Clinical trial NCT01931163
Conditions: Breast Cancer Triple Negative Breast Cancer
Sponsor: Jenny C. Chang, MD
Start date: 2013-07-01; Completion date: 2019-01-01
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Everolimus plus Cisplatin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PURPOSE: The purpose of this study is to test how effective combining Cisplatin chemotherapy with Everolimus is in treating subjects with triple negative breast cancer who have residual disease after chemotherapy.

Detailed description:
This is a phase II clinical trial of everolimus, an mTOR inhibitor, plus cisplatin chemotherapy in patients with triple negative breast cancer (TNBC) who have residual disease after completion of neoadjuvant chemotherapy. Everolimus and cisplatin will be administered for 12 weeks. Patients will undergo surgery after treatment completion. Patients will have breast biopsy prior to receiving the study treatment.

Arms: arm 1: Cisplatin 20 mg/m2 IV infusion over 60 minutes, weekly (Days 1, 8, 15) x 4 cycles Everolimus 10mg by mouth daily
Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
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NECTAR Trial 
 
NEOADJUVANT PHASE II STUDY OF EVEROLIMUS PLUS CISPLATIN IN TRIPLE 
NEGATIVE BREAST CANCER PATIENTS WITH RESIDUAL DISEASE AFTER 
STANDARD CHEMOTHERAPY. 
 
 
 
 
 
 
 
 
 
 
Authors 
Jenny Chang, M.D. 
Jaime A. Mejia, M.D. 
Document type 
Everolimus (RAD0001) Use Protocol  
EUDRACT number 
N/A 
Version number 
V1 
Development  phase 
II  
Document status 
Final 
Release date 
(28/04/2013) 
Referenced Investigator Brochure Edition  
10, release date 07-Nov-2011  


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Table of contents 
Table of contents ..................................................................................................................................... 2 
List of figures ........................................................................................................................................... 3 
List of tables ............................................................................................................................................ 3 
List of abbreviations................................................................................................................................. 4 
Glossary of terms .................................................................................................................................... 5 
1 
Background ............................................................................................................................................. 6 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .................................. 6 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) .................................. 6 
1.2.1 
Overview of Everolimus........................................................................................... 7 
1.2.2 
Overview of Cisplatin............................................................................................... 9 
2 
Rationale ................................................................................................................................................. 9 
3 
Objectives and endpoints ...................................................................................................................... 11 
4 
Study design .......................................................................................................................................... 12 
4.1 
Description of study design ...................................................................................................... 12 
5 
Population ............................................................................................................................................. 13 
5.1 
Inclusion and Exclusion criteria ................................................................................................ 13 
6 
Treatment .............................................................................................................................................. 16 
6.1 
Study treatment ........................................................................................................................ 16 
6.1.1 
Dosing regimen ..................................................................................................... 17 
6.2 
Dose modifications ................................................................................................................... 17 
6.2.1 
Dose modification and dose delay ........................................................................ 17 
6.2.2 
Management of specific toxicities .......................................................................... 19 
6.3 
Cisplatin General Information ................................................................................................... 24 
6.4 
Concomitant medications ......................................................................................................... 30 
6.4.1 
Permitted concomitant therapy .............................................................................. 30 
6.4.2 
Prohibited concomitant therapy ............................................................................. 31 
7 
Visit schedule and assessments ........................................................................................................... 31 
7.1 
Study flow and visit schedule ................................................................................................... 31 
7.2 
Assessment types .................................................................................................................... 34 
7.2.1 
Pregnancy and assessments of fertility ................................................................. 35 
7.2.2 
Laboratory evaluations .......................................................................................... 35 
7.2.3 
Drug levels and pharmacokinetic assessments N/A ............................................. 36 
8 
Safety monitoring and reporting ............................................................................................................ 36 
8.1 
Adverse events ........................................................................................................................ 36 
8.1.1 
Definitions and reporting ....................................................................................... 36 
8.1.2 
Laboratory test abnormalities ................................................................................ 37 
8.1.3 
Adverse events of special interest (optional) ......................................................... 37 


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8.2 
Serious Adverse Events ........................................................................................................... 38 
8.2.1 
Definitions ............................................................................................................. 38 
8.2.2 
Reporting ............................................................................................................... 38 
8.3 
Emergency unblinding of treatment assignment ...................................................................... 39 
8.4 
Pregnancy ................................................................................................................................ 39 
9 
Statistical methods ................................................................................................................................ 39 
9.1 
Sample Size. ............................................................................................................................ 39 
10 Protocol amendments, or changes in study conduct ............................................................................. 40 
11 References: ........................................................................................................................................... 41 
12 Appendices ............................................................................................................................................ 43 
Appendix A: ECOG/ Karnofsky Performance Status Criteria ................................................................. 43 
13 CTCAE Files .......................................................................................................................................... 45 
 
List of figures 
Figure 1-1 
Chemical structure of Everolimus ............................................................................ 7 
Figure 1-2 
Chemical structure of Cisplatin ................................................................................ 9 
 
List of tables 
 
Table 1-1 
Everolimus - Drug substance ....................................................................... 7 
Table 6-1 
Study treatment schedule adjustments and dose levels ............................... 17 
Table 6-2 
Dosing guidelines for Everolimus-related non-hematologic toxicities ............. 18 
Table 6-3 
Dosing guidelines for Everolimus-related hematologic toxicities .................... 19 
Table 6-4 
Management of non-infectious pneumonitis ................................................ 22 
Table 6-5 
Action to be taken based on screening hepatitis B results ............................ 23 
Table 6-6 
Guidelines for the management of hepatitis B reactivation ........................... 23 
Table 6-7 
Guidelines for the management of hepatitis C flare ...................................... 24 
Table 6-8 
Clinically relevant drug interactions: inducers, and inhibitors of isoenzyme 
CYP3A .................................................................................................... 30 
Table 7-1 
Visit evaluation schedule ........................................................................... 32 
 


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List of abbreviations 
 


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Glossary of terms 
 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment 
Adjuvant chemotherapy is currently a component of standard treatment for most women with newly 
diagnosed invasive breast cancer. The development of adjuvant chemotherapy began with the 
demonstration of a survival benefit in node-positive patients treated with cyclophosphamide, methotrexate, 
and fluorouracil (CMF)1.  Since then, survival benefits have been demonstrated in additional patient subsets, 
and the incorporation of innovative chemotherapy combinations, novel agents, and new administration 
schedules has further improved the efficacy of adjuvant therapy. Recently, multiple large trials have 
demonstrated improved efficacy when a taxane (paclitaxel or docetaxel) is added to the adjuvant 
chemotherapy regimen2.  In the United States, one of the most commonly used taxane-containing adjuvant 
regimens consists of 4 cycles of doxorubicin/cyclophosphamide, followed by 4 cycles of paclitaxel2.  This 
sequential regimen was one of the first taxane-containing adjuvant programs to be investigated, and was 
proven superior when compared with doxorubicin/cyclophosphamide (AC) alone (5-year disease-free 
survival [DFS] 75% vs. 65%, respectively).  In the PACS01 trial, the sequential addition of 3 cycles of 
docetaxel following 3 cycles of FEC100 proved superior to 6 cycles of FEC100 (5-year DFS 78.3% vs. 
73.2%, hazard ratio:0.83)3.  Subsequent studies have compared the efficacy of various taxane schedules. 
Paclitaxel or docetaxel, given either weekly or every 3 weeks, were compared following 4 cycles of AC4.   In 
this trial, weekly paclitaxel was more effective than paclitaxel administered every 3 weeks, and showed equal 
efficacy but less toxicity when compared with docetaxel. The use of a taxane with standard anthracycline 
regimen is now regarded as the standard of care. 
 
In spite of the improvements resulting from the addition of the taxanes, a large number of women continue to 
relapse with breast cancer. Certain patient subsets have been shown to benefit disproportionately from 
taxane-containing regimens. Specifically, the benefit produced in estrogen receptor (ER)-negative patients is 
consistently larger than the benefit of ER-positive patients receiving identical regimens5.  Patients with “triple 
negative” breast cancer (ER, progesterone receptor [PR], and HER2 negative) benefit from taxane-
containing chemotherapy, but remain a poor prognosis group, with higher relapse rates and shorter survival 
than other subgroups6. Novel therapies, especially those targeting resistance pathway in patients who do not 
respond to standard chemotherapy, may be of benefit to TNBC patients who traditionally have poor 
prognosis. 
 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) 
Everolimus is a novel derivative of rapamycin. It has been in clinical development since 1996 as an 
immunosuppressant in solid organ transplantation. Everolimus is approved in Europe and other global 
markets (trade name: Certican®) for cardiac and renal transplantation, and in the United States (trade name: 
Zortress®) for the prevention of organ rejection of kidney transplantation. 
Everolimus was developed in oncology as Afinitor® and was approved for advanced renal cell carcinoma 
(RCC) in 2009. In 2010, Afinitor® received United States (US) approval for patients with subependymal giant 
cell astrocytoma (SEGA) associated with tuberous sclerosis (TS). Everolimus is also available as Votubia® 
in the European Union (EU) for patients with SEGA associated with TS. Afinitor® was approved for 
“progressive pancreatic neuroendocrine tumor (PNET) in patients with unresectable, locally advanced, or 
metastatic disease” in 2011 in various countries, including the US and Europe. In 2012 Afinitor® received 
approval for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2- 
negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with 
letrozole or anastrozole. Furthermore in 2012, Afinitor® received approval for the treatment of patients with 
TSC who have renal angiomyolipoma not requiring immediate surgery. 
Approximately 18,730 cancer patients have been treated with everolimus as of  30-Sep-2011: 
 
9,528 patients in Novartis-sponsored clinical trials 


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 
2,559 patients in the individual patient supply program 
 
6,638 in investigator-sponsored studies. 
 
In addition, healthy volunteer subjects and non-oncology hepatically impaired subjects have  participated 
in the clinical pharmacology  studies as described in Section 7.2. 
The following is a brief summary of the main characteristics of Everolimus. More complete information can 
be obtained from the Everolimus Investigator’s Brochure (IB). 
 
1.2.1 
Overview of Everolimus 
Everolimus is a derivative of rapamycin which acts as a signal transduction inhibitor (Table 1-1, Figure 1-1). 
Everolimus selectively inhibits mTOR (mammalian target of rapamycin), specifically targeting the mTOR-
raptor signal transduction complex. mTOR is a key serine-threonine kinase in the PI3K/AKT signaling 
cascade, which is known to be dysregulated in a wide spectrum of human cancers 7. 
Everolimus is being investigated as an anticancer agent based on its potential to act 
 
directly on the tumor cells by inhibiting tumor cell growth and proliferation; 
 
indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent inhibition of 
tumor cell VEGF (vascular endothelial growth factor) production and VEGF-induced proliferation of 
endothelial cells). 
 
