Conditions: Childhood Germ Cell Tumor Ovarian Cancer Teratoma
Keywords: childhood extragonadal germ cell tumor childhood malignant ovarian germ cell tumor childhood malignant testicular germ cell tumor stage III malignant testicular germ cell tumor testicular choriocarcinoma and seminoma testicular embryonal carcinoma and seminoma testicular embryonal carcinoma and teratoma with seminoma testicular embryonal carcinoma and yolk sac tumor with seminoma testicular yolk sac tumor and teratoma with seminoma testicular choriocarcinoma and embryonal carcinoma testicular choriocarcinoma and teratoma testicular choriocarcinoma and yolk sac tumor testicular choriocarcinoma testicular embryonal carcinoma and teratoma testicular embryonal carcinoma and yolk sac tumor testicular embryonal carcinoma testicular yolk sac tumor and teratoma testicular yolk sac tumor testicular seminoma stage IV extragonadal non-seminomatous germ cell tumor stage IV extragonadal seminoma stage I extragonadal non-seminomatous germ cell tumor stage I extragonadal seminoma stage II extragonadal non-seminomatous germ cell tumor stage II extragonadal seminoma stage III extragonadal non-seminomatous germ cell tumor stage III extragonadal seminoma stage II ovarian germ cell tumor stage I malignant testicular germ cell tumor stage II malignant testicular germ cell tumor adult teratoma childhood teratoma testicular immature teratoma testicular mature teratoma adult central nervous system germ cell tumor childhood central nervous system germ cell tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: no

Brief summary:
RATIONALE: Germ cell tumors (GCT) are highly sensitive to chemotherapy such that even with metastatic disease at diagnosis, many patients can be cured. Patients who fall into the poor risk category or others who relapse can be successfully salvaged with high dose chemotherapy and autologous stem cell transplant (AuSCT). As in other diseases such as myeloma, sequential high dose chemotherapy and AuSCT may improve overall and disease free survival.

PURPOSE: Because prior investigations in GCT suggest that a subset of high risk or relapsed patients may be cured with sequential cycles of high dose chemotherapy and AuSCT, we propose investigating how well non-cross resistant conditioning regimens work in treating patients with relapsed or high risk GCT.

Detailed description:
OBJECTIVES:

Primary

* Determine overall survival (OS) of patients with germ cell tumors treated with tandem autologous stem cell transplantation with non-cross-resistant conditioning regimens.

Secondary

* Determine disease-free survival (DFS) of patients treated with this regimen.
* Determine the toxicity of tandem transplants
* Determine the time to engraftment of neutrophils and platelets in patients treated for each transplant
* Determine the number of patients unable to adequately mobilize sufficient peripheral blood stem cells (PBSC) for tandem transplantation.
* Identify prognostic factors of patients unlikely to mobilize sufficient PBSC for tandem transplantation.
* Compare OS and DFS of patients undergoing single vs tandem transplantation.

OUTLINE:

* Peripheral blood stem cell (PBSC) mobilization with filgrastim (G-CSF): Patients receive G-CSF subcutaneously (SC) beginning on day 1 and continuing until stem cell collection is complete. Patients undergo stem cell collection beginning on day 5 of G-CSF administration and continuing for at least 3 collections until the collection goal is met.
* Second PBSC mobilization with chemotherapy: Patients not meeting the collection goal receive cyclophosphamide IV over 2 hours on day 1 and G-CSF SC beginning on day 4 and continuing until stem cell collection is complete. Patients meeting the collection goal after PBSC mobilization via G-CSF alone or in combination with chemotherapy will undergo tandem autologous transplantation. If collection goal is not met but the patient has collected \> or = 2 x 10\^6 CD34 cells/kg, a single autologous transplant will be performed.
* Single stem cell transplantation (SCT): Patients receive paclitaxel IV over 3 hours on day -7 and ifosfamide IV on days -6 to -4. Patients undergo reinfusion of stem cells on day 0. Patients also receive G-CSF SC or IV beginning on day 1 and continuing until blood counts recover.
* Tandem SCT: Patients receive treatment as in single SCT. Beginning 30-90 days later, patients receive carboplatin IV over 60 minutes and thiotepa IV over 30 minutes on days -6 to -4 and etoposide IV over 60 minutes on days -6 to -3. Patients undergo reinfusion of stem cells on day 0. Patients also receive G-CSF SC or IV beginning on day 5 and continuing until blood counts recover.

After completion of study treatment, patients are followed at 6, 9, and 12 months and then every 6 months for up to 2 years.

PROJECTED ACCRUAL: A total of 25 patients will be accrued for this study.

Arms:
arm 1: 2 Transplants: Patients with Germ Cell Tumors (GCT) treated with a second tandem autologous stem cell transplant (AuSCT) with non-cross-resistant conditioning regimens.

1 Transplants:Patients with Germ cell tumors who receive one transplant only.

Interventions: intervention 1: carboplatin intervention 2: etoposide intervention 3: ifosfamide intervention 4: paclitaxel intervention 5: thiotepa intervention 6: autologous hematopoietic stem cell transplantation intervention 7: Mesna intervention 8: filgrastim
Intervention descriptions: intervention 1: Days -6, -5, -4: 500mg/m2\^/day intravenously (IV) over 60 minutes intervention 2: 600mg/m\^2/day intravenously (IV) over 60 minutes on Days -6 through -3. intervention 3: 2500 mg/m\^2/day continuous infusion intravenously on Days -6, -5 and -4. intervention 4: 225 mg/m\^2 intravenous over 3 hours on Day -7. intervention 5: 150mg/m\^2/day intravenously IV over 30 minutes; Days -6, -5 and -4 intervention 6: Peripheral blood stem cell infusion (\< 4 x 10\^6 CD34+ cells/kg) intervention 7: 2500 mg/m\^2/day continuous infusion intravenously on Days -6, -5 and -4. intervention 8: Beginning Day 5, G-CSF 5 μg/kg/day until absolute neutrophil count (ANC) ≥ 1500/UL for 3 consecutive days.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
UNIVERSITY OF MINNESOTA BONE MARROW TRANSPLANTATION 
PROGRAM 
 
 
MT2005-21  
AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANT 
FOR GERM CELL TUMORS 
VERSION 4 
 
Principal Investigator: 
Najla El Jurdi, MD  
 
Co-Investigators: 
Claudio Brunstein, MD, PhD  
Daniel Weisdorf, MD 
Jeffrey S. Miller, MD 
Todd Defor, MS (Statistician) 
 
 
 
 
July 12, 2019


Auto PBSCT in GCT 
 
7/12/2019 
Page 2 of 29 
confidential 
TABLE OF CONTENTS 
 
SCHEMA …………………………………………..……………………………………. P4 
1.0 BACKGROUND AND RATIONALE….…………………………………………………..P6 
2.0 OBJECTIVES………………………………………………..………………………….P9 
3.0 ELIGIBILITY AND EXCLUSION CRITERIA………………………………………………P9 
4.0 SUBJECT REGISTRATION…………………………..…………………………………P11 
5.0 TREATMENT PLAN……………………………..…………………………………….P12 
6.0 REQUIRED OBSERVATIONS………………………………………………………..…P16 
7.0 TRANSPLANT RELATED TOXICITIES AND COMPLICATIONS……………….………….P17 
8.0 ADVERSE EVENT REPORTING………………………………………………………..P20 
9.0 DATA AND SAFETY MONITORING……………………………………………………P21 
10.0 EXPERIMENTAL DESIGN AND STATISTICAL CONSIDERATIONS……………………..P22 
10.0 RETENTION OF RECORDS…………………………………….……………………..P23 
11.0 REFERENCES………………………………………………………………………..P23 
APPENDICIES 
APPENDIX I:  INTERNATIONAL GERM CELL CANCER CONSENSUS CLASSIFICATION 
APPENDIX II:  KARNOFSKY AND LANSKY PERFORMANCE SCALE 
APPENDIX III: REQUIRED OBSERVATIONS  
APPENDIX IV:  RECIST CRITERIA FOR MEASUREMENT OF DISEASE RESPONSE 
 
 
PI Contact Information: 
Najla El Jurdi, MD 
Division of Hematology/Oncology/Transplantation 
MMC 480 
420 Delaware Street SE 
Minneapolis, MN 55455 
612 625-8942 (phone) 
neljurdi@umn.edu (email) 


Auto PBSCT in GCT 
 
7/12/2019 
Page 3 of 29 
confidential 
Revision History 
 
Date 
Revision details 
Consent change/ 
version date 
1-29-07 
The goal collection is 10 X 106 CD34+ cells/kg instead of 6 X 106 
CD34+ cells/kg to reflect a goal of 5 x106 CD34+ cells/kg for infusion 
for each transplant. 
 
