Clinical trial NCT01962896
Conditions: Relapsed / Recurrent Germ Cell Tumors
Sponsor: Theodore Laetsch
Start date: 2014-01-08; Completion date: 2018-01-27
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out if the combination of an mTOR inhibitor (sirolimus) with an EGFR inhibitor (erlotinib) is effective at treating relapsed or refractory germ cell tumors, and to find out what the side-effects of this regimen are.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Erlotinib intervention 2: Sirolimus
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase II Study of Sirolimus and Erlotinib in 
Recurrent/Refractory Germ Cell Tumors 
 
 
Principal Investigator:  
Theodore Laetsch, MD 
 
 
UT Southwestern Medical Center 
Mail Code A3.01 
Department of Pediatrics - Oncology 
5323 Harry Hines Blvd. 
Dallas, TX 75390 
Fax: 214-648-5475 
 
Email: ted.laetsch@utsouthwestern.edu 
 
 
 
Associate Investigators: 
James Amatruda, MD, PhD 
 
 
UT Southwestern Medical Center 
 
 
 
Kirthi Kumar, MD, PhD 
 
 
UT Southwestern Medical Center 
 
 
 
Dinesh Rakheja, MD 
 
 
UT Southwestern Medical Center 
 
 
 
Lindsay Frazier, MD 
Dana-Farber Boston Children's Cancer and 
Blood Disorders Center 
Division of Pediatric Hematology/Oncology 
450 Brookline Avenue - D137 
Boston, Massachusetts 02215 
 
Version 1.5 
Initial Date: 11-14-2013 
Revision Date: 11-28-2016; 01-27-2017 
 
 


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Abstract 
While platinum-based current front-line therapy for malignant germ cell tumor results (MGCT) 
in greater than 80% overall survival, major challenges remain.  15-20% of patients still 
eventually die of their disease, either from primarily refractory disease or recurrent disease.  
Currently, therapy for patients with relapsed MGCT consists of further platinum-based 
chemotherapy regiments with or without stem cell rescue.  While a second course of such 
therapy can cure some patients, there are no curative options for patients whose disease fails to 
respond to platinum based therapy. There have been few studies of relapsed and refractory 
MGCT, and nearly all utilize combinations of previously utilized chemotherapeutics.  New 
approaches based on novel agents are needed for this population.  Our recent work has shown 
high levels of mTORC1 activity and EGFR pathway activation in pediatric and adult MGCT 
tumors as well as response to mTOR and EGFR inhibition in vitro.  Targeted mTOR inhibitors 
such as sirolimus and EGFR inhibitors such as erlotinib have been developed and shown to have 
little toxicity when given in combination.  Thus, this is a Phase II study to determine the efficacy 
of the mTOR inhibitor sirolimus in combination with the EGFR inhibitor Erlotinib in recurrent 
or refractory malignant germ cell tumors.   
 
Experimental Design and Schema 
Sirolimus will initially be given orally at 1 mg/m2 daily (maximum 2mg).  The dose will be 
adjusted weekly based on trough sirolimus levels to a goal trough of 10-15 ng/mL. Erlotinib will 
initially be given orally at 85mg/m2 daily (maximum 150mg/day). Intrapatient dose escalation is 
planned at cycle 2 for patients without toxicity to maximize EGFR pathway inhibition. 
Each cycle is 28 days (or every 4 weeks). Cycle 2 and subsequent cycles begin on day 29 if 
treatment parameters outlined in study are met. Therapy will be discontinued if there is drug-
related dose-limiting toxicity or progressive disease.  Patients with stable disease or better who 
do not meet any criteria for removal from protocol therapy or off study criteria may continue 
receiving protocol therapy for a total of up to 25 cycles. Evaluation for tumor response will occur 
after every 2nd cycle. 
Correlative biology studies are planned.  This will include an evaluation of the incidence of 
mTOR and EGFR pathway activation in primary tumors and correlation of pathway activation 
with response.  
 
 


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Table of Contents 
1.0 Goals and Objectives ......................................................................................................... 5 
1.1 Primary Aims .............................................................................................................................. 5 
1.2 Secondary Aims .......................................................................................................................... 5 
2.0 Background ....................................................................................................................... 5 
2.1 Toxicity and Pharmacokinetic Data ............................................................................................. 9 
2.2 Overview of the Proposed Study ............................................................................................... 12 
3.0 Eligibility Criteria ............................................................................................................. 12 
3.1 Inclusion Criteria ....................................................................................................................... 12 
3.2 Exclusion Criteria ...................................................................................................................... 14 
4.0 Treatment Plan ............................................................................................................... 15 
4.1 Overview .................................................................................................................................. 15 
4.1.1 Sirolimus Dose and Escalation ................................................................................................... 15 
4.1.2 Erlotinib Dose and Escalation .................................................................................................... 16 
4.1.3 Erlotinib Dose Reduction ........................................................................................................... 17 
4.2 Concomitant Therapy Restrictions ............................................................................................ 17 
4.3 Criteria for Starting Subsequent Cycles ..................................................................................... 18 
4.4 Grading of Adverse Events ........................................................................................................ 18 
4.5 Definition of Dose-Limiting Toxicity .......................................................................................... 18 
4.5.1  Definition of a Hematological Dose-Limiting Toxicity .............................................................. 18 
4.5.2 Definition of a Non-Hematological Dose-Limiting Toxicity ....................................................... 18 
4.5.3 Dose Modification for Hematological Toxicity .......................................................................... 18 
4.5.4 Dose Modification for Non-Hematological Toxicity .................................................................. 19 
4.6 Supportive Care ........................................................................................................................ 19 
4.6.1 Rash: .......................................................................................................................................... 19 
5.0 Observations ................................................................................................................... 20 
5.1 Studies to Be Obtained ............................................................................................................. 21 
5.2 Tumor Sample for Correlative Biology Studies ........................................................................... 22 
5.2.1 Description of Assay .................................................................................................................. 22 
5.2.2 Sampling Schedule .................................................................................................................... 22 
5.2.3 Sample Collection and Handling Instructions ............................................................................ 22 
5.3 Serum for Erlotinib Levels ......................................................................................................... 22 
5.4 Serum for Erlotinib Pharmacokinetics ....................................................................................... 22 
5.5 Removed from Protocol Version 1.3 .......................................................................................... 23 
5.6 Central Review .......................................................................................................................... 23 
6.0 Criteria for Removal From Protocol Therapy and Off Study Criteria ................................. 23 
6.1 Criteria for Removal From Protocol Therapy ............................................................................. 23 
6.2 Off Study Criteria ...................................................................................................................... 23 


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7.0 Statistical Considerations ................................................................................................ 23 
7.1 Sample Size and Study Duration ................................................................................................ 23 
7.2 Study Design ............................................................................................................................. 24 
7.3 Methods of Analysis ................................................................................................................. 24 
7.4 Evaluation Criteria .................................................................................................................... 25 
7.5 Definitions ................................................................................................................................ 25 
7.5.1  Evaluability for Response ......................................................................................................... 25 
7.5.2 Evaluability for Toxicity ............................................................................................................. 25 
7.5.3 Measurable Disease .................................................................................................................. 26 
7.5.4 Non-measurable Disease .......................................................................................................... 26 
7.5.5 Target Lesions ........................................................................................................................... 26 
7.5.6 Non-target Lesions .................................................................................................................... 27 
7.6 Methods for Evaluation of Measurable Disease ........................................................................ 27 
7.6.1 Quantification of Disease Burden ............................................................................................. 27 
7.6.2 End-of-Cycle Response .............................................................................................................. 27 
7.6.3 Overall Best Response Assessment ........................................................................................... 28 
7.6.4 Evaluation of Non-Target Lesions ............................................................................................. 28 
7.7 Best Response ........................................................................................................................... 28 
8.0 Safety and Adverse Events .............................................................................................. 29 
8.1 Adverse Event Monitoring ........................................................................................................ 29 
8.1.1 Definitions ................................................................................................................................. 29 
8.1.2 Reporting ................................................................................................................................... 31 
8.2 Steps to Determine If an Adverse Event Requires Expedited Reporting ......... Error! Bookmark not 
defined. 
8.3 Data Safety and Monitoring ...................................................................................................... 33 
8.4 Protection of Subjects ............................................................................................................... 34 
8.5 Stopping Rules .......................................................................................................................... 34 
9.0 Data Handling and Record Keeping .................................................................................. 34 
9.1 Confidentiality .......................................................................................................................... 34 
9.2 Source Documents .................................................................................................................... 35 
9.3 Case Report Forms .................................................................................................................... 35 
10.0 Consent Procedures ...................................................................................................... 35 
11.0 Study Management ....................................................................................................... 36 
11.1 
Required Documentation .................................................................................................... 36 
11.2 
Registration Procedures ...................................................................................................... 36 
11.3 
Adherence to the Protocol .................................................................................................. 36 
11.3.1 
Emergency Modifications .................................................................................................... 37 
11.3.2 
Other Protocol Deviations/Violations ................................................................................. 37 
11.4 
Amendments to the Protocol .............................................................................................. 37 
11.5 
Obligations of Investigators ................................................................................................ 37 


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Appendix 1: CYP3A4/5 Inducers and Inhibitors ..................................................................... 39 
Appendix 2: Sample Consent Form ........................................................................................ 40 
Appendix 3: References ........................................................................................................ 56 
Appendix 4: Patient Diary ..................................................................................................... 58 
 
 
1.0 Goals and Objectives 
1.1 Primary Aims 
1.1.1 To determine the PFR, defined as the proportion of patients with refractory germ cell tumors 
free of objective disease progression after 4 cycles (16 weeks) of therapy with erlotinib and 
sirolimus  
1.1.2 To describe the toxicities (including dose-limiting toxicities) of the combination of sirolimus 
and erlotinib administered on this schedule. 
1.2 Secondary Aims  
1.2.1 To assess the incidence of EGFR and mTOR pathway activation in banked tumor specimens. 
1.2.2 To compare the progression-free interval (PFI) for patients with germ cell tumors with and 
without evidence of EGFR/mTOR pathway activation with this drug combination. 
1.2.3 To determine the effect of concurrent administration of sirolimus on the pharmacokinetics 
of erlotinib 
 
2.0 Background 
Malignant germ cell tumors.  Malignant germ cell tumors (MGCTs) are cancers of the gonads 
and extragonadal sites such as retroperitoneum, mediastinum, and brain and affect infants, 
children, and adults.  MGCTs account for 15% of malignancies diagnosed during childhood and 
adolescence, and testicular GCT is the most common cancer in men aged 15 to 40[1, 2]. MGCTs 
arise from pluripotent embryonic germ cells[2].  Reflecting this pluripotency, MGCTs can present 
in a wide range of histologic forms.  MGCTs that retain features of pluripotent, primitive germ 
cells are called seminomas in the testis and dysgerminomas in the ovary (collectively referred to 
as germinomas (GERs)).  In contrast, non-germinomatous MGCTs exhibit differentiation into 
forms resembling somatic tissues (i.e., teratomas) or extraembryonic structures such as yolk sac.  
Yolk sac tumors (YSTs) are the most common malignant MGCTs in children.  MGCTs are highly 
responsive to upfront cisplatin-based therapy such as bleomycin, etoposide, and cisplatin (BEP).  
However, standard regimens fail to cure about 15-20% of patients (and up to 50-60% of patients 


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with primary mediastinal GCT) and are associated with significant long-term toxicity in survivors, 
including ototoxicity, nephrotoxicity, and risk of secondary malignancy[3, 4].   
Current therapy for relapsed / refractory malignant germ cell tumors.  The need exists for 
novel approaches to therapy for patients who germ cell tumor relapse after upfront therapy.  There 
are few reports on salvage regimens in pediatric MGCTs, with most containing further platinum 
containing compounds[3].  Most pediatric patients are treated on salvage regimens based on adult 
data.  Three primary salvage regimens have been developed and comparative efficacy data among 
them is lacking.  In the early 1990s when BEP became the standard upfront therapy for malignant 
germ cell tumors, VeIP (vinblastine, ifosfamide, and cisplatin) was the most common salvage 
regimen.  This regimen was shown to have a 50% CR rate and 25% long-term PFS rate for first 
salvage in the largest case series published [5].   During the 1990s, paclitaxel was demonstrated to 
have activity against germ cell tumors, and TIP (paclitaxel, ifosfamide, and cisplatin) was studied 
in relapsed patients and was shown to have a 70% CR rate with 63% long-term survival in a 
carefully selected population predicted to have a good outcome after salvage therapy[6].  The only 
randomized trial to compare these regimens closed early due to poor accrual (CALBG 90106).  
Most recently, there has been much interest in high dose chemotherapy with carboplatin and 
etoposide with stem cell rescue.  The two largest series of patients published to date demonstrated 
an overall 29% 3 year EFS in 1996 [7], and more recently 63% EFS at a median of 3 years with 
two tandem cycles of this therapy [8].  While retrospective studies have shown a survival 
advantage to high dose chemotherapy over conventional salvage regimens, there has been no 
published randomized trial comparing these regimens.  Such as study is currently under 
development through a collaboration of Alliance and EBMT [9]. Regardless, the outcome for 
patients who relapse after, or don’t respond to, both an upfront and a salvage platinum-containing 
regimen is poor, justifying the need for trials of novel agents in this group of patients. 
 
 
The mTORC1 pathway is active in Yolk Sac Tumors (YSTs).  mTORC1 is a central regulator 
of cell growth, proliferation, and differentiation.  A variety of human cancers have been found to 
have activation of the mTORC1 signaling pathway, with activation of this pathway correlating 
with tumor progression and reduced survival in several cancer types[10, 11].  To date, however, 
mTORC1 signaling in GCTs has not been investigated.  Recently mTORC1 was shown to control 
 
Figure 1. mTORC1 and Ras/MAPK signaling is active in yolk sac tumors.  Immunohistochemical staining of 
GCT samples for mTORC1 signaling components including the phosphorylated forms of mTORC1 (B,F) and 
ribosomal protein S6 (C,G), and ERK (D ,H). Yolk sac tumors (E-H) exhibit increased mTORC1 pathway activity 
compared to germinomas (A-D). 
Dinesh Rakheja


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the development of germline stem cells 
during development[12].  To assess the state 
of mTORC1 signaling in GCTs, we 
assembled a tissue microarray from 23 
clinically-annotated childhood GCTs, and 
compared mTOR signaling in germinomas 
(GERs) and yolk sac tumors (YST).  The 
cohort of yolk sac tumors included 14 cases, 
of which 8 were testicular, 4 were ovarian, 1 
was sacral, and 1 was hepatic. The cohort of 
GERs included 9 cases, of which 1 was 
testicular (seminoma), 6 were ovarian 
(dysgerminomas), 
1 
was 
from 
an 
indeterminate gonad (dysgerminoma) and 1 
was mediastinal (germinoma).  Using 
phosphospecific antibodies, we determined 
that YSTs but not GERs express activated 
forms of mTOR and its downstream target, 
RPS6 (Fig 1).  Furthermore, YSTs expressed 
higher levels of the mTORC1 target genes 
Cyclin D1, HIF1A (not shown). The results 
of immunohistochemistry indicate a robust 
activation of mTORC1 signaling in YSTs, 
the most common histology of pediatric germ cell tumors. 
 
