesions to qualify for PR (taking as reference the initial baseline measurements), nor 
sufficient increase in a single target lesion to qualify for PD, (taking as reference the smallest disease 
measurement since the treatment started). 
 
Sufficient Response (SR): Complete response, partial response, or stable disease, without Dexamethasone 
dependency. 
 
Progressive Disease (PD): 40% or more increase in the product of perpendicular diameters of any target 
lesion, taking as reference the smallest product observed since the start of treatment, or the appearance of 
one or more new lesions. 
 
11.3.2.2 In the rare circumstance that the length of a lesion cannot be determined, then comparison of 2 
dimensional measurements, T x W (product of the longest diameter and its longest perpendicular 
diameter) can be used: 
 
Complete Response (CR): Disappearance of all target lesions. 
 
Complete Response with Unconfirmed Residual (CRU): Small residual lesion, unclear if scar versus tiny 
resdidual tumor, no greater than 1cm in maximal tumor diameter excluding any area of calcification. 
 
Very Good Partial Response (VGPR): Small residual lesion, representing > 80% decrease in the sum of the 
products of the two perpendicular diameters of all target lesions (up to 5), taking as reference the initial 
baseline measurements. 
 
Partial Response (PR): ≥50% decrease in the sum of the products of the two perpendicular diameters of all 
target lesions (up to 5), taking as reference the initial baseline measurements. 
 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of the two perpendicular 
diameters of all target lesions to qualify for PR (taking as reference the initial baseline measurements), nor 
sufficient increase in a single target lesion to qualify for PD, (taking as reference the smallest disease 
measurement since the treatment started). 
 

 
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Sufficient Response (SR): Complete response, partial response, or stable disease, without Dexamethasone 
dependency. 
Progressive Disease (PD): 25% or more increase in the product of perpendicular diameters of any target 
lesion, taking as reference the smallest product observed since the start of treatment, or the appearance of 
one or more new lesions. 
 
11.3.3   Response Criteria for Non-target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions. 
 
Partial Response/Stable Disease (PR/SD): The persistence of one or more non-target lesions. 
 
Progressive Disease (PD): The appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. 
 
11.3.3 Response criteria for tumor markers  
 
Tumor markers will be classified simply as being at normal levels or at abnormal levels. 
 

 
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12.0 
STATISTICAL CONSIDERATIONS  
          
12.1  
Design overview 
 
This is a phase II study of GemPOx treatment followed with HDC and AuHPCR for recurrent CNS GCT. 
The primary objectives of the study are first to estimate the response rate (CR/CRU/VGPR/PR) of patients 
with MMGCT that are able to proceed to HDC and AuHPCR after up to 4 courses of induction treatment for 
MMGCT patients, and second to assess the toxicities of this regimen in all CNS GCT patients. The patients 
who proceed to HDC and AuHPCR are those who achieve complete response (CR), complete response 
with unconfirmed residual (CRU), very good partial response (VGPR), or stable disease (SD), and thus 
these will be considered a sufficient response to treatment. The primary efficacy analysis will focus on 
MMGCT patients, and pure germinoma patients are included primarily for evaluation of toxicity. Less than a 
50% sufficient response rate among the MMGCT patients after up to 4 courses of induction treatment is 
regarded insufficiently efficacious to warrant further consideration for the GemPOx regimen, and a 70% 
sufficient response rate is the minimum response rate of clinical interest for this regimen. 
 
The study will be performed with a two stage design. First, 15 MMGCT patients will be enrolled and treated. 
If 8 or more patients exhibit a sufficient response after up to 4 courses of induction treatment, then 13 
additional MMGCT patients will be enrolled and treated. The treatment regimen will be considered 
sufficiently efficacious if 18 or more of the 28 MMGCT patients treated achieve a response after up to 4 
courses of induction treatment.  
 
12.2  
Endpoints  
 
The primary endpoint of the study is achievement of sufficient response that enables a patient to proceed to 
HDC and AuHPCR after up to 4 courses of induction treatment. Patients who fail to complete induction 
therapy due to toxicity or complications of disease are considered evaluable for response and are classified 
as not having achieved a sufficient response to treatment.  
 
Secondary endpoints for the study include:  
• Time to treatment failure (TTF), which is defined as the minimum of the time to failure to achieve a 
sufficient response at the end of the 4th course, the time to disease progression, the time to 
disease recurrence following achievement of a  sufficient response , or the time to death from any 
cause, whichever is first. TTF will be used to compute the actuarial estimate of event-free survival 
(EFS) percent.  
• Time to death from any cause, from which the actuarial estimate of overall survival (OS) percent 
will be computed.  
 
12.3  
Patient accrual and statistical consideration 
 
It is expected that approximately 10 recurrent MMGCT and 2 recurrent pure germinomas will be enrolled on 
this study per year. If a sufficient number of responses are observed at the end of the first stage of the 
study, the study will meet the accrual goal of 28 MMGCT patients within approximately 3 years. 
Approximately 6 recurrent pure germinomas are expected to be enrolled.    
 

 
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The figure below shows the power to conclude that the regimen is efficacious, as well as the average 
number of patients that will be treated, as a function of the true sufficient response rate after up to 4 
courses of induction treatment. Note that if the regimen was not effective, e.g., if it induced sufficient 
responses only in 50% of MMGCT patients, then there is only a 9% chance that it would be accepted, and 
an average of only 22 MMGCT patients would be treated with the regimen. On the other hand, if the 
regimen was effective, e.g., if it induced sufficient responses in 70% of MMGCT patients, then there is a 
80% chance that it would be accepted, and an average of 28 MMGCT patients would be enrolled in this 
case. Hence, this rule is sufficiently discriminatory to reliably rule out this regimen when it has poor efficacy 
but will reliably accept it when it has good efficacy.  
 
Figure: Power and 
Average Sample 
Size for Two-Stage 
Response Rule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.4 Interim Monitoring of Toxic Death 
 
The occurrence of toxic death (TD) at any time will be a primary endpoint for safety monitoring. A toxic 
death rate that exceeds p0=5% will be considered unacceptable. No formal statistical rule will be employed. 
Rather, if the crude proportion of patients experiencing a toxic death exceeds p0=5% at any time, the cause 
and circumstances of these deaths will be reviewed with the study committee and with the Data and Safety 
Monitoring Committee to determine whether modifications to or termination of the study is warranted. This 
study will be monitored by appointed Data and Safety Monitoring Board, which is a standing committee 
comprising expert physicians and a biostatistician at Nationwide Children’s Hospital. 
 
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
Average N
0.0
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0.9
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Complete Response Probability
Power
Average N
Sufficient Response Probability 

 
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13.0     NEUROSURGICAL GUIDELINES 
 
There are no "standard" neurosurgical procedures for central nervous system germ cell tumors.  However, 
certain general guidelines, detailed below, should be considered in planning neurosurgical intervention in 
patients suspected of harboring such tumors. 
 