3-13-2008 
Clarified exclusion criteria to state that patients with progressive 
disease will not be eligible for a second transplant,  added RECIST 
criteria (as appendix IV), fixed typo in section 5.5 
Removed Dr. Nasfat Shehadeh from protocol team 
 
6-15-09 
Dr. Brian McClune takes over as PI; Dr Tomblyn removed from study 
 
9/9/2009 
Typo correction in schema  
 
9/27/2010 
Typo correction in schema 
 
1/10/11 
Error correction in peds fluid hydration rate 
 
09/12/2018 
Dr Brunstein is PI 
 
07/12/2019 
Dr. El Jurdi takes over as Principal Investigator 
Y 
 
 
 
 
 


Auto PBSCT in GCT 
 
7/12/2019 
Page 4 of 29 
confidential 
SCHEMA 
 
MOBILIZATION AND STEM CELL COLLECTION 
 
Subject Enrollment 
 
 
PBSC Mobilization with G-CSF 
G-CSF 10 µg/kg/day beginning  on day 1 and ending when stem cell collection is complete 
Stem Cell Collection 
Apheresis begins day 5 of G-CSF with the goal of collecting 10 x 106 CD34 cells/kg from a 
minimum of 3 collections unless the collection goal is met. 
Minimum collection criteria for continuing collection: 
≥ 0.1 x 106 CD34 cells/kg after first collection AND a total of ≥  0.3 x 106 CD34 cells/kg after 
second collection or collection is discontinued and move forward with chemotherapy 
mobilization. 
 
Continue based on number of cells collected: 
Total Collection of  ≥ 4 x 106 
CD34 cells/kg 
 
Collection of < 4 x 106 CD34 
cells/kg  
 
 
 
 
Eligible for Tandem transplant 
(see next page) 
 
2nd PBSC Mobilization with 
chemotherapy  
cyclophosphamide 4gm/m2 day 1 
G-CSF 10 µg/kg/day begin 72 
hours  later (day 4)  
Resume collections first day 
after ANC > 700 
(if minimum collection criteria from 
above not met and total collection 
< 2 x 106 CD34/kg– off study, 
explore other options) 
 
 
 
 
 
 
Collection of  ≥ 2 x 106 CD34 but  
< 4 x 106 CD34 cells/kg 
 
 
 
 
 
 
Eligible for Single transplant 
(see next page) 
 


Auto PBSCT in GCT 
 
7/12/2019 
Page 5 of 29 
confidential 
 
 
TRANSPLANT 
 
Admit within 2 weeks of completing Cell Collection  
 
Tandem Transplant (Transplant 1 and 2) 
Single Transplant (Transplant 1 only) 
 
Transplant 1 (all subjects) 
Day 
Treatment  
-8 
Admission for IV fluids 
-7 
Paclitaxel 
-6 
Ifosfamide + Mesna 
-5 
Ifosfamide + Mesna 
-4 
Ifosfamide + Mesna 
-3 
Rest 
-2 
Rest 
-1 
Rest  
0 
Cell re-infusion (transplant) 
+5 
G-CSF 5 µg/kg/day until ANC ≥ 1500/UL 
for 3 consecutive days 
 
 
Assess for Transplant 2  
admission for transplant must be no earlier 
than day +30 and no later than day +90  
(goal day +40- +60) 
If not eligible for transplant 2 
  
If eligible, admit for transplant 2 
 
 
 
Standard transplant follow-up 
(see appendix IIIA) 
 
 
 
 
 
Transplant 2 (if eligible) 
Day 
Treatment  
-7 
Admit, begin hydration 
-6 
carboplatin, thiotepa, etoposide 
-5 
carboplatin, thiotepa, etoposide 
-4 
carboplatin, thiotepa, etoposide 
-3 
etoposide 
-2 
rest 
-1 
rest 
0 
Cell re-infusion (transplant) 
+5 
G-CSF 5 µg/kg/day until ANC ≥ 
1500/UL for 3 consecutive days 
 
 
 
 
Standard transplant follow-up  
(see appendix IIIB) 
 
 
  


Auto PBSCT in GCT 
 
7/12/2019 
Page 6 of 29 
confidential 
                            
 
1.0 
Background And Rationale 
 
1.1 BACKGROUND 
 
Germ cell tumors (GCT) are highly sensitive to chemotherapy such that even with 
metastatic disease at diagnosis, many patients can be cured—greater than 90% 5-year 
overall survival—at the time of diagnosis1.  The International Germ Cell Consensus 
Classification divides patients based on risk factors into good, intermediate and poor 
prognostic categories to better estimate outcomes [Appendix I]2.  Many patients who 
fall into the poor risk category or other patients who relapse are successfully 
salvaged with high dose chemotherapy and autologous stem cell transplant 
(AuSCT)3-6.   
 
Beyer and colleagues analyzed 310 patients at four institutions to determine 
prognostic factors in patients with relapsed GCT treated with AuSCT7.  Four factors 
were found to be important in multivariate analysis (Beyer Index):   
• progressive disease after salvage therapy immediately prior to transplant 
• absolute cisplatin refractory disease (defined as progressive increase in serum 
markers despite on-going cisplatin chemotherapy) or cisplatin refractory disease 
(defined as disease progression within 4 weeks of a the last cycle of 
chemotherapy)  
• an hCG level of > 1000 IU/L  
• primary mediastinal non-seminomatous GCT 
 
Patients with more than 2 of these factors were considered poor risk with a 2 year 
relapse free survival of only 5% versus 51% for patients with no risk factors and 27% 
in patients with 1 or 2 risk factors.   
 
There are other diseases, such as myeloma, in which sequential high dose 
chemotherapy and AuSCT have demonstrated improved overall and disease free 
survival8.  Prior investigations in GCT suggest that a subset of high risk or relapsed 
patients may be cured with sequential cycles of high dose chemotherapy and 
AuSCT4,9.  Interestingly, in the initial prognostic study by Beyer, only 20% of 
patients were treated with two transplants.  An initial pilot study from Margolin et al, 
demonstrated feasibility of tandem high-dose chemotherapy with AuSCT in a cohort 
of patients with either high-risk primary disease in partial response or platinum-
sensitive relapse9.  Both conditioning cycles consisted of ifosfamide, carboplatin, and 
etoposide (ICE).  Treatment related mortality was zero and at almost 4 years, 9 of 20 
patients enrolled were alive and disease-free.  Other studies have looked at sequential 
therapy with regimens including paclitaxel, a drug found effective in cisplatin-
refractory patients10.   A recent study utilized paclitaxel in both conditioning 
regimens in 33 patients11.  At a median follow-up of 5 years, 36% of patients were 


Auto PBSCT in GCT 
 
7/12/2019 
Page 7 of 29 
confidential 
alive without disease although only 2 (18%) patients with a Beyer index of ≥ 2 
remained progression-free after therapy.  Table 1 gives a summary of several studies 
investigating AuSCT for GCT. 
 