 
Figure 2.  mTOR inhibitors impair the growth and 
survival of germ cell tumor cells.  A, B, 10 µM 
Rapamycin impairs cell proliferation in GCT cell lines 
NTERA-2 (A) and NCCIT (B).  C, Rapamycin 
treatment decreases the viability of GCT cells (EC50 
17 µM for NTERA-2 and 19 µM for NCCIT).  D, 
Treatment with the dual PI3 Kinase/mTOR inhibitor 
NVP-BEZ235 decreases GCT cell viability (EC50 37 
nM for NTERA-2 and 14 nM for NCCIT). 


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mTOR inhibitors suppress proliferation and survival of GCT cells in vitro.  Our finding that 
YSTs frequently exhibit high levels of mTORC1 signaling activity suggested that the mTORC1 
pathway may confer a survival advantage on the tumor cells, and that pharmacologic inhibitors 
mTORC1 signaling might have activity against GCTs.  To test this idea, we exposed NTERA-2 
and NCCIT cells (GCT derived embryonal carcinoma cell lines that have mTOR activity and 
express EGFR) to the mTORC1 inhibitor, sirolimus. 10 µM sirolimus blocked phosphorylation of 
S6 and inhibited the proliferation of NTERA-2 and NCCIT cells.  Higher doses of sirolimus 
impaired the viability of both cell lines. (Figure 2C, EC50 17 µM for NTERA-2 and 19 µM for 
NCCIT).  While these results demonstrate the 
dependence 
of 
MGCT 
on 
mTORC1 
signaling, these concentrations of sirolimus 
are not clinically achievable. Treatment of 
cancer cells with sirolimus and its analogs 
has been shown to cause a feedback 
upregulation of the PI3K/Akt and MAPK 
pathways, representing a possible source of 
resistance. Thus, we hypothesized that 
inhibition of feedback upregulation of 
upstream 
signaling 
components 
would 
sensitize MGCT to mTOR inhibitors. 
EGFR is highly expressed in pediatric and 
adult GCT.  Epidermal growth factor 
receptor (EGFR) is a receptor tyrosine kinase 
upstream 
of 
mTOR 
(Figure 
3).  
Overexpression 
of 
EGFR 
has 
been 
demonstrated by immunohistochemistry in 
metastatic embryonal carnicomas (a form of 
GCT) in adult patients [13].  Thus, we 
interrogated 
EGFR 
expression 
by 
quantitative RT-PCR in a panel of pediatric 
germ cell tumors and found high expression 
in yolk sac tumors (the most common 
histology), 
but 
low 
expression 
in 
germinomas (Fig 4A).  Consistent with EGFR activation in YST, we found high levels of 
phosphorylated ERK, a downstream marker of activity of the Ras/MAPK pathway in YST (Figure 
1). 
Combined EGFR and mTOR inhibition is synergistic in GCT in vitro.  Given our finding that 
mTOR inhibitors show activity in vitro in germ cell tumor cell lines, we hypothesized that 
combined mTOR and EFGR inhibition may be synergistic by blocking two common mTOR 
resistance pathways, feedback upregulation of AKT and activation of the Ras/MAPK pathway 
(Figure 3).  Consistent with this hypothesis we found that combined treatment of the relatively 
mTOR resistant NCCIT cell line with 1uM erlotinib and only 10nM rapamycin demonstrated a 
synergistic reduction in viability (Figure 4B).  This represents a 1000-fold sensitization to 
sirolimus over the EC50 seen without EGFR inhibition. 
 
Figure 3.  mTOR and EGFR pathway.  EGFR is an 
upstream receptor tyrosine kinase that activates both 
the 
PI3K/AKT/mTOR 
pathway 
and 
the 
Ras/Raf/MEK/ERK pathways.  The biologic effect of 
mTORC1 inhibition with sirolimus is limited by 
feedback upregulation of AKT and by activation of 
competing signaling pathways including Ras/MAPK.  
We have shown that EGFR inhibition with erlotinib is 
synergistic with mTOR inhibition in germ cell tumors 
in vitro, which we hypothesize is due to blocking this 
feedback upregulation as well as by inhibition of 
Ras/MAPK activation. 


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Thus, there is robust pre-clinical rationale to test the combined inhibition of mTOR and EGFR in 
relapsed/refractory pediatric and adult germ cell tumors.   
 
2.1 Toxicity and Pharmacokinetic Data 
Sirolimus: Sirolimus (Rapamune) was FDA approved in 1999 for patients > 13 years of age 
receiving renal transplants at doses of 5mg/day and 2mg/day for high and low immunologic risk 
patients. It is a generally well tolerated oral medication. In renal transplant patients, the most 
significant toxicities reported at a rate greater than in placebo were peripheral edema (54-58% vs 
48% in placebo), lipid abnormalities: hypertriglyceridemia (45-57% vs 23% in placebo) and 
hypercholesterolemia (43-46% vs 23% in placebo), constipation (36-38% vs 31% in placebo), 
cytopenias: anemia (23-33% vs 21% in placebo) and thrombocytopenia (14-30% vs 9% in 
placebo), and rash (10-20% vs 6% in placebo).  Rare but serious interstitial lung disease has been 
reported after treatment with sirolimus[14]. Its use in pediatric patients <13 years has been 
reported in patients as young as 1 year for auto-immune lymphoproliferative symdrome (ALPS) 
and for prevention of rejection in patients after liver transplant, including in two patients with 
hepatoblastoma and six with PTLD[15, 16]. Starting doses ranged from 0.8 - 3mg/m2/day with 
dose adjustment to achieve serum trough levels of 4-15 ng/mL [15, 17]. Toxicities potentially 
attributable to sirolimus were mild and similar to those seen in adults and included 
hyperlipidemia, leukopenia, thrombocytopenia, peripheral edema, and diarrhea. Additionally two 
of eight patients treated after liver transplant and two of six patients with ALPS were noted to 
have mouth ulcers or grade I-II mucositis and one patient had grade IV culture negative sepsis 16 
months after starting treatment with sirolimus. 
 
Figure 4.  EGFR is highly expressed in Yolk Sac Tumors and EGFR inhibition in synergistic with 
mTOR inhibitors. (A) EGFR mRNA is highly expressed in primary yolk sac tumors compared with 
germinomas.  (B) immunohistochemistry demonstrates mTOR pathway activation (pS6 expression) and 
EGFR expression in a patient with recurrent metastatic choriocarcinoma. Similar results were obtained 
from a case series of 14 pediatric patients with yolk sac tumors of which 13 had pS6 positivity. (C) The 
germ cell tumor cell line NCCIT was treated with 1uM erlotinib, 10nM rapamycin, or the combination 
of these drugs.  Little effect is seen with treatment with either drug alone, but the combination results in 
synergistic growth inhibition. (Rakheja, et al, submitted) 


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Sirolimus exhibits wide inter and intra-patient variation in clearance and thus is typically dosed 
based on therapeutic drug monitoring.  It is a substrate of the ABCB1 pump (p-glycoprotein) and 
metabolized by the CYP3A4 and CYP3A5 enzymes, and its metabolism is effected by 
polymorphisms in the IL-10 gene (1082G>A, [18]). 
Erlotinib: Erlotinib (Tarceva) was FDA approved in 2004 and is now approved as maintenance 
therapy for adults with non-small cell lung cancer alone at a dose of 150mg/day and for 
pancreatic cancer at an oral dose of 100mg/day in combination with gemcitabine. The most 
common adverse events are skin rash and diarrhea, with nausea, anorexia, fatigue, and infection 
also reported.  Rare but serious adverse events have been reported with erlotinib therapy, 
including interstitial lung disease, acute renal failure, hepatic failure and hepatorenal syndrome, 
GI perforations, bullous skin rash, thrombotic events and microangiopathic hemolytic 
anemia[19]. Erlotinib use in pediatric patients has been reported in a phase I trial of 46 patients 
aged 3-20 years with refractory solid tumors (in combination with temozolamide, [20]).  Daily 
administration to a maximum tolerated dose (MTD) of 85mg/m2/day was well tolerated with one 
of six patients with dose limiting toxicity (painful grade II rash lasting >7 days). At a dose 
110mg/m2/day, one of four patients developed a painful grade II rash and one developed grade 
III hyperbilirubinemia.  An additional 17 patients were treated at the MTD and two had dose 
limiting toxicity - one developed a painful grade II rash and one had grade III diarrhea.  Non-
dose limiting toxicities included diarrhea in 56% of patients, rash in 43% of patients, and 
hyperbilirubinemia in 26%.  Of note, the incidence of rash was age related with 10% of patients 
less than 12 years vs 92% of patients greater than 12 years developing a grade II or worse 
rash[20]. 
Erlotinib has also been studied concurrently with radiotherapy in a Phase I study of 23 children 
and young adults with high-grade glioma, ages 3.7-22.5 years [21].  In this study, the MTD was 
defined as 120mg/m2/day.  One patient at the MTD developed grade III diarrhea.  At 
160mg/m2/day, one of six patients developed grade III skin rash and one developed grade III 
lipase elevation.  Non-dose-limiting toxicities included grade III hypokalemia and 
hypophosphatemia that were readily reversed with oral supplementation, hyperbilirubinemia, and 
lymphopenia [21].  A third phase I trial of Erlotinib in patients aged 2-20 years with brain tumors 
determined an MTD of 125mg/m2/day [22].  Toxicities included one of six patients with grade 5 
intratumoral hemorrhage at the MTD and one patient of four at 150mg/m2/day with grade III 
asthenia and one patient of four at 150mg/m2/day with grade IV intratumoral hemorrhage.  One 
of eight additional patients enrolled at the MTD developed grade III hyperbilirubinemia[22]. 
Erlotinib is primarily metabolized by CYP3A4, with a minor component of its metabolism from 
other cytochrome p450 enzymes[23]. It is also a substrate of the ABCB1 transporter (p-
glycoprotein).  Approximately 5% of circulating erlotinib is the biologically active OSI-420 
metabolite.  Erlotinib pharmacokinetics are effected by CYP3A4 genotype and pharmacological 
inhibitors, with patients with the CYP3A4*1 allele having a 42% increase in clearance, patients 
with the ABCB1 2677G > T/A SNP having a 19% decrease in metabolism and patient’s taking 
ketoconazole having a two fold increase in AUC[23, 24]. Thus, there is significant inter-patient 
variability in erlotinib exposure at a single dose level[21]. Erlotinib clearance has been found to 
be greater in children than adults, with the risk of skin rash and diarrhea correlating with 
exposure, possibly explaining the decreased risk of rash seen in young children[24, 25]. There 
are suggestions that exposure also influences anti-tumor efficacy with an increased percentage of 
EFGR wild-type patients with NSCLC demonstrating a response to therapy (38% in the highest 
quartile of exposure vs 5% in the remainder, p=0.058) [25]. Further, the development of rash on 


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erlotinib has been shown to correlate with prolonged overall survival and event free survival in 
patients with NSCLC, possibly as a biomarker of EGFR inhibition as EGF is involved in 
epidermal growth and healing[26]. 
Combination of sirolimus and erlotinib: A phase I dose escalation study and two phase II trials 
have reported on the combined administration of sirolimus and erlotinib. In the phase I study, 19 
adult patients with malignant gliomas were treated at 3 dose levels, starting at 150 mg daily of 
erlotinib and 5 mg daily of sirolimus (11 patients) and escalating to 200 mg of erlotinib with 5 
mg of sirolimus (3 patients) or 150mg of erlotinib with 10 mg of sirolimus (5 patients).   Of note, 
the dose of sirolimus was not adjusted for trough concentrations in this study.  2 patients in each 
of the dose escalated arms developed DLT, with 1 of 11 patients in the 150mg/5mg arm 
developing DLT (1 each of grade III mucositis, rash, hyperphosphatemia, and altered mental 
status[27]). 
In a phase II study, 24 adult patients with recurrent glioblastoma were enrolled in a study of 
sirolimus and erlotinib at 5mg and 150mg doses respectively ([28]). One heavily pretreated 
patient developed grade IV thrombocytopenia, 6 patients developed grade III rash, 2 patients 
each developed grade III mucositis, thrombocytopenia, and fatigue, and 1 patient each developed 
grade III hypertriglyceridemia, hypokalemia, hypophosphatemia, infection, and neutropenia. The 
remaining toxicities were grade II or lower and included rash (59%), mucositis (34%), diarrhea 
(31%), fatigue (28%), and hyperlipidemia (25%, [28]). No anti-tumor responses were observed; 
however the CSF penetration of erlotinib is <5%, and ascertainment of pathway inhibition was 
not performed[29].  Thus, there may have been insufficient drug exposure in these patients with 
intracranial tumors. 
In a separate phase II study, 19 pediatric patients (age 3-16 years) with low-grade gliomas were 
treated with sirolimus 0.8mg/m2/day and erlotinib 65mg/m2/day [17]. This regimen was very 
well tolerated with 1 patient developing grade III cellulitis while not neutropenic and one patient 
developing grade III neutropenia. Grade I and II toxicities included rash (58%), aphthous ulcers 
(47%), and gastrointestinal symptoms (37%, [17]).  There was no convincing anti-tumor 
responses in this group of patients with CNS tumors; however, the dose of erlotinib was below 
the established pediatric or adult MTD and CNS drug penetration may have been insufficient.   
This will be the first study combining erlotinib and sirolimus for extra-cranial solid tumors.  
There have been no reported grade IV non-hematologic toxicities or grade V toxicities with this 
combination, and no reported cases of the development of interstitial lung disease.  We 
hypothesize that these agents will show activity in this group of patients given the higher drug 
delivery extra-cranially, and the pre-clinical data showing synergy between these agents in germ 
cell tumors. 
Drug interactions: Erlotinib and sirolimus are both metabolized hepatically by the CYP3A4 
enzyme.  There are significant differences in metabolism of both of these drugs with the 
concomitant use of enzyme inducing and inhibiting agents[18, 23].  The interaction between 
erlotinib and sirolimus metabolism has not been well studied.  In the Phase I study in adult 
patients with gliomas, there was no significant difference in steady state trough sirolimus levels 
at doses of 150 and 200 mg of erlotinib (13 ng/mL and 10 ng/mL respectively, p=NS.[27])  
However, only 3 patients were treated at the higher dose of erlotinib, limiting the power to detect 
a difference, and erlotinib levels were not measured, so the influence of sirolimus on erlotinib 
metabolism can not be determined. 