13.1    Control of Raised Intracranial Pressure 
 
In the majority of cases in which there is symptomatically elevated intracranial pressure (ICP), this will be 
secondary to obstructive hydrocephalus.  It should be possible, in the short term, to control raised ICP, 
pending results of tumor marker (AFP and HCGβ) studies on the peripheral blood as well as head and 
spine MRI studies, by the administration of dexamethasone, which should be accompanied by an antacid 
and/or an H2 antagonist. 
 
However, in those patients in whom there is severely raised ICP, or in whom a delay in completing such 
evaluations or commencing chemotherapy is anticipated, then hydrocephalus will need to be controlled by 
establishment of a formal cerebrospinal fluid (CSF) diversion; in these patients, a ventriculo-peritoneal 
shunt or third ventriculostomy is recommended.  Fears of dissemination of tumor cells to extraneural sites 
are largely unfounded.  Additionally, the insertion of filters to "prevent" transmission of tumor cells into the 
abdomen is unnecessary. 
 
At the time of shunt insertion, the opportunity should be taken to perform CSF sampling for cytology and for 
tumor marker studies (AFP and HCGβ) as well as CSF protein and exosomal micro RNAs (the latter 
performed in the laboratory of Dr. Jeffrey Leonard at NCH).  
 
13.2 
Cerebrospinal Fluid (CSF) Sampling 
 
It is essential to obtain CSF for tumor marker studies and for cytology in this study.  Clearly, the presence 
of an intracranial mass will raise concerns about the safety of CSF sampling in individual patients. 
 
It is suggested that, if there are intracranial masses of less than 2 cm maximal diameter, without either 
symptomatic raised ICP or hydrocephalus on CAT or MRI scans, then CSF sampling by lumbar puncture is 
safe and appropriate.  In the presence of larger intracranial masses, or symptomatic raised ICP or 
hydrocephalus on CAT or MRI scans, then lumbar puncture may be contraindicated and should be 
undertaken only after consultation between the neurosurgeon, neuro-oncologist, and neuroradiologist.  In 
the latter circumstance, CSF could be obtained by ventricular puncture, either at the time of shunt insertion, 
or even at a separate procedure, if shunting is not to be performed.  Such a procedure is amply justified, as 
the finding of positive markers in the ventricular CSF may avoid the need for an open, potentially more 
hazardous surgical procedure to obtain a diagnosis.  Ventricular puncture could be combined with other 
procedures, such as insertion of an indwelling venous access catheter for chemotherapy. 
 

 
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13.3    Direct Tumor Surgery 
 
13.3.1   At Diagnosis: 
 
Study eligibility mandates pathological confirmation of germinomatous histology, in the absence of other, 
non-germinomatous malignant elements (e.g. yolk sac tumor, choriocarcinoma, embryonal carcinoma). 
Thus, all patients with no normal serum and CSF tumor makers must undergo at least a biopsy prior to 
study enrollment. Individual neurosurgeons may choose to consider, where appropriately indicated by 
tumor size and location, a radical open surgical procedure. 
 
One scenario in which the benefits of more radical surgical resection may outweigh the risks is the patient 
with negative tumors markers in the serum and CSF and an enlarging mass on the brain MRI to rule out the 
presence of mature teratoma.  
 
13.3.2     Second Look Surgery 
 
In those patients with evidence of residual disease radiographically following the fourth course of protocol-
specified chemotherapy, regardless of their tumor markers levels, an open surgical procedure is strongly 
recommended to excise the residual tumor and to determine the subsequent therapeutic plan.  Such 
residual radiographic "tumor" may represent non-viable fibrotic tissue, mature teratoma, immature 
teratoma, malignant germ cell tumor, or some mixture of each.   
 
In those patients with evidence of increasing tumor size radiographically following either second or fourth 
protocol-specified induction chemotherapy cycle and in whom tumor markers are normal at such time, then 
a surgical procedure is mandated to excise the tumor or obtain a biopsy in order to rule out “ Growing 
Teratoma Syndrome.” Patient’s disease response should be deemed as progressive disease only after 
“Growing Teratoma Syndrome” has been ruled out. Should the patient indeed have growing teratoma 
syndrome, patient must continue receiving protocol therapy. 
 
13.4    Extent of Surgical Resection 
 
Classification of overall extent of resection for this study shall be based upon the volume of residual tumor 
after the final attempt at tumor resection. 
 
13.4.1   Biopsy only: 
 
After an open surgical or closed (stereotactic) removal of tissue for the sole purpose of establishing a 
pathological diagnosis, if tumor removal is less than 10% of the total tumor mass, this will be considered a 
biopsy only. 
 
13.4.2   Partial Resection: 
 
 
Partial resection is defined as removal of greater than 10% but less than 50% of the tumor mass. A partial 
resection is at all times considered to be an incomplete resection for the purpose of this study. 
 

 
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13.4.3  Subtotal Resection: 
 
Removal of greater than 50% but less than or equal to 90% of the tumor mass, or greater than 1.5 cm 
maximal diameter residual tumor mass by post-operative radiological studies. 
 
13.4.4  Near Total Resection: 
 
Removal of greater than 90% but less than 100% of the tumor mass and less than 1.5 cm maximal 
diameter of the residual tumor mass. 
 
13.4.5 Gross Total Resection: 
 
No visible tumor is left following surgery, and this is confirmed by post-operative gadolinium enhanced MRI 
scan.  It is recommended that cavity (tumor bed) biopsies be obtained following radical surgical resection, 
to affirm gross total resection status. 
 
13.5 
Neurosurgical On-Study Requirements 
 
13.5.1 Completion of protocol-specific Neurosurgical Tumor Resection Form and Upload institutional 
operative report to REDCap, electronic data capture system.  This should be undertaken 
separately for each neurosurgical procedure.  
 
13.5.2 Submission of the operating neurosurgeon's institutional operative report for each separate 
neurosurgical procedure, to REDCap. 
 
13.5.3 CSF sampling intra-operatively, as indicated above (see section 13.2) for tumor marker (AFP and 
HCGβ)_ studies cytology and optional MiRNAs.  
 
13.5.4 Tumor Specimen Submission: 
 
Maximal tumor tissue should be sent UNFIXED to the institutional pathologist for histological diagnosis. 
See section 14.8.2 for more information regarding the submission of tissue samples. 
 

 
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14.0     NEUROPATHOLOGY GUIDELINES 
 
Intracranial germ cell tumors do not differ histologically from those germ cell tumors arising extra-neurally.  
Thus, the same diagnostic criteria can be applied, and the tumors classified according to World Health 
Organization classification. 
 
In most cases, the histologic diagnosis can be affirmed by conventional light microscopy.  However, in 
some 
cases 
it 
is 
necessary 
to 
perform 
established 
adjunctive 
investigations, 
including 
immunohistochemistry. 
 
14.1 
Criteria for Diagnosis of Germinoma 
 
Microscopic appearance: 
 
Tumor composed of large round, oval or polygonal cells with abundant clear cytoplasm and large round 
nuclei with prominent nucleoli.  These cells are arranged in nests separated by bands of fibrous tissue in 
which numerous lymphocytes are identified.  Foci of necrosis are present and syncytial giant cells may be 
seen.  These tumor cells are positive for placental alkaline phosphatase. 
 
All such patients with pure germinoma will be eligible for enrollment on this study. 
 