 
1.2 RATIONALE 
 
The use of either non-cross resistant therapy or more than two high dose therapy 
cycles are areas of interest4,10.  In this study, we propose to use tandem transplant 
with non-cross resistant conditioning regimens to further study these issues.  Pre 
clinical and clinical studies have found that taxanes can salvage patients with 
cisplatin-refractory GCT10-14.  As documented in Table 1, most prior studies have not 
used non-cross resistant conditioning regimens for AuSCT but rather identical 
conditioning for both transplants.  We propose that patients with high-risk or 
relapsed disease may benefit from using chemotherapeutic agents that have differing 
mechanisms of action and differing resistance patterns as high dose therapy.  This 
would permit tumor kill prior to development of further resistance.   
 
Mobilization of sufficient numbers of peripheral blood stem cells may not occur in 
all patients.  For those patients collecting ≥ 2 x 106 CD34+ cells/kg but < 4 x 106 
CD34+ cells/kg, only a single transplant can safely be performed.  However, it would 
be inappropriate to deny them AuSCT which is a demonstrated salvage regimen with 
potential for cure.  This protocol accounts for this possibility by providing a 
treatment option for patients with insufficient PBSC collection for tandem 
transplantation.  The conditioning regimen for the single transplant is identical to the 
conditioning regimen of Transplant 1 for planned tandem patients. 
 


Auto PBSCT in GCT 
 
7/12/2019 
Page 8 of 29 
confidential 
Table 1 
Author 
Study Type 
Treatment 
Patients 
N 
Response 
EFS 
OS 
Vaena15 
Retrospective 
Carbo + VP16 conditioning; 
tandem AuSCT if possible 
Relapsed, cisplatinum 
refractory 
80 (56 received 
x2 AuSCT) 
45% 
32% (2y) 
40% (2y) 
Rick16 
Phase II 
TIP x3 then 
Carbo+VP16+TT 
conditioning 
Relapsed disease 
80 (62 SCT) 
78% (of patients 
transplanted) 
25% (3y) 
30% (3y) 
Motzer10 
Phase I/II 
Paclitaxel + Ifos x 2 then 
Carbo + VP16 conditioning 
Relapsed cisplatinum 
refractory and poor 
prognostic features 
37 
62% 
49% (31 
months) 
54% (31 
months) 
Motzer17 
Phase II 
Carbo + VP16 + Cy; tandem 
AuSCT if possible 
Relapsed/refractory 
disease 
58 (27 received 
x2 AuSCT) 
40% CR 
21% (2y) 
31% (2y) 
Bhatia3 
Retrospective 
Carbo + VP16 x2 
Relapsed/refractory 
disease 
65 (58 received 
x2 AuSCT) 
63% CR 
57% (3y) 
68% (3y) 
Nichols6 
Phase II 
(multicenter) 
Carbo + VP16; x2 if possible 
Relapsed or 
refractory disease 
38 (22 received 
x2 AuSCT) 
45%  
(24% CR) 
13% (1y) 
35% (1y) 
Mandanas5 
Retrospective 
Cy + Carbo + VP16 (68% of 
patients) 
Relapsed or 
refractory 
21 (1 received x2 
AuSCT) 
79% 
52% (3y) 
52% (3y) 
Lotz4 
Phase II 
(multicenter) 
Epi + Paclitaxel x2 then TT 
+CY conditiong for SCT1 
then ICE conditioning for 
SCT 2 and 3 
Relapsed, poor 
prognosis disease 
45 (7 received x2 
SCT, 22 x3 SCT) 
38% 
24% (3y) 
24% (3y) 
Rosti18 
Retrospective 
Carbo + VP16 (19); ICE 
(30); Carbo + VP16 + CY 
(35) 
Relapsed disease 
84 (19 received 
x2 SCT, 1 x 3 
SCT) 
45% CR 
30% (5y) 
33% (5y) 
Margolin9 
Phase I/II 
ICE conditioning; tandem 
AuSCT 
Poor prognosis, 
chemotherapy 
sensitive disease 
20 (18 received 
x2 AuSCT) 
60% 
45% (3y) 
45% (3y) 
Margolin11 
Phase I/II 
Paclitaxel + Carbo + VP16 
(SCT1); Paclitaxel + Carbo + 
Ifosfamide (SCT2) 
Relapsed or 
refractory GCT 
33 (2 received no 
SCT; 19 received 
x2 AuSCT) 
Not reported 
36% (5y) 
42% (5y) 
Carbo = carboplatinum, VP16 = etoposide, TT = thiotepa, Cy = cyclophosphamide, Epi = epirubicin, ICE = Ifosfamide + Carboplatinum + Etoposide 
EFS = Event-free survival, OS = overall survival, Response = CR + PR unless otherwise stated


Auto PBSCT in GCT 
 
7/12/2019 
Page 9 of 29 
confidential 
2.0 
ObjectiveS 
 
End organ toxicities such as myelosuppression often dictate the maximal doses of 
chemotherapy that can be administered safely.  Autologous peripheral blood stem 
cell transplant (AuSCT) after high-dose chemotherapy circumvents this marrow 
toxicity allowing for dose intensification.  This has been demonstrated to be useful in 
the salvage setting for patients with relapsed germ cell tumor (GCT)3-6  The use of 
non-cross resistant chemotherapy regimens should increase the overall and disease-
free survival in patients with high risk or relapsed GCT. 
 
    2.1  Primary Objective 
To determine overall survival for patients with GCT treated with tandem AuSCT 
with non-cross-resistant conditioning regimens. 
 
2.2  Secondary Objectives 
2.2.1 To determine disease-free survival for patients with GCT treated with 
tandem AuSCT with non-cross-resistant conditioning regimens 
2.2.2 Evaluate toxicity of tandem AuSCT 
2.2.3 Evaluate time to engraftment of neutrophils and platelets for each 
transplant 
2.2.4 Determine numbers of patients unable to adequately mobilize 
sufficient peripheral blood stem cells (PBSC) for tandem transplant 
2.2.5 Identify prognostic factors of those patients unlikely to mobilize 
sufficient PBSC for tandem transplant 
2.2.6 Compare outcomes of overall and disease free survival for patients 
undergoing single versus tandem transplant due to biologic 
randomization 
 
3 Eligibility Criteria 
     
3.1 
Diagnosis: Poor Prognosis Non-Seminomas Germ Cell Tumor in ≥ 
PR1/CR1 or Good or Intermediate Prognosis Seminomas and Non-
Seminomas Germ Cell Tumor in  ≥ PR1 or ≥ CR2 as defined by the 
International Germ Cell Cancer Consensus Classification (appendix I) 
Patients with increasing tumor markers only (i.e. no imaging evidence of 
progressive disease) are eligible for transplant. 
 