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2.2 Overview of the Proposed Study 
This will be a phase II study to determine the response rate of children, adolescents, and young 
adults with relapsed / refractory germ cell tumors to the combination of sirolimus and erlotinib.  
Patients will be treated with these medications daily on a continuous schedule.  The initial dose 
of sirolimus will be 1mg/m2 daily (max 2mg) and adjusted to obtain trough concentrations of 10-
15ng/mL.  The initial dose of erlotinib will be 85mg/m2 daily (max 150mg/day).  The initial dose 
of erlotinib will be higher than used in the pediatric phase II study of sirolimus and erlotinib for 
low grade gliomas[17].  The dose of 65mg/m2/day used in the prior phase II study was 
empirically chosen and not a defined MTD.  It was very well tolerated with no grade IV or V 
adverse events and only two grade III adverse events: cellulitis without neutropenia in one 
patient and neutropenia in one patient.  The dose of 85mg/m2/day used in this study was chosen 
given that there are suggestions that erlotinib concentration correlates with efficacy in NSCLC 
patients, especially those with wildtype EGFR [25]. Further, erlotinib clearance is faster in 
pediatric patients and the incidence of the on target rash is lower, both again suggesting the need 
for a higher dose in this population[20, 24].  This dose was the pediatric MTD in the Children’s 
Oncology Group phase I study of erlotinib in combination with temozolamide[20], and 
equivalent to the well tolerated adult dose of 150mg/day in the adult phase II study of sirolimus 
and erlotinib[28].  Note that the maximum dose of 150mg/day is equal to the adult phase II study 
and FDA approved dose, so this only represents a dose increase for pediatric patients.   
There is significant inter-patient variability in the pharmacokinetics of erlotinib and drug 
exposure and the development of low grade rash have been shown to correlate with outcome in 
adult studies of this agent.  Therefore, patients who do not develop grade II or greater drug-
related rash (which is maximal at 2-3 weeks of therapy) or any dose limiting toxicities during 
cycle 1 will be dose-escalated to 120mg/m2/day (max 200mg) for the second and subsequent 
cycles (the MTD of erlotinib in combination with radiotherapy and approximately the MTD of 
single agent erlotinib (125mg/m2/day) in two studies pediatric brain tumor patients.)  While dose 
escalation of erlotinib to 200mg/day when administered concomitantly with 5mg daily sirolimus 
was not tolerated in a phase I study in adults with the development of grade III DLTs in 2 of 3 
patients (mucositis and rash), we hypothesize that this is due to intrapatient variation in erlotinib 
and sirolimus metabolism[27].  Thus, in this study, sirolimus will be adjusted weekly based on 
trough concentrations, and only patients who do not show evidence of grade II or worse rash or 
mucositis in the first cycle of therapy will have the dose of erlotinib escalated. 
To assess biological correlates of efficacy, we will assess banked tumor specimens (from the 
enrolled patients) for evidence of mTOR pathway activation by immunohistochemical staining 
for ERBB1 and ERBB2 receptors as well as phosphor-specific antibodies for (pERBB2, pAKT1, 
pERK1/2, pmTOR, p70S6, and pRPS6.)  Expression of these targets will be correlated with 
response to therapy. 
 
3.0 Eligibility Criteria 
3.1 Inclusion Criteria 


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• Patients must be greater than 12 months and less than 50 years of age at the time of study 
enrollment. 
• Patients must have had histologic verification of an extracranial germ cell tumor that is not 
a pure teratoma (mature or immature), pure germinoma, or pure seminoma. 
• Patients must have relapsed or refractory disease following at least two prior platinum-
containing chemotherapy regimens. 
• Patients must have measurable disease, documented according to RECIST criteria, or 
evaluable disease with a standard tumor marker (AFP and/or HCG) greater than 10 times 
the upper limit of normal. 
• Patients must have a Lansky or Karnofsky performance status score of ≥ 50. Use Karnofsky 
for patients > 16 years of age and Lansky for patients ≤ 16 years of age. 
• Patients must have a life expectancy of greater than 8 weeks. 
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer 
therapy. 
o Patients must not have received myelosuppressive chemotherapy within 3 weeks of 
enrollment. 
o Patients must be >7 days since treatment with hematopoetic growth factors (>14 
days for Neulasta). 
o Patients must be >7 days since therapy with a biologic agent and beyond the period 
for which adverse events of the biologic agent are known to occur if longer. 
o Patients must be >3 half-lives since therapy with a monoclonal antibody. 
o Patients must be >42 days since completion of any immunotherapy (i.e. tumor 
vaccines). 
o Patients must be greater than 2 weeks since most recent palliative XRT and greater 
than 6 weeks since substantial bone marrow irradiation. 
o Patients must be greater than 8 weeks since prior stem cell transplant or infusion 
and without evidence of active graft vs. host disease. 
• Adequate bone marrow function defined as: 
o Peripheral absolute neutrophil count (ANC) of at least 1,000/ L 
o Platelet count of at least 100,000/L (transfusion independent, defined as not 
receiving platelet transfusions within a 7-day period prior to enrollment) 
o Hemoglobin  8.0 g/dL (may receive RBC transfusions). 
• Adequate renal function defined as: 
o Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or 
o Maximum serum creatinine (mg/dL) based on age/gender as follows: 
Age (yrs) 
Male 
Female 
1-1.99 
0.6 
0.6 
2-5.99 
0.8 
0.8 
6-9.99 
1 
1 
10-12.99 
1.2 
1.2 
13-15.99 
1.5 
1.4 
>16 
1.7 
1.4 
• Adequate liver function defined as: 
o Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age 
o SGPT (ALT) ≤ 2.5 x ULN (for the purpose of this study, the ULN for SGPT is 45 
U/L) 
o Serum albumin ≥ 2 g/dL. 


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• Adequate central nervous system function defined as: 
o Patients with seizure disorder may be enrolled if receiving non-enzyme inducing 
anticonvulsants and well controlled. 
• Serum cholesterol levels must be less than Grade 2 (< 300 mg/dL), and serum triglyceride 
levels must be less than Grade 2 (< 2.5 x ULN). 
 
3.2 Exclusion Criteria 
• Patients with active brain metastases are not eligible as lethal intratumoral hemorrhages 
have been reported with erlotinib therapy.  Patients with brain metastases that have been 
treated and stable for > 30 days following treatment will be eligible. 
• Patients who are pregnant or breast feeding will not be entered into the study as erlotinib 
is teratogenic.  Pregnancy tests must be obtained in females who are post-menarchal. Post-
menarchal females with HCG secreting tumors will be excluded as pregnancy can’t be 
excluded. Males or females of reproductive potential may not participate unless they have 
agreed to use an effective contraceptive method for the duration of the study.  
• Concomitant medications 
o Investigational Drugs: Patients who are currently receiving another investigational 
drug are not eligible. 
o Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents 
are not eligible. 
o Anticonvulsants: Patients who are receiving enzyme-inducing anticonvulsants are 
not eligible (see Appendix 1 for a list of enzyme- inducing anticonvulsants). 
o Anticoagulants: Use of warfarin is not allowed while on study. Patients already on 
warfarin should use alternative anticoagulants while on this study. Warfarin must 
not have been administered within 7 days of enrollment. 
o Smoking: Smoking induces CYP3A4/5 enzymes and decreases exposure to 
sirolimus and erlotinib.  Thus, patients must not smoke for 10 days prior to 
enrollment and for the duration of therapy. 
• Infection: Patients who have an uncontrolled infection are not eligible. 
• Drug interactions: Sirolimus and erlotinib are primarily metabolized by the CYP3A4/5 
enzymes.  Drug exposure is substantially effected by CYP inhibitors (increased exposure) 
and inducers (decreased exposure).  Thus, concomitant administration of strong CYP3A4/5 
inhibitors or inducers is prohibited while on therapy.  See Appendix 1 for a list of these 
medications.  Patients must not have received these medications for a minimum of 10 days 
prior to enrollment. 
• Patients who have received prior therapy targeting EGFR with small molecule tyrosine 
kinase inhibitors or monoclonal antibodies are NOT eligible.  
• Prior treatment with mTOR or TORC1/2 inhibitors (eg, rapamycin, temsirolimus, 
everolimus, deferolimus) is NOT allowed. 
• Patients who have had major surgery within 3 weeks prior to enrollment are not eligible. 
Procedures such as placement of a central vascular catheter, or limited tumor biopsy, are 
not considered major surgery. 
• Patients who in the opinion of the investigator may not be able to comply with the safety 
monitoring requirements of the study are not eligible. 
• Patients who are unable to swallow erlotinib tablets are not eligible. 


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4.0 Treatment Plan 
4.1 Overview 
After enrollment and obtaining required baseline studies, therapy will consist of 28 day cycles of 
once daily sirolimus and erlotinib.  These medications will be concurrently administered orally on 
an empty stomach (1 hour before or 2 hours after a meal.) Both medications will be purchased 
from commercially available supplies (erlotinib tablets and sirolimus tablets or oral solution). 
 
Study related procedures and observations may be adjusted for various logistical, scheduling, or 
patient preference reasons within a +/- 3 day window during cycle 1 of therapy.  During subsequent 
cycles of therapy there is a +/- 7 day window for study related procedures and observations. 
 
4.1.1 Sirolimus Dose and Escalation 
The initial dose of sirolimus will be 1 mg/m2/day (maximum 2mg).  The dose of sirolimus will be 
adjusted at least weekly to obtain a goal trough level of 10-15ng/mL.  Trough levels will be 
measured locally at each treating institution. For patients able to take the tablet form of Sirolimus, 
up to 10% dose adjustment to the nearest tablet size is acceptable. A commercially available oral 
solution (1mg/mL) of Sirolimus may be substituted for patients who are unable to take the tablet 
form of the medication.   The dosing instructions for the suspension are the same as for the tablets. 
For patients 18 years and older, if the trough level is less than 10ng/mL or greater than 15ng/mL, 
the new sirolimus dose will be calculated by the following formula: 
Subsequent 
cycles
Day
1
8
15
28
1
28
28
Erlotinib
Daily
Dose 
escalation if 
eligible
Daily
Sirolimus
Daily
Dose 
modification 
based on 
trough
Dose 
modification 
based on 
trough
Daily
Daily
Sirolimus level
X
X (weekly 
until in goal 
range twice)
X
X
X
Erlotinib level
X
X
Erlotinib PK
X
Cycle 1
Cycle 2


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𝑁𝑒𝑤 𝑠𝑖𝑟𝑜𝑙𝑖𝑚𝑢𝑠 𝑑𝑜𝑠𝑒 (𝑚𝑔) =  𝐶𝑢𝑟𝑟𝑒𝑛𝑡 𝑠𝑖𝑟𝑜𝑙𝑖𝑚𝑢𝑠 𝑑𝑜𝑠𝑒 (𝑚𝑔) ∗
12.5 𝑛𝑔
𝑚𝐿
𝑆𝑖𝑟𝑜𝑙𝑖𝑚𝑢𝑠 𝑡𝑟𝑜𝑢𝑔ℎ (𝑛𝑔
𝑚𝐿)
 
Note:  The maximum new sirolimus dose is three times the current sirolimus dose.  Further dose 
adjustment (increases or decreases) may be made based on subsequent trough levels on the new 
dose. 
If the sirolimus trough is greater than 20ng/mL, one daily dose should be held prior to resuming 
dosing per the calculated dose above.  If the sirolimus trough is greater than 25ng/mL, two daily 
doses should be held and a repeat sirolimus level obtained confirming a level less than 15ng/mL 
prior to resuming therapy per the calculated dose above. 
Note: If the treating physician believes that lack of compliance with study medication has 
significantly affected the measured sirolimus trough, the current sirolimus dose may be continued 
with a repeat trough drawn within 1 week.   
Note: Steady state sirolimus levels are not achieved until 3-6 days after dose adjustments.  Care 
should be taken to avoid dose stacking if adjusting the dose more often than weekly. 
For patients less than 18 years of age, the sirolimus dose will be adjusted at least weekly until in 
the goal range of 10-15ng/mL per the local institutional dose adjustment standards. 
4.1.2 Erlotinib Dose and Escalation  
 
 
 
The initial dose of erlotinib for all patients will be 85mg/m2/day (maximum 150mg/day, dose level 
1) and dose adjustment will be performed as below.  Erlotinib will be administered as a tablet and 
the dose rounded to the nearest 25mg per the following table: 
Calculated erlotinib dose 
Rounded dose 
12.5 mg to 37.5 mg 
25 mg 
>37.5 mg to 62.5 mg 
50 mg 
>62.5 mg to 87.5 mg 
75 mg 
>87.5 mg to 112.5 mg 
100 mg 
>112.5 mg to 137.5 mg 
125 mg 
>137.5 mg to 162.5 mg 
150 mg 
Erlotinib Dose Level 
Erlotinib Dose 
0 
65 mg/m2/day, max of 100 mg/day 
1 
85 mg/m2/day, max of 150 mg/day 
2 
120 mg/m2/day, max of 200 mg/day 


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>162.5 mg to 187.5 mg 
175 mg 
>187.5 mg 
200 mg 
 
Intrapatient dose escalation of erlotinib is planned for qualifying patients eligible to receive cycle 
2 or higher of therapy provided the patient did not experience any of the following toxicities during 
cycle 1: 
1. Grade II or greater rash or mucositis 
2. Any grade III toxicity that is possibly, probably, or definitely attributable to study drugs 
with the exception of grade III electrolyte abnormalities that resolve to <= grade II within 
7 days or grade III nausea or vomiting that are controlled to less than or equal to grade II 
with anti-emetics within 5 days 
For patients who meet these criteria, the dose of erlotinib will be increased to 120mg/m2/day 
(maximum 200mg, dose level 2) for the second and subsequent cycles. 
4.1.3 Erlotinib Dose Reduction 
See section 4.5 for details of specific toxicities that would require dose reduction of erlotinib.  If a 
dose reduction is necessary, the dose for patients assigned to receive 85mg/m2/day (dose level 1) 
will be reduced to 65mg/m2/day (maximum 100mg, dose level 0) and the dosage for patients 
assigned to 120mg/m2/day (dose level 2) will be 85mg/m2/day (maximum 150mg, dose level 1).  
If a patient requires dose reduction of erlotinib, the dose will not be escalated in the future even if 
there are no adverse events at the lower dose level. 
4.2 Concomitant Therapy Restrictions 
• Concurrent Anticancer Therapy: Concurrent cancer therapy, including chemotherapy, 
radiation therapy, immunotherapy, or biologic therapy may NOT be administered to 
patients receiving study drug. If these treatments are administered the patient will be 
removed from protocol therapy. 
• The study chair must be notified prior to the use of growth factors that stimulate white 
cell number of function (eg GCSF, GMCSF) 
• Investigational Agents: No other investigational agents may be given while the patient is 
on study. 
• Strong inducers or inhibitors of CYP3A4/5 (Appendix 1) change the pharmacokinetics of 
sirolimus and erlotinib.  Administration of these medications must be avoided until 
treatment discontinuation.  Smoking is a strong inducer of CYP3A4/5 and is not 
permitted while on therapy. 
• The combination of mTOR inhibitors and angiotensin converting enzyme (ACE) has 
resulted in angioedema type reactions (including delayed reactions occurring up to 2 
months after initiation of therapy). During treatment, the coadministration of (ACE) 
inhibitors should be avoided. 
• Warfarin should not be used. 