14.2 
Criteria for Diagnosis of Immature Teratoma 
  
Immature teratomas will be graded according to the classification of Gonzales-Cruzi:  
 
Grade I:  
Less than 10% immature tissue with 90% mature elements 
Grade II: 
Between 10% and 50% immature elements 
Grade III: 
Greater than 50% immature elements 
 
Immature teratomas may not have any foci (even microscopic) of germinoma, yolk sac tumor, embryonal 
carcinoma, choriocarcinoma, squamous carcinoma, primitive neuroectodermal tumor or adenocarcinoma.  
Any such foci alter the classification to teratoma with malignant elements. 
 
Pure immature teratomas, without a pure germinoma or other mixed malignant component, will not be 
eligible for enrollment on this study. 
 
14.3     Criteria for Diagnosis of Mature Teratoma 
 
Mature teratoma will be graded according to the classification of Gonzales-Cruzi: 
 
Mature teratoma (Grade 0):  No immature elements.  100% mature tissue. 
 
Mature teratomas may not have any foci (even microscopic) of germinoma, yolk sac tumor, embryonal 
carcinoma, choriocarcinoma, squamous carcinoma, primitive neuroectodermal tumor or adenocarcinoma.  
Any such foci alter the classification to teratoma with malignant elements. 
 

 
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Pure mature teratomas, without a pure germinoma or other malignant components will not be eligible for 
enrollment on this study. 
 
14.3.1 Criteria for diagnosis of Growing Teratoma Syndrome 
    
Growing teratoma syndrome (GTS) is the term applied to an enlarging intracranial germ cell tumor size 
during or after chemotherapy with histology of mature teratoma in the resected tumor specimen.  The mass 
shows enlargement in the presence of normalization of initially elevated serum and/or CSF tumor markers.  
 
14.4 
Criteria for Diagnosis of Teratoma with Malignant Elements 
 
Any teratoma in which a microscopic focus of malignancy exists, be it either malignant germ cell tumor or 
teratoma with foci of primitive neuroectodermal tissue or squamous carcinoma, will be characterized as 
malignant. Only patients with teratoma combined with germinoma or mixed malignant germ cell tumor will 
be eligible for enrollment on this study. 
 
14.5 
Criteria for Diagnosis of Endodermal Sinus Tumor (Yolk Sac Tumor) 
 
Tumor composed of: 
 
A. Small pale cells with scanty cytoplasm and round to oval nuclei with small, in apparent nucleoli.  These 
cells are arranged in:  1) a loose microcytic pattern, 2) in solid sheets, or 3) in gland-like structures lined by 
a single layer of cells (polyvitelline pattern). 
 
B. Or cells with slightly larger nuclei, which frequently have moderately prominent nucleoli.  These cells are 
arranged into tubulopapillary structures with at least a few Schiller-Duval bodies.  (Schiller-Duval bodies not 
usually present in microcystic, solid, or polyvitelline patterns.) 
 
A loose, frequently myxoid, or vascular stroma. 
 
Intracytoplasmic and extracellular hyaline globules and strands, which stain positively with PAS and are 
resistant to diastase digestion. 
 
The criteria listed above are the essential features necessary for a diagnosis of yolk sac tumor.  
Immunohistochemical or immunoflourescent demonstration of alpha-fetoprotein and/or alpha-1-antitrypsin 
in the PAS positive globular material would be an interesting additional piece of information, but is not 
necessary for the diagnosis, since most globules do not contain either protein.  Alpha-fetoprotein (if looked 
for) should be present in at least some of the cells. 
 
All patients with CNS GCT containing elements of endodermal sinus tumor (yolk sac tumor) will be eligible 
for enrollment on this study. 
 
 
 
 
 
 

 
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14.6 
Criteria for Diagnosis of Embryonal Carcinoma 
 
Microscopic appearance: 
 
Tumor composed of: 
 
Sheets of large epithelial-like cells with round to irregularly oval nuclei containing one or more large nucleoli 
and having a coarse nuclear membrane.  The cells may vary considerably in size and shape and contain 
abundant cytoplasm. 
 
Cells may assume a tubulopapillary arrangement in foci, but must not be associated with intracytoplasmic 
and extracellular hyaline globules and strands, which are PAS positive, diastase resistant.  (These latter 
findings are characteristic of yolk sac tumors). 
 
Tumors will usually have large foci of necrosis, frequently occupying a central location within sheets of 
cells.  Some necrotic cells may resemble the hyaline globules seen in yolk sac tumors, but can generally be 
differentiated by their location in association with dying cells. 
 
A few embryoid bodies may be present.  (NOTE:  If tumor is composed solely or predominantly of embryoid 
bodies, then it should be classified as a polyembryoma.) 
 
The stroma may vary from loose and edematous, to fibrous, to occasionally quite cellular. 
 
Immunohistochemical staining of tumor tissue for CD-30 reactivity should be routinely performed as this 
marker has high specificity for embryonal carcinoma. 
 
All patients with CNS GCT containing elements of embryonal carcinoma will be eligible for enrollment on 
this study. 
 
14.7 
Criteria for Diagnosis of Choriocarcinoma 
 
Gross tumor composed primarily of hemorrhagic, friable tissue, with or without a few patches of grayish-
white tissue. 
 
Microscopic appearance: 
 
Tumor composed of two cell types:  the syncytiotrophoblast and the cytotrophoblast.  The 
syncytiotrophoblast is a large, somewhat bizarre cell, with one too many hyperchromatic nuclei and 
generally abundant eosinophilic cytoplasm, which may or may not be vacuolated.  The cytotrophoblast is 
present in closely packed nests and is a medium-sized, relatively uniform cell with clear cytoplasm, distinct 
cell margins and a vesicular nucleus.  These two cell types must both be present, as individual 
syncytiotrophoblasts (positive for the  HCGβ) may be seen in any of the malignant germ cell tumors. 
Patients with CNS GCT containing elements of choriocarcinoma, will be eligible for enrollment on this 
study.  
 
 
 
 

 
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14.8 
Minimal Required Studies (only if tumor tissue of recurrence obtained) 
 
14.8.1 Pathology Studies: 
 
• Routine histology on paraffin sections stained with hematoxylin and eosin (H & E), periodic acid 
Schiff's (PAS) reagent, and reticulin stain. 
• Immunohistochemistry, using antibodies against AFP, HCGβ, PLAP (placental alkaline 
phosphatase), c-kit (CD119), OKT4 and CD30. 
• For differential diagnosis from non-germ cell tumors, it may be necessary to include antibodies 
against different types of intermediate filaments (e.g. vimentin, cytokeratins, desmin, GFAP, 
neurofilament proteins). 
 