3.2 
Age: ≥ 10 years and < 70 years of age. 
 
3.2 
Performance status: Karnofsky ≥ 80%  (subjects ≥ 16 years of age) 
Lansky  ≥ 80%  for subject 10 – 15 years of age   [Appendix II] 
 
3.3 
Life expectancy: Greater than 8 weeks. 


Auto PBSCT in GCT 
 
7/12/2019 
Page 10 of 29 
confidential 
 
3.4 
Patients must have normal organ function as defined below: 
 
3.4.1 Hematologic:   
Hemoglobin > 8 gm/dL without transfusion and off erythropoietin 
for 14 days or Aranesp for 21 days 
WBC > 2.5 x 109/L with an ANC > 1.5 x 109/L and off G-CSF or 
GM-CSF for 10 days or Neulasta for 21 days 
Platelets > 100 x 109/L without transfusion and/or a bone marrow 
cellularity of ≥ 20% 
3.4.2 Renal: Creatinine ≤ 2.0 mg/dl or creatinine clearance > 50 ml/min. 
3.4.3 Hepatic: Total bilirubin ≤ 2.0 mg/dl, AST and alkaline phosphatase 
< 5 x upper limit of normal.  No history of severe prior or ongoing 
chronic liver disease. 
3.4.4 Cardiac:  Patients must be free of symptoms of uncontrolled 
cardiac disease including unstable angina, decompensated 
congestive heart failure, or arrhythmia.  LVEF ≥45% by 
MUGA/ECHO 
3.4.5 Pulmonary:  Patients must have no significant obstructive airways 
disease (FEV1 must be ≥ 50% of predicted) and must have 
acceptable diffusion capacity (corrected DLCO > 50% of 
predicted). 
 
3.5 Patients with a history of CNS tumor involvement are eligible if they have 
completed treatment for CNS disease (radiotherapy or surgery or 
chemotherapy), have recovered from or stabilization of the side effects 
associated with the therapy and have no evidence of progressive CNS disease 
at the time of enrollment 
 
3.6 Patients with serious uncontrolled infections will not be eligible. 
 
3.7 Male and female patients of reproductive potential must use an approved 
contraceptive method if appropriate (for example, intrauterine device [IUD], 
birth control pills, or barrier device) during and for the duration of study 
participation. The drugs used in this study are pregnancy category D – clear 
evidence of risk in pregnancy.  Pregnant and breast feeding women will not be 
eligible. 
 
3.8 Voluntary written informed consent before performance of any study-related 
procedure not part of normal medical care, with the understanding that consent 
may be withdrawn by the subject at any time without prejudice to future 
medical care. 
 
 


Auto PBSCT in GCT 
 
7/12/2019 
Page 11 of 29 
confidential 
3.9 Additional Eligibility prior to Transplant Two  
3.9.1 
Total Collection of  ≥ 4 x 106 CD34 cells/kg prior to transplant 
one  
 
3.9.2 
Transplant able to occur between day +30 and day +90 from 
transplant one 
 
3.9.3 
Recovery of blood counts as demonstrated by: 
WBC > 2.5 x 109/L with an ANC > 1.5 x 109/L and off G-CSF for 
3 days  
  
Platelets > 50 x 109/L without transfusion in the prior 7 days 
 
3.9.4 
Renal: Creatinine ≤ 2.0 mg/dl or creatinine clearance > 50 ml/min  
 
3.9.5 
Hepatic: Total bilirubin ≤ 2.0 mg/dl, AST and alkaline 
phosphatase < 5 x upper limit of normal 
 
3.9.6 
Infection:  Patients with serious uncontrolled infections at the time 
of planned transplant will be excluded 
 
3.9.7 
Patients with progressive disease by RECIST criteria (Appendix 
IV) by imaging techniques are not eligible to proceed to the 
second transplant.  Tumor marker increase alone is not sufficient 
to diagnose disease progression.  
 
4 
Subject Registration 
 
Informed consent must be signed prior to the performance of any study related 
procedures or assessments. 
 
To be eligible for registration to this study, the patient must meet each criteria listed 
on the eligibility checklist based on the eligibility assessment documented in the 
patient’s medical record.  No exemptions or waivers will be granted for patients 
who do not meet the eligibility criteria. 
 
4.1 Registration with the University of Minnesota Clinical Trials Office (CTO) 
To register a patient to this study, complete the Subject Registration Form and 
study specific eligibility checklist and fax it to the Clinical Trials Office 
Registrar at (612) 625-3624.  Confirmation of registration with the study 
assigned patient ID number will be returned by email and/or fax within 1 
working day.  
 
4.2 Patients who are registered and do not begin study treatment 


Auto PBSCT in GCT 
 
7/12/2019 
Page 12 of 29 
confidential 
 
If a patient is registered to the study, and is later found not able to begin the 
planned study treatment, for whatever reason, the patient will be removed 
from study and treated at the physician’s discretion.  The CTO Registrar will 
be notified of the patient’s non-treatment status. Study data will be collected 
until the time the patient is off study.  The reason for removal from study will 
be clearly indicated on the case report forms.  The registration number cannot 
be reassigned. 
 
 
5 TREATMENT PLAN 
 
5.1 G-CSF Mobilization of Peripheral Blood Hematopoietic Stem Cells 
 
Patients will be treated with Granulocyte colony stimulating factor (G-CSF) 
10µg/kg/day (rounded to the nearest vial size) beginning 5 days before the 
first planned apheresis and continuing until the last aphereresis. 
 
Begin peripheral blood stem cell collection per section 5.2 on day 5 of G-CSF 
mobilization.  
 
5.2 Peripheral blood stem cell collection 
 
Daily peripheral blood stem cell collection will continue for a minimum of 3 
days unless the goal of 10 x 106 CD34+/kg is reached earlier. 
 
Minimum collection criteria for continuing collection: 
The first collection must yield ≥ 0.1 x 106 CD34 cells/kg  
After the second collection a total of ≥ 0.3 x 106 CD34 cells/kg must have 
been collected.  If either of these conditions is not met, apheresis is 
discontinued and the subject will begin Chemotherapy Mobilization per 
section 5.3.   
 
Total cell collection of  ≥ 4 x 106 CD34+ cells/kg  
A total cell collection of ≥ 4 x 106 CD34+ cells/kg is considered sufficient for 
the tandem transplant (Transplant 1 plus Transplant 2).  The collected PBSC 
will be cryopreserved such that approximately 50% of the leukapheresed 
product can be thawed and infused for each transplant.  Patient will proceed to 
transplant 1 per section 5.4. 
 
Total cell collection of ≥ 2 x 106 CD34+ cells/kg but < 4 x 106 CD34+ 
cells/kg 
If patients cannot be adequately collected with GCSF mobilization (< 4 x 106 
CD34+ cells/kg) Chemotherapy Mobilization will be done per section 5.3. 


Auto PBSCT in GCT 
 
7/12/2019 
Page 13 of 29 
confidential 
 
5.3 Chemotherapy Mobilization and cell collection (for patients with a total cell 
collection of < 4 x 106 CD34+ cells/kg) 
 
 
Chemotherapy mobilization: 
Mesna 800mg/m2 IV  
Cyclophosphamide 4gm/m2 intravenously (IV) over 2 hours 
Mesna 800mg/m2 IV 3 hours, 6 hours, 9 hours, and 12 hours following the 
cyclophosphamide 
G-CSF 10µg/kg/day (rounded to nearest vial size) beginning 72 hours 
after completion of cyclophosphamide (day 4) and continuing until 
leukapheresis is completed 
 
The dose of cyclophosphamide will be calculated using actual body 
weight unless the patient is ≥120% of Ideal Body Weight (IBW) in which 
case, the Cyclophosphamide dose will be based on Adjusted Ideal Body 
Weight (AIBW). 
 
IBWmen =  50kg + 2.3kg (inches of height over 60in) 
IBWwomen = 45kg + 2.3kg (inches of height over 60in) 
 
AIBW = IBW + 1/3(ABW - IBW) 
 
Standard Cyclophosphamide hydration orders will be used. 
 
Monitor CBC daily starting on day 4.  Leukapheresis will start on the first 
day following an absolute neutrophils count (ANC) ≥ 700/µL. 
 