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4.3 Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease and has met 
laboratory parameters as defined in the eligibility section. Study drugs should not be interrupted 
between cycles unless required by Section 4.5.3 or 4.5.4 or Section 6.1.  
4.4 Grading of Adverse Events 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for adverse event reporting. 
4.5 Definition of Dose-Limiting Toxicity 
4.5.1  Definition of a Hematological Dose-Limiting Toxicity 
Grade 4 neutropenia or thrombocytopenia. 
4.5.2 Definition of a Non-Hematological Dose-Limiting Toxicity 
Any Grade 4 or 5 non-hematologic toxicity 
Any Grade 3 non-hematologic toxicity EXCLUDING: 
• Grade 3 nausea or vomiting controlled to less than or equal to grade II with anti-emetics 
within 5 days 
• Grade 3 hepatic transaminase (ALT, AST, GGT) elevation that returns to Grade ≤ 2 or 
baseline within 7 days of study drug interruption and that does not recur upon retreatment 
with study drugs 
• Grade 3 febrile neutropenia of less than 5 days duration  
• Grade 3 infection or fever while not neutropenic (ANC >1000/mm3) 
• Grade 3 hypophosphatemia, hypokalemia, hypocalcemia and/or hypomagnesemia that 
resolve to < grade 2 within 7 days (oral supplementation permitted) 
• Grade 3 acneiform or maculopapular rash unless deemed intolerable by the patient or 
guardian. 
• Non-fasting grade 3 hypercholesterolemia or hypertriglyceridemia.  Such studies should be 
repeated while fasting within 1 week. 
Grade 3 or worse bullous dermatitis if possibly, probably, or definitely drug related is a dose 
limiting toxicity. 
4.5.3 Dose Modification for Hematological Toxicity 
For patients who have grade IV neutropenia or thrombocytopenia, the treatment should be 
withheld.  Complete blood counts should be obtained twice weekly until grade III or less.  If 
toxicity resolves to meet on study parameters within 14 days of drug discontinuation, the patient 
may resume treatment with sirolimus at the previous dose and erlotinib at the next lower dose 
level.  If toxicity does not resolve within 14 days of drug discontinuation, the patient must be 


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removed from protocol therapy.  If dose-limiting hematological toxicity occurs in a patient on 
the lowest dose level (65mg/m2/day) of erlotinib, the patient must be removed from protocol 
therapy. 
The days of the cycle should continue to be counted when drug is being held. The next cycle will 
start when criteria are met for that cycle. The day the next cycle is started will be day 1 of that 
cycle. 
4.5.4 Dose Modification for Non-Hematological Toxicity 
Dose modification for the first episode of AST and/or ALT elevations: 
If a patient experiences grade 3 AST and/or ALT elevation, treatment will be withheld.  Liver 
function tests will be repeated twice weekly until resolution to less than grade 3.  If toxicity 
resolves to less than grade 3 within 7 days and the patient has not previously had grade 3 or 
worse AST and/or ALT elevation, the treatment may resume at the previous doses of sirolimus 
and erlotinib.  If the patient experiences recurrent grade 3 or worse AST and/or ALT elevation at 
any time after resuming therapy, this will be considered a dose-limiting toxicity and the doses of 
study drugs should be modified as below. 
Dose modification for other non-hematological toxicity and/or the second or greater 
episode of AST and/or ALT elevations: 
If a patient experiences non-hematological dose-limiting toxicity, the treatment will be withheld. 
4.5.4.1 When the toxicity resolves to meet on study parameters within 14 days of drug 
discontinuation, the patient may resume treatment with sirolimus at the previous dose and 
erlotinib at the next lower dose level. 
4.5.4.2 If toxicity does not resolve to meet on study parameters within 14 days of drug 
discontinuation, the patient must be removed from protocol therapy. 
4.5.4.3 If non-hematological dose-limiting toxicity recurs in a patient on the lowest dose level of 
erlotinib (65mg/m2/day), the patient must be removed from protocol therapy. 
The days of the cycle should continue to be counted when drug is being held. The next cycle will 
start when criteria are met for that cycle. The day the next cycle is started will be day 1 of that 
cycle. 
4.6 Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive 
care are to be used as necessary, taking care to avoid CYP3A4/5 inducers and inhibitors. 
4.6.1 Rash: 
An acnieform rash is a common toxicity with EGFR inhibitors, including erlotinib, with 9.4% 
being grade III or higher [30].  This rash typically begins 1 week after drug initiation and is at 
maximal severity after 2-3 weeks of therapy.  The rash is thought to be due to inhibition of 


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EGFR in the skin (i.e. an on target effect) leading impaired keratinocyte migration and bacterial 
overgrowth [30]. The development of rash has been shown to correlate with prolonged survival 
in some studies of EGFR inhibitors [26].  The rash may improve despite continuation of anti-
EGFR therapy [31]. Prompt symptomatic care of rash may improve patient tolerance of erlotinib.  
Thus, topical clindamycin 2% and hydrocortisone 1% lotion is recommended for any rash 
thought likely or definitely related to drug until improvement of the rash by at least 1 grade.  For 
patients > 8 years of age, the addition of oral doxycycline 2.2mg/kg/day (maximum 100mg) as a 
single dose should be strongly considered for at least 1 month and until the rash resolves. 
 
5.0 Observations 
All enrollment/eligibility studies must be performed within 1 week prior to study enrollment 
(unless otherwise specified). If more than 7 calendar days elapse between the date eligibility 
studies were obtained and the start date of treatment, then the following studies must be repeated 
prior to treatment: CBC with differential, bilirubin, AST, ALT, serum creatinine, AFP, and 
HCG. If any of these repeat laboratory studies are outside the parameters required for eligibility 
(labs may again be repeated within 48-72 hours), then the patient is off protocol therapy. 
Imaging studies are required within 14 days prior to start of protocol therapy (repeat the tumor 
imaging if necessary). 
Study related procedures and observations may be adjusted for various logistical, scheduling, or 
patient preference reasons within a +/- 3 day window during cycle 1 of therapy.  During subsequent 
cycles of therapy there is a +/- 7 day window for study related procedures and observations. 
 
 


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5.1 Studies to Be Obtained 
 
Baseline 
During cycle 1 (and 
cycle 2 if erlotinib dose 
is escalated) 
Before the 
start  of 
subsequent 
cycles 
History 
X 
Weekly 
X 
PE 
X 
Weekly 
X 
Height, weight, BSA 
X 
Before the start of 
cycle 2 
X 
Performance Status 
X 
Before the start of 
cycle 2 
X 
CBC, electrolytes including Ca, 
Mg, Phos, AST, ALT, bilirubin, 
creatinine 
X 
Weekly 
X 
Fasting Triglyceride, 
Cholesterol (Total, HDL, LDL) 
X 
Before the start of 
cycle 2 
X 
Urinalysis 
X 
Before the start of 
cycle 2 
X 
Albumin, total protein 
X 
Before the start of 
cycle 2 
X 
HCG, AFP 
X 
Before the start of 
cycle 2 
X 
CT/MRI of primary and 
metastatic sites 
X 
End of Cycle 2 
End of even 
numbered 
cycles 
Serum for Erlotinib level 
 
Day 28 Prior to 
Starting Next Cycle 
X1 
Serum for Erlotinib 
pharmacokinetics 
 
Days 8-9 of Cycle 1 
 
Sirolimus level 
 
Weekly2 
X2 
Patient diary 
 
End of each cycle 
X 
Tumor tissue 
X3 
 
 
Tumor cytogenetics4 
X 
 
 
Pregnancy test (if appropriate) 
X 
 
 
1. Erlotinib trough levels will be obtained on day 28 of cycle 1 and day 28 of any cycle that 
includes an erlotinib dose change (escalation or reduction). 
2. Sirolimus trough levels will be obtained at least weekly until two consecutive levels are 
within the goal range (10-15ng/mL).  Levels will then be obtained at the end of each 
cycle.  If subsequent dose adjustment is necessary, levels will be obtained at least weekly 
after dose adjustment and then weekly until two consecutive levels are within range.  
Sirolimus levels will be performed at the local institution. 


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3. Required if available.  Dr. Laetsch must approve enrollment if no tumor tissue is 
available. 
4. Tumor cytogenetic reports to be collected if available, including karyotypes and SNP 
arrays. 
5.2 Tumor Sample for Correlative Biology Studies 
Submission of a tumor sample from diagnosis or relapse for correlative biology studies is 
required for study entry if available.  Enrollment of patients without archival tumor tissue must 
be approved by Dr. Laetsch, the PI of the study. 
5.2.1 Description of Assay 
Archival tumor tissue must be submitted if available. If multiple biopsies have been performed, 
tissue from the most recent biopsy is preferred. Tumor tissue will be analyzed by 
immunohistochemistry for AFP, EGFR, AKT, ERK, and mTOR pathway activation and banked 
for other future studies. 
5.2.2 Sampling Schedule 
Either a paraffin-embedded tissue block or unstained slides are required for enrollment. Tumor 
tissue or slides from the most recent resection or biopsy with available tissue are required.  If 
there have been multiple procedures, samples from the initial diagnostic biopsy or resection are 
also requested if available.  A block or slides from any resections or biopsies occurring after the 
start of protocol therapy are also requested. 
5.2.3 Sample Collection and Handling Instructions 
A paraffin-embedded tissue block should be submitted. If a tissue block is unavailable, at least 
15 unstained standard sections of 3 to 4 μM thickness must be sent (20 slides are recommended). 
5.3 Serum for Erlotinib Levels 
1 mL of blood will be drawn into a heparinized tube (green top) between 0 and 60 minutes 
before the next scheduled daily dose of erlotinib.  Blood will be centrifuged within 30 minutes of 
collection for 10 minutes at 1500g and the plasma removed and frozen at -80o C.  Samples will 
be shipped on dry ice and stored at -80o C until analysis.  Samples will be analyzed for levels of 
erlotinib and its active metabolite OSI-420 by HPLC with tandem MS as previously 
described[32]. 
5.4 Serum for Erlotinib Pharmacokinetics 
2 mL of blood will be drawn into a heparinized tube (green top) between 0 and 60 minutes 
before, and 1 hour (+/- 15 minutes), 2 hours (+/- 15 minutes), 4 hours (+/- 30 minutes), 8 hours 
(+/- 60 minutes), and 24 hours (+/- 2 hours and before the next scheduled erlotinib dose) after the 
scheduled day 8 dose of erlotinib.  Blood will be centrifuged within 20 minutes of collection for 
for 10 minutes at 1500g and the plasma removed and frozen at -80o C.  Samples will be shipped 


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on dry ice and stored at -80o C until analysis. Samples will be analyzed for levels of erlotinib and 
its active metabolite OSI-420 by HPLC with tandem MS as previously described[32]. 
5.5 Removed from Protocol Version 1.3 
5.6 Central Review 
Patients enrolled on study will have their pathologic diagnosis centrally reviewed by the UTSW 
pathologist Dr. Dinesh Rakheja after study entry. 
 
6.0 Criteria for Removal From Protocol Therapy and Off Study Criteria  
6.1 Criteria for Removal From Protocol Therapy  
a) Progressive disease. 
b) Adverse Events requiring removal from protocol therapy.  
c) Patients who receive concurrent anticancer or investigational therapy. 
d) Refusal of further protocol therapy by patient/parent/guardian. 
e) Completion of 25 cycles of therapy. 
f) Physician determines it is in patient’s best interest. 
g) Repeat eligibility studies (if required) are outside the parameters required for eligibility. 
h) Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
i) Patients who develop a second malignant neoplasm. 
 
Patients who are removed from protocol therapy (except for g) are to be followed until they meet 
the criteria for Off Study (see below). Follow-up data will be required unless consent was 
withdrawn. 
6.2 Off Study Criteria  
a) Death. 
b) Lost to follow-up. 
c) Entry into another research study with tumor therapeutic intent (e.g., at recurrence) or 
initiation of another systemic therapy with tumor therapeutic intent 
d) Withdrawal of consent for any further data submission. 
e) The fifth anniversary of study entry. 
 