14.8.2  Submission of Tissue Samples 
 
The neuropathologist at each participating institution should submit the following to Nationwide 
Children’s Hospital: 
 
• Copies of the Institutional Pathology Reports uploaded to REDCap (from tumor specimen obtained 
at the time of recurrence) 
• Specimen Transmittal Form 
• All paraffin embedded tissue blocks with tumor.  From these blocks the NCH Neuropathologist  will 
prepare slides, as detailed below, and then return the blocks to the submitting institution: 
• H & E stained slide of each representative lesion. 
• AFP, HCGβ, PLAP, and other stained slides, as indicated. 
• If paraffin embedded blocks are not available for submission to the Pathology Center, then the 
following pathological samples are ESSENTIAL FOR PROTOCOL COMPLIANCE, and should be 
forwarded to the Pathology Center: 
1. One H & E stained slide for each representative lesion. 
2. Six unstained slides of tumor per block. 
 
Biopathology Center 
Nationwide Children’s Hospital, 
700 Children's Drive, Room WA1340 
Columbus, Ohio, 43205, USA 
Telephone: (001) 614-722-2894 
FAX:     (001) 614-722-2897 
Email:  BPCBank@nationwidechildrens.org 
  
ATTN: Gempox protocol-FINLAY (Boue) 
 
14.8.3    Cerebrospinal Fluid Samples for Biology Study: 
 
At the time of routine, study required lumbar punctures (performed for cytology and tumor markers) an 
additional 1.0 ml of CSF should be collected provided appropriate informed consent has been obtained to 
do so.  
 

 
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A volume of 1.0 ml CSF should be collected and spun down (Cytospin) at the treating institution and the 
supernatant frozen by the treating institution. This is requested to enable testing, in the laboratory of Dr. 
Jeffrey Leonard at NCH, for exosomal microRNAs in the supernatant (without interference from cell 
proteins and RNA).  Many institutions routinely add bovine serum albumin (BSA) to the CSF sample prior to 
centrifugation; in this case, we request that a second CSF sample be spun down without addition of 
albumin, for submission. 
 
Submit frozen CSF supernatant on dry ice to:  
Biopathology Center 
Nationwide Children’s Hospital, 
700 Children's Drive, Room WA1340 
Columbus, Ohio, 43205, USA 
Telephone: (001) 614-722-2894 
FAX:     (001) 614-722-2897 Email:  BPCBank@nationwidechildrens.org 
 
ATTN: Gempox protocol-FINLAY (Leonard Lab) 
 
 
14.9 
 Central Pathology Review Process 
 
14.9.1  Primary Review by Study Neuropathologist: 
 
All materials submitted from the individual institutions will be collected and collated at Nationwide Children’s 
Hospital.  Neuropathology Review will occur at time of receipt by the Primary Review Neuropathologist, Dr. 
Daniel Boue. 
 
Biopathology Center 
Nationwide Children’s Hospital, 
700 Children's Drive, Room WA1340, 
Columbus, Ohio, 43205, USA 
Telephone: (001) 614-722-2894 
FAX:     (001) 614-722-2897 
Email:  BPCBank@nationwidechildrens.org 
  
ATTN: Gempox protocol-FINLAY (Boue) 
 
 
14.9.2  Final Neuropathology Report 
 
Upon conclusion of the NCH Neuropathology Review process, a final report will be sent to the institutional 
neuropathologist.  The process of collection of samples and the review process are intended to assure 
accuracy of diagnosis in preference to rapid turnover time.  If the final review of a case results in the 
opinion that the original histological diagnosis represented a protocol deviation, then the study 
neuropathologist will communicate this information to the Study Operations Office. 
 
 

 
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15.0 
NEURORADIOLOGY GUIDELINES 
 
15.1 
MRI Scanning 
 
There is no single best radiological examination for primary CNS germ cell tumors.  MRI is superior to CT 
scanning in the posterior fossa, due to the lack of Hounsfield artifact from the petrous bones.  There is, 
however, artifact in the brain stem and temporal lobes from basilar artery pulsations and CSF flow, if motion 
suppression techniques are not utilized.  MRI is also more sensitive than CT scanning in detecting 
increased water content in tumor bearing tissue, but this is very non-specific when one considers that most 
pathological processes, including peri-tumoral vasogenic edema, increase water content.  Furthermore, 
enhancing tumor is not adequately imaged on non-contrast MRI, that is, without intravenous gadolinium 
DTPA (Gd-DTPA).  MRI is also insensitive to small calcifications. 
 
15.1.1 On Study Examinations 
 
• A pre- and post-contrast MRI scan post-operatively is mandatory for study entry.  The institutional 
reports of these scans, and a copy of the Initial Neuro-radiology Report Form, are to be uploaded 
to REDCap. 
 
• An MRI of the entire spine with and without gadolinium is mandatory for study entry.  The 
institutional reports of these studies are to be uploaded to REDCap. 
 
15.1.2 Follow-Up Examinations 
 
Minimum requirement for follow-up studies is an MRI scan with and without gadolinium-DTPA. 
 
15.1.3 Reference Scans 
 
The reference scan is the post-operative scan obtained at the time of on-study evaluation, unless a 
subsequent scan demonstrates decreased tumor volume.  Then the scan with the smallest tumor mass will 
become the reference scan.  It is essential that the same imaging technique is used and compared, and 
that all cuts used for comparison, are in the same plane as those of the reference scan. 
 
15.1.4 Disease Progression/Off Protocol Status 
 
At the time of disease progression, the appropriate radiographic reports and the Follow-up Neuroradiology 
Report Form will be uploaded to REDCap. 
 
15.2 
Scan Parameters 
 
15.2.1 MRI Scan of Brain 
 
Both short (T1 weighted) and long (T2 weighted) TR sequences are essential.  Plane section and TR 
sequences will be dependent on location of the tumor.  The minimum examinations are: 
 
• midline posterior fossa tumors - sagittal T1, axial T2, axial FLAIR 

 
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• lateral posterior fossa tumors - axial T1, axial T2, axial FLAIR 
• suprasellar/hypothalamic tumors - sagittal T1, coronal T1, T2 and FLAIR 
• other supratentorial tumors - coronal T1, axial T1,T2 and FLAIR 
• For brainstem and temporal lobe tumors, motion suppression techniques such as cardiac gating 
and/or flow compensation, are recommended. 
 
15.2.2 MRI Scan of Spine 
 
A T1 weighted sequence should be obtained in the sagittal plane, 3mm thickness, with no interslice gap.  
This must be repeated with gadolinium.  Axial T1 weighted images with gadolinium enhancement should be 
obtained for the upper cervical spine, conus, dorsal sac, and any areas of abnormality seen in sagittal 
imaging. 
  
15.2.3 Use of Contrast 
 
An additional post Gd-DTPA T1 sequence comparable to the pre-contrast T1 sequence is mandated for all 
MRI studies. 
 
15.3 
Timing of Radiologic Studies  
 
15.3.1 Head MRI scans:  
 
 
Head MRI scans must be obtained at the following times, and the institutional neuroradiology reports 
uploaded to REDCap at the completion of protocol-specified chemotherapy, along with the Neuroradiology 
Follow-up Form: 
 
• Pre Induction/study entry [pre and post-op if surgery]. 
• Following second induction cycle.  
• Post Induction (which is also pre-surgery if second look surgery is indicated). 
• Post Second Surgery (either within 72 hours of surgery OR within 10-21 days after surgery)  
• Post-consolidation 
• Post Radiation therapy (if the patient is treated with Radiation therapy). 
•  At the time of progressive disease or relapse. 
• At three month intervals, following completion of protocol-specified chemotherapy, for the first year 
from diagnosis. 
• At four month intervals during the second year from diagnosis. 
• At six month intervals during the third through fifth years from diagnosis. 
• Annually following completion of five years from diagnosis. 
 