Minimum collection criteria for continuing collection: 
The first collection must yield ≥ 0.1 x 106 CD34 cells/kg  
After the second collection a total of ≥ 0.3 x 106 CD34 cells/kg must have 
been collected.   
If patient has received chemotherapy mobilization and the minimum criteria 
cannot be met, the cell collection should be stopped.  If the patient has 
collected > 2 x 106 CD34 cells/kg with the combined aphereses, the patient is 
eligible for a single transplant.  If the total collections are < 2 x 106 CD34 
cells/kg, the patient is removed from study, and other treatment options 
discussed. 


Auto PBSCT in GCT 
 
7/12/2019 
Page 14 of 29 
confidential 
 
5.4 Transplant One   
 
Admit for transplant within two weeks of completing cell collection. 
 
Day 
Drug 
Administration 
-8 (Admit) 
 
Admit to start premedications per section 5.4.1 and 
hydration per section 5.4.2  
- 7 
Paclitaxel 
225 mg/m2 IV over 3 hours starting at 0900 
• Dilute in 5% dextrose or 0.9% saline to a 
concentration of 0.3 – 1.2 mg/mL 
• Administer using a 0.22µM filter and polyethylene-
lined administration set 
-6, -5, -4 
Ifosfamide 
Mesna 
2500mg/m2/day continuous infusion IV starting at 0900 
2500mg/m2/day continuous infusion IV starting at 0900 
• See section 5.4.3 for ifosfamide dose calculation 
• Combine mesna and ifosfamide in 1L D5W 
0 
 
PBSC infusion 
+5 until ANC ≥ 
1500/µL for 3 
consecutive days 
G-CSF 
5µg/kg/day (round to nearest vial size) SC or IV.  May 
be restarted if ANC falls below 1000/µL 
 
5.4.1 Premedication for Paclitaxel administration 
• Dexamethasone 20 mg PO at 12 hours and 6 hours before 
administration.  For pediatric patients, 5 mg/m2 q 12 hrs 
 
• Diphenhydramine 50mg IV 30 minutes before administration.  For 
pediatric patients, 1 mg/kg q 6 hrs 
 
• Ranitidine 50mg IV 30 minutes before administration. For 
pediatric patients, 1-2 mg/kg/day divided q 8 hrs 
 
5.4.2 Hydration 
Normal Saline at 100mL/hour starting 10 hours before paclitaxel 
administration.  For pediatric patients, slower infusion rates may 
be used with a goal infusion of 1500 ml/m2 over 24 hours 
 
At the completion of paclitaxel infusion, hydration should be 
increased to 2000 – 3000 mL/m2/day until 24 hours after 
completion of ifosfamide.   
 
Adequate diuretics should be given and patients urged to urinate 
every 1 - 2 hours to ensure urinary output of at least 200 mL every 
2 hours and to maintain appropriate fluid balance.  Patients should 


Auto PBSCT in GCT 
 
7/12/2019 
Page 15 of 29 
confidential 
be weighed BID during ifosfamide administrations to aid in 
managing fluid balance. 
 
 
5.4.3 Dosing of Ifosfamide 
 
Dosing of ifosfamide will be per actual body weight unless the patient 
is ≥120% of Ideal Body Weight (IBW) in which case, the Ifosfamide 
dose will be based on Adjusted Ideal Body Weight (AIBW) 
 
IBWmen =  50 kg + 2.3kg (inches of height over 60in) 
IBWwomen = 45 kg + 2.3kg (inches of height over 60in) 
 
AIBW = IBW + 1/3(ABW - IBW) 
 
For patients qualifying to have only a single transplant (due to a collection of < 4 
x 106 CD34+ cells/kg) follow-up will be per appendix IIIA. 
 
For patients qualifying to have a tandem transplant (transplant one and transplant 
two), study participation will continue per section 5.5. 
 
 
5.5 Transplant Two 
Admission for transplant two will be no earlier than day 30 from first 
transplant and no later than day 90.  Goal for admission is day 40-60.  See 
section 3.9 for additional eligibility criteria for continuing with transplant 2. 
 
 
Day 
Drug 
Administration 
-7 (Admit) 
 
Admit to start hydration per section 5.5.1  
-6, -5, -4 
Carboplatin 
500mg/m2/day IV over 60 minutes 
-6, -5, -4 
Thiotepa 
150mg/m2/day IV over 30 minutes; see section 5.5.2 
for skin care 
-6, -5, -4, -3 
Etoposide 
600mg/m2/day IV over 60 minutes 
0 
 
PBSC infusion 
+5 until ANC 
≥ 1500/µL for 
3 consecutive 
days 
G-CSF 
5µg/kg/day (round to nearest vial size) SC or IV.  May 
be restarted if ANC falls below 1000/µL 
 
5.5.1 Hydration 
0.45% saline at 100mL/hour starting 10 hours before chemotherapy 
administration.  
For pediatric patients, slower infusion rates may be used with a goal 
infusion of 1500ml/m2 over 24 hours 
 


Auto PBSCT in GCT 
 
7/12/2019 
Page 16 of 29 
confidential 
5.5.2 Thiotepa 
Because Thiotepa can be excreted through the skin, the following 
precautions should be followed until 24 hours after the last dose is 
given: 
• Beginning 3 – 4 hours after the first dose, bathing with soap and 
water should be done 3 – 5 times per day and pat dry to avoid 
skin irritation. 
• Change lines, clothes, and central line dressing after each bath 
• Avoid moisturizer, barrier creams, antiperspirants, and 
deodorants during treatment 
 
6 Required Observations (Appendix III A and III B) 
 
6.1 Required observations are listed in Appendix III.  The required observations for 
Transplant 1 (Appendix IIIA) will continue until 2 weeks before admission for 
Transplant 2 (Appendix IIIB).   
 
6.1.1 If the patient is not eligible to move forward to Transplant 2 (see 
section 3.11) then all required observations for Transplant 1 will 
continue.   
6.1.2 If the patient is eligible for Transplant 2 between day +30 and day +90, 
then the required observations for Transplant 2 will become effective at 
the time eligibility is determined.  If the patient has had investigations 
performed (i.e. serum tumor markers on day +42) within the 2 weeks 
prior to admission for Transplant 2 (day +50 scheduled admission), 
these will not need repeated and the values obtained from the 
Transplant 1 observations will be used. 
 
6.2 Staging studies prior to enrollment to define the extent of disease will include 
unilateral bone marrow aspiration and bilateral bone marrow biopsy, PET/CT 
scans of chest, abdomen, pelvis and brain, serum tumor markers including AFP, 
β-hCG, and LDH 
 
If patient has had no prior bone marrow involvement, then bone marrow 
biopsies will be performed to determine eligibility and then at yearly intervals 
unless otherwise clinically indicated. 
 
6.3 Imaging will be performed prior to enrollment in study; at Day +28, at Day 
+100, at Day +180, at 1 year and then at 6 month intervals in the second post-
transplant year. Day +28 staging will be with a CT scan only.  All other imaging 
will be with a PET/CT. 
 
6.4 Serum tumor markers including AFP, β-hCG, and LDH will be checked every 2 
weeks from transplant until day+100 and then at 6, 9, and 12 months post 


Auto PBSCT in GCT 
 
7/12/2019 
Page 17 of 29 
confidential 
transplant.  After 1 year, tumor markers will be checked every 6 months until 2 
years post-transplant. 
 
 
7 Transplant Related Toxicities and Complications 
 
7.1 G-CSF mobilization:  
 
Frequency 
Toxicity 
Common 
• Bone or muscle aches 
• Fever or chills 
• Discomfort at the injection site 
• Malaise 
Uncommon 
• Skin rash 
• Headache 
Rare 
• Polyserositis 
  
 
7.2 Peripheral blood stem cell collections 
 
Frequency 
Toxicity 
Common 
• Mild discomfort at the site of catheter placement 
Uncommon 
• Hypotension 
• Thrombocytopenia might develop transiently following 
the leukopheresis and, if necessary, irradiated Blood 
Bank platelet concentrates will be transfused. 
 