7.0 Statistical Considerations  
7.1 Sample Size and Study Duration 
The University of Texas Southwestern Medical Center / Children’s Medical Center has averaged 
10 newly diagnosed pediatric malignant germ cell tumor patients per year over the last 6 years 


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(CCDB Tumor Registry).  With approximately 20% of patients expected to relapse, this will 
result in 2 eligible pediatric patients per year at UTSW/CCDB.  For this rare tumor, we plan to 
submit this protocol for approval through the MaGIC (Malignant Germ Cell Tumor International 
Collaborative) consortium and 4-5 additional large pediatric cancer centers, including the 
Boston’s Children’s Hospital, Children’s Hospital of Philadelphia, Children’s Healthcare of 
Atlanta, and Texas Children’s Hospital (Houston).  Between these sites, we expect to accrue 5-
10 response evaluable patients per year. A minimum of 11 patients and a maximum of 30 
patients are anticipated to account for possible ineligible and inevaluable patients.  Thus, we 
expect this study to complete accrual in 2 - 4 years. 
7.2 Study Design 
PFR, defined as the proportion of response evaluable patients free of objective disease 
progression after 4 cycles (16 weeks), will be the primary endpoint.  Response evaluable patients 
who demonstrate a best response of CR or PR and are removed from protocol therapy prior to 
completion of cycle 4 for any reason other than death or progressive disease will be considered 
free of objective disease progression.  The PFR will be examined using Simon's two-stage 
design[36]. The null hypothesis, H0: p ≤ p0, that the PFR p is less than or equal to p0 = 10% will 
be tested against the one-sided alternative, H1: p >= p1, that the PFR p is greater than or equal to 
p1 = 35%. In the first stage, 11 response evaluable patients will be evaluated. If there is less than 
or equal to 1 patient free of objective disease progression at 16 weeks (4 months) among these 11 
patients, the study will be stopped early for futility. Otherwise, 16 additional response evaluable 
patients will be accrued for a total of 27. The null hypothesis will be rejected if greater than or 
equal to 6 patients free of objective disease progression are observed in 27 patients. This design 
yields a type I error rate of 5% and power of 90% when the true response rate is 35%. 
7.3 Methods of Analysis 
Aim 1.1.1: A responder is defined as a patient free of objective disease progression 4 cycles (16 
weeks) of therapy. Response rates will be calculated as the percent of evaluable patients who are 
responders, and confidence intervals will be constructed accounting for the two-stage design. A 
secondary analysis will be reported including only patients with a best response of CR or PR as 
responders. 
Aim 1.1.2: Toxicity tables will be constructed to summarize the observed incidence by type of 
toxicity and grade. The relative frequency of each type of toxicity will be quantified as the 
number of toxicity-evaluable patients in which the AE was noted and considered by the treating 
physician to be possibly, probably or definitely related to one of the agents in the regimen 
divided by the number of toxicity-evaluable patients enrolled on the trial. The proportion of 
patients who experience dose- limiting toxicity on the first cycle and at any time during protocol 
therapy will be calculated. The analytic population for these analyses will be all patients 
considered evaluable for toxicity (see below). 
Aim 1.2.1: Expression for activation of the listed pathways will be scored as 0 = negative; 1+ = 
weak staining; 2+ = moderate staining; and 3+ = strong staining. The proportion of patients 
falling into each category (relative to the total number of patients evaluated) will be calculated. If 
10% or more of patients demonstrate a response, the response status of each patient will be 
cross-tabulated with expression of the proteins of interest. 


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Aim 1.2.2:  Patients evaluable for response will be included in analysis of progression free 
survival as a secondary outcome measure. Progression-free interval (PFI) will be calculated as 
the date of enrollment until the end PFI date, where that date is calculated as the date of disease 
progression, date of death, date of removal of all tumor by surgery or last patient contact, 
whichever occurs first. Patients whose end PFI date is disease progression or death will be 
considered to have experienced an event. Patients whose end PFI date is date of removal of all 
tumor by surgery will be considered removed from the analytic set at that time by a competing 
event. Patients whose end PFI date is the date of last patient contact will be considered censored 
for PFI analysis. The probability of remaining progression-free as a function of days since 
enrollment will be calculated according to the method of Gray accounting for censoring and the 
competing events.  The data for those patients with immunohistochemically defined mTOR 
pathway activation (grades 2 and 3+ staining for pS6) will be compared to those without 
pathway activation (grades 0 and 1+ staining for pS6) by the method of Gray. 
Aim 1.2.3: Blood samples drawn between 0 and 60 minutes before, and 1, 2, 4, 8, and 24 (before 
the next scheduled erlotinib dose) hours after the scheduled day 8 dose of erlotinib will be analyzed 
for levels of erlotinib and its active metabolite OSI-420 by HPLC with tandem MS as previously 
described[32]. The pharmacokinetics of erlotinib in subjects on this trial will be analyzed by a non-
compartmental method using WINNonlin and comparied to prior published data for pediatric 
subjects not taking sirolimus [20]. 
7.4 Evaluation Criteria 
This study will use the Response Evaluation Criteria in Solid Tumor (RECIST) from the NCI v  
1.1. and the response of initially elevated tumor markers (AFP and/or B-HCG).  Tumor markers 
must be initially elevated to >10X the upper limit of normal (ULN) to be used for response 
determination. 
7.5 Definitions 
7.5.1  Evaluability for Response 
Any patient who is enrolled and receives at least one dose of sirolimus and erlotinib will be 
considered evaluable for response provided: (1) the patient demonstrates progressive disease or 
death while on protocol therapy; (2) the patient is observed on protocol therapy for at least one 
cycle and the tumor is not removed surgically prior to the time complete response or partial 
response is confirmed; or (3) the patient is observed on protocol therapy for at least four cycles 
and the tumor is not removed surgically prior to the time stable disease after 4 cycles is 
confirmed. Patients who demonstrate a complete or partial response confirmed by central review 
will be considered to have experienced a response for the application of the rule above. All other 
patients will be considered non-responders. All patients considered to have a response (CR or 
PR) according to the institutional investigator must have imaging studies reviewed centrally.  
7.5.2 Evaluability for Toxicity 
Eligible patients who receive at least one dose of sirolimus and erlotinib will be included in 
analysis of toxicity. 


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7.5.3 Measurable Disease 
The presence of at least one lesion that can be accurately measured in at least one dimension 
with the longest diameter at least 10 mm. With spiral CT scan or clinical exam using calipers, 
lesions must be at least 5 mm. All tumor measurements will be recorded in millimeters (or 
decimal fractions of centimeters). The investigator will identify up to 5 measurable lesions to be 
followed for response. 
Serial measurements of lesions are to be done with CT or MRI. The same method of assessment 
is to be used to characterize each identified and reported lesion at baseline and during follow-up. 
Note: Tumor lesions that are situated in a previously irradiated area may be considered 
measurable only if there is unequivocal evidence of disease progression at that site following 
irradiation, or if there is histologic proof of viable tumor at that site following irradiation. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness no 
greater than 5 mm). At baseline and in follow- up, only the short axis will be measured and 
followed. 
7.5.4 Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered non- measurable 
disease. Bone lesions, ascites, pleural or pericardial effusions, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non- measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
7.5.5 Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion that can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 


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7.5.6 Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
7.6 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. The 
same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
Conventional CT and MRI: The measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable 
in certain situations (e.g. for body scans). Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible to prior scans. Body 
scans should be performed with breath-holding techniques if possible. 
7.6.1 Quantification of Disease Burden 
The sum of the longest diameter (non-nodal masses) and shortest axis (lymph nodes) for all 
target lesions will be calculated and reported as the disease measurement. 
7.6.2 End-of-Cycle Response 
a) Complete Response (CR) 
Disappearance of all target lesions if present and normalization of tumor markers if elevated. 
Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to 
< 10 mm. 
b) Partial Response (PR) 
Either at least a 30% decrease in the disease measurement, taking as reference the baseline sum 
diameters, OR a decline of at least 90% of initially elevated tumor markers (>10X ULN) in the 
absence of progressive disease by criteria below. If the patient initially has evaluable disease 
without measurable target lesions, a reduction of >90% but less than normalization of tumor 
markers qualifies as a partial response.  
c) Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest disease measurement recorded since the start of treatment OR an increase in tumor 
markers by greater than 50% from the smallest measurement since immediately prior to or after 
the start of treatment and to greater than 10 times the upper limit of normal qualifies as 
progressive disease. The sum of diameters must also demonstrate an absolute increase of at least 


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5 mm. In addition, the appearance of one or more new lesions is also considered progressive 
disease. 
d) Stable Disease (SD) 
Neither sufficient shrinkage or tumor marker decline to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest disease measurement since the treatment started.  
7.6.3 Overall Best Response Assessment 
Each patient will be classified according to their “best response” for the purposes of analysis of 
treatment effect. Best response is determined from the sequence of the objective statuses 
described in Section 7.7. 
7.6.4 Evaluation of Non-Target Lesions 
(a) Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker levels. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
(b) Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits 
(c) Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances. 
If a patient has evaluable disease without measurable target lesions, an increase in tumor markers 
by greater than 50% from the smallest measurement since immediately prior to or after the start 
of treatment and to greater than 10 times the upper limit of normal qualifies as progressive 
disease. 
7.7 Best Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. Two objective status 
determinations of CR before progression are required for best response of CR. Two 
determinations of PR or better before progression, but not qualifying for a CR, are required for a 
best response of PR. Two determinations of stable/no response or better before progression, but 
not qualifying as CR or PR, are required for a best response of stable disease; if the first 
objective status is unknown, only one such determination is required. Patients with an objective 


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status of progression on or before the second evaluations (the first evaluation is the first 
radiographic evaluation after treatment has been administered) will have a best response of 
progressive disease. Best response is unknown if the patient does not qualify for a best response 
of progressive disease and if all objective statuses after the first determination and before 
progression are unknown. 
8.0 Safety and Adverse Events 
8.1 Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during a trial. Additionally, certain adverse events must be reported in an expedited 
manner to allow for optimal monitoring of subject  safety and care.  
All subjects experiencing an adverse event, regardless of its relationship to study drug, will be 
monitored until:  
Ø the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
Ø any abnormal laboratory values have returned to baseline;  
Ø there is a satisfactory explanation other than the study drug for the changes 
observed; or 
Ø death. 
8.1.1 Definitions 
An adverse event is defined as any untoward or unfavorable medical occurrence in a human 
research study participant, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, clinical event, or disease, temporarily associated with the subject’s 
participation in the research, whether or not it is considered related to the subject’s participation 
in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events occur 
most commonly in the context of biomedical research, although on occasion, they can occur in 
the context of social and behavioral research. Adverse events may be expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI Common 
Terminology Criteria for Adverse Events (NCI CTCAE) and version number specified in the 
protocol. Adverse events not specifically defined in the NCI CTCAE will be scored on the 
Adverse Event log according to the general guidelines provided by the NCI CTCAE and as 
outlined below.   
• Grade 1: Mild  


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• Grade 2: Moderate 
• Grade 3: Severe or medically significant but not immediately life threatening 
• Grade 4: Life threatening consequences 
• Grade 5: Death related to the adverse event 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, occurring 
at any dose, which meets any of the following criteria:  
• 
Results in death   
• 
Immediately life-threatening  
• 
Results in inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity  
• 
Results in a congenital anomaly/birth defect  
• 
Based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition. 


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Note: A “Serious adverse event” is by definition an event that meets any of the above criteria. 
Serious adverse events may or may not be related to the research project. A serious adverse event 
determination does not require the event to be related to the research. That is, both events 
completely unrelated to the condition under study and events that are expected in the context of 
the condition under study may be serious adverse events, independent of relatedness to the study 
itself. As examples, a car accident requiring overnight hospitalization would be a serious adverse 
event for any research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death  which occurs during the protocol-specified period of monitoring for 
adverse and serious adverse events would be a serious adverse event, even if the event observed is a 
primary clinical endpoint of the study.  
 
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The term “unanticipated problem” is found, but not defined in the regulations for the Protection 
of Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. Guidance from the 
regulatory agencies considers unanticipated problems to include any incident, experience, or 
outcome that meets each of the following criteria: 
• 
Unexpected (in terms of nature, severity or frequency) AND 
• 
Definitely, or probably, related to participation in the research AND  
• 
 In the opinion of the PI , suggests that the research places subjects or others at a 
greater risk of harm (including physical, psychological economic or social harm) 
than was previously known or recognized. Note: Any serious adverse event would 
always suggest a greater risk of harm. 
Follow-up  
All adverse events will be followed up according to good medical practices.  
8.1.2 Reporting 
The UTSW IRB requires reporting of all UPIRSOs according to the guidance below. For 
participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events. All SAEs occurring during the protocol-specified monitoring 
period should be submitted to the UTSW study team within 2 business days of the center 
learning of the event.  
UPIRSOs occurring on the study require expedited reporting, and are submitted to the UTSW 
IRB through the UTSW eIRB by the UTSW study team and to the SCCC DSMC Coordinator.  
Hardcopies or electronic versions of the eIRB report; FDA Form #3500A forms, or other sponsor 
forms, if applicable; and/or any other supporting documentation available should be submitted to 
the UTSW study team and will be forwarded to the DSMC Coordinator.  The DSMC 
Coordinator forwards the information onto the DSMC Chairman who determines if immediate 
action is required.  Follow-up eIRB reports, and all subsequent documentation that is available 
are also submitted to the DSMC Chair who determines if further action is required.   (See 


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Appendix IV of the SCCC DSMC Plan for a template Serious Adverse Event Form which may 
be utilized when a sponsor form is unavailable and SAE submission to the eIRB is not required). 
All local serious adverse events which occur on research subjects on protocols for which the 
SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. Hardcopies or electronic versions of the FDA Form #3500A forms, or other 
sponsor forms, if applicable; and/or any other supporting documentation available should be 
forwarded to the DSMC Coordinator.   
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW.  Simmons 
Cancer Center, the DOT Manager or the lead coordinator ensures that all participating sites are 
notified of the event and resulting action, according to FDA guidance for expedited reporting.  
DSMC Chairperson reviews all serious adverse events  upon receipt from the DSMC 
Coordinator.  The DSMC Chairperson determines whether action is required and either takes 
action immediately, convenes a special DSMC session (physical or electronic), or defers the 
action until a regularly scheduled DSMC meeting.  
  
Telephone reports to: 
Theodore Laetsch, MD 
Principal Investigator 
214-648-5475 
UTSW SCC Data Safety Monitoring Committee Coordinator (if fax report is not available) 
within 2 working days to 214-648-7097. 
 