Clinical management may dictate more frequent examinations. 
 
15.3.2 Spine MRI 
 
Spine MRI scans must be obtained at the following times, and the institutional neuroradiology reports 
uploaded to REDCap at the completion of protocol-specified chemotherapy, along with the Neuroradiology 
Follow-up Form: 

 
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• Pre Induction/study entry [pre and post-op if surgery]. 
• Following second induction cycle ONLY if positive at the time of study entry. 
• Post induction (which will serve as pre-surgery if second look surgery is planned or pre-
consolidation if the consolidation cycle is started within 4 weeks from the study). 
• Post Second Surgery (either prior to surgery or within 72 hours of surgery OR within 21 days after 
surgery)  
• Post-consolidation  
• Post Radiation therapy (if the patient is treated with Radiation therapy). 
•  At the time of progressive disease or relapse. 
• At three month intervals, following completion of protocol-specified chemotherapy, for the first year 
from diagnosis only if previously positive. 
• At four month intervals during the second year from diagnosis only if previously positive. 
• At six month intervals during the third through fifth years from diagnosis only if previously positive. 
• Annually following completion of five years from diagnosis only if previously positive. 
 
Clinical management may dictate more frequent examinations. 
 
15.4 
Centralized Neuroradiology Review 
 
A process of centralized review of neuroradiological studies will be undertaken at Nationwide Children's 
Hospital. The study Neuroradiologists or Nicholas Zumberg in conjunction with the study P.I., Dr. Jonathan 
Finlay will review the radiology and report their summary to the DSMB .  
 
 
All CD copies of MRI scans requested for central neuroradiology submission will be stored in locked secure 
areas with research staff access only.  
 
Address for Submission of Reports and Scans 
 
Dr. Jonathan Finlay, MB, Ch.B. 
Nationwide Children’s Hospital  
700 Children’s Dr. Room ED544 
Columbus, Ohio 43205 
jonathan.finlay@nationwidechildrens.org  

 
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16.0    RADIATION THERAPY GUIDELINES 
 
Since response to radiation therapy is neither a primary nor a secondary aim of the study, and since a 
majority of patients with MMGCT might have previously received some form of irradiation, the guidelines to 
administer radiation therapy at the time of relapse will be left to the discretion of the treating oncologist.  
 

 
Version 1.05.2017 
 
 
 
 
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17.0  DATA SAFETY AND MONITORING PLAN 
 
The “GemPOx” Clinical Trials Data Safety Monitoring Board (DSMB) will act in an advisory capacity to the 
Principal Investigator this study.  Monitoring will occur every six months (and more frequently as needed) 
from the date the study is opened at Nationwide Children’s Hospital. Reports to the Data Safety and 
Monitoring Board will include the following information: 
 
1. Accruals 
2. Responses 
3. Adverse events and evidence of reporting to appropriate review committees 
 
The responsibility of the DSMB is to review the research protocol, inform consent and plans for data safety 
monitoring during the entire course of the study. This committee will evaluate the progress of the trial, 
including periodic assessments of data quality and timeliness, participant recruitment, accrual and 
retention, participant risk versus benefit, trial site performance and other factors that may have impact on 
participant outcomes. This DSMB will follow the Hem/Onc/BMT Data Safety Monitoring Board Charter. 
 
17.1 Study Monitoring and Adverse Event Reporting  
 
The monitoring of study data is an ongoing process by the DSMB  The data for each patient (eligibility, 
evaluability and course by course) is submitted from the GemPOx sites via the electronic case report forms 
(eCRF's) built into the database system (REDCap) hosted by NCH. Adverse events will be reported to the 
NCH using the eCRF's according to Section 18.0.  
 
The DSMB will have a timetable in which to review the accumulating data (adverse events, treatment 
records, disease assessments, specimen collection, last follow-up and other protocol specific data) for 
completeness and consistency. Data queries are generated via email to the Institutional Clinical Research 
Coordinators (CRCs) using the GemPOx Data Query Form to resolve incomplete data, data 
inconsistencies or errors identified while verifying eligibility data, and evaluability data. Data review and 
corresponding queries also occur at the completion of each course of therapy, when patients cease 
treatment, and when patients are off study. The PI must sign-off on all data submitted for eligibility, 
evaluability, and each protocol course via a web-based sign-off system. The subsequent ‘freeze’ of data 
records is on a per-patient, prospective, course by course basis.  
 
All serious adverse events (SAEs) will be immediately (within 24 hours of knowledge of the event) reported 
by site personnel according to the protocol specifications that shall include notification of the protocol study 
PI, DSMB, local IRB. Refer to Section 18.0 for Adverse Event Reporting.  
 
17.2 Reviews by Protocol Chairs and Co-Chairs  
 
The PI is required to review and confirm that all interpretations are consistent with the protocol on which the 
patient is treated.  The Lead Data Clinical Research Coordinator works with the PI to resolve any data 
questions that may arise. Reports of the accumulating data including patient accrual and status, along with 
toxicities will be available to PI and co-chairs over the Internet via a secure, encrypted connection to the 
server. These will be updated daily. Access to this site is recorded to track protocol study chair monitoring.  
 
 

 
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17.3 Automated Data Delinquency Reporting System  
 
The GemPOx sites are expected to enter patient data in the database within the timelines specified per 
MOP. The Lead Data Clinical Research Coordinator and PI are expected to review the data and sign-off 
according to MOP specifications. The Lead Data Clinical Research Coordinator utilizes e-mail data 
delinquency reminders to remind the member sites’ CRCs, site attending physicians and protocol study 
chairs of the expected data entry per the specified timetable.  
 
1. Data deficiency reminders corresponding to eligibility and evaluability  
GemPOx sites are expected to provide complete eligibility and evaluability data within specified 
time lines detailed in the MOP. Notifications that the data are incomplete are automatically sent to 
the site and include the date that all issues must be resolved. Failure to comply by the specified 
date will result in suspension of all institutional registration privileges.  
  
2. Data deficiency reminders corresponding to course data.  
GemPOx sites are expected to provide complete course data within specified timelines. 
Notifications that the data are incomplete are automatically sent to the site. Missing data elements 
are identified in the report. 
 
 
17.4 Semi-annual GemPOx Meeting Minutes 
 
Protocol summary reports of patient accrual, eligibility, toxicity and other study objectives are generated 
semi-annually by the DSMB and distributed via the SharePoint website. The reports will be a collaborative 
effort of the Lead Data Clinical Research Coordinator, study statistician, PI, correlative study investigators, 
and other protocol collaborators. Outcome data are not reported until released by the GemPOx DSMB. 
 
 
17.5  Auditing and Subsites 
 
Audits are conducted as needed to document the accuracy of data submitted and to verify investigator 
compliance with protocol and regulatory requirements. Auditing is accomplished by verifying against the 
institution’s source documents patient data, eligibility and consent information submitted to Nationwide 
Children's Hospital  via eCRFs. Additionally, IRB documentation is reviewed.  
 