 
7.3 Chemotherapy Mobilization: 
 
Cyclophosphamide (Cytoxan) 
Frequency 
Toxicity 
Common 
• Nausea and vomiting (aggressive anti-emetic therapy 
may minimize) 
• Diarrhea  
• Alopecia usually reversible, but changes in hair color or 
texture after regrowth may occur 
• Permanent sterility is likely at this dose of 
cyclophosphamide, particularly when given with other 
drugs 
Uncommon 
• Skin rash  
• Hemorrhagic cystitis may occur following the use of 
cyclophosphamide despite aggressive fluid replacement, 
frequent voiding and Mesna  


Auto PBSCT in GCT 
 
7/12/2019 
Page 18 of 29 
confidential 
Rare 
• Pericarditis 
•  Cardiomyopathy: cyclophosphamide can cause fatal 
cardiac necrosis with clinical irreversible heart failure.  
•  EKG changes are not infrequent and reduction in EKG 
voltage may be observed. Patients with compromised 
ejection fraction, previously treated with anthracyclines, 
or with mediastinal irradiation may be at higher risk. 
 
Plus G-CSF (see section 7.1) 
 
 
7.4 Transplant 1 
 
Paclitaxel (Taxol) 
Frequency 
Toxicity 
Common 
• Nausea and vomiting 
• Diarrhea 
• Mucositis 
• Alopecia 
Uncommon 
• Hypersensitivity reactions characterized by generalized 
skin rash, flushing, erythema, hypotension, dyspnea, 
and/or bronchospasm.  Usually occurs within the first 2 
– 10 minutes of infusion and is decreased by pre-meds 
• Transient Bradycardia  
• Peripheral Neuropathy - generally numbness and 
paresthesias 
Rare 
• Arrythmias including Mobitz I, Mobitz II, 3rd degree 
heart block, and Ventricular arrhythmias  
• Motor and autonomic neuropathies 
 
 
Ifosphamide (Ifex) 
Frequency 
Toxicity 
Common 
• Nausea and vomiting with associated anorexia.  An 
aggressive anti-emetic regimen should be used including 
prophylactic serotonin antagonists plus dexamethasone 
prior to infusion. 
• Alopecia usually reversible but changes in hair color or 
texture after regrowth may occur 
Uncommon 
• Hemorrhagic cystitis may occur despite aggressive fluid 
replacement, frequent voiding, and Mesna 
Rare 
• Neurotoxicity including lethargy, confusion, weakness 
and hallucinations may occur.  This is more common in 
patients with impaired renal function 
 


Auto PBSCT in GCT 
 
7/12/2019 
Page 19 of 29 
confidential 
Plus G-CSF (see section 7.1) 
 
 
 
 
7.5 Transplant 2 
 
Carboplatin (Paraplatin) 
Frequency 
Toxicity 
Common 
• Nausea and vomiting 
• Hypocalcemia 
• Hypokalemia 
• Hypomagnesemia 
Uncommon 
• Peripheral neuropathy 
• Hyponatremia 
• Renal toxicity 
Rare 
• Allergic reaction with infusion presenting as a skin rash, 
urticaria (hives), and pruritis (itching) 
 
 
Thiotepa (Thioplex) 
Frequency 
Toxicity 
Common 
• Nausea and vomiting 
• Mucositis 
• Skin changes including rash, bronzing of the skin, 
erythema, flaking, and desquamation 
Uncommon 
• Allergic reaction including skin rash, hives, and rarely 
bronchospasm 
Rare 
• Hemorrhagic cystitis 
 
 
Etoposide (VP-16) 
Frequency 
Toxicity 
Common 
• Nausea and vomiting 
• Diarrhea  
• Mucositis 
Uncommon 
• Hypersensitivity reaction with chills and fever 
Rare 
• Bronchospasm during infusion 
• Hypotension (low blood pressure) during infusion 
 
 
7.6 Myelosuppression 
 
7.6.1 Both the chemomobilization and the pre-transplant conditioning 
(chemotherapy) induce significant myelosuppression requiring re-


Auto PBSCT in GCT 
 
7/12/2019 
Page 20 of 29 
confidential 
infusion of viable hematopoietic stem cells for prompt hematologic 
recovery.  
7.6.2 During the period of pancytopenia, the patient is highly vulnerable to 
infection and/or bleeding. Irradiated red cell transfusions will be given 
to maintain adequate oxygen delivery (hemoglobin > 8.0 gm/dL) and 
platelet transfusions will be given in an attempt to maintain a platelet 
count >10 x 109/L.  
7.6.3 Prophylactic measures to reduce risks of infection and to vigorously 
treat any infections will also be required according to UMMC BMT ID 
guidelines. 
 
7.7 Second malignancy 
The potential carcinogenic effects of the pre-transplant chemotherapy and 
may compound the inherent risks of second malignancy already induced by 
treatment the patient may have already received. Both late second epithelial 
malignancies and early treatment-associated neoplasms (particularly 
myelodysplastic syndrome and/or leukemia) may develop after 
transplantation. 
 
8 Adverse Event Reporting   
Toxicity and adverse events will be classified according to NCI's Common 
Terminology Criteria for Adverse Events V 4.0 (CTCAE).  A copy of the CTCAE 
can be downloaded from the CTEP home page (http://ctep.cancer.gov). 
 
8.1  Reporting Requirements 
 
For the purposes of this study, all subjects will be monitored at least monthly 
continuously for all serious unexpected and selected serious adverse events (SAE) 
during the first 100 days after cell infusion.  SAEs include:  graft failure (severe 
pancytopenia with a marrow cellularity <5% at day +28 post transplant), relapse, 
and death.   
 
Toxicities, complications of therapy and other adverse events, which are 
considered expected as part of therapy in general, are listed in section 7 of the 
protocol. 
 
In the event of an adverse event, the first concern will be for the safety of the 
subject.  Investigators are required to contact the PI (Dr. Claudio Brunstein,) to 
discuss the event and subject care.   
 
 
 
 
 
 


Auto PBSCT in GCT 
 
7/12/2019 
Page 21 of 29 
confidential 
 
 
ADVERSE EVENT REPORTING REQUIREMENTS 
Unexpected Event* 
Expected Event* 
During first 100 
days; grades 3 - 5 
After first 100 
days; only death or 
selected SAE** 
During first 100 
days; selected 
SAE** 
After first 100 days 
Report using 
UMCC SAE form  
Report using 
UMCC SAE form  
Report using 
UMCC SAE form  
Knowledge of Death 
and relapse reported 
annually as part of 
study continuing 
review 
*  Unexpected Events are any toxicities, complications of therapy, and adverse events NOT 
appearing in the Transplant Related Toxicities and Complications Section 7 of protocol. 
** Serious adverse events include: graft failure (severe pancytopenia with a marrow 
cellularity <5% at day +28 post transplant), relapse, and death. 
 
Events that meet the reporting requirements should be simultaneously reported to 
the IRB and the Clinical Trials Office (CTO) within 10 working days.  
 
The University of Minnesota Serious Adverse Event Report form may be 
downloaded from http://www.cancer.umn.edu/page/docs/sae.pdf 
 
 
9 Data and Safety Monitoring 
 
This study will be in compliance with the University of Minnesota Cancer 
Center's Data & Safety Monitoring Plan, which can be accessed at 
http://www.cancer.umn.edu/page/resource/dataplan.html  
 
Regular meetings of the study's principal investigator and staff will be held to 
discuss matters related to the safety of protocol participants, validity and integrity 
of the data, enrollment rate, retention of participants, adherence to protocol, and 
data completeness. 
 