Written reports to: 
Theodore Laetsch, MD 
Mail Code A3.01 
Department of Pediatrics - Oncology 
5323 Harry Hines Blvd. 
Dallas, TX 75390 
Fax: 214-648-5475 
Email: ted.laetsch@utsouthwestern.edu 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-7018 or deliver to NB 2.418 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting documentation 
1. SAEs 


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Serious adverse events (SAEs) for studies where SCCC DSMC is the DSMC of record require 
reporting to the DSMC coordinator within 2 working days of PI awareness or as described n the 
protocol.   
2. Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) 
Local Serious Adverse Event UPIRSOs  require reporting to the UTSW IRB within 48 hours of PI 
awareness of the event (life threatening or fatal events experienced by subjects enrolled by the 
investigator(s) under UTSW IRB jurisdiction).   
Local UPIRSOs (non-serious events experienced by subjects enrolled by the investigator(s) 
under UTSW IRB jurisdiction) require reporting to the UTSW IRB within 5 business days of PI 
awareness.  
External UPIRSOs including those that occur as non-local events, require reporting to the UTSW 
IRB within 10 working days of PI awareness of the event.  
For further guidance for Investigators regarding safety reporting requirements for INDs and 
BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM227351.pdf 
8.3 Data Safety and Monitoring 
The PI at each participating center will monitor the clinical outcome of each patient treated on 
the trial, and UTSW (Overall PI Theodore Laetsch, MD), as the coordinating center will monitor 
the overall safety and efficacy of the treatment.  The UTSW PI, responsible research nurse, data 
manager, and study team will meet on an at least bi-weekly schedule to review enrollment and 
observed toxicities. Documentation of the study team meetings will be maintained along with 
other protocol related documents and will be reviewed during internal audit.   
Trial monitoring will be conducted no less than annually and refers to a regular interval review 
of trial related activity and documentation performed by the study team, which includes but is 
not limited to accuracy of case report forms, protocol compliance, timeless and accuracy of 
Velos entries and AE/SAE management and reporting. Documentation of trial monitoring will be 
maintained along with other protocol related documents and will be reviewed during internal 
audit.   
Individual patient dose escalations will be reviewed and monitored by the treating physician.  
After data has been submitted for the first two cycles of therapy for the first 5 pediatric patients, 
the trough based dose adjustment of sirolimus in pediatric patients will be reviewed.  Toxicity 
and efficacy review will be performed after enrollment of the first eleven response evaluable 
patients (prior to opening the second stage).  This review will be documented in an Excel 
spreadsheet that will be maintained along with other protocol documents. 
The UTSW Simmons Comprehensive Cancer Center (SCC) Data Safety Monitoring Committee 
(DSMC) is responsible for monitoring data quality and patient safety for all UTSW SCCC 
clinical trials. As part of that responsibility, the DSMC reviews all local serious adverse events 


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and UPIRSOs in real time as they are reported. The quality assurance activity for the Clinical 
Research Office provides for periodic auditing of clinical research documents to ensure data 
integrity and regulatory compliance. A copy of the DSMC plan is available upon request. 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of ongoing 
clinical trials, for which it serves as the DSMC of record. The QAC works as part of the DSMC 
to conduct regular audits based on the level of risk. Audit findings are reviewed at the next 
available DSMC meeting. In this way, frequency of DSMC monitoring is dependent upon the 
level of risk. Risk level is determined by the DSMC Chairman and a number of factors such as 
the phase of the study; the type of investigational agent, device or intervention being studied; and 
monitoring required to ensure the safety of study subjects based on the associated risks of the 
study. Protocol-specific DSMC plans must be consistent with these principles.  
Further detail may be found in the SCC-DSMC Plan.  
8.4 Protection of Subjects 
Complementing the safety measures noted above, additional procedures will be followed to 
protect the safety of the research subjects. Potential Subjects will be screened for medical 
illnesses that would preclude the use of sirolimus or erlotinib. Subjects selected for the study will 
be evaluated weekly while receiving study drug treatments for the first cycle and then at least 
every 4 weeks. AEs will be monitored weekly and a study physician will be available at all times 
to evaluate and treat adverse effects of the medication. Significant AEs will result in exclusion 
from the study (see Clinical Trial Discontinuation Criteria). Venipuncture or blood draws from 
central venous catheters (CVCs) will be carried out with good aseptic technique by an 
experienced phlebotomist, registered nurse, nurse practitioner or physician. Venipuncture sites 
will be monitored carefully for signs of infection. The PI or treating physician will clinically 
follow all subjects who are discontinued due to a serious AEs until the AE resolves and becomes 
completely stable, unless a referral to another physician (i.e. specialist) is clinically indicated or 
requested by the subject.  
8.5 Stopping Rules 
The study will pause enrollment after the first 11 response evaluable patients are enrolled until 
efficacy (cycles 1-4) and toxicity (cycles 1 and 2) data are complete for these patients.  A toxicity 
and efficacy review will occur at this time point prior to opening enrollment for an additional 16 
response evaluable patients (see section 8.2).  Only dose limiting toxicities occurring during 
cycles 1 and 2 will be considered for these stopping rules.  If greater than 25% of toxicity 
evaluable patients experience a dose-limiting toxicity as defined in section 4.5 of this protocol, 
the study will be stopped early for toxicity.  If less than or equal to 1 of 11 response evaluable 
patients demonstrate a response to therapy (as per section 7.2), the study will be stopped early for 
futility.  If neither of these conditions are met, the study will open to accrual of an additional 16 
response evaluable patients. 
9.0 Data Handling and Record Keeping 
9.1 Confidentiality 


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Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Information Portability and Accountability Act (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following:  
 
The personal health information (PHI) to be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
To whom the data may be disclosed and the reasons for this disclosure 
 
The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period.  
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All 
data requested on the CRF must be recorded. All missing data must be explained. If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”. If the item is not applicable to the individual case, write “N/A”. All entries should be 
printed legibly in black ink. If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it. All such 
changes must be initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
10.0 Consent Procedures 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. See Appendix 2 for a copy of the Subject Informed Consent Form. This consent form will 


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be submitted with the protocol for review and approval by the IRB for the study. The formal 
consent of a subject, using the IRB-approved consent form, must be obtained before that subject 
is submitted to any study procedure. This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional obtaining the consent.  
The PI or study physician will obtain informed consent from all patients and/or their parents or 
legal guardians before any study procedures occur, explaining all procedures in detail in an 
individual session. The consent form and explanation will include; detailed information about 
sirolimus and erlotinib, the rationale for why they are being studied, frequency of dosing, and 
length of treatment, potential side effects and risks, safeguards and emergency procedures. The 
collection of all lab specimens will be described in detail. Subjects will be assured that their 
participation is voluntary and that withdrawal from the study would not jeopardize current or 
future treatment. All subjects will be informed of potential risks and benefits involved in the 
study, including side effects of sirolimus and erlotinib. 
11.0 Study Management 
11.1 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be provided to 
the UT Southwestern Pediatric Oncology Clinical Research Office. 
• 
A copy of the official IRB approval letter for the protocol and informed consent 
• 
IRB membership list or Federal wide Assurance letter 
• 
CVs and medical licensure for the principal investigator and any associate investigators 
who will be involved in the study 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 
(NOTE: this is required if {institution} holds the IND. Otherwise, the affiliate Investigator’s 
signature on the protocol is sufficient to ensure compliance) 
• 
A copy of the IRB approved consent form 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Executed clinical research contract 
11.2 
Registration Procedures 
All subjects must be registered with the UT Southwestern Pediatric Oncology Clinical Research 
Office before enrollment to study. Prior to registration, eligibility criteria must be confirmed with 
the UT Southwestern Pediatric Oncology Clinical Research Office Study Coordinator. To 
register a subject, call 214-456-8138 Monday through Friday, 9:00AM 5:00PM, Central 
Standard Time.  
11.3 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study subject requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol.  


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11.3.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior IRB approval.  
For any such emergency modification implemented, a IRB modification form must be completed 
within five (5) business days of making the change. 
11.3.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal 
Investigator and the IRB. According to the IRB, a protocol deviation is any unplanned variance 
from an IRB approved protocol that:  
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or the value of the 
data collected  
• 
Did not result from willful or knowing misconduct on the part of the investigator(s).  
An unplanned protocol variance is considered a violation if the variance: 
• 
Has harmed or increased the risk of harm to one or more research participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, State laws, 
or University policies. 
If a deviation or violation occurs without prior approval from the Principal Investigator, please 
follow the guidelines below: 
Protocol Violations: Study personnel should report violations within two (2) weeks of the 
investigator becoming aware of the event using the same IRB online mechanism used to report 
Unanticipated Problems and to their local IRB according to institutional guidelines.  
11.4 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining proposed 
changes as well as rationale for changes, when appropriate, is highly recommended.  When an 
amendment to the protocol substantially alters the study design or the potential risk to the patient, 
a revised consent form might be required.  
The written amendment, and if required the amended consent form, must be sent to the IRB for 
approval prior to implementation.  
11.5 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 


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The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, monitoring 
visits may be conducted and the Principal Investigator will provide access to his/her original 
records to permit verification of proper entry of data. At the completion of the study, all case 
report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
 
 
 


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Appendix 1: CYP3A4/5 Inducers and Inhibitors 
The following medications are not permitted for 10 days prior to study enrollment or at any time 
while receiving protocol therapy due to their effect on sirolimus and erlotinib pharmokinetics. 
Inhibitors: 
• Antibiotics: clarithromycin, telithromycin, troleandomycin, roxithromycin  
• Protease inhibitors: ritonavir, indinavir, saquinavir, nelfinavir, amprenavir,  
lopinavir  
• Antifungals: itraconzaole, ketoconazole, voriconazole  
• Antidepressants: nefazodone  
 
Inducers: 
• 
Glucocorticoids for greater than 2 weeks duration: cortisone (>50 mg), hydrocortisone 
(>40 mg), prednisone (>10 mg), methylprednisolone (>8 mg), dexamethasone (>1.5 mg)  
• 
Anticonvulsants: phenytoin, carbamezepine, phenobarbital, oxcarbazepine, primidone, 
fosphenytoin  
• 
HIV antivirals: efavirenz, nevirapine, tipranavir  
• 
Antibiotics: rifampin (rifampicin), rifabutin, rifapentene  
• 
Miscellaneous: St. John’s Wort, modafinil, pioglitazone 
 
 


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Appendix 2: Sample Consent Form 
 
CONSENT TO PARTICIPATE IN RESEARCH 
 
 
Title of Research: 
A Phase II Study of Sirolimus and Erlotinib in 
Recurrent/Refractory Germ Cell Tumors 
 
Funding Agency/Sponsor: 
UT Southwestern Medical Center 
 
 
Study Doctors: 
[Insert Study Doctors] 
 
 
You may call these study doctors or research personnel during regular office hours at [insert 
phone number].  At other times, you may call them at [insert phone number]. 
 
Note: If you are a parent or guardian of a minor and have been asked to read and sign this 
form, the “you” in this document refers to the minor. 
 
Instructions: 
Please read this consent form carefully and take your time making a decision about whether to 
participate.  As the researchers discuss this consent form with you, please ask him/her to explain 
any words or information that you do not clearly understand.  The purpose of the study, risks, 
inconveniences, discomforts, and other important information about the study are listed below.  
If you decide to participate, you will be given a copy of this form to keep. 
 
Why is this study being done? 
This study is being done to find out how effective the combination of sirolimus and erlotinib is 
at treating relapsed and refractory germ cell tumors.  Sirolimus is a drug that is an FDA 
approved drug to prevent rejection of kidney transplants in patients over 13 years of age.  
Erlotinib is an FDA approved drug to treat adults with some types of lung an pancreatic cancers.  
We are using this combination of drugs because they work together to inhibit a growth 
pathway that is felt to be important in how germ cell tumors grow.  This combination of drugs 
has been administered to both adults and children who have brain tumors, but have never 
been given to participants with germ cell tumors.  The dosages of sirolimus and erlotinib given 
in this study may be higher than given in the previous studies.   
 


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Research blood tests will be conducted before and while you are taking these drugs.  These 
research tests include measurement of the concentration of the drugs in your blood and 
measurement of the effect of the drugs on your white blood cells.  We will also obtain research 
blood tests over a 24-hour period to determine whether these drugs have an interaction in how 
they are metabolized by your body.  Further, we will do special stains on tissue from a previous 
biopsy of your tumor to determine the degree of activation of pathway that these drugs inhibit.  
Finally, using tissue from a previous biopsy of your tumor, we will look for genetic mutations in 
this pathway. You will not need to have a new biopsy of your tumor to participate in this study. 
 
Why is this considered research?  
This is a research study because this combination of erlotinib and sirolimus has never been 
given together to patients with germ cell tumors.  We will collect data on the safety and 
effectiveness of these drugs on patients with relapsed germ cell tumors.  
 
The following definitions may help you understand this study:  
• Standard medical care means the regular care you would receive from your personal 
doctor if you choose not to participate in this research. 
• Researchers means the study doctor and research personnel at the University of Texas 
Southwestern Medical Center at Dallas and its affiliated hospitals and at your treating 
institution. 
 
Why am I being asked to take part in this research study? 
You are being asked to take part in this study because you have a malignant germ cell tumor 
that has come back (relapsed) after or failed to respond to at least two standard therapies.   
 
Do I have to take part in this research study? 
No.  You have the right to choose whether you want to take part in this research study.  If you 
decide to participate and later change your mind, you are free to stop participation at any time. 
 
If you decide not to take part in this research study it will not change your legal rights or the 
quality of health care that you receive at this center. 
 
How many people will take part in this study? 
This study also is planned at a number of other medical facilities around the country.  There will 
be a total of between about 11 and 30 people participating in this research study throughout 
the United States.  Of these, about [insert expected accrual] people will take part in this study 
at [insert local institution]. 
 
What is involved in the study? 


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If you volunteer to take part in this research study, you will be asked to sign this consent form 
and will have the following tests and procedures.  Some of the procedures may be part of your 
standard medical care, but others are being done solely for the purpose of this study. 
 
Baseline 
During 
Cycle 1 
Before the Start 
of Following 
Cycles 
 
Medical History & 
Physical Exam 
X 
X 
X 
Blood Test 
X 
X 
X 
MRI/CT scan 
X 
 
End of even 
numbered cycles 
Patient Diary 
 
X 
X 
Pregnancy Test 
X 
X 
X 
Urine Test 
X 
X 
X 
Research Blood 
Tests 
X 
X 
Only if erlotinib 
dose changes 
Sirolimus Levels 
(to adjust dose) 
 
X 
X 
Receive Study 
Drug 
X 
X 
X 
 
Screening Procedures 
To help decide if you qualify to be in this study, the researchers will ask you questions about 
your health, including medications you take and any surgical procedures you have had. 
 
You may also have to fill out certain forms or have the following exams, tests or procedures: 
• Physical exam and medical history; 
• Vital signs; 
• Blood tests; 
• Urine tests; 
• Pregnancy test; 
• Demographic information (age, sex, ethnic origin); 
• A CT or MRI of your tumor(s) 
 
Study Medication/Intervention 
Each treatment cycle lasts 4 weeks during which time you will be taking both of the study 
drugs daily: 
• Sirolimus tablets or suspension at a starting dose of 1mg/m2 daily 


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o During Cycle 1, the amount of this drug will be measured in your blood each 
week on Day 1, Day 8, Day 15 and Day 28. Your dose will be increased or 
decreased if necessary to achieve the desired amount in in your blood.  
During Cycle 2 and any cycles after that, the drug will be measured in your 
blood at the end of the cycle only on Day 28.   
• Erlotinib tablets at a starting dose of 85mg/m2 daily (maximum dose 150mg) 
o Your dose of this drug will be increased if you do not have significant side 
effects after the first 28 days of therapy.  Your dose may be decreased if you 
have significant side effects from this drug. 
 
Procedures and Evaluations during the Research 
You will have the following tests and procedures during the study.  They are part of 
standard cancer care. 
• Physical exam and medical history; 
• Vital signs; 
• Blood tests; 
• Urine tests; 
• Pregnancy test; 
• A CT or MRI of your tumor(s) 
 
Clinic visits will occur every week for the first one to two 4-week cycles of the study.  After 
the first 8 weeks, clinic visits will occur monthly.  Clinic visits are expected to take 1-2 hours.  
You will have a CT or MRI of your tumor every 8 weeks while on this study. 
 
You will be asked to keep a diary of the time and dose of the drugs that you take and any 
symptoms that you experience while participating in this research study. 
 
You will have the following additional research blood tests during the study.  These will 
occur before you take the first dose of drug and at the end of each 28 day cycle of therapy.  
These blood tests will occur at the same time as blood is being drawn for other standard 
laboratory tests.  These are done to help better understand the effect of these drugs on 
your body and the way your body metabolizes these drugs. 
• Blood tests for drug levels (1/2 teaspoon of blood) 
 
Additionally, on the eighth day after you start taking the study drugs, you will have 5 
research blood tests over an 8-hour period and an additional blood test on the ninth day.  In 
total, we will draw about 2.5 teaspoons of blood for these tests.  These tests may be drawn 
from a central line if you have one.  If you do not have a central line, an IV will be placed 
and your blood drawn for the IV for these tests.  These tests will help us understand the 
pharmacokinetics of erlotinib (how your body metabolizes the drug.) 


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The research blood tests in this study are designed for research, not for medical purposes.  
They are not useful for finding problems or diseases.  Even though the researchers are not 
looking at your blood tests to find or treat a medical problem, you will be told if they notice 
something unusual.  You and your regular doctor can decide together whether to follow up 
with more tests or treatment.  Because the research blood tests done in this study are not 
for medical purposes, the research results will not be sent to you or to your regular doctor.  
 
 
Procedures for storing of extra or left over samples 
At the time of your enrollment on this study, leftover tissue from at least one biopsy of your 
tumor must be supplied to us by the hospital where your biopsy was obtained.  We will use 
this sample to look for activation of the metabolic pathways inhibited by sirolimus and 
erlotinib and to test for mutations in the genes that may make some tumors more or less 
sensitive to these drugs.  The principal investigators of this study will keep your remaining 
samples in a research laboratory at the UT Southwestern Medical Center until they are all 
gone, become unusable or until they decide to discard the sample.  If you withdraw from 
the study, you may request that any unused samples from your tumor be destroyed. 
 
Your samples will be stored labeled with a unique identification number.  A table that links 
this identification number to your personal information will be kept in a secure facility with 
limited access and password protection.  The computer maintained by UT Southwestern is 
protected by a firewall which prevents unauthorized access to the information.  Any results 
collected will not be released in a personally identifiable manner, and thus no information 
will be given to your insurance provider, employer, family, etc. without your permission. 
 
When you provide a sample for purposes of this study your sample becomes the property of 
The University of Texas Southwestern Medical Center and may be used for future studies or 
provided to other investigators at other medical research facilities without any identifiers. 
The principal investigators of this study will decide which researchers at this medical center 
and at other medical centers may receive samples.  Your samples may be used in other 
research only if the other research has been reviewed and approved by an Institutional 
Review Board (IRB). 
 
If your sample remains stored beyond your lifetime, your sample will be used as described 
in this document. 
 
How long can I expect to be in this study? 


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You may be in the study for up to 24 months if you are responding to therapy. Your doctor may 
decide to take you off study if any of the following occur: 
• The side effects of the combination of sirolimus and erlotinib are too harmful for you 
• You need a treatment that is not allowed on this study 
• Your tumor does not improve or worsens 
• You are not able to follow study-related treatment instructions 
• New information becomes available 
• The study is not in your best interest 
• The study is stopped 
 
You can choose to stop participating for any reason at any time.  However, if you decide to stop 
participating in the study, we encourage you to tell the researchers.  You may be asked if you 
are willing to complete some study termination tests. 
 
What are the risks of the study? 
Study Drugs 
Because of your participation in this study, you are at risk for the following side effects. You 
should discuss these with the researchers and your regular health care provider.  
 
Sirolimus and erlotinib may cause some, all or none of the side-effects listed below. Because 
there is limited information about the use of these drugs in combination, other unexpected 
side-effects, which may be serious, may also occur. 
 
 
Sirolimus 
Erlotinib 
Frequent  
(>20% of 
subjects) 
• 
High blood pressure 
• 
Nausea/vomiting 
• 
Diarrhea and/or constipation 
• 
Increased risk of infection that 
may be serious or life-
threatening 
• 
Fever 
• 
Liver problems: Abnormally 
high levels of enzymes 
produced by the liver that 
are found in the blood and 
indicate that yourliver is not 
functioning properly. The 
high enzyme levels can 
cause fatigue and jaundice 
(yellowing of the skin and 
eyes). Although this is 
usually mild and reversible, 
• 
Rash, itching, dry skin 
• 
Diarrhea 
• 
Nausea/vomiting 
• 
Pancreatitis (elevated 
enzymes in the pancreas 
which may cause pain, 
nausea and vomiting.)   
• 
Mouth sores 
• 
Conjunctivitis (pink eye) 
• 
Irritation to the liver 
• 
Shortness of breath or 
cough 
Increased risk of infection which 
may be serious or life-
threatening 


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this can be serious or life 
threatening 
• 
Abnormal kidney function tests, 
which means the kidneys aren’t 
working properly. When the 
kidneys do not work properly, 
wastes can build up in your 
blood, leading to swelling in the 
arms and legs, tiredness and 
weakness. This could become 
severe, requiring hospitalization 
and dialysis to clean the wastes 
out of your blood. If the wastes 
are not removed from your 
blood, this could cause seizures 
and be life threatening. 
• 
Weight gain 
• 
Muscle pain 
• 
High cholesterol 
Acne 
Occasional  
(5-20% of 
subjects) 
• 
Chest pain 
• 
Insomnia (unable to 
sleep) 
• 
Shortness of breath 
• 
Low blood counts which may 
increase your risk of infection 
(low number of white blood 
cells) or increase your risk for 
bleeding (low number of 
platelets)  
• 
Skin rashes or hives 
Slow wound healing 
• 
Weight loss 
Inflammation of the lung tissue 
that may cause difficulty 
breathing and can be 
• 
life-threatening 
• 
Scarring of the lungs 
Severe skin rash 
Rare  
(<5% of 
subjects) 
• 
Low blood pressure this may 
cause dizziness 
• 
Lung problems, 
including asthma 
• 
Loss of appetite 
• 
Serious infections 
• 
Blood clots  
• 
Skin problems (serious peeling, 
redness and itching) 
• 
Kidney failure 
• 
Secondary cancers 
Bone degeneration (break down)  
• 
Liver problems or failure 
which can cause fatigue, 
and jaundice (yellowing of 
the skin and eyes). 
Although this is usually mild 
and reversible, this can be 
serious or life threatening 
and may require 
hospitalization and surgery.  
• 
Kidney failure which is when 
both of your kidneys fail and 
your body holds fluid which 
can be serious or life 
threatening. Your blood 
pressure rises and harmful 
wastes build up in your 
body. You may experience 


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fatigue, nausea, and loss of 
appetite. When this 
happens, you need 
treatment to replace the 
work of your failed kidneys 
such as dialysis. 
• 
Hearing loss 
Bleeding in the gastrointestinal 
tract 
 
Loss of Confidentiality 
Any time information is collected; there is a potential risk for loss of confidentiality.  Every 
effort will be made to keep your information confidential; however, this cannot be guaranteed.  
 
Risks to Sperm, Embryo, Fetus or Breast-fed Infant 
Males: Being in this research may damage your sperm, which could cause harm to a child that 
you may father while on this study. If you take part in this study and are sexually active, you 
must agree to use a medically-acceptable form of birth control. Medically-acceptable forms of 
birth control include: 
(1) surgical sterilization (vasectomy), or 
(2) a condom used with a spermicide (a substance that kills sperm). 
 
Females: If you are part of this study while pregnant or breast-feeding an infant, it is possible 
that you may expose the unborn child or infant to risks.  For that reason, pregnant and breast-
feeding females cannot participate in the study.  If you can become pregnant, a blood 
pregnancy test will be done (using 1 teaspoon of blood drawn from a vein by needle-stick), and 
it must be negative before you participate in this study. If you take part in this study and you 
are sexually active, you and any person that you have sex with must use medically-acceptable 
birth control (contraceptives) during the study.  Medically-acceptable birth control 
(contraceptives) includes: 
(1) surgical sterilization (such as hysterectomy or “tubes tied”), 
(2) approved hormonal contraceptives ( such as birth control pills, patch or ring; Depo-
Provera, Implanon), 
(3) barrier methods (such as condom or diaphragm) used with a spermicide (a substance 
that kills sperm), or  
(4) an intrauterine device (IUD). 
If you do become pregnant during this study, you must tell the researchers immediately. 
 
If your parents or guardian asks, we will tell them the results of your pregnancy test or that you 
are using birth control. 


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Risks of MRI 
There are no known risks from exposure to magnetic fields.  You may experience nervousness 
and/or anxiety due to the loud banging made by the machine while it is taking pictures and 
from confinement in a tight space (claustrophobia). If you become anxious, you can stop the 
procedure at any time 
 
You may also experience some discomfort and fatigue from lying still during imaging. 
 
If you have any metal clips or plates in your body, you should tell the investigator. 
MRI may not be appropriate if you are pregnant or are trying to become pregnant. MRI 
may not be appropriate if you have permanent eyeliner or eyebrows or any pieces of 
metal in your body, such as the following: 
 
• heart pacemaker, heart valve replacement, or aortic clips 
• metal fragments in your eyes, skin, or elsewhere in your body 
• brain clips or pieces of metal used in aneurysm surgery or intercranial bypass 
• venous umbrella 
• pieces of metal in the body resulting from work as a sheet-metal worker or welder 
• clips placed in an internal organ 
• prosthetic devices, such as middle ear, eye, joint, or penile implants 
• joint replacement. 
• hearing aid that cannot be removed 
• neurostimulator 
• insulin pump 
• intrauterine device (IUD) 
• shunts or stents 
• metal mesh or coil implants 
• metal plate, pin, screws, or wires, or any other metal implants  
 
Risks of Radiation – Diagnostic Test 
The radiation dose that you will get from diagnostic tests is medically indicated for your 
condition and it is the same that you would get if you were not involved in this research study. 
 
Risks of Blood Drawing 
Risks associated with drawing blood from your arm include minimal discomfort and/or bruising.  
Risks associated with drawing blood from a central line are rare but a central line infection is 
possible, although unlikely. 
 


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You will have approximately 2 tablespoons of blood collected because you are in this research 
study. 
 
Other Risks 
There may possibly be other side effects that are unknown at this time. If you are concerned 
about other, unknown side effects, please discuss this with the researchers. 
 
How will risks be minimized or prevented?   
Potential risks and discomforts must be minimized to the greatest extent possible.  All 
personnel conducting this study will be appropriately trained. You will be closely monitored 
with physical exams, medical histories, and blood tests during the time you are participating in 
this study.  If the researchers determine that the study drugs are causing you too much harm, 
they may instruct you to stop taking the drugs for a period of time, reduce your dose, or stop 
your participation in this study. If any of these side effects of therapy require treatment that 
the researchers or your oncologist are unable to provide, you will be referred to an appropriate 
physician. If your cancer grows despite the study drugs, your participation in the study will be 
stopped to limit the risk of the drugs causing you harm.   
 
What will my responsibilities be during the study?   
While you are part of this study, the researchers will follow you closely to determine whether 
there are problems that need medical care.  It is your responsibility to do the following: 
• Ask questions about anything you do not understand. 
• Keep your appointments. 
• Follow the researchers’ instructions. 
• Let the researchers know if your telephone number or address changes. 
• Store study tablets in a secure place at home away from anyone who is unable to read 
and understand labels, especially children. 
• Tell the researchers before you take any new medication, even if it is prescribed by 
another doctor for a different medical problem or something purchased over the 
counter. 
• Tell your regular doctor about your participation in this study. 
• Carry information about sirolimus and erlotinib in your purse or wallet. 
• Report to the researchers any injury or illnesses while you are on study even if you do 
not think it is related.  
 
If I agree to take part in this research study, will I be told of any new risks that may be found 
during the course of the study? 


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Yes.  You will be told if any new information becomes available during the study that could 
cause you to change your mind about continuing to participate or that is important to your 
health or safety. 
 
What should I do if I think I am having problems? 
If you have unusual symptoms, pain, or any other problems while you are in the study, you 
should report them to the researchers right away.  Telephone numbers where they can be 
reached are listed on the first page of this consent form. 
 
If you have a sudden, serious problem, like difficulty breathing or severe pain, go to the nearest 
hospital emergency room, or call 911 (or the correct emergency telephone number in your 
area).  Tell emergency personnel about any medications you are taking, including any 
medications you are taking for this study.   
 
 
What are the possible benefits of this study? 
If you agree to take part in this study, there may be direct benefits to you.  The potential 
benefit of the treatment with the combination of sirolimus and erlotinib is that it may cause 
your cancer to stop growing or to shrink for a period of time. It may lessen the symptoms, such 
as pain, that are caused by the cancer. Because there is no information about the effect this 
combination on germ cell tumors in humans, we do not know if you will benefit from taking 
part in this study. The researchers cannot guarantee that you will benefit from participation in 
this research. 
 
We hope the information learned from this study will benefit others with germ cell tumors in 
the future.  Information gained from this research could lead to better treatment of relapsed 
disease. 
 
What options are available if I decide not to take part in this research study? 
You do not have to participate in this research to receive care for your medical problem. Instead 
of being in this study, you have the following options: 
• Receive standard chemotherapy or radiation 
• Participate in a research study of another therapy 
• Choose to not receive treatment at all 
 
Please talk to the researchers or your personal doctor about these options.  
 
Will I be paid if I take part in this research study? 


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No. You will not be paid to take part in this research study.  There are no funds available to pay 
for parking expenses, transportation to and from the research center, lost time away from work 
and other activities, lost wages, or child care expenses. 
 
Will my insurance provider or I be charged for the costs of any part of this research study? 
Yes.  The costs of sirolimus and erlotinib tablets and sirolimus drug levels will be billed to you or 
your insurance provider.   
 
What will happen if I am harmed as a result of taking part in this study? 
It is important that you report any illness or injury to the research team listed at the top of this 
form immediately. 
 
Compensation for an injury resulting from your participation in this research is not available 
from the University of Texas Southwestern Medical Center at Dallas or Children’s Medical 
Center or your local treating institution. 
 
You retain your legal rights during your participation in this research 
 
Can I stop taking part in this research study? 
Yes.  If you decide to participate and later change your mind, you are free to stop taking part in 
the research study at any time. 
 
If you decide to stop taking part in this research study, it will not affect your relationship with 
the UT Southwestern staff or doctors.  Whether you participate or not will have no effect on 
your legal rights or the quality of your health care. 
 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your status will not 
be affected in any way. 
 
Your doctor may be a research investigator in this study.  S/he is interested in both your 
medical care and the conduct of this research study.  At any time, you may discuss your care 
with another doctor who is not part of this research study.  You do not have to take part in any 
research study offered by your doctor. 
 
If I agree to take part in this research study, can I be removed from the study without my 
consent? 
Yes.  The researchers may decide to take you off this study if: 
• Your medical problem remains unchanged or becomes worse. 


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• The researchers believe that participation in the research is no longer safe for you. 
• The researchers believe that other treatment may be more helpful. 
• The sponsor or the FDA stops the research for the safety of the participants. 
• The sponsor cancels the research. 
• You are unable to keep appointments or to follow the researcher’s instructions. 
 
Will my information be kept confidential? 
Medical information collected during this study and the results of any test or procedure that 
may affect your medical care may be included in your medical record. The information included 
in your medical record will be available to health care providers and authorized persons 
including your insurance company. 
 
You should know that certain organizations that may look at and/or copy your medical records 
for research, quality assurance, and data analysis include: 
 
• The UT Southwestern study committee; 
• Representatives of government agencies, like the U.S. Food and Drug Administration 
(FDA), involved in keeping research safe for people; 
• The Institutional Review Board at your treating institution; and 
• The UT Southwestern Institutional Review Board.  
 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the Web 
site will include a summary of the results.  You can search this Web site at any time. 
 
In addition to this consent form, you will be asked to sign an "Authorization for Use and 
Disclosure of Protected Health Information."  This authorization will give more details about 
how your information will be used for this research study, and who may see and/or get copies 
of your information. 
 
Are there procedures I should follow after stopping participation in this research? 
Yes.  If you, the researchers, or the sponsor stops your participation in the research, you may be 
asked to do the following: 
 
• Let the researchers know immediately that you wish to withdraw from the research. 
• Return to the research center for tests that may be needed for your safety. 
• Discuss your future medical care, if any, with the researchers and/or your personal 
doctor. 


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Whom do I call if I have questions or problems? 
For questions about the study, contact [insert local PI] at [insert phone number] during regular 
business hours and at [insert phone number] after hours and on weekends and holidays.   
 
For questions about your rights as a research participant, contact the Institutional Review Board 
(IRB) Office at [insert phone number]. 
 
 
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP. 
 
 
 


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SIGNATURES: 
 
Your signature below certifies the following: 
 
• You have read (or been read) the information provided above. 
• You have received answers to all of your questions and have been told who to call if 
you have any more questions. 
• You have freely decided to participate in this research. 
• You understand that you are not giving up any of your legal rights. 
• You understand that a copy of this signed consent document, information about this 
study, and the results of any test or procedure that may affect your medical care, may 
be included in your medical record.  Information in your medical record will be available 
to health care providers and authorized persons including your insurance company. 
 
 
____________________________________________ 
 
 
Name of Participant (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Participant 
Date 
Time 
 
____________________________________________ 
 
 
Legally Authorized Representative’s Name (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Legally Authorized Representative’s Signature 
Date 
Time 
 
____________________________________________ 
 
 
Name of Person Obtaining Consent (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Person Obtaining Consent 
Date 
Time 
 
 
 


Version 1.5 
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01-27-2017 
 
 
ASSENT OF A MINOR: 
I have discussed this research study with my parent or legal guardian and the researchers, and I 
agree to participate. 
____________________________________________ 
________ 
_______ AM / PM 
Participant’s Signature (age 10 through 17) 
Date 
Time 
 
 
Interpreter Statement (if applicable): 
I have interpreted this consent form into a language understandable to the participant and the 
participant has agreed to participate as indicated by their signature on the associated short 
form. 
____________________________________________ 
 
 
Name of Interpreter (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Interpreter 
Date 
Time 
 
 
 
 
 


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Appendix 3: References 
1. 
Frazier, A.L. and J.F. Amatruda, Germ Cell Tumors, in Nathan and Oski’s Textbook of Pediatric 
Hematology-Oncology D.E. Fisher, D. Nathan, and A.T. Look, Editors. 2009, Elsevier: London. 
2. 
Oosterhuis, J.W. and L.H. Looijenga, Testicular germ-cell tumours in a broader perspective. Nat 
Rev Cancer, 2005. 5(3): p. 210-22. 
3. 
Rodriguez-Galindo, C., et al., Children's Oncology Group's 2013 blueprint for research: rare 
tumors. Pediatr Blood Cancer, 2013. 60(6): p. 1016-21. 
4. 
Albany, C. and L.H. Einhorn, Extragonadal germ cell tumors: clinical presentation and 
management. Curr Opin Oncol, 2013. 25(3): p. 261-5. 
5. 
Loehrer, P.J., et al., Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in 
recurrent germ cell tumor. J Clin Oncol, 1998. 16(7): p. 2500-2504. 
6. 
Kondagunta, G.V., et al., Combination of paclitaxel, ifosfamide, and cisplatin is an effective 
second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol, 2005. 
23(27): p. 6549-55. 
7. 
Beyer, J., et al., High-dose chemotherapy as salvage treatment in germ cell tumors: a 
multivariate analysis of prognostic variables. J Clin Oncol, 1996. 14(10): p. 2638-45. 
8. 
Einhorn, L.H., et al., High-dose chemotherapy and stem-cell rescue for metastatic germ-cell 
tumors. N Engl J Med, 2007. 357(4): p. 340-8. 
9. 
Beyer, J., et al., High-dose versus conventional-dose chemotherapy as first-salvage treatment in 
patients with non-seminomatous germ-cell tumors: a matched-pair analysis. Ann Oncol, 2002. 
13(4): p. 599-605. 
10. 
Schultz, L., et al., Immunoexpression status and prognostic value of mTOR and hypoxia-induced 
pathway members in primary and metastatic clear cell renal cell carcinomas. Am J Surg Pathol, 
2011. 35(10): p. 1549-56. 
11. 
Castellvi, J., et al., Phosphorylated 4E binding protein 1: a hallmark of cell signaling that 
correlates with survival in ovarian cancer. Cancer, 2006. 107(8): p. 1801-11. 
12. 
Hobbs, R.M., et al., Plzf regulates germline progenitor self-renewal by opposing mTORC1. Cell, 
2010. 142(3): p. 468-79. 
13. 
Miyai, K., et al., Protein overexpression and gene amplification of epidermal growth factor 
receptor in adult testicular germ cell tumors: potential role in tumor progression. Cancer Sci, 
2010. 101(9): p. 1970-6. 
14. 
Pfizer, Rapamune Package Insert. 
15. 
Teachey, D.T., et al., Treatment with sirolimus results in complete responses in patients with 
autoimmune lymphoproliferative syndrome. Br J Haematol, 2009. 145(1): p. 101-6. 
16. 
Jimenez-Rivera, C., et al., Sirolimus for pediatric liver transplant recipients with post-transplant 
lymphoproliferative disease and hepatoblastoma. Pediatr Transplant, 2004. 8(3): p. 243-8. 
17. 
Yalon, M., et al., A feasibility and efficacy study of rapamycin and erlotinib for recurrent pediatric 
low-grade glioma (LGG). Pediatr Blood Cancer, 2013. 60(1): p. 71-6. 
18. 
Sam, W.J., et al., Associations of ABCB1 3435C>T and IL-10-1082G>A polymorphisms with long-
term sirolimus dose requirements in renal transplant patients. Transplantation, 2011. 92(12): p. 
1342-7. 
19. 
Genentech, Tarceva Package Insert. 
20. 
Jakacki, R.I., et al., Pediatric phase I and pharmacokinetic study of erlotinib followed by the 
combination of erlotinib and temozolomide: a Children's Oncology Group Phase I Consortium 
Study. J Clin Oncol, 2008. 26(30): p. 4921-7. 


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21. 
Broniscer, A., et al., Phase I and pharmacokinetic studies of erlotinib administered concurrently 
with radiotherapy for children, adolescents, and young adults with high-grade glioma. Clin 
Cancer Res, 2009. 15(2): p. 701-7. 
22. 
Geoerger, B., et al., Innovative Therapies for Children with Cancer pediatric phase I study of 
erlotinib in brainstem glioma and relapsing/refractory brain tumors. Neuro Oncol, 2011. 13(1): 
p. 109-18. 
23. 
Rakhit, A., et al., The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based 
simulation (SimCYP) predicts in vivo metabolic inhibition. Eur J Clin Pharmacol, 2008. 64(1): p. 31-
41. 
24. 
White-Koning, M., et al., Population analysis of erlotinib in adults and children reveals 
pharmacokinetic characteristics as the main factor explaining tolerance particularities in 
children. Clin Cancer Res, 2011. 17(14): p. 4862-71. 
25. 
Fukudo, M., et al., Population pharmacokinetics/pharmacodynamics of erlotinib and 
pharmacogenomic analysis of plasma and cerebrospinal fluid drug concentrations in Japanese 
patients with non-small cell lung cancer. Clin Pharmacokinet, 2013. 52(7): p. 593-609. 
26. 
Wacker, B., et al., Correlation between development of rash and efficacy in patients treated with 
the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III 
studies. Clin Cancer Res, 2007. 13(13): p. 3913-21. 
27. 
Nghiemphu, P.L., et al., A dose escalation trial for the combination of erlotinib and sirolimus for 
recurrent malignant gliomas. J Neurooncol, 2012. 110(2): p. 245-50. 
28. 
Reardon, D.A., et al., Phase 2 trial of erlotinib plus sirolimus in adults with recurrent 
glioblastoma. J Neurooncol, 2010. 96(2): p. 219-30. 
29. 
Broniscer, A., et al., Plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active 
metabolite OSI-420. Clin Cancer Res, 2007. 13(5): p. 1511-5. 
30. 
Jia, Y., et al., Risk of skin rash associated with erlotinib in cancer patients: a meta-analysis. J 
Support Oncol, 2009. 7(6): p. 211-7. 
31. 
Jatoi, A., et al., Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin 
rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group 
(N03CB). Cancer, 2008. 113(4): p. 847-53. 
32. 
Masters, A.R., C.J. Sweeney, and D.R. Jones, The quantification of erlotinib (OSI-774) and OSI-420 
in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt 
Technol Biomed Life Sci, 2007. 848(2): p. 379-83. 
33. 
Chan, G., M.T. Nogalski, and A.D. Yurochko, Activation of EGFR on monocytes is required for 
human cytomegalovirus entry and mediates cellular motility. Proc Natl Acad Sci U S A, 2009. 
106(52): p. 22369-74. 
34. 
Perl, A.E., et al., Single-cell pharmacodynamic monitoring of S6 ribosomal protein 
phosphorylation in AML blasts during a clinical trial combining the mTOR inhibitor sirolimus and 
intensive chemotherapy. Clin Cancer Res, 2012. 18(6): p. 1716-25. 
35. 
Dieterlen, M.T., et al., Assay validation of phosphorylated S6 ribosomal protein for a 
pharmacodynamic monitoring of mTOR-inhibitors in peripheral human blood. Cytometry B Clin 
Cytom, 2012. 82(3): p. 151-7. 
36. 
Simon, R., Optimal two-stage designs for phase II clinical trials. Control Clin Trials., 1989. 10(1): 
p. 1-10. 
 
 
 


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Appendix 4: Patient Diary 
Patient:_____________________________ Institution :________________________________ 
Complete each day with the time and dose of sirolimus and erlotinib given. Make note of other drugs 
and supplements taken. Please note if a dose was missed or if there was vomiting after any dose of 
medication and whether the medication was given again.  Add the dates to the calendar below and 
return the completed diary to your institution after each treatment cycle. Your institution will send this 
form to the UTSW study team after each treatment cycle. 
Notes:  If a dose is missed and you remember within 8 hours of when the dose was supposed to be 
taken, take the dose immediately.  Resume your usual schedule the following day. 
If you throw up a dose of medication within 30 minutes of taking it, the dose should be given again.  You 
may take a medication for nausea first and allow 30 minutes to 1 hour for this to work prior to redosing 
the medication(s). 
Example: 
WEEK 1 
Date 
Time 
Sirolimus 
Dose 
(mg) 
Sirolimus 
Dose 
(mL) 
Erlotinib 
Dose 
(mg) 
Comments 
Day 1 
9/1/13 7:00 AM 2 mg 
  
150 mg 
Felt nauseated an hour after drugs, 
but did not vomit. Had mildly itchy 
rash on arms. 
 
Diary: 
Cycle #: ____  Erlotinib Dose: ______ Start Date: ___/___/___ End Date: ___/___/___ 
WEEK 1 
Date 
Time 
Sirolimus 
Dose 
(mg) 
Sirolimus 
Dose 
(mL) 
Erlotinib 
Dose 
(mg) 
Comments 
Day 1 
  
  
  
  
  
  
Day 2 
  
  
  
  
  
  
Day 3 
  
  
  
  
  
  
Day 4 
  
  
  
  
  
  
Day 5 
  
  
  
  
  
  
Day 6 
  
  
  
  
  
  
Day 7 
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  


Version 1.5 
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WEEK 2 
Date 
Time 
Sirolimus 
Dose 
(mg) 
Sirolimus 
Dose 
(mL) 
Erlotinib 
Dose 
(mg) 
Comments 
Day 8 
  
  
  
  
  
  
Day 9 
  
  
  
  
  
  
Day 10 
  
  
  
  
  
  
Day 11 
  
  
  
  
  
  
Day 12 
  
  
  
  
  
  
Day 13 
  
  
  
  
  
  
Day 14 
  
  
  
  
  
  
  
  
  
  
  
  
  
WEEK 3 
Date 
Time 
Sirolimus 
Dose 
(mg) 
Sirolimus 
Dose 
(mL) 
Erlotinib 
Dose 
(mg) 
Comments 
Day 15 
  
  
  
  
  
  
Day 16 
  
  
  
  
  
  
Day 17 
  
  
  
  
  
  
Day 18 
  
  
  
  
  
  
Day 19 
  
  
  
  
  
  
Day 20 
  
  
  
  
  
  
Day 21 
  
  
  
  
  
  
  
  
  
  
  
  
  
WEEK 4 
Date 
Time 
Sirolimus 
Dose 
(mg) 
Sirolimus 
Dose 
(mL) 
Erlotinib 
Dose 
(mg) 
Comments 
Day 22 
  
  
  
  
  
  
Day 23 
  
  
  
  
  
  
Day 24 
  
  
  
  
  
  
Day 25 
  
  
  
  
  
  
Day 26 
  
  
  
  
  
  
Day 27 
  
  
  
  
  
  
Day 28