 
17.6 Data, Safety Monitoring Board (DSMB) Membership  
 
The Chair of the GemPOx Steering Committee shall appoint a senior neuro-oncology investigator to chair 
the DSMB; additional members shall be identified in consultation with the DSMB Chair and appointed by 
the Chair of the GemPOx. A minimum of 5 voting members shall comprise the DSMB, including (1) the 
Chair, (2) a physician member of GemPOx Committee, (3) a pediatric oncologist, a biostatistician, and a 
radiation oncologist who is not an investigator at GemPOx institution.  The additional member(s) shall be 
appointed such that a majority of the voting members are from outside the Consortium and the Board 
includes at least two neuro-oncologists trained in pediatric oncology or neurology. Appointments will be for 
3-4 year terms, renewable once by the Chair of GemPOx. Any member of the DSMB shall excuse himself 
or herself from discussion of any protocol for which they have a perceived conflict of interest. All members 

 
Version 1.05.2017 
 
 
 
 
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of the DSMB will complete the GemPOx conflict of interest disclosure forms at least annually. Premature 
disclosure of confidential DSMB discussions by members of the GemPOx DSMB will result in censure of 
that member by the GemPOx Steering Committee in accordance with the GemPOx Charter 
 
17.7  Meetings  
 
The DSMB shall convene at least twice each year by telephone conference\ At other times, the DSMB chair 
shall utilize electronic communication or scheduled telephone conferencing at his/her discretion in 
continuing the responsibilities of the DSMB. The DSMB will establish committee procedures; all decisions 
of the DSMB must reflect participation of a majority of the committee’s member. Decisions of the DSMB 
may be rendered during any of the aforementioned sessions or by electronic voting of the membership. Any 
GemPOx investigator can request that the Chair of the DSMB convene a teleconference call to discuss a 
specific GemPOx protocol.  
 
17.8 DSMB Decisions and Recommendations  
Decisions and recommendations of the DSMB will be approved by the Chair of the DSMB then forwarded 
to the committee members.  
 
1. Comments requiring an immediate response  
The GemPOx study chair will be responsible for responses requiring an immediate response. PI 
and biostatisticians may be asked to assist in the response. The responses will be sent to the 
DSMB within six weeks from receipt of the comments by the PI.  
 
2. Comments requiring responses for the next DSMC meeting  
Protocol specific comments will be sent to the GemPOx study chair. Responses are requested 
within four weeks. PI and biostatisticians may assist the protocol study chairs with responses 
concerning data issues if requested.  
 
 
18.0     REPORTING OF ADVERSE EVENTS AND TOXICITIES/ADVERSE EVENT CRITERIA 
 
Toxicities are reported in a routine manner at scheduled times during a trial.  These routine 
reporting requirements are provided in the MOP. Certain events must be reported in an expedited 
manner to allow for timely monitoring of patient safety and care.   
 
18.1 
Routine Toxicity Reporting 
 
Toxicities will be graded according to the CTCAE criteria, version 4.0.  The site, measure, and grade for all 
Grade 3 and higher toxicities are to be reported on the appropriate data collection forms and submitted 
within 2 weeks of the completion of each cycle of therapy.  CTC AE version 4.0 may be downloaded from 
the CTEP web site (http://ctep.cancer.gov). 
 
 
 
 
 

 
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18.2   Guidelines for Reporting Adverse Drug Reactions for Commercial Agents in an Expedited 
Manner 
 
Commercial agents are those agents not provided under an IND but obtained instead from a commercial 
source.  In some cases an agent obtained commercially may be used for indications not included in the 
package label.  In GemPOx all of the agents used are commercially available. 
 
 
18.3 ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents. 
 
Determination of Reporting Requirements includes the following considerations: 1) the characteristics of the 
adverse event including the grade (severity); 2) the relationship to the study therapy (attribution); and 3) the 
prior experience (expectedness) of the adverse event. 
 
Expected events are those that have been previously identified as resulting from administration of the 
agent. An adverse event is considered unexpected, for reporting purposes only, when either the type of 
event or the severity of the event is not listed in: the current known toxicities for each commercial agent as 
provided in the Drug Information Section of this protocol; or the drug package insert (for treatments with 
commercially available agents). 
 
Routine Adverse Event Reporting: 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) within the study 
database, REDCap. For this study, routine reporting will include all Grade 3 and higher Adverse Events. 
 
Serious Adverse Events Reporting: 
 
An adverse event is considered serious if it results in ANY of the following outcomes:  
 
1) Death 
2) A life-threatening adverse event 
3) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours. 
This does not include hospitalizations which are part of routine medical practice 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions.  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6.) 
 
Use the GemPOx protocol-specific patient ID provided during trial registration on SAE forms.  The 
SAE form is located in the “GemPOx” REDCap database. 
 

 
Version 1.05.2017 
 
 
 
 
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Attribution 
Grade 4 
Report to Nationwide 
Children’s Hospital by fax    
614-722-4635 within 3 days of 
occurrence. 
Grade 5* 
Report to Nationwide Children’s Hospital by fax  
614-722-4635 within 24 hours of occurrence. 
 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
or Unlikely 
 
Not required 
Not required 
REDCap 
REDCap 
Possible, 
Probable, 
Definite 
REDCap 
REDCap 
REDCap 
REDCap 
*This includes all deaths within 30 days of the last dose of treatment with a commercial agent, regardless 
of attribution. Any death that occurs more than 30 days after the last dose of treatment with a commercial 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not due to cancer 
recurrence must be reported. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Version 1.05.2017 
 
 
 