The Principal Investigator will provide at least monthly monitoring of patient 
safety with attention to the stopping rules (section 10.5) with quarterly reporting 
to the Clinical Trials Office (CTO) for distribution to the Data and Safety 
Monitoring Council (DSMC).  
 
At the time of the IRB continuing review, the Principal Investigator will submit to 
the CPRC a copy of all documentation submitted to the IRB for continuing 
review. 
 
 


Auto PBSCT in GCT 
 
7/12/2019 
Page 22 of 29 
confidential 
10 Experimental Design and Statistical Considerations 
 
10.1 
Primary Clinical Endpoint: Probability of one year survival for 
tandem AuSCT 
 
10.2 
Secondary Endpoints and Comparisons 
 
10.2.1 Probability of one year disease-free survival for tandem AuSCT 
10.2.2 Toxicity rate of tandem AuSCT 
10.2.3 Probability of  engraftment of neutrophils and platelets 
10.2.4 Determine numbers of patients unable to adequately mobilize sufficient 
peripheral blood stem cells (PBSC) for tandem transplant 
10.2.5 Identify prognostic factors of those patients unlikely to mobilize 
sufficient PBSC for tandem transplant 
10.2.6 Compare outcomes of overall and disease free survival for patients 
undergoing single versus tandem transplant due to biologic 
randomization 
 
10.3 
Statistical Analysis 
 
Survival and disease-free survival will be estimated by the Kaplan-Meier method. 
Engraftment will be estimated by cumulative incidence using competing risk 
methods. 95% confidence intervals will be used to make inferences. Comparison 
of survival and disease free survival between patients receiving single versus 
tandem transplant will be completed by the log-rank test or left descriptive 
depending on patient numbers. The toxicity rate and analysis of prognostic factors 
will be descriptive using proportions. 
 
10.4 
 Sample Size Considerations 
 
We only expect to enroll 2 to 4 patients per year over a five year period based on 
a SEER incidence rate of testicular cancer in 2003 of 5.3/100,000 with a higher 
incidence in Caucasians, our predominant population. Since AuSCT is considered 
a standard salvage therapy for relapsed GCT, these patients will be seen in our 
clinic and most will be anticipated eligible for this study.  50-60% of patients are 
expected to receive a tandem AuSCT. Assuming that we enroll the maximum 
number of 25, we will then have 15 patients among the tandem patients to get an 
estimate of the survival. Assuming a survival estimate of 0.5, the 95% confidence 
bandwidth will have a width of 0.5. 
 
10.5 
  Stopping Rules 
 
Monitoring guidelines for non-relapse mortality were developed using the 
sequential probability ratio test with the level of significance and power preset at 
5% and 80% respectively. Monitoring guidelines will only be used for the tandem 


Auto PBSCT in GCT 
 
7/12/2019 
Page 23 of 29 
confidential 
AuSCT as single transplants have been shown to be safe in terms of non-relapse 
mortality. 
 
Day 100 non-relapse mortality 
Given a hypothesized non-relapse mortality rate of less than 5% and a maximum 
tolerated level of 15% among the tandem AuSCT, the trial will be halted and 
reviewed if 3 deaths occur in the 1st 3 evaluable patients, 5 deaths occur in the 1st 
8 evaluable patients or 6 occur in the 1st 15 evaluable patients. 
 
 
11 Retention of Records 
 
The investigator will retain study records, including source data, copies of case 
report form, study drug receipt and dispensation, and all study correspondence 
indefinitely in a secured facility.  In addition, the Clinical Trials Office (CTO) will 
keep a master log of all patients participating in the study, with sufficient 
information to allow retrieval of the medical records for that patient. 
 
Research data is collected in the BMT database indefinitely.   
 
  
12 References 
1. Loehrer PJ, TE Ahlering, A Pollack. Testicular Cancer. In: Pazdur R, LR Coia, WJ 
Hoskins, LD Wagman, ed. Cancer Management: A Multidisciplinary Approach (ed 
9th Edition). New York: The Oncology Group; 2005:407 -428. 
2. International Germ Cell Consensus Classification: a prognostic factor-based staging 
system for metastatic germ cell cancers. International Germ Cell Cancer 
Collaborative Group. J Clin Oncol. 1997;15:594-603. 
3. Bhatia S, Abonour R, Porcu P, et al. High-dose chemotherapy as initial salvage 
chemotherapy in patients with relapsed testicular cancer. J Clin Oncol. 2000;18:3346-
3351. 
4. Lotz JP, Bui B, Gomez F, et al. Sequential high-dose chemotherapy protocol for 
relapsed poor prognosis germ cell tumors combining two mobilization and 
cytoreductive treatments followed by three high-dose chemotherapy regimens 
supported by autologous stem cell transplantation. Results of the phase II multicentric 
TAXIF trial. Ann Oncol. 2005;16:411-418. 
5. Mandanas RA, Saez RA, Epstein RB, Confer DL, Selby GB. Long-term results of 
autologous marrow transplantation for relapsed or refractory male or female germ cell 
tumors. Bone Marrow Transplant. 1998;21:569-576. 
6. Nichols CR, Andersen J, Lazarus HM, et al. High-dose carboplatin and etoposide 
with autologous bone marrow transplantation in refractory germ cell cancer: an 
Eastern Cooperative Oncology Group protocol. J Clin Oncol. 1992;10:558-563. 


Auto PBSCT in GCT 
 
7/12/2019 
Page 24 of 29 
confidential 
7. Beyer J, Kramar A, Mandanas R, et al. High-dose chemotherapy as salvage treatment 
in germ cell tumors: a multivariate analysis of prognostic variables. J Clin Oncol. 
1996;14:2638-2645. 
8. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell 
transplantation for multiple myeloma. N Engl J Med. 2003;349:2495-2502. 
9. Margolin BK, Doroshow JH, Ahn C, et al. Treatment of germ cell cancer with two 
cycles of high-dose ifosfamide, carboplatin, and etoposide with autologous stem-cell 
support. J Clin Oncol. 1996;14:2631-2637. 
10. Motzer RJ, Mazumdar M, Sheinfeld J, et al. Sequential dose-intensive paclitaxel, 
ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J 
Clin Oncol. 2000;18:1173-1180. 
11. Margolin KA, Doroshow JH, Frankel P, et al. Paclitaxel-based high-dose 
chemotherapy with autologous stem cell rescue for relapsed germ cell cancer. Biol 
Blood Marrow Transplant. 2005;11:903-911. 
12. Chou TC, Motzer RJ, Tong Y, Bosl GJ. Computerized quantitation of synergism and 
antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell 
growth: a rational approach to clinical protocol design. J Natl Cancer Inst. 
1994;86:1517-1524. 
13. Kollmannsberger C, Nichols C, Bokemeyer C. Recent advances in management of 
patients with platinum-refractory testicular germ cell tumors. Cancer. 2006;106:1217-
1226. 
14. Motzer RJ, 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. 
1994;12:2277-2283. 
15. Vaena DA, Abonour R, Einhorn LH. Long-term survival after high-dose salvage 
chemotherapy for germ cell malignancies with adverse prognostic variables. J Clin 
Oncol. 2003;21:4100-4104. 
16. Rick O, Bokemeyer C, Beyer J, et al. Salvage treatment with paclitaxel, ifosfamide, 
and cisplatin plus high-dose carboplatin, etoposide, and thiotepa followed by 
autologous stem-cell rescue in patients with relapsed or refractory germ cell cancer. J 
Clin Oncol. 2001;19:81-88. 
17. Motzer RJ, Mazumdar M, Bosl GJ, Bajorin DF, Amsterdam A, Vlamis V. High-dose 
carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell 
tumors: treatment results and prognostic factors for survival and toxicity. J Clin 
Oncol. 1996;14:1098-1105. 
18. Rosti G, De Giorgi U, Salvioni R, et al. Salvage high-dose chemotherapy in patients 
with germ cell tumors: an Italian experience with 84 patients. Cancer. 2002;95:309-
315. 
 