Table 1-1 
Everolimus - Drug substance 
Chemical name 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-2-
[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-
15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-
tetraene-2,3,10,14,20-pentaone 
International non-
proprietary name 
Everolimus 
Figure 1-1 
Chemical structure of Everolimus 
N
O
OH
C
H3
O
O
CH3
CH3
OH
C
H3
O
O
O
O
H
C
H3
O
CH3
O
C
H3
O
O
CH3
CH3
O
C
H3
 
1.2.1.1 
mTOR pathway and cancer 
At the cellular and molecular level, Everolimus acts as a signal transduction inhibitor. It selectively inhibits 
mTOR (mammalian target of rapamycin), a key protein kinase which regulates cell growth, proliferation and 
survival. The mTOR kinase is mainly activated via the phosphatidylinositol 3-kinase (PI3-Kinase) pathway 
through AKT/PKB and the tuberous sclerosis complex (TSC1/2). Mutations in these components or in PTEN, 
a negative regulator of PI3-kinase, may result in their dysregulation. Abnormal functioning of various 
components of the signaling pathways contributes to the pathophysiology of numerous human cancers. 
Various preclinical models have confirmed the role of this pathway in tumor development 8. 


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The main known functions of mTOR include the following 9: 
 
mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels; 
 
Facilitating cell-cycle progression from G1-S phase in appropriate growth conditions; 
 
The PI3K/mTOR pathway itself is frequently dysregulated in many human cancers, and oncogenic 
transformation may sensitize tumor cells to mTOR inhibitors; 
 
PI3-kinase mutations have been reported in the primary tumor in 10-20% of human colorectal cancers 
10; 
 
The loss of PTEN protein, either through gene deletion or functional silencing (promoter 
hypermethylation), is reported in approximately 60% of primary human colorectal cancers 11 
 
The mTOR pathway is involved in the production of pro-angiogenic factors (i.e., VEGF) and inhibition of 
endothelial cell growth and proliferation; 
 
Through inactivating eukaryotic initiation factor 4E binding proteins and activating the 40S ribosomal S6 
kinases (i.e., p70S6K1), mTOR regulates protein translation, including the HIF-1 proteins. Inhibition of 
mTOR is expected to lead to decreased expression of HIF-1. 
 
1.2.1.2 
Non-clinical experience 
Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro including lines originating 
from lung, breast, prostate, colon, melanoma and glioblastoma. IC50s range from sub/low nM to µM. 
Everolimus also inhibits the proliferation of human umbilical vein endothelial cells (HUVECS) in vitro, with 
particular potency against VEGF-induced proliferation suggesting that Everolimus may also act as an anti-
angiogenic agent. The anti-angiogenic activity of Everolimus was confirmed in vivo. Everolimus selectively 
inhibited VEGF-dependent angiogenic response at well tolerated doses. Mice with primary and metastatic 
tumors treated with Everolimus showed a significant reduction in blood vessel density when compared to 
controls. 
The potential of Everolimus as an anti-cancer agent was shown in rodent models. Everolimus is orally 
bioavailable, residing longer in tumor tissue than in plasma in a subcutaneous mouse xenograft model, and 
demonstrating high tumor penetration in a rat pancreatic tumor model. The pharmacokinetic profile of 
Everolimus indicates sufficient tumor penetration, above that needed to inhibit the proliferation of endothelial 
cells and tumor cell lines deemed sensitive to Everolimus in vitro. 
Everolimus administered orally daily was a potent inhibitor of tumor growth, at well tolerated doses, in 11 
different mouse xenograft models (including pancreatic, colon, epidermoid, lung and melanoma) and two 
syngeneic models (rat pancreatic, mouse orthotopic melanoma). These models included tumor lines 
considered sensitive and “relatively resistant” in vitro. In general, Everolimus was better tolerated in mouse 
xenograft models than standard cytotoxic agents (i.e., doxorubicin and 5-fluorouracil), while possessing 
similar anti-tumor activity. Additionally, activity in a VEGF-impregnated subcutaneous implant model of 
angiogenesis and reduced vascularity (vessel density) of Everolimus-treated tumors (murine melanoma) 
provided evidence of in vivo effects of angiogenesis. 
It is not clear which molecular determinants predict responsiveness of tumor cells to Everolimus. Molecular 
analysis has revealed that relative sensitivity to Everolimus in vitro correlates with the degree of 
phosphorylation (activation) of the AKT/PKB protein kinase and the S6 ribosomal protein; in some cases 
(i.e., glioblastoma) there is also a correlation with PTEN status. 
In vivo studies investigating the anti-tumor activity of Everolimus in experimental animal tumor models 
showed that Everolimus monotherapy typically reduced tumor cell growth rates rather than produced 
regressions. These effects occurred within the dose range of 2.5 mg to 10 mg/kg, orally once a day. 
In preclinical models, the administration of Everolimus is associated with reduction of protein phosphorylation 
in target proteins downstream of mTOR, notably phosphorylated S6 (p-S6) and p-4E-BP1, and occasionally 
with an increase in phosphorylated AKT, a protein upstream of mTOR signaling pathway. 


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All significant adverse events observed in toxicology studies with Everolimus in mice, rats, monkeys and 
mini-pigs were consistent with its anticipated pharmacological action as an anti-proliferative and 
immunosuppressant and at least in part reversible after a 2 or 4-week recovery period with the exception of 
the changes in male reproductive organs, most notably testes. 
1.2.2 
Overview of Cisplatin 
Cisplatin is similar to the bifunctional alkylating agents. It covalently binds to DNA and disrupts DNA function. 
After cisplatin enters the cells, the chloride ligands are replaced by water molecules.   This reaction results in 
the formation of positively charged platinum complexes that react with the nucleophilic sites on DNA. These 
platinum complexes covalently bind to DNA bases using intra-strand and inter-strand cross-links creating 
cisplatin-DNA adducts thus preventing DNA, RNA and protein synthesis. This action is cell cycle phase-
nonspecific. Cisplatin also has immunosuppressive, radiosensitizing, and antimicrobial properties.12 
 
Figure 1-2 
Chemical Structure of Cisplatin 
 
 
Cisplatin was the first chemotherapeutic agent of its subclass to be discovered.  It is an inorganic, water 
soluble complex containing a central platinum atom surrounded by 2 chlorine atoms and ammonia moieties 
in the cis position in the horizontal plane.  Cisplatin forms irreversible covalent links with DNA, causing cross 
linking of DNA chains as well as breaks in the DNA chain and missense mutations.  The DNA injury triggers 
programmed cell death (apoptosis) and inhibits RNA and protein synthesis, particularly in rapidly dividing 
cells.  Cisplatin has activity against multiple tumor types and was approved for use by the United States in 
1978.  Current indications include testicular, ovarian, bladder, head and neck, breast, lung and colon cancer. 
2 
Rationale 
Recent DNA microarray profiling studies on breast tumors have identified distinct subtypes of breast 
carcinomas that are associated with different clinical outcomes13. Breast cancer can now be categorized into 
5 groups: luminal A (ER+), luminal B (ER+), HER2 overexpressing, normal breast-like and basal-like13. The 
basal-like breast cancers tend to be clinically aggressive and usually have a poor outcome.  
The phenotype of breast cancer can be reliably identified by a panel of 4 immunohistochemical antibodies: 
ER (negative), HER2 (negative), EGFR (positive), and cytokeratin 5/6 (positive)13. Tumors arising in BRCA1 
carriers have many similarities to basal-like sporadic breast tumors, including a characteristic phenotype: 
they tend to be high-grade, ER/PR-negative, HER2-negative, and harbor mutant p5314. Basal keratins are 
expressed by both sporadic basal-like tumors and tumors with BRCA1 mutations, and both groups cluster 
together by gene expression profile14. Other studies support these data, in which familial-BRCA1 breast 
cancers have shared features with a subset of sporadic tumors, indicating a common or similar etiology. 
Hallmarks of this “BRCAness” include basal-like phenotype (associated with the BRCA1 phenotype but not 
with the BRCA2 phenotype), ER-negativity, EGFR expression, c-MYC amplification, TP53 mutations, loss of 
RAD51-focus formation, extreme genomic instability and sensitivity to DNA-crosslinking agents15, 16. The 


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clinical implications of the definition of a group of tumors with a “BRCAness” hallmark lies in its potential to 
influence the clinical management of these tumors, allowing for rational trials exploring the role of 
chemotherapy and biologic agents targeted towards DNA repair defects. In support of this hypothesis, 
Garber et al.17 showed in a small phase II study remarkable activity of cisplatin single agent in the 
neoadjuvant setting treatment of patients with locally advanced triple-negative breast cancers, where the 
observed pCR was 23%. In another small study, 9/10 patients with stage I-III breast cancer harboring 
BRCA1 mutations achieved a pathological complete remission after neoadjuvant therapy with cisplatin18. 
Thus, these results support the use of cisplatin in TNBC patients who are refractory to standard taxane and 
anthracyclines chemotherapy, as in this proposal.  
 
There are just a few studies that focus in the management of those TNBC with residual disease once they 
complete the systemic therapy and local therapy. TNBC patients with residual disease after neoadjuvant 
chemotherapy have a very poor prognosis with a recurrence rate up to 65% within the first two years19.  
 
Our recent data in profiling of ~450 TNBC patients with residual disease after neoadjuvant chemotherapy 
showed two distinct subpopulations with chemoresistant disease. We established a 7-gene prognostic 
signature using dChip and gene set enrichment analyses. In the independent validation cohort, the classifier 
predicted correctly with positive predictive value of 75.0% and negative predictive value (i.e., relapse-free 
survival [RFS]) of 76.9% at 3 years. Those predicted to relapse had a hazard ratio (HR) of 4.67 (95% CI, 
1.27-17.15) for relapse in 3 years. In extended validation cohort, patients predicted not to relapse exhibited 
3-year RFS of 78.9%, while in comparison, the 3-year RFS was 48.5% for patients predicted to relapse (log 
rank P<0.0001), with HR of 2.61 (95% CI, 1.52-4.49). The subgroup of TNBC patients predicted to have 
relatively favorable prognosis was characterized by high expression of “luminal-like” genes (androgen-
receptor [AR] and GATA3); while the subgroup with worse prognosis was characterized by expression of 
cancer stem cell markers (WNT11 and MMP28). This group of TNBC with stem cell markers cluster with 
mesenchymal stem like (MSL) and mesenchymal subgroups of TNBC.  
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIILLLLLLLLLLLLLLLLLLLLLLLLLLLLLLMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMM
BL1
BL2
IM
LAR
M
MSL
GATA3
AR
ESR2
MMP28
WNT11
GBX2
KRT16
-3.0 -2.7 -2.3 -2.0 -1.7 -1.3 -1.0 -0.7 -0.3
0
0.3
0.7
1.0
1.3
1.7
2.0
2.3
2.7
3.0
 
M and MSL subtypes are enriched in gene expression for epithelial-mesenchymal transition, 
and growth factor pathways and cell models responded to a PI3K/mTOR inhibitor (NVP-BEZ235). 
 