 
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19.0     REFERENCES 
  
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21. Bouffet E, Baranzelli MC, Patte C et al. High-dose etoposide and thio-TEPA for recurrent malignant 
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22. Einhorn L, Stender M. Phase II trial of gemcitabine in refractory germ cell tumors. JClin Oncol 17 (2): 
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25. Dunn, T.A., Grunwald et al: Pre-clinical activity of Taxol in non-seminomatous germ cell tumor cell lines 
and nude mouse xenografts. Invest New drugs 15: 91-98, 1997.  
26. Motzer R. J, Bajorin DF, Schwartz LH et al: Phase II trial of paclitaxel shows antitumor activity in 
Patients with previously treated germ cell tumors. J Clin Oncol: 12:  2277-2283, 1994. 
27. Bokemeyer C, Beyer J, Metzner B et al: Phase II study of paclitaxel in patients with relapsed or 
cisplatin- refractory testicular cancer. Ann Oncol ;7:13-34, 1996.  
28. Woynarowski JM, Faivre et al: Oxaliplatin-induced damage of cellular DNA. Mol Pharmacol 58:920-927 
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31. Dunn TA, Schmoll HJ, Grunwald V et al: Comparative cytotoxicity of oxaliplatin and cisplatin in non-
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32. B.Geoerger, F doz et al: Dose finding and pharmacokinetic study of weekly oxaliplatin in pediatric solid 
malignancies. Proc Am Soc Clin Oncol: Abstract, 2003. 
33. Spunt SL, Freeman BB, Billups CA et al: Phase I clinical trial of oxaliplatin in children and adolescents 
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34. Fouladi M, Blaney SM et al; Phase II study of oxaliplatin in children with recurrent or refractory 
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36. Hinton S, Catalano P, Einhorn LH et al. Phase II study of paclitaxel plus gemcitabine in refractory germ 
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37. Einhorn LH, Williams SD Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ 
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38. Hui KG, Mitchell PL, et al. A phase I and pharmacokinetic study of gemcitabine and oxaliplatin in 
patients with solid tumors. Cancer chemother Pharmacol; 58: 157-164, 2006. 
39. Kollmannsberger C, Beyer J, Liersch R et al. Combination chemotherapy with gemcitabine plus 
oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: A study of the German 
Testicular Cancer Study Group. J Clin Oncol; 122:108 –114, 2004. 
40. Pectasides D, Pectasides M, Farmakis D et al. Gemcitabine and oxaliplatin (GEMOX) in patients with 
cisplatin-refractory germ cell tumors: A phase II study. Ann Oncol; 15:493– 497, 2004. 
41. Ugo De Giorgi, Gionanni Rosti et al. Phase II study of oxaliplatin and gemcitabine salvage 
chemotherapy in patients with cisplatin-refractory nonseminomatous germ cell tumor. Eur Urology; 
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42. Bokemeyer C, Oeschle K, Honecker F et al. Combination chemotherapy with gemcitabine, oxaliplatin, 
and paclitaxel in patients with cisplatin-refractory or multiply relapsed germ-cell tumors: a study of the 
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43. Strong JM, Collins JM, Lester c, et al: Pharmacokinetics of intraventricular and intravenous N, N’, N’-
triethylenethiophosphoramide (thiotepa) in rhesus monkeys and humans. Cancer Res 46:6101-6104, 
1986. 
44. Mason WP, Grovas a, Halpern S et al. Intensive chemotherapy and bone marrow rescue for young 
children with newly-diagnosed malignant brain tumors. J Clin Oncol 16: 210-221, 1998. 
45. Nichols CR, Tricot G, Williams SD, et al. Dose-intensive chemotherapy in refractory germ cell cancer: A 
phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation. J 
Clin Oncol 7:932-939, 1989. 
46. Wolff SN, Johnson DH, Hainsworth JD, et al: High-dose VP-16-213 monotherapy for refractory 
germinal malignancies: a phase II study. J Clin Oncol 2:271-274, 1984. 
47. U De Giorgi, G. Rosti, S.Slavin et al. Salvage high-dose chemotherapy for children with extragonadal 
germ-cell tumors. British J Cancer; 93, 412-417, 2005.  
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diabetes insipidus in children. The Endocrinologist 6:301-306, 1996. 
 
 
 
 
 
 
 

 
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Appendix I 
 
PERFORMANCE STATUS CRITERIA  
Karnofsky and Lansky performance scores are intended to be multiples of 10  
Karnofsky  
Lansky*  
Score 
Description  
Score  
Description  
100  
Normal, no complaints, no 
evidence of disease  
100  
Fully active, normal.  
90  
Able to carry on normal activity,  
90  
Minor restrictions in physically  
 
minor signs or symptoms of  
 
strenuous activity.  
 
disease.  
 
 
80  
Normal activity with effort; some 
signs or symptoms of disease.  
80  
Active, but tires more quickly  
70  
Cares for self, unable to carry on  
70  
Both greater restriction of and less  
 
Normal activity or do active work.  
 
Time spent in play activity.  
 
Required occasional assistance,  
60  
Up and around, but minimal active play; 
60  
but is able to care for most of  
 
Keeps busy with quieter activities. 
 
his/her needs.  
 
 
50  
Requires considerable assistance  
50  
Gets dressed, but lies around much of the 
 
and frequent medical care.  
 
day; no active play, able to participate in 
 
 
 
all quiet play and activities. 
 
 
 
 
40  
Disabled, requires special care and 
assistance.  
40  
Mostly in bed; participates in 
quiet activities.  
 
30 
Severely disabled, hospitalization  
30  
In bed; needs assistance even for quiet play. 
 
indicated. Death not imminent.  
 
 
20  
Very sick, hospitalization indicated. 
Death not imminent.  
20  
Often sleeping; play entirely limited to very 
passive activities.  
10  
Moribund, fatal processes  
10  
No play; does not get out of bed.  
 
progressing rapidly.  
 
 
 
 
 

 
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Appendix II 
 
Anticonvulsant ELIGIBLE  
Not or minimal enzyme inducing 
  
 
 
 
 
Generic Name  
  
 
Trade Name  
 
Gabapentin  
  
 
Neurontin  
 
Lamotrigine 
  
 
Lamictal  
 
Levetiracetam  
  
 
Keppra  
 
Tigabine 
  
 
Gabitril  
 
Topiramate  
  
 
Topamax  
 
Valproic Acid  
  
 
Depakote, Depakene  
 
Zonisamide  
  
 
Zonegran  
 
Enzyme inducing anticonvulsant drugs (EIACD): NOT ELIGIBLE  
Generic Name  
Trade Name  
Carbamazepine  
Tegretol  
Felbamate  
Felbatol  
Phenobarbital  
Phenobarbital  
Phenytoin  
Dilantin  
Primidone  
Mysoline  
Oxcarbazepine  
Trileptal  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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GemPOx Induction for Recurrent or Progressive CNS Germ Cell Tumor 
Diagnosis:  
Name __________________________ 
     Provider _________________________ 
MRN 
_______________ 
DOB 
_______________ 
 
Induction 
Weight               kg 
Height               cm 
BSA               m2 
 
Cycle length 14 days, planned for maximum of 4 cycles 
Criteria to start each cycle: ANC 750 or greater, and platelets 75,000 or greater. 
 
PACLitaxel 
Premedicate with dexamethasone, ranitidine and diphenhydramine before paclitaxel. 
170 mg/m2/dose IV ONCE. Give on Day 1. Start at Hour 0. Infuse over 3 hours. 
gemcitabine 
800 mg/m2/dose IV ONCE. Give on Day 1. Start at Hour 3. Infuse over 1 hour. 
oxaliplatin 
100 mg/m2/dose IV ONCE. Give on Day 1. Start at Hour 4. Infuse over 2 hours. 
optional 
filgrastim 
Routine use of filgrastim during Induction is not recommended. 
Add if patient has a delay of 7 – 14 days in starting the next cycle due to neutropenia. 
5 mcg/kg/dose subcutaneous QDAY. MAXIMUM DOSE 480 mcg 
Start on Day 2, at least 24 hours after oxaliplatin is completed. 
Continue until postnadir ANC is greater than 1000. 
 