 


Auto PBSCT in GCT 
 
7/12/2019 
Page 25 of 29 
confidential 
Appendix I:  International Germ Cell Cancer Consensus Classification 
 
NON-SEMINOMAS 
SEMINOMAS 
Good Prognosis 
• 
Testicular or retroperitoneal primary AND 
• 
No non-pulmonary visceral metastases AND 
• 
Good Markers defined as (requires all) 
        AFP < 1000 ng/mL 
         hCG < 5000 IU/L 
        LDH < 1.5 x Upper limit of normal 
• 
Any primary site AND 
• 
No non-pulmonary visceral metastases 
AND 
• 
Markers 
        AFP: normal 
        hCG and LDH:  normal or elevated 
Intermediate Prognosis 
• 
Testicular or retroperitoneal primary AND 
• 
No non-pulmonary visceral metastases AND 
• 
Intermediate Markers defined as any of 
              AFP 1000 – 10,000 ng/mL 
              hCG 5000 – 50,000 IU/L 
              LDH 1.5 – 10 x Upper limit of normal 
• 
Any primary site AND 
• 
Non-pulmonary visceral metastases AND 
• 
Markers 
       AFP: normal 
       hCG and LDH:  normal or elevated 
Poor Prognosis 
• 
Mediastinal primary OR 
• 
Non-pulmonary visceral metastases OR 
• 
Poor Markers defined as any of 
              AFP > 10,000 ng/mL 
              hCG > 50,000 IU/L 
              LDH > 10 x Upper limit of normal 
• 
No patients with pure seminomas are 
classified as poor prognosis 
 


Auto PBSCT in GCT 
 
7/12/2019 
Page 26 of 29 
confidential 
Appendix II – Lansky and Karnofsky Performance Status 
 
LANSKY (persons < 16 years old) 
 
KARNOFSKY (persons ≥ 16 years old) 
Fully active, normal 
  100   
Normal no complaints; no evidence of disease. 
Minor restrictions in physically strenuous 
activity 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
Active, but tires more quickly 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Both greater restriction of and less time 
spent in play activity  
70 
Cares for self; unable to carry on normal activity 
or to do active work. 
Up and around, but minimal active play; 
keeps busy with quieter activities 
60 
Requires occasional assistance, but is able to care 
for most of his personal needs. 
Gets dressed but lies around much of the 
day, no active play but able to participate 
in all quiet play and activities 
50 
Requires considerable assistance and frequent 
medical care.  
Mostly in bed; participates in quiet 
activities  
40 
Disabled; requires special care and assistance. 
In bed; needs assistance even for quiet play 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
Often sleeping; play entirely limited to 
very passive activities 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
No play; does not get out of bed  
10 
Moribund; fatal processes progressing rapidly. 
Unresponsive 
0 
Dead 
 


Auto PBSCT in GCT 
 
7/12/2019 
Page 27 of 29 
confidential 
Appendix IIIA:   
Required Observations Transplant 1  
 
 
within 30 
days of 
enrollment 
Prior to 
Admit for 
transplant 
 
day 
+14 
 
day 
+28 
 
day +42 
day +60 
 
day +74 
 
day +88 
** 
day 
+100 
day 
+180 
 
9 mo 
1 yr 
18 mo 
2yr 
Medical History 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Physicial Exam  
x 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
Weight/Height 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Performance status 
x 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
Adverse Event/toxicity notation 
x 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
Comprehensive chemistry panel 
x 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
Hepatic Panel 
x 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
CBC with diff 
x 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
AFP 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
LDH 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
β-hCG 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Viral Hepatitis serologies 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Quantitative Immunoglobulin 
x 
 
 
 
 
 
 
 
x 
x 
 
x 
 
 
pb CD4+  
x 
 
 
  
 
  
 
 
x 
x 
 
x 
 
 
pb CD8+ 
x 
 
 
 
 
  
 
 
x 
x 
 
x 
 
 
CT scan – chest, abdomen, pelvis, and 
head.  PET/CT will be done at all 
timepoints except d+28. 
x 
 
 
x 
 
 
 
 
x 
x 
 
x 
x 
x 
Bone Scan 
x 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
MRI brain (if prior CNS lesions) 
x 
 
 
x 
 
 
 
 
x 
 
 
x 
 
 
Bilateral bm biopsy unilateral aspirate 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
BM Cytogenetics 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
An attempt should be made to obtain the scheduled activity as close as possible to the scheduled date.  However, scheduling 
difficulties (for procedures and around weekends) may make this difficult.  Therefore, the scheduled activity will be obtained within 
14 days of that schedule (30 days for dates after day +100). 
**For patients NOT having a second transplant, all follow-up procedures will continue out to 2 years based on the Required 
Observations table for Transplant 1.  For patients having a second transplant, required observations will be per the Required 
Observations table for Transplant 2 and no further Transplant 1 observations will be collected.


Auto PBSCT in GCT 
 
7/12/2019 
Page 28 of 29 
confidential 
Appendix IIIB:   
Required Observations Transplant 2 (This will start between day +30 and day +90 from transplant 1) 
 
 
Within 2 wks 
of planned 
admission  
 
day 
+14 
 
day 
+28 
 
day +42 
day +60 
 
day +74 
 
day +88 
day 
+100 
day 
+180 
 
9 mo 
1 yr 
18 mo 
2yr 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Physicial Exam  
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
Weight/Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Performance status 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
Adverse Event/toxicity notation 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
Comprehensive chemistry panel 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
Hepatic Panel 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
CBC with diff 
x 
 
x 
 
x 
 
 
x 
x 
 
x 
x 
x 
AFP 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
LDH 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
β-hCG 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Viral Hepatitis serologies 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
Quantitative Immunoglobulin 
x 
 
 
 
 
 
 
x 
x 
 
x 
 
 
pb CD4+  
x 
 
  
 
  
 
 
x 
x 
 
x 
 
 
pb CD8+ 
x 
 
 
 
  
 
 
x 
x 
 
x 
 
 
CT scan – chest, abdomen, pelvis, and 
head. PET/CT will be done at all 
timepoints except d+28. 
x 
 
x 
 
 
 
 
x 
x 
 
x 
x 
x 
Bone Scan 
 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
MRI brain (if prior CNS lesions) 
x 
 
x 
 
 
 
 
x 
 
 
x 
 
 
Bilateral bm biopsy unilateral aspirate 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
BM Cytogenetics 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
An attempt should be made to obtain the scheduled activity as close as possible to the scheduled date.  However, scheduling 
difficulties (for procedures and around weekends) may make this difficult.  Therefore, the scheduled activity will be obtained 
within 14 days of that schedule (30 days for dates after day +100). 


Auto PBSCT in GCT 
 
7/12/2019 
Page 29 of 29 
confidential 
APPENDIX IV:  RECIST Criteria 
 
Response Criteria 
Evaluation of target lesions * 
Complete Response (CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking 
as reference the baseline sum LD 
 Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, taking as reference the 
smallest sum LD recorded since the treatment started or the appearance of one or 
more new lesions 
 Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD since the treatment started 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor marker level 
Incomplete Response/          
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker 
level above the normal limits 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions **  
 
*  Target lesions:  any lesion measurable prior to therapy.  Lesions must be ≥ 1cm in longest diameter at 
time of disease evaluation prior to autologous transplant. 
 
**Although a clear progression of “non target” lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail and the progression status should be confirmed later on by 
the review panel (or study chair).