Our collaborators at Vanderbilt University have generated a p73 gene expression signatures in H1299 cells 
(which lack expression of all p53 family members) transfected with TAp73β, an isoform of p73 capable of 
strong transactivation20. A combination of microarray profiling and chromatin immunoprecipitation followed by 
sequencing (ChIPSeq) was used to develop a p73 expression signature. Because microarray analyses do 
not allow discrimination between direct or indirect regulation by a transcription factor of interest, they also 
performed whole genome ChIP to identify sequences to which p73 is bound (ChIPSeq). Over 4,000 p73-
bound DNA sequences were isolated, sequenced, and mapped to the mammalian genome. Tags that 
mapped inside or within 10 kb of genes were considered for further analysis. Several known p73 target 
genes, such as p2127 and MDM228, were identified by both microarray and ChIPSeq, thus validating their 
datasets. In addition, known genes ontologies were enriched in their datasets, including genes involved in 


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apoptosis and cell-cycle arrest. By using multiple genomic technologies, they generated a signature 
annotated with multiple levels of gene expression and p73 genomic location information. Overlay of their 
microarray dataset with the whole genome ChIP dataset gave a more refined list of potential candidate 
targets. Additional information was obtained from fold-change expression levels that were used to create 
rank-ordered lists of candidate target genes from this analysis, they also generated an initial set (1000 
probes) of p73-regulated genes that could be used to query the Connectivity Map. The Connectivity Map is a 
collection of genome-wide transcriptional expression data from human cells treated with bioactive small 
molecules and simple pattern-matching algorithms that together enable the discovery of decisive functional 
connections between drugs, genes, and diseases through the transitory feature of common gene expression 
changes21. Genes whose transcript levels increased or decreased two-fold after ectopic p73 expression were 
analyzed using the Connectivity Map. Because they were interested in identifying pathways upstream of p73 
rather than just drugs per se, they focused on the well-annotated “pharmaceutical” subset of perturbagens. 
Several of the top perturbagens in their list were either direct or indirect inhibitors of mammalian Target of 
Rapamycin (mTOR). More importantly, profiling by targeted next generation sequencing (NGS) for 182 
oncogenes and tumor suppressors (Foundation Medicine, Cambridge, MA) and gene expression profiling 
(NanoString) of the residual cancer after neoadjuvant chemotherapy was conducted in 102 patients with 
TNBC.  Of the tumors evaluated by NGS, 72/81 (89%) demonstrated mutations in TP53, 22 were MCL1-
amplified (27%), and 17 were MYC-amplified (21%).  Alterations in the PI3K/mTOR pathway (AKT1-3, 
PIK3CA, PIK3R1, RAPTOR, PTEN, and TSC1) were identified in 27 (33%) of TNBC tumors with residual 
disease after neoadjuvant chemotherapy.  
 
In summary, these data strongly support the use of mTOR inhibitors with cisplatin in patients with 
residual disease following standard neo-adjuvant chemotherapy, in whom the majority will have a 
very high chance of relapse within two years.    
Thus, we propose here to evaluate the benefit of mTOR inhibition with everolimus in combination with 
cisplatin in triple negative breast cancer patients with residual. We have demonstrated that the driving 
pathway in resistance in TNBC patients with chemotherapy-resistant disease is the mTOR/PI3K pathway. 
Thus, the effect of mTOR inhibition will be accentuated in patients with residual disease, rather than in 
patients treated with upfront neo-adjuvant everolismus, as the proportion of tumors will be enriched for MSL 
and M subtypes dependent on mTOR/PI3K pathway.  
              
We hypothesize that using everolimus with cisplatin will increase pCR rates in TNBC patients who are 
refractory to standard chemotherapy.  
 
3 
Objectives and endpoints 
Primary 
 
To evaluate the pathological response rate (pCR) after treatment with everolimus plus cisplatin in 
women with triple-negative breast cancer with documented residual disease after standard neo-
adjuvant treatment. 
Secondary 
 
To assess correlative markers in biopsies. 
Exploratory objectives (if necessary) 
 
To assess effect of everolimus on cancer stem cells, DNA damage markers, and other markers. 
(We will correlate pCR with studies exploring changes in the p63/p73 and PI3K/Akt/mTOR 
pathways). 
 


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4 
Study design 
4.1 
Description of study design 
EVEROLIMUS 10 mg once daily
administered oral with or without food over twelve weeks
STUDY DESIGN AND TREATMENT
NECTAR Trial
NEOADJUVANT PHASE II STUDY OF EVEROLIMUS PLUS CISPLATIN IN TRIPLE 
NEGATIVE BREAST CANCER PATIENTS WITH RESIDUAL DISEASE AFTER STANDARD 
CHEMOTHERAPY.
TRIPLE NEGATIVE BREAST 
CANCER PATIENTS
WHO COMPLETED SYSTEMIC 
TREATMENT IN THE NEO-
ADJUVANT SETTING WITH 
PROVED CLINICAL AND  
PATHOLOGICAL RESIDUAL 
DISEASE
CISPLATIN
20 mg/m2 IV infusion over 60 minutes, at the specified doses weekly 
(Days 1, 8, 15)  x 4 cycles
+
S
U
R
G
E
R
Y
RESIDUAL DISEASE WILL BE CORRELATED WITH PHYSICAL EXAM, ULTRASOUND AND MAMMOGRAM PRIOR STUDY INITIATION
  
We propose to perform a phase II clinical trial in triple negative breast cancer (TNBC) patients who have 
completed systemic neoadjuvant chemotherapy and have documented clinical/pathological residual disease.  
Biopsies will be obtained from accessible sites at baseline only (Research procedure); biopsied tumor must 
measure at least 1cm at any direction; if main tumor is not detected, an abnormal (clinically or radiologically) 
axillary lymph node can be biopsied.  
 
The correlation of specific molecular markers such as Ki67, mitotic index, apoptosis, levels of S6K and 
phospho S6K, p53, p63, and p73 levels as well as p73 and p63 gene signatures with clinical parameters 
such as tumor response and pathological complete response will help define a biomarker signature 
associated with p63/p73 and/or PI3K/Akt dependence in triple negative breast cancers as well as 
identification of new therapeutic options for this group of patients. We plan to store all the tissue collected 
during the study for future analysis including genomic studies. 
 
As with all drugs, there is always the possibility that there may be unknown or impossible to predict risks/side 
effects. The use of everolimus plus cisplatin as part of the treatment may or may not increase the severity of 
side effects, and all risks associated with this research will be explained in the protocol and consent form. 
Nevertheless, this study may help provide better insight into new therapeutic options for breast cancer. The 
patients involved in this study will have a diagnosis of locally advanced triple negative breast cancer and are 
at high risk for developing metastatic recurrence of their disease. The doses proposed for this phase II study 
is the one that is already approved for renal cell carcinoma (RCC) which is 10 mg once daily administer oral 
with or without food over six months. 


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There are no other treatment options for triple negative breast cancer (TNBC) patients who have residual 
disease after systemic treatment in the neo-adjuvant setting. Historically, these patients have chemotherapy 
resistant disease, and the anticipated pCR rate is 0%, and we hypothesize that the addition of everolimus 
plus cisplatin will increase the pCR to least 5%.      
 
5 
Population 
Female patients ≥18 years of age 
Study Duration:   
The duration of patient participation in the study treatment will be a total of 3 to 4 months, which is counted 
from the start of treatment.  Study Follow-up for all patients will include medical history update (30 days after 
the last dose of the study drug)   
Safety Criteria:   
All participants will be assessed by a physician for pre-existing medical conditions and baseline physical 
abnormalities prior to the initiation of investigational therapy. Patients presenting with any medical history, 
physical exam, or laboratory abnormality that, in the in the opinion of the treating physician, would put the 
subject’s safety at risk will be excluded. Baseline signs and symptoms are to be recorded and followed 
throughout the trial.  These will be monitored throughout the study and recorded if they increase in severity 
or frequency during treatment or within the follow up period. Participants will be assessed for adverse events 
by a physician or designated midlevel provider prior to each chemotherapy infusion while the patient is on 
study. Vital signs including blood pressure, heart rate and temperature should be performed at each physical 
exam.  Assessments may be performed more frequently if clinically indicated. In addition, hematology and 
serum chemistry profiles will be drawn prior to the initiation of treatment and prior to every infusion to 
determine whether the study drug combination affects hematologic values, electrolytes or liver function tests. 
Laboratory assessments will be performed more frequently if clinically indicated. This clinical and laboratory 
data will be used to determine whether these women in the study with everolimus plus cisplatin therapy have 
any symptoms or side effects associated with the study medications. Subjects will be followed for adverse 
events for a period of 30 days after the completion of investigational therapy (Six (6) months). Patients with 
abnormal laboratory or clinical findings that are believed to be treatment related will be followed every four 
weeks until the condition resolves or stabilizes, or until the laboratory values are no longer considered 
clinically significant.  CTC Version 4.0 will be used to grade toxicities.  Laboratory tests may be done more 
frequently if medically indicated. If CTC Grade 4 hematologic toxicity is seen; CBC + differential + platelets 
should be repeated every 3 - 4 days until recovery. 
At suspected recurrence: CT scans of the chest, abdomen, pelvis, and additional directed evaluation as 
appropriate.  Recurrence should be documented by biopsy and/or evidence of metastatic disease on 
radiologic studies. Abnormal blood studies alone (e.g., elevated liver function tests, CA 15-3, CEA, etc.) are 
not sufficient evidence of relapse. 
5.1 
Inclusion and Exclusion criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must meet all 
inclusion and exclusion criteria. Results of all baseline evaluations, which assure that all inclusion and 
exclusion criteria have been satisfied, must be reviewed by the Principal Investigator or his/her designee 
prior to enrollment of that patient. In addition, the patient must be thoroughly informed about all aspects of 
the study, including the study visit schedule and required evaluations and all regulatory requirements for 
informed consent. The written informed consent must be obtained from the patient prior to enrollment. The 
following criteria apply to all patients enrolled onto the study unless otherwise specified. 
 


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Inclusion criteria: 
1. Female patients ≥18 years of age. 
2. Clinical/pathological documentation of residual disease after neo-adjuvant therapy. 
3. Patients with synchronous bilateral cancers are eligible only if: 
 
Index cancer is triple-negative, defined as ER-, PR-, and HER2-. 
4. HER2 negative tumors. HER2 negativity must be confirmed by one of the following: 
 
FISH-negative (FISH ratio <2.2), or 
 
IHC 0-1+, or 
 
IHC 2-3+ AND FISH-negative (FISH ratio <2.2). 
5. Estrogen receptor negative and progesterone receptor negative (<10% staining by IHC for estrogen 
receptor and progesterone receptor). 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 
7. Adequate hematologic function, defined by: 
 
Absolute neutrophil count 2 >1000/mm3 
 
Platelet count ≥100,000/mm3 
 
Hemoglobin >9 g/dL 
8. Adequate liver function, defined by: 
 
AST and ALT ≤2.5 x the upper limit of normal (ULN) 
 
Total bilirubin ≤1.5 x ULN (unless the patient has grade 1 bilirubin elevation due to Gilbert’s disease 
or a similar syndrome involving slow conjugation of bilirubin). 
9. Adequate renal function, defined by: 
 
Serum creatinine ≤1.5 x ULN 
10. Complete staging work-up ≤24 weeks prior to initiation of study treatment with computed tomography 
(CT) scans of the chest and abdomen/pelvis (abdomen/pelvis preferred; abdomen accepted), a CT scan of 
the head or MRI of the brain (if symptomatic), and either a positron emission tomography (PET) scan or a 
bone scan. 
11. Adequate cardiac function, defined by a left ventricular ejection fraction (LVEF) value of >50% (or normal 
per institutional guidelines) by MUGA scan or echocardiogram (ECHO). 
12. Patients with previous history of invasive cancers (including breast cancer) are eligible if definitive 
treatment was completed more than 5 years prior to initiating current study treatment, and there is no 
evidence of recurrent disease. 
13. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 
days prior to start of treatment. If a woman becomes pregnant or suspects she is pregnant while participating 
in this study, she must agree to inform her treating physician immediately. 
14. Patient must be accessible for treatment and follow-up. 
15. Women of childbearing potential must agree to use an acceptable method of birth control to avoid 
pregnancy for the duration of study treatment, and for 3 months thereafter.. 
16. Able to swallow and retain oral medication.  
17. Patient must be willing to undergo breast biopsies as required by the study protocol. 
18. All patients must be able to understand the investigational nature of the study and give written informed 
consent prior to study entry. 
Exclusion criteria: 
1. Women who are pregnant or breastfeeding. 
2. History of previously treated ductal carcinoma in situ (DCIS) is acceptable. 
3. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the 
stomach or small bowel.  


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4. Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs (e.g. sirolimus, 
temsirolimus); 
5. Previous cancer (with the exception of non-melanoma skin cancer or cervical carcinoma in situ) in the past 
5 years. 
6. Patients who have any severe and/or uncontrolled medical conditions such as: 
a. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months 
prior to start of Everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically 
significant cardiac disease 
b. Symptomatic congestive heart failure of New York heart Association Class III or IV 
c. active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, 
decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive 
HbsAg, quantifiable HCV-RNA), 
d. known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 
saturation 88% or less at rest on room air), 
e. active, bleeding diathesis; 
7. Patients may not receive any other investigational or anti-cancer treatments while participating in this 
study. 
8. Concurrent severe, uncontrolled infection or intercurrent illness including, but not limited to, ongoing or 
active infection, or psychiatric illness/social situations that would limit compliance with study requirements. 
9. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the 
study. 
10. Inability to comply with study and/or follow-up procedures. 
11. Patients who have received live attenuated vaccines within 1 week of start of Everolimus and during the 
study. Patient should also avoid close contact with others who have received live attenuated vaccines. 
Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, 
BCG, yellow fever, varicella and TY21a typhoid vaccines; 
12. Known history of HIV seropositivity; 
13. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of contraception during dosing of study 
treatment. Highly effective contraception  methods include combination of any two of the following (a+b 
or a+c or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or; 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/ vaginal suppository; 
d. Total abstinence or; 
e. Male/female sterilization. 
 
Women are considered post-menopausal and not of child-bearing potential if they have had 12 months 
of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks prior to treatment. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child-bearing potential. 
14. Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled 
corticosteroids are allowed; 
 


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Screening for patients with hepatitis B 
Prior to start Everolimus, the following three categories of patients should be tested for hepatitis B viral load 
and serologic markers, that is, HBV-DNA, HBsAg, HBs Ab, and HBc Ab: 
 
All patients who currently live in (or have lived in) Asia, Africa, Central and South America, Eastern 
Europe, 
Spain, 
Portugal 
and 
Greece. 
[http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-
b.htm] 
 
Patients with any of the following risk factors: 
 
known or suspected past hepatitis B infection, 
 
blood transfusion(s) prior to 1990, 
 
current or prior IV drug users, 
 
current or prior dialysis, 
 
household contact with hepatitis B infected patient(s), 
 
current or prior high-risk sexual activity, 
 
body piercing or tattoos, 
 
mother known to have hepatitis B 
 
history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper quadrant pain. 
 
Additional patients at the discretion of the investigator 
The management guidelines, in Section 6.2.2.7, are provided according to the results of the baseline 
assessment of viral load and serological markers for hepatitis B. 
Screening for patients with hepatitis C 
Patients with any of the following risk factors for hepatitis C should be tested using quantitative RNA-PCR: 
 
known or suspected past hepatitis C infection (including patients with past interferon ‘curative’ 
treatment), 
 
blood transfusions prior to 1990, 
 
current or prior IV drug users, 
 
current or prior dialysis, 
 
household contact of hepatitis C infected patient(s), 
 
current or prior high-risk sexual activity, 
 
body piercing or tattoos. 
At the discretion of the investigator, additional patients may also be tested for hepatitis C. 
The management guidelines, in Section 6.2.2.7, are provided according to the results of the baseline 
assessment of hepatitis C viral load. 
 
6 
Treatment 
6.1 
Study treatment 
Everolimus will be administered at 10 mg p.o daily. 
All dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded. 
Medication labels will comply with US legal requirements and be printed in English. They will supply no 
information about the patient. The storage conditions for Everolimus will be described on the medication 
label. 
Everolimus is supplied by Novartis. Everolimus is formulated as tablets for oral administration of 1mg,  
2.5mg, 5mg, 10mg strength. Tablets are blister-packed under aluminum foil, which should be opened only at 
the time of administration as drug is both hygroscopic and light-sensitive.  
Phase I data suggest a Recommended Phase 2 Dose (RP2D) of Cisplatin at 20 mg/m2 with Everolimus at 
10 mg/day in combination. 


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The proposed regimen will be: Everolimus 10 mg/day, Plus Cisplatin 20 mg/m2 (days 1, 8, and 15) on a 28-
day cycle , for 4 cycles. 
 
6.1.1 
Dosing regimen 
The investigator should promote compliance by instructing the patient to take the study drug exactly as 
prescribed and by stating that compliance is necessary for the patient’s safety and the validity of the study. 
The patient should be instructed to contact the investigator if he/she is unable for any reason to take the 
study drug as prescribed. 
Everolimus should be administered orally once daily at the same time every day, either consistently with or 
consistently without food 
Tablets 
The tablets should be swallowed whole with a glass of water and should not be chewed or crushed.  
If vomiting occurs, no attempt should be made to replace the vomited dose. Patients should be instructed 
that if they miss a dose on one day, they must not take any extra dose the next day, but instead to 
immediately contact the study center as soon as possible to ask for advice.  
6.2 
Dose modifications  
6.2.1 
Dose modification and dose delay 
6.2.1.1 
Hepatic impairment dose modifications 
Hormone receptor-positive advanced breast cancer, advanced neuroendocrine tumors of 
gastrointestinal, lung, or pancreatic origin, advanced renal cell carcinoma, and TSC with renal 
angiomyolipoma: 
 
Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily. 
 
Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 2.5 mg daily. 
 
Severe hepatic impairment (Child-Pugh C) – not recommended. If the desired benefit outweighs the risk, 
a dose of 2.5 mg daily must not be exceeded. 
 
Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment. 
Afinitor is not recommended for patients with hepatic impairment who require doses below 2 mg every other 
day or 2.5 every other day. 
 
6.2.1.2 
Dosing modifications 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are permitted in 
order to allow the patient to continue the study treatment. Details of study treatment schedule adjustments 
and dose levels are provided in Table 6-1. 
Table 6-1 
Study treatment schedule adjustments and dose levels  
Dose level 
Dose and schedule 
0 (starting dose) 
10 mg p.o daily 
-1 
7.5 mg p.o daily 
-2 
5.0 mg p.o daily 
 
If a patient has already decreased 2 dose levels, no further dose reduction is permitted. Patients who need 
an additional dose reduction will be required to discontinue Everolimus/placebo or comparator drug. 
Table 6-2 and Table 6-3 list the dosing guidelines for Everolimus-related non-hematologic and hematologic 
toxicities.  
 


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Table 6-2 
Dosing guidelines for Everolimus-related non-hematologic toxicities 
Toxicity 
Action 
Non-Infectious Pneumonitis 
Please refer to Table 6-4. 
Reactivation of HBV or HCV flare 
Please refer to Table 6-6 and Table 6-7. 
AST or ALT elevation 
Grade 1 (> ULN - 3.0 x ULN) 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain current dose level 
AST or ALT elevation 
Grade 3 (> 5.0 - 20.0 ULN)* 
Interrupt Everolimus administration until resolution to ≤ grade 1 (or ≤ grade 2 if 
baseline values were within the range of grade 2). If resolution occurs ≤ 7 
days, Everolimus should be re-started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, hold Everolimus 
until recovery to ≤ grade 1 or baseline grade / value and reintroduce 
Everolimus at one dose level lower, if available. 
AST or ALT elevation 
Grade 4 (> 20 x ULN)* 
 
 
 
Recurrence of grade 4 after dose reduction 
or toxicity requiring Everolimus interruption 
for > 28 days 
Interrupt Everolimus administration until resolution to ≤ grade 1 (or ≤ grade 2 if 
baseline values were within the range of grade 2). If resolution occurs ≤ 7 
days, Everolimus should be re-started at one dose level lower. If resolution 
takes > 7 days, discontinue Everolimus. 
Discontinue Everolimus. 
Intolerable grade 2 mucositis, or grade 3 
AE, except hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia (see Section 6.2.2.5) 
Interrupt Everolimus administration until resolution to ≤ grade 1 or baseline 
grade / value. 
If resolution occurs within ≤ 7 days, Everolimus should be re-started at the 
dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, hold Everolimus 
until recovery to ≤ grade 1 or baseline grade / value and reintroduce 
Everolimus at one dose level lower, if available. 
Patients will be withdrawn from the study if they fail to recover to  grade 1 or 
baseline grade / value within 28 days. 
Any other grade 4 
Hold Everolimus until recovery to grade  1 or baseline value 
Reintroduce Everolimus at one dose level lower, if available. 
Grade 3 or 4 clinical liver failure (asterixis 
or encephalopathy/coma) 
Discontinue Everolimus 
Recurrence of intolerable grade 2 
mucositis or grade 3 event after dose 
reduction 
Reduce dose to the next lower dose level, if available. The lowest possible 
dose level of Everolimus is 2.5 mg daily. Below this level, Everolimus must be 
discontinued. 
Recurrence of grade 4 after dose reduction 
Discontinue Everolimus 
Any non-hematologic toxicity requiring 
Everolimus interruption for > 28 days 
Discontinue Everolimus 
* Should HCV flare be confirmed, the guidelines for flare must take precedence (Table 6-7) 


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Table 6-3 
Dosing guidelines for Everolimus-related hematologic toxicities 
Toxicity 
Action 
Grade 2 thrombocytopenia (platelets <75, ≥ 
50x109/L) 
No action 
 
Grade 3 thrombocytopenia (platelets <50, ≥ 
25 x109/L) 
Interrupt Everolimus until resolution to grade 1  
If resolution occurs ≤ 7 days, reintroduce Everolimus at the dose level prior 
to interruption. 
If resolution occurs > 7 days, or event occurs within 28 days, reintroduce 
Everolimus at one dose level lower, if available. 
Grade 4 thrombocytopenia (platelets < 25 
x109/L) 
Interrupt Everolimus until recovery to grade  1. Then reintroduce 
Everolimus at one dose level lower, if available. 
Grade 3 neutropenia or anemia (neutrophil <1, 
≥0.5 x109/L) 
Interrupt Everolimus until resolution to grade ≤1 or baseline value 
If AE resolution occurs ≤ 7 days, reintroduce Everolimus at the same dose 
level. 
If AE resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce Everolimus at one dose level lower, if available. 
Grade 4 neutropenia or anemia 
Interrupt Everolimus until recovery to grade  1 or baseline value. 
Reintroduce Everolimus at one dose level lower, if available.* 
Febrile neutropenia 
Interrupt Everolimus until resolution to grade  1 (or baseline value) and no 
fever. Reintroduce Everolimus at one dose level lower, if available.* 
Recurrence of grade 3 toxicity after dose 
reduction 
Reduce dose to the next lower dose level, if available. The lowest possible 
dose level of Everolimus is 5 mg every other day (2.5 mg daily). Below this 
level, Everolimus must be discontinued. 
*Recurrence of grade 4 toxicity (including 
febrile neutropenia) after dose reduction 
Discontinue Everolimus 
*Any hematologic toxicity requiring 
Everolimus interruption for > 28 days 
Discontinue Everolimus 
 
6.2.2 
Management of specific toxicities 
Overall, safety data available from completed, controlled and uncontrolled studies indicate that everolimus is 
generally well tolerated at weekly or daily dose schedules. The safety profile is characterized by manageable 
adverse events (AEs). These AEs are generally reversible and non-cumulative. 
Adverse events most frequently observed with everolimus are rash, stomatitis /oral mucositis, non-infectious 
pneumonitis, fatigue, headache, anorexia, nausea, vomiting, diarrhea, and infections. Overall, the most 
frequently observed laboratory abnormalities include neutropenia, thrombocytopenia, hypercholesterolemia, 
and/or hypertriglyceridemia. The majority of these AEs have been of mild to moderate severity (NCI CTC 
grade 1-2). Recommendations for dose adjustments, should any of these treatment-related adverse events 
occur, are given in Table 3-2, Table 3-3 and Table 3-4, 3-5, and 3-6 
 
6.2.2.1 
Management of infections 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or 
protozoal infections, including infections with opportunistic pathogens. Localized and systemic infections, 
including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis or 
candidiasis and viral infections including reactivation of hepatitis B virus, have been described in patients 
taking Everolimus Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) 
and occasionally have had a fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with Everolimus Treat pre-existing 
infections prior to starting treatment with Everolimus. While taking Everolimus, be vigilant for symptoms and 


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signs of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider 
interruption or discontinuation of Everolimus. 
If a diagnosis of invasive systemic fungal infection is made, discontinue Everolimus and treat with 
appropriate antifungal therapy. 
 
6.2.2.2 
Management of skin toxicity 
For patients with grade 1 toxicity, no specific supportive care is usually needed or indicated. Rash must be 
reported as an AE. Patients with grade 2 or higher toxicity may be treated with the following suggested 
supportive measures at the discretion of the investigator: oral minocycline, topical tetracycline, topical 
clindamycin, topical silver sulfadiazine, diphenhydramine, oral prednisolone (short course), topical 
corticosteroids, or pimecrolimus. 
 
6.2.2.3 
Management of stomatitis / oral mucositis / mouth ulcers 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with gastrointestinal morbidity 
associated with mouth/dental infections, irritation of esophageal mucosa e.g. gastroesophageal reflux 
disease (GERD) and pre-existing stomatitis/mucositis must be monitored even more closely. Patients should 
be instructed to report the first onset of buccal mucosa irritation/reddening to their study physician 
immediately. 
Stomatitis/oral mucositis/mouth ulcers due to Everolimus should be treated using local supportive care. 
Please note that investigators in earlier trials have described the oral toxicities associated with Everolimus as 
mouth ulcers, rather than mucositis or stomatitis. If your examination reveals mouth ulcers rather than a 
more general inflammation of the mouth, please classify the adverse event as such. Please follow the 
paradigm below for treatment of stomatitis/oral mucositis/mouth ulcers: 
1. For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouth wash or salt water 
(0.9%) mouth wash several times a day until resolution. 
2. For more severe toxicity (grade 2 in which case patients have pain but are able to maintain adequate 
oral alimentation, or grade 3 in which case patients cannot maintain adequate oral alimentation), the 
suggested treatments are topical analgesic mouth treatments (i.e., local anesthetics such as, 
benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without topical 
corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
3. Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to worsen mouth 
ulcers. It is preferable to avoid these agents. 
4. Antifungal agents should be avoided unless a fungal infection is diagnosed. In particular, systemic 
imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should be avoided in all 
patients due to their strong inhibition of Everolimus metabolism, therefore leading to higher Everolimus 
exposures. Therefore, topical antifungal agents are preferred if an infection is diagnosed. 
 
6.2.2.4 
Management of diarrhea 
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with supportive care such 
as loperamide, initiated at the earliest onset (for example 4 mg orally followed by 2 mg orally every 2 hours 
until resolution of diarrhea). 
 
6.2.2.5 
Management of hyperlipidemia and hyperglycemia 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary habits of the 
patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 
hypertriglyceridemia or higher (>2.5x upper normal limit) should be treated with a 3-hydroxy-3-methyl-glutaryl 
(HMG)-CoA reductase inhibitor (e.g. atorvastatin, pravastatin, fluvastatin) or appropriate triglyceride-lowering 
medication, in addition to diet. 


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Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated with an 
increased risk of a rare but serious skeletal muscle toxicity manifested by rhabdomyolysis, markedly 
elevated creatine phosphokinase (CPK) levels and myoglobinuria, acute renal failure and sometimes death. 
The risk versus benefit of using this therapy should be determined for individual patients based on their risk 
of cardiovascular complications of hyperlipidemia. 
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is recommended prior 
to the start of Everolimus and periodically thereafter. Optimal glycemic control should be achieved before 
starting a patient on Everolimus. 
 
6.2.2.6 
Management of non-infectious pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious pneumonitis 
(including interstitial lung disease) have also been described in patients taking Everolimus. Some of these 
have been severe and on rare occasions, a fatal outcome was observed. 
 A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific 
respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnea, and in whom 
infectious, neoplastic and other non-medicinal causes have been excluded by means of appropriate 
investigations. Patients should be advised to report promptly any new or worsening respiratory 
symptoms. 
 Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no 
symptoms may continue Everolimus therapy without dose alteration. 
Individuals participating in this trial will be routinely questioned as to the presence of new or changed 
pulmonary symptoms consistent with lung toxicity. Moreover, potential lung radiological changes can be 
detected by the chest CT/MRI scans that are performed on all patients every 4 weeks for tumor assessment 
according to the schedule of events (Table 7-1). In addition, pulmonary function tests (PFTs) will be 
conducted, if clinically indicated, to monitor for pneumonitis. If non-infectious pneumonitis develops, the 
guidelines in Table 6-4 should be followed. Consultation with a pulmonologist is recommended for any case 
of pneumonitis that develops during the study. 


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Table 6-4 
Management of non-infectious pneumonitis 
Worst grade 
pneumonitis 
Required investigations 
Management of 
pneumonitis 
Everolimus dose adjustment 
Grade 1 
CT scans with lung windows. 
No specific therapy 
is required 
No dose adjustment required.  
Initiate appropriate monitoring. 
Grade 2 
CT scan with lung windows. Consider 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Consider a 
bronchoscopy with biopsy and/or BAL. 
Monitoring at each visit until return to ≤ 
grade 1. Return to initial monitoring 
frequency if no recurrence. 
Symptomatic only. 
Consider 
corticosteroids 
and/or other 
supportive therapy if 
symptoms are 
troublesome. 
Rule out infection and consider 
interruption of Everolimus until 
symptoms improve to Grade ≤ 1. 
Re-initiate Everolimus at one dose 
level lower.  
Discontinue Everolimus if failure to 
recover within ≤ 28 days. 
Grade 3 
CT scan with lung windows and 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Monitoring at each 
visit until return to ≤ grade 1. Return to 
initial monitoring frequency if no 
recurrence. Bronchoscopy with biopsy 
and/or BAL is recommended. 
Consider  
corticosteroids 
if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Rule out infection and interrupt 
Everolimus until symptoms improve to 
Grade ≤ 1. 
Consider re-initiating Everolimus at 
one dose level lower.  
Discontinue Everolimus if failure to 
recover within ≤ 28 days. 
Grade 4 
CT scan with lung windows and 
required pulmonary function testing, if 
possible, includes: spirometry, DLCO, 
and room air O2 saturation at rest. 
Monitoring at each visit until return to ≤ 
grade 1. Return to initial monitoring 
frequency 
if 
no 
recurrence. 
Bronchoscopy with biopsy and/or BAL 
is recommended if possible. 
Consider 
corticosteroids 
if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Rule out infection and discontinue 
Everolimus. 
 
6.2.2.7 
Management of hepatitis reactivation / flare 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving chemotherapy 22. 
Sporadic cases of Hepatitis B reactivation have also been seen in this setting with everolimus. Use of 
antivirals during anti-cancer therapy has been shown to reduce the risk of Hepatitis B virus reactivation and 
associated morbidity and mortality 22. A detailed assessment of Hepatitis B/C medical history and risk factors 
must be done for all patients at screening, with testing performed prior to the first dose of everolimus.  
Monitoring and prophylactic treatment for hepatitis B reactivation 
Table 6-5 provides detail of monitoring and prophylactic therapy according to the screening results of viral 
load and serologic markers testing. 


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Table 6-5 
Action to be taken based on screening hepatitis B results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBsAb 
+ or - 
+ or - 
+ 
and no prior HBV 
vaccination 
+ or - 
- 
or + with prior HBV 
vaccination 
HBcAb 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment should be 
started 1-2 weeks prior to first 
dose of Everolimus 
 
Monitor HBV-DNA approximately 
every 4-8 weeks 
 
 
No prophylaxis 
 
Monitor HBV-DNA approximately 
every 3-4 weeks  
No specific action 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of Everolimus. For HBV 
reactivation definition and management guidelines, seeTable 6-6. 
Table 6-6 
Guidelines for the management of hepatitis B reactivation 
HBV reactivation (with or without clinical signs and symptoms)* 
For patients with baseline 
results:  
Positive HBV-DNA 
OR 
positive HBsAg 
-------------------------------------- 
reactivation is defined as: 
[Increase of 1 log in HBV-DNA 
relative to baseline HBV-DNA 
value OR new appearance of 
measurable HBV-DNA] 
 
Treat: Start a second antiviral medication 
AND 
Interrupt Everolimus administration until resolution:  
 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days, Everolimus should be re-started at one dose 
lower, if available. (see Table 6-1 for dose levels available) If the patient is already 
receiving the lowest dose of Everolimus according to the protocol, the patient should 
restart at the same dose after resolution. Both antiviral therapies should continue at 
least 4 weeks after last dose of Everolimus.  
If resolution occurs > 28 days Patients should discontinue Everolimus but continue 
both antiviral therapies at least 4 weeks after last dose of Everolimus. 
For patients with baseline 
results: 
Negative HBV-DNA and HBsAg 
AND 
[Positive HBsAb (with no prior 
history of vaccination against 
HBV), OR positive HBcAb] 
------------------------------------- 
Reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat : Start first antiviral medication 
AND 
Interrupt Everolimus administration until resolution: 
 
≤ undetectable (negative) HBV-DNA levels 
If resolution occurs within ≤ 28 days, Everolimus should be re-started at one dose 
lower, if available (see Table 6-1 for dose levels available). If the patient is already 
receiving the lowest dose of Everolimus according to the protocol, the patient should 
restart at the same dose after resolution. Antiviral therapy should continue at least 4 
weeks after last dose of Everolimus. 
If resolution occurs > 28 days Patients should discontinue Everolimus but continue 
antiviral therapy at least 4 weeks after last dose of Everolimus. 
* All reactivations of HBV are to be recorded as grade 3 (e.g. CTCAE Version 3.0 - Investigations/Other: Viral Reactivation), 
unless considered life threatening by the investigator, in which case they should be recorded as grade 4. Date of viral 
reactivation is the date on which the rise or reappearance of HBV-DNA was recorded. 


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Monitoring for hepatitis C flare 
The following two categories of patients should be monitored every 4–8 weeks for HCV flare: 
 
Patients with detectable HCV RNA-PCR test at screening. 
 
Patients known to have a history of HCV infection, despite a negative viral load test at screening 
(including those that were treated and are considered ‘cured’) 
For definitions of HCV flare and actions to be taken in the event of a flare, please refer to Table 6-7. 
 
Table 6-7 
Guidelines for the management of hepatitis C flare 
Baseline results 
HCV flare definition* 
HCV flare management 
Detectable HCV-RNA 
 
> 2 log10 IU/mL increase in HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline level, 
whichever is higher. 
Discontinue Everolimus 
Knowledge of past hepatitis C 
infection with no detectable HCV-
RNA 
New appearance of detectable HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline level, 
whichever is higher. 
Discontinue Everolimus 
* All flares of HCV are to be recorded as grade 3 (e.g. CTCAE Version 3.0 - Investigations - Other: Viral Flare), unless 
considered life threatening by the investigator; in which case they should be recorded as grade 4. Date of viral flare is the 
date on which both the clinical criteria described above were met. (e.g., for a patient whose HCV-RNA increased by 2 logs on 
01 JAN 2011 and whose ALT reached > 5 x ULN on 22 JAN 2011, the date of viral flare is 22 JAN 2011). 
 
6.3 
Cisplatin General Information 
  Table 6.7.1 PHARMACOKINETICS:12 
 Interpatient variability  
systemic clearance resulting in variable blood platinum concentrations or AUCs 
Oral Absorption  
not absorbed 
Distribution  
rapidly diffuses into tissues highest concentrations found in the liver, prostate and kidney; 
rapidly distributed into pleural effusions and ascitic fluid  
cross blood brain barrier?  
not readily 
volume of distribution 
ultrafilterable platinum*: 41 L/m²  
plasma protein binding  
>90% 
Metabolism  
undergoes non-enzymatic conversion to several inactive metabolites which are highly 
bound to plasma proteins 
active metabolite  
yes  
inactive metabolite  
yes 
Excretion  
primarily in the urine 
urinary excretion of ultrafilterable platinum* was substantially greater after a 6-hour infusion 
than after a 15-minute injection  
urine  
> 90%8; 25% excreted during the first 24 h 
feces  
insignificant  
terminal half life of 
ultrafilterable platinum* 
20-45 min  
terminal half life of total 
platinum* 
5 days or longer  
clearance  
6.3 mL/min/kg  
Gender  
no clinically important differences found  
Elderly  
no clinically important differences found  
Children  
terminal half life of ultrafilterable platinum* < 1 h 
terminal half life of total platinum* 24-72 h 
Ethnicity  
no clinically important differences found  


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SPECIAL PRECAUTIONS:  
Administer with caution to individuals with pre-existing renal impairment, myelosuppression or hearing 
impairment. 12 
Breastfeeding is not recommended as cisplatin is excreted in human milk. 
Carcinogenicity: found to have a carcinogenic effect in laboratory animals.  
Contraindicated: in patients who have a history of a hypersensitivity reaction to cisplatin or other platinum-
containing compounds.  
Fertility: Cisplatin therapy is associated with at least temporary infertility in the majority of patients. Among 
males receiving cisplatin for testicular cancer, almost all became azospermic within the first two cycles of 
therapy, but recovery of normal sperm morphology, motility, and sperm count occurred in 40% within 1.5-2 
years.  
Hydration is required to minimize nephrotoxicity. The manufacturer recommends pre-treatment hydration 
with 1 or 2 L of fluid infused 8-12 hours prior to a cisplatin dose. Hydration with NS, hypertonic saline 
infusion, and mannitol, or furosemide-induced diuresis is used to effectively decrease cisplatin-induced 
nephrotoxicity.8 Lower doses of cisplatin are given with less intensive hydration. For example, patients 
receiving doses of 35 mg/m2 have been pre-treated with 500 mL NS over 1 hour, with no post-hydration. 
Patients receiving doses of 25 mg/m2 have been pre-treated with vigorous oral hydration (e.g., 600-900 mL) 
the morning of treatment and 8 glasses (e.g., 2000 mL/day) daily for a few days following treatment. Please 
refer to the “Nephrotoxicity” paragraph, found below the Side Effects table for a suggested hydration 
guideline.  
Inadvertent substitution of cisplatin for carboplatin can result in a potentially fatal overdosage. Precautions 
should be taken to avoid overdosing such as writing the cisplatin dose as a daily dose, not as a total cisplatin 
dose used in one course of therapy. The manufacturer recommends that an alerting mechanism be instituted 
to verify any order for cisplatin >100 mg/m2 per course every 3-4 weeks. 12 
 
Mutagenicity: shown to be a mild to moderate mutagen in the Ames test. 
 
Pregnancy: FDA Pregnancy Category D. There is positive evidence of human fetal risk, but the benefits 
from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-
threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).  
SIDE EFFECTS:  
The table includes adverse events that presented during drug treatment but may not necessarily have a 
causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the 
adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are 
generally included if they were reported in more than 1% of patients in the product monograph or pivotal 
trials, and/or determined to be clinically important. 12 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 6.7.2 
ORGAN SITE  
SIDE EFFECT  
ONSET  
Clinically important side effects are in bold, italics I = immediate [onset in hours to days]; E = early[days to weeks]; D = 
delayed [weeks to months] L = late [months to years]  
allergy/immunology  
hypersensitivity (rare)  
I  
auditory/hearing  
ototoxicity (31%)  
E  
audiogram abnormalities (24%)  
E  
tinnitus (9%)  
E  
vestibular toxicity (rare)  
E  
blood/bone marrow/ febrile 
neutropenia  
myelosuppression (25-30%) WBC nadir 18-23 days (range 7.5-45), 
platelet nadir 18-23 days (range 7.5-45), recovery 39 days (range 13-
62)  
I  
anemia (25-30)%  
I  
cardiovascular (arrhythmia)  
arrhythmias1 
E  
cardiovascular (general)  
bradycardia (rare)  
E  
vascular toxicities may include myocardial infarction, cerebrovascular accident, thrombotic 
microangiopathy or cerebral arteritis  
E  
constitutional symptoms  
hiccoughs  
I  
dermatology/skin  
extravasation hazard: irritant 
alopecia (uncommon)  
E  
rash (uncommon)  
E  
local soft tissue toxicity (rare)  
E  
endocrine  
glucose intolerance 
gastrointestinal  
emetogenic potential: high 
nausea and vomiting (> 90%)  
I  
delayed nausea and vomiting  
I  
diarrhea  
E  
loss of taste  
E  
pancreatitis 
E  
stomatitis 
E  
hepatic  
transient elevation of hepatic enzymes and bilirubin  
I  
metabolic/laboratory  
elevated serum amylase  
I  
electrolyte disturbances2  
I  
hyperuricemia  
E  
musculoskeletal  
muscle cramps  
E  
neurology  
autonomic neuropathy  
E  
dorsal column myelopathy  
E  
Lhermitte’s sign  
E  
neurotoxicity, usually peripheral neuropathies  
E  
seizures (rare) 
E  
ocular/visual  
visual impairment (rare)  
E  
altered colour perception  
E  
blurred vision  
E  
cerebral blindness (infrequent)  
E  
optic neuritis  
E  
papilledema  
E  
renal/genitourinary  
nephrotoxicity (28-36%)  
E  
secondary malignancy  
acute leukemia (rare)  
L  
syndromes  
inappropriate antidiuretic hormone syndrome  
E  


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Anemia observed with cisplatin use may be caused by a decrease in erythropoietin or erythroid stem cells. 
Cisplatin has been shown to sensitize red blood cells, sometimes resulting in a direct Coombs’ positive 
hemolytic anemia. 
Electrolyte disturbances can be serious and mainly includes hypomagnesemia, hypocalcemia and 
hypokalemia. Hypophosphatemia and hyponatremia have occurred in some patients receiving cisplatin 
combination regimens. These effects are due to renal tubular damage. Cisplatin greatly increases the urinary 
excretion of magnesium and calcium; increased excretion of potassium, zinc, copper and amino acids also 
occurs. Hypomagnesemia and or hypocalcemia may become symptomatic, with muscle irritability or cramps, 
clonus, tremor, carpopedal spasm and/or tetany. Children may be at greater risk for developing 
hypomagnesemia. 12 
Emetogenic effects are common with cisplatin therapy and may be serotonin-mediated. Acute nausea and 
vomiting may occur within 1-6 (usually 2-3) hours after administration of cisplatin. This early period is the 
most severe and usually lasts 8 hours, but can last up to 24 hours. Various levels of nausea, vomiting and 
anorexia may persist for up to 5-10 days. Delayed nausea and vomiting can occur 24 hours or longer 
following chemotherapy when complete emetic control had been attained on the day of cisplatin therapy. The 
incidence and severity of cisplatin-induced nausea and vomiting appear to be increased in: females, the 
young, high doses, rapid infusion and combinations with other emetogenic drugs. Incidence and severity 
may be decreased in patients with a history of chronic alcohol use. Acute nausea and vomiting can be 
prevented by pre-treatment with a 5-HT3 antagonist (e.g., granisetron, ondansetron) plus a corticosteroid; 
this can be continued for the first 24 hours following chemotherapy. Delayed nausea and vomiting should 
not routinely be treated with 5-HT3 antagonists; although there is anecdotal evidence that some patients can 
benefit from 5-HT3 antagonists, generally these agents are ineffective more than 24 hours after 
chemotherapy. Corticosteroids are the cornerstone of the treatment for delayed nausea, although other 
combinations are widely used.  
Nephrotoxicity is a major concern when prescribing cisplatin. Renal dysfunction due to cisplatin may 
manifest as renal insufficiency, hypokalemia and hypomagnesemia. The risk for these adverse effects is 
related to the dose and interval of cisplatin and may be minimized by adequate hydration. Geriatric patients 
may also be at increased risk.  
 
The manufacturer recommends pre-treatment hydration with 1 or 2 L of fluid infused 8-12 hours 
prior to a cisplatin dose. Others suggest hydration with NS, hypertonic saline infusion, and mannitol, or 
furosemide-induced diuresis to effectively decrease cisplatin-induced nephrotoxicity.  
Numerous hydration regimens exist. Hydration regimens should take into account the following conditions for 
the patient ; adequate renal function, clinically euvolemic prior to administration of cisplatin, no 
contraindication to saline loading (e.g., uncompensated cardiac conditions, anasarca), and ability to comply 
with recommended oral hydration protocol, or expectation that volume status can be maintained (e.g., with 
fluids via enteral feeding tube or IV). Below is one suggested hydration regimen for adults. 12 
Table 6.7.3 
Cisplatin (mg/m2) 
Hydration 
Electrolyte 
Additives* 
Comments 
> 80  
4000 mL* NS over 4 h  
KCl 20 mEq  
MgSO4 1 g  
Mannitol 30 g  
inpatient or medical daycare unit admission to 
monitor urine output  
60-80  
2000 mL* NS over 2 h  
KCl 20 mEq  
MgSO4 1 g  
Mannitol 30 g  
40-60  
1000 mL* NS over 1 h  
KCl 10 mEq  
MgSO4 0.5 g  
includes regimens with cisplatin administered over 
multiple days  
<40  
500 mL* NS over 30 min  
none  
includes regimens with cisplatin administered over 
multiple days  
 


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*Volume may include hydration associated with the administration of other drugs (e.g., other chemotherapy 
agents, supportive IV medications). The volumes and durations are minimum administration standards to 
accommodate the wide variation in clinical practice in delivery of cisplatin. They should be individualized 
based on the clinical situation, which may affect the hydration regimen and addition of electrolytes.  
 
Nervous system effects are usually peripheral neuropathies and sensory in nature (e.g., parethesias of the 
upper and lower extremities). They can also include motor difficulties (especially gait); reduced or absent 
deep-tendon reflexes and leg weakness may also occur. Peripheral neuropathy is cumulative and usually 
reversible, although recovery is often slow. Geriatric patients may be at greater risk for these cisplatin-
induced neuropathies. Muscle cramps have been reported, and usually occurred in patients with 
symptomatic peripheral neuropathy who received relatively high cumulative doses of cisplatin. Lhermitte’s 
sign (a sensation during neck flexion resembling electric shock) often is present with cisplatin-induced 
neuropathy. The occurrence of Lhermitte’s sign may coincide with the onset of peripheral neuropathies, and 
can last for 2-8 months. When signs of neuropathy occur, cisplatin should be discontinued. 12 
 
Otic effects include tinnitus, with or without clinical hearing loss, and occasional deafness. Ototoxicity is 
cumulative and irreversible and results from damage to the inner ear. These effects may be more severe in 
children than in adults. The manufacturer recommends that audiograms be performed prior to initiating 
therapy and prior to each subsequent dose of drug. Initially, there is loss of high frequency acuity (4000 to 
8000 Hz). When acuity is affected in the range of speech, cisplatin should be discontinued under most 
circumstances and carboplatin substituted where appropriate. Ototoxicity appears to be dose related. Higher 
cumulative doses, higher individual doses and administration by IV bolus resulted in more severe ototoxicity, 
corresponding with higher plasma levels of ultrafilterable platinum. Ototoxicity may be enhanced in patients 
with prior or simultaneous cranial irradiation. Vestibular ototoxicity may increase with increasing cumulative 
dosage and may be more likely to occur in patients with pre-existing vestibular dysfunction. 12 
 
Sensitivity reactions can include anaphylactoid reactions consisting of facial edema, flushing, wheezing or 
respiratory difficulties, tachycardia, and hypotension. These reactions can occur within a few minutes after IV 
administration of cisplatin; diaphoresis, nasal stuffiness, rhinorrhea, conjunctivitis, generalized erythema, 
apprehension, and sensation of chest constriction may also occur. Cisplatin-induced anaphylactoid reactions 
usually have occurred after multiple cycles of cisplatin (e.g., at least 5 doses), but also can occur after the 
first dose. There is a case report of a patient who experienced an anaphylaxis to cisplatin following nine 
previous uncomplicated cycles. Some reactions may also be due to the mannitol that is given with cisplatin 
to prevent nephrotoxicity. Occasionally, patients who experienced anaphylactoid reactions have been safely 
retreated with cisplatin following pre-treatment with corticosteroids and/or antihistamines; however, such 
prophylaxis is not uniformly effective in preventing recurrence. 12 
Table 6.7.4 INTERACTIONS: 
AGENT 
EFFECT 
MECHANISM 
MANAGEMENT 
etoposide  
synergistic antineoplastic 
activity against testicular, 
small cell lung and, non-
small cell lung cancers  
possible impaired 
elimination of etoposide in 
patients previously treated 
with cisplatin  
some protocols are 
designed to take advantage 
of this effect; monitor toxicity 
closely  
nephrotoxic drugs such as 
aminoglycoside antibiotics 
and amphotericin  
increased risk of 
nephrotoxicity  
cumulative nephrotoxoixity  
use with extreme caution 
during or shortly after 
cisplatin  
ototoxic drugs such as 
aminoglycoside antibiotics 
or loop diuretics (e.g., 
ethacrynic acid, furosemide)  
increased risk of ototoxicity  
cumulative ototoxicity  
carefully monitor for signs of 
ototoxicity  


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phenytoin  
decreased phenytoin serum 
levels  
decreased absorption 
and/or increased 
metabolism of phenytoin  
monitor serum levels of 
phenytoin  
pyridoxine 
decrease in cisplatin activity  
further investigation required  avoid concomitant use of 
pyridoxine with cisplatin  
renally excreted drugs  
increase the serum levels of 
renally excreted drugs  
reduced renal function 
caused by cisplatin  
monitor toxicity  
 
SUPPLY AND STORAGE: 12 
Injection: Cisplatin is available as sterile, unpreserved; single-dose vials (10 mg/10 mL, 50 mg/50 mL and 
100 mg/100 mL) at a concentration of 1 mg/mL.17 Unopened vials are stored at room temperature. Do not 
refrigerate or freeze cisplatin solutions as a precipitate will form. Protect from light. 
Do not use IV needles, syringes or sets that have aluminum components in the preparation or administration 
of cisplatin. An interaction between aluminum and platinum will occur resulting in the formation of a black 
precipitate, accompanied with a loss of potency.  
Diluted solution for infusion: Dilute the prepared cisplatin injection in 2 L of D51/2S or 0.3%NS, containing 
37.5 g of mannitol. The solution is not preserved and should be used within 24 hours. Any unused portion 
should be discarded. In children, the administration volume of cisplatin should be maintained at >125 
mL/m²/hr, and contain mannitol 15 g/m2 and MgSo4 20 mEq/L.23 Urine output should be maintained at > 90 
mL/m²/hr during administration. 
Compatibility: The following are compatible with cisplatin via Y-site injection: allopurinol, aztreonam, 
bleomycin, chlorpromazine, cimetidine, cladribine, cyclophosphamide, dexamethasone, diphenhydramine, 
doxorubicin, doxorubicin liposome, droperidol, famotidine, filgrastim, fludarabine, fluorouracil, furosemide, 
ganciclovir, gatifloxacin, gemcitabine, granisetron, heparin, hydromorphone, leucovorin, linezolid, lorazepam, 
melphalan, methotrexate, methylprednisolone, metoclopramide, mitomycin, morphine, ondansetron, 
paclitaxel, prochlorperazine, promethazine, propofol, ranitidine, sargramostim, teniposide, topotecan, 
vinblastine, vincristine, vinorelbine.  
The following are compatible with cisplatin in the same syringe in certain concentrations: bleomycin, 
cyclophosphamide, doxapram, doxorubicin, droperidol, fluorouracil, furosemide, heparin, leucovorin, 
methotrexate, metoclopramide, mitomycin, vinblastine, and vincristine.  
The following are compatible with cisplatin in the same infusion bag in certain concentrations and diluents: 
carboplatin, cyclophosphamide with etoposide, etoposide, etoposide with floxuridine, etoposide with mannitol 
and KCL, floxuridine, floxuridine with leucovorin, hydroxyzine, ifosfamide, and ifosfamide with etoposide, 
leucovorin, magnesium, mannitol, ondansetron and paclitaxel.  
The following solutions are compatible with cisplatin at the stated concentrations: cisplatin 50 mg, 500 mg, 
300 mg in D51/2NS 1L; cisplatin 50 mg, 300 mg, 500 mg in D5NS 1L; cisplatin 50 mg, 100 mg, 200 mg in 
D51/2NS with mannitol 1.875%; cisplatin 300 mg in D5W 1L; cisplatin 50 mg, 100 mg, 167 mg, 200 mg, 300 
mg, 500 mg, 600 mg, 900 mg in NS 1L; cisplatin 50 mg, 100 mg, 200 mg in 1/2NS.  
Incompatibility 28: The following are incompatible with cisplatin via Y-site injection: amifostine, 
amphotericin, cefepime, piperacillin-tazobactam and thiotepa.  
The following are incompatible with cisplatin in the same infusion solution at the stated concentrations: 
cisplatin 200 mg with etoposide 400 mg, mannitol 1.875%, KCl 20 mEq in NS 1L; cisplatin 200 mg with 
fluorouracil 1 g in NS 1L; cisplatin 500 mg with fluorouracil 10 g in 1L NS; cisplatin 67 mg with mesna 3.33 g 
in NS 1L; cisplatin 67 mg with mesna 110 mg in NS 1L; cisplatin 200 mg with paclitaxel 1.2 g in NS 1L; 
cisplatin 200 mg with thiotepa 1 g in NS 1L.  
The following solutions are incompatible with cisplatin at the stated concentrations: cisplatin 100 mg/L in 
D5W 5%; cisplatin 75 mg/L in D5W; cisplatin 50 mg/L in Sodium bicarbonate 5%; cisplatin 500 mg/L in 
Sodium bicarbonate 5%. 


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6.4 
Concomitant medications 
Patients must be instructed not to take any medications (over-the-counter or other products) during the 
protocol treatment period without prior consultation with the investigator. The investigator should instruct the 
patient to notify the study site about any new medications he/she takes after the start of study drug. All 
medications (other than study drug) and significant non-drug therapies (including physical therapy and blood 
transfusions) taken within 28 days of starting study treatment through the 30-day safety follow up visit should 
be reported on the CRF. 
6.4.1 
Permitted concomitant therapy 
Standard Cisplatin premedications only 
Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates 
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall. 
Therefore, the following are recommended: 
 
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) or P-
glycoprotein (PgP) inhibitor should be avoided. 
 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or PgP inhibitors 
should be used with caution. If a patient requires co-administration of moderate CYP3A4 inhibitors or 
PgP inhibitors, reduce the dose of everolimus . Additional dose reductions to every other day may be 
required to manage toxicities. If the inhibitor is discontinued, the Everolimus dose should be returned to 
the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor after a washout period of 2 to 3 
days. 
 
Grapefruit or citrus juices affect P450 and PgP activity. Concomitant use should be avoided. 
 
Co-administration with strong inducers of CYP3A4 should be avoided. If a patient requires co-
administration of strong CYP3A4 inducers (i.e., phenytoin, carbamazepine, rifampin, rifabutin, 
phenobarbital, St. John’s wort), an increase in the dose of Everolimus up to twice the currently used 
daily dose should be considered, 5mg increments. Enzyme induction usually occurs within 7-10 days; 
therefore Everolimus dose should be increased by one increment 7 days after the start of the inducer 
therapy.  If no safety concerns are seen within the next 7 days, the dose can be increased again one 
additional increment up to a maximum of twice the daily dose used prior to initiation of the strong 
CYP3A4 inducer. 
 
This dose adjustment of Everolimus is intended to achieve similar AUC to the range observed without 
inducers. However, there are no clinical data with this dose adjustment in patients receiving strong 
CYP3A4 inducers. If the strong inducer is discontinued the Everolimus dose should be returned to the 
dose used prior to initiation of the strong CYP3A4/PgP inducer. 
Please refer to Table 6-8 listing relevant inducers and inhibitors of CYP3A and Table 6-9 for a list of relevant 
substrates, inducers, and inhibitors of PgP.  
 
Table 6-8 
Clinically relevant drug interactions: inducers, and inhibitors of isoenzyme CYP3A 
Inducers 
carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. 
John’s wort, troglitazone, efavirenz, nevirapine, topiramate, avasimibe, bosentan, etravirine, nafcillin, ritonavir, talviraline (not 
available in US market), tipranavir, amprenavir, aprepitant, armodafinil (R-modafinil), dexamethasone, nevirapine, 
prednisone, pleconaril (not available in US market), rufinamide 
Inhibitors 
Strong inhibitors: 
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, ritonavir, 
saquinavir, telithromycin, troleandamycin, voriconazole, tipranavir, elvitegravir, Posaconazole 24 
Moderate inhibitors: 
aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, darunavir, diltiazem, erythromycin, fluconazole, grapefruit juice 
(citrus parasidi fruit juice), imatinib, tofisopam, verapamil, amprenavir, fosamprenavir, dronedarone 
 


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Table 6-9 
Clinically relevant drug interactions: substrates, inducers, inhibitors of PgP and PgP/CYP3A 
dual inhibitors 
Substrates 
digoxin, fexofenadine, indinavir, vincristine, colchicine, topotecan, paclitaxel 
Inducers 
rifampin, St John’s wort 
PgP Inhibitors and PgP/CYP3A Dual Inhibitors 
amiodarone, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, erythromycin, felodipine, 
fexofenadine, ginkgo (ginkgo biloba), indinavir, itraconazole, , lopinavir, mibefradil, milk thistle (silybum marianum), 
nifedipine, nitrendipine, quercetin, quinidine, ranolazine, ritonavir, saquinavir, Schisandra chinensis, St John’s wort 
(hypericum perforatum), talinolol, telmisartan, tipranavir, valspodar, verapamil 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 2011, which summarizes DDI 
data from three sources including the FDA’s “Guidance for Industry, Drug Interaction Studies”, the University of Washington’s 
Drug Interaction Database, and Indiana University School of Medicine's Drug Interaction Table. 
 
Vaccinations 
Immunosuppressants may affect the response to vaccination and vaccination during treatment with 
Everolimus may therefore be less effective. The use of live vaccines should be avoided during treatment with 
Everolimus Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, 
yellow fever, varicella, and TY21a typhoid vaccines. 
 
6.4.2 
Prohibited concomitant therapy 
Anti-neoplastic therapies 
Prior neo-adjuvant treatment for triple negative breast cancer disease is allowed. A clinical an pathological 
residual desiase must be documented. 
Treatment with systemic anticancer agents (chemotherapy, hormone therapy, targeted or biologic agents) 
other than the protocol treatment is not permitted until disease progression is documented per RECIST.  
 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule


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Table 7-1 
Visit evaluation schedule 
 


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* All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B and hepatitis C infection.  It is highly recommended that patients positive 
HBV-DNA or HBsAg are treated prophylactically with an antiviral (i.e. Lamivudine) for 1-2 weeks prior to receiving study drug (see Section 3.2). The antiviral treatment 
should continue throughout the entire study period and for at least 4 weeks after the last dose of everolimus. Patients with viral hepatitis C risk factors should be screened 
for HCV RNA-PCR. 
** Patients on antiviral prophylaxis treatment or positive HBV antibodies should be tested for HBV-DNA on Cycle 1 Day 1 and Day 1 of all subsequent cycles (every 28 
days) to monitor for re-activation. If re-activation is confirmed, everolimus must be interrupted or discontinued according to the guidance in Table 3-3. Patients with 
positive HCV RNA-PCR results at screening and/or a history of past infection (even if treated and considered ‘cured’) should have HCV RNA-PCR testing performed on 
Cycle 1 Day 1 and Day 1 of all subsequent cycles (every 28 days) to monitor for reactivation. everolimus must be discontinued if HCV reactivation is confirmed according 
to the guidance in Table 3-4. 


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7.2 
Assessment types 
ECOG Performance Status of 0-1 is required for study entry. ECOG performance status will be recorded at 
baseline, prior to each cycle, at the end of treatment and at the end of the study assessment. 
Document signs and symptoms and adverse events at least every 4 weeks until all study drug-related 
toxicities resolve, stabilize, return to baseline, or are deemed irreversible. 
Pregnancy tests (serum or urine) should be performed within 72 hours of study start, or whenever pregnancy 
is suspected. 
Unilateral and/or bilateral mammogram and ultrasound should have been performed any time within 4 weeks 
prior to beginning of the study treatment.    *MRI (magnetic resonance imaging) should be performed only if 
requested by the physician. 
Biopsies will be obtained from accessible sites at baseline only (Research procedure); biopsied tumor must 
measure at least 1cm at any direction; if main tumor is not detected, an abnormal (clinically or radiologically) 
axillary lymph node can be biopsied. Exploratory analyses may include, but are not limited to p63/p73 and 
PI3K/Akt/mTOR pathways. 
   * Surgical specimen will be used to correlate mTOR related biomarkers. 
A 12-lead EKG at baseline; QRS measurement is required. Electrocardiogram (EKG) with QRS 
measurement will be repeated whenever clinically indicated. 
LVEF may be assessed by MUGA scan or ECHO. Follow-up LVEF assessments are required ONLY for 
symptomatic patients. 
Evaluate tumor response using RECIST criteria before chemotherapy and every 6 weeks from the beginig of 
the treatment till disease progression. 
Everolimus will be given at 10mg p.o. daily.  Everolimus will be self-administered daily with water with or 
without meal. The site must perform all appropriate drug accountability. 
Pill Diary dispensed with study drug and retrieved the day after the treatment is completed. The Research 
Coordinator will revise it at every visit. 
Cisplatin infusion 20 mg/m2 IV infusion over 60 minutes, at the specified doses weekly (Days 1, 8, 15) x 4 
cycles. 
Subjects will be pre-medicated approximately 1 hour before Cisplatin therapy.  Standard anti-emetics for 
moderately emetogenic regimen, together with standard premedication will be prescribed with 
chemotherapy. Recommended prophylaxis for fluid retention/hypersensitivity reactions will be provided per 
institution standards.  
Monitor the subject for hypersensitivity reactions during and after all infusions. 
End of study visit will occur due to disease progression, as determined by the investigator until intolerable 
AEs, death, voluntary withdrawal from the study by the patient, or discontinuation of the study by the 
sponsor. Vital signs including blood pressure, heart rate and temperature will be performed during this visit. 
Toxicity assessment will be continuous throughout the study. CTC Version 4.0 will be used to grade 
toxicities. 
Clinical evaluation will include a record of the date and site(s) of recurrence, subsequent breast cancer 
treatment administered, and late treatment-related toxicity. 
The duration of patient participation in the study will be a total of three (3) to four (4) months from the start of 
treatment. Every patient has to have a two (2) weeks washout period before starting the trial. Follow-up for 
all patients will include: ·Medical history update (30 days after the last dose of the study drug) Evaluate 
subjects who discontinue the protocol for reasons other than disease progression (AEs) every 4 weeks until 
progression or until they receive additional anti-cancer therapy. 
 
 
 
 
 


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7.2.1 
Pregnancy and assessments of fertility 
Pregnancy testing is required at screening or whenever pregnancy is suspected.  Serum pregnancy testing 
should be performed at screening and at the end of the study. Urine pregnancy testing will be performed at 
each visit (every 4 weeks).  
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must 
use highly effective contraception during the study and for 8 weeks after stopping treatment. Highly effective 
contraception is defined as either: 
 
Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. [Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception] 
 
Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at 
least six weeks before taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level assessment 
 
Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm 
in the ejaculate). [For female subjects on the study, the vasectomised male partner should be the sole 
partner for that subject]. 
 
Use of a combination of any two of the following (a+b or a+c or b+c): 
a. Use of oral, injected, implanted or other hormonal methods of contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/vaginal suppository 
 
In case of use of oral contraception, women should have been stable on the oral agent before taking 
study treatment. 
Sexually active males must use a condom during intercourse while taking the drug and for 8 weeks after 
stopping treatment and should not father a child in this period. 
A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via 
seminal fluid. 
Female partners of male patients must also be advised to use one of the following contraception methods: 
Use of (1) oral, injected, implanted or other hormonal methods of contraception, or (2) intrauterine device 
(IUD) or intrauterine system (IUS), or (3) prior male/female sterilization. 
 
7.2.2 
Laboratory evaluations  
Comprehensive Metabolic Panel must include sodium, potassium, magnesium, chloride, calcium, glucose, 
BUN, creatinine, AST, ALT, alkaline phosphatase, total bilirubin, and albumin.  Complete blood count must 
include Hemoglobin, Hematocrit, RBC, WBC, Platelets with differential Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils.  CrCL “CrCl = [(140 - age) x IBW] / (Scr x 72) (x 0.85 for females)” 
before every cycle for patients with an abnormal creatinine.  
Perform laboratory tests within 72 hours of beginning each cycle. Perform baseline laboratory tests within 
four (4) weeks before administration of study drug. 
 
7.2.2.1 
HBV testing for patients with hepatitis B 
Prior to start the treatment, the