Date 
Due 
Date 
Given 
Cycle 
Day 
PACLitaxel 
gemcitabine 
oxaliplatin 
filgrastim 
optional 
Observations 
 
 
1 
1 
______ mg 
_______ mg 
______ mg 
 
a b c d% e% h j 
k l  
 
 
 
2 
 
 
 
_____ mcg 
 
 
 
 
8 
 
 
 
 
d% e% 
 
 
 
14 
 
 
 
 
 
 
 
2 
1 
______ mg 
_______ mg 
______ mg 
 
a b c d% e%   
 
 
 
2 
 
 
 
_____ mcg 
 
 
 
 
8 
 
 
 
 
d% e% 
 
 
 
14 
After Cycle 2 is completed, 
if in CR, then proceed to Consolidation. 
If less than CR, then give 2 more cycles of Induction 
a c d% e% h j k l 
 
 
3 
1 
______ mg 
_______ mg 
______ mg 
 
a b c d% e%   
 
 
 
2 
 
 
 
_____ mcg 
 
 
 
 
8 
 
 
 
 
d% e% 
 
 
 
14 
 
 
 
 
 
 
 
4 
1 
______ mg 
_______ mg 
______ mg 
 
a b c d% e%   
 
 
 
2 
 
 
 
_____ mcg 
 
 
 
 
8 
 
 
 
 
d% e% 
 
 
 
14 
After Cycle 4 is completed, 
perform extent of disease evaluation 
a c d% e% j k l 
 

 
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Observations 
a. height, weight, BSA 
b. HCG, urine qualitative for females of childbearing potential 
c. blood for alpha-1-fetoprotein, tumor and BHCG, tumor marker 
Obtain around same time when CSF markers are obtained 
d. CBC with automated diff, reflex to manual. 
% Obtain weekly 
e. ALT, AST, bilirubin, BUN, creatinine, electrolytes, glucose, calcium, magnesium, phosphorous. 
% Obtain weekly 
f. 
Urinalysis 
g. Endocrine evaluation 
free T4, TSH, IGF1, IGFBP3, LH (males over age 10, females over age 9),  
FSH (males over age 10, females over age 9), testosterone (males over age 10),  
estradiol (females over age 9), Tanner stage, cortisol at 8 AM, BUN, creatinine, electrolytes, and  
urine specific gravity on first morning void. 
If any endocrine parameter is abnormal, then referral to a pediatric endocrinologist for further 
evaluation, dynamic testing, and treatment is required. 
h. Audiology evaluation 
i. 
Creatinine clearance or GFR renal scan 
j. 
MRI Brain and Spine 
k. lumbar puncture for Cytology, cell count CSF, alpha-1-fetoprotein, tumor, and BHCG, tumor marker 
l. 
lumbar puncture for CSF microRNA study (optional). See section 14.8.3 
 
 
 
 

 
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GemPOx Consolidation for Recurrent or Progressive CNS Germ Cell Tumor 
Diagnosis:  
Name __________________________ 
          Provider _________________________ 
MRN 
_______________ 
DOB 
_______________ 
 
Consolidation 
Weight               kg 
Height               cm 
BSA               m2 
Cycle length 42 days, planned for 1 cycle 
Criteria to start each cycle: ANC 750 or greater, and platelets 75,000 or greater. 
 
CARBOplatin 
Calculate dose using both the Calvert formula and body size. 
Use the LOWER DOSE from the CALVERT FORMULA or the MAXIMUM DOSE 
 
CALVERT FORMULA based on age with target AUC = 7 mg•min/mL 
Dose calculated with the Calvert formula is the total dose in milligrams, not mg/ m2. 
 
AGE 0 to 9.99 years 
carboplatin total dose in mg = 7 x [ ( GFR in mL/min ) + ( 0.36 x weight in kg ) ] 
 
AGE 10 years and above 
Maximum GFR 125 mL/min 
carboplatin total dose in mg = 7 x [ ( GFR in mL/min ) + 25 ] 
 
MAXIMUM DOSE 
AGE 0 to 2.99 years         16.7 mg/kg/dose IV QDAY for 3 doses 
AGE 3 years and above  500   mg/m2/dose IV QDAY for 3 doses 
 
Give on Days –8, –7 and –6. Start at Hour 0. Infuse over 4 hours. 
thiotepa 
AGE 0 to 2.99 years          10 mg/kg/dose IV QDAY for 3 doses 
AGE 3 years and above  300 mg/m2/dose IV QDAY for 3 doses 
Give on Days –5, –4 and –3. Start at Hour 0. Infuse over 3 hours 
etoposide 
AGE 0 to 2.99 years           8.3 mg/kg/dose IV QDAY for 3 doses 
AGE 3 years and above  250   mg/m2/dose IV QDAY for 3 doses 
Give on Days –5, –4 and –3. Start at Hour 3. Infuse over 3 hours 
filgrastim 
5 mcg/kg/dose IV or subcutaneous QDAY. MAXIMUM DOSE  480 mcg 
Start on Day +1 
Continue until post nadir ANC is greater than 1000 for 3 consecutive days 
If the ANC is less than 500 on Day +21, then increase dose to 10 mcg/kg/dose 
 
Date 
Due 
Date 
Given 
Day 
CARBOplatin 
thiotepa 
etoposide 
filgrastim 
Observations 
 
 
– 8 
_______ mg 
 
 
 
a b c d e f h i j k l 
 
 
– 7 
_______ mg 
 
 
 
i 
 
 
– 6 
_______ mg 
 
 
 
 
 
 
– 5 
 
_______ mg 
_______ mg 
 
 
 
 
– 4 
 
_______ mg 
_______ mg 
 
 
 
 
– 3 
 
_______ mg 
_______ mg 
 
 
 
 
– 2 
 
 
 
 
 
 
 
– 1 
 
 
 
 
 
 
 
0 
Autologous Hematopoietic Progenitor Cell Rescue 
a d* e* 
 
 
+ 1 
 
 
 
_______ mcg 
 
 
 
+ 2 
 
 
 
 
 
 
 
+ 42 
 
 
 
 
a c d e g h i j k l 

 
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Observations 
a. height, weight, BSA 
b. HCG, urine qualitative for females of childbearing potential 
c. blood for alpha-1-fetoprotein, tumor and BHCG, tumor marker 
d. CBC with automated diff, reflex to manual. 
* Obtain at least twice weekly starting on Day 0 until engraftment. 
e. ALT, AST, bilirubin, BUN, creatinine, electrolytes, glucose, calcium, magnesium, phosphorous.  
* Obtain at least twice weekly starting on Day 0 until engraftment. 
f. 
Urinalysis 
g. Endocrine evaluation 
free T4, TSH, IGF1, IGFBP3, LH (males over age 10, females over age 9),  
FSH (males over age 10, females over age 9), testosterone (males over age 10),  
estradiol (females over age 9), Tanner stage, cortisol at 8 AM, BUN, creatinine, electrolytes, and  
urine specific gravity on first morning void. 
If any endocrine parameter is abnormal, then referral to a pediatric endocrinologist for further 
evaluation, dynamic testing, and treatment is required. 
h. Audiology evaluation 
i. 
Creatinine clearance or GFR renal scan 
j. 
MRI Brain and Spine 
k. lumbar puncture for Cytology, cell count CSF, alpha-1-fetoprotein, tumor, and BHCG, tumor marker 
l. 
lumbar puncture for CSF microRNA study (optional). See section 14.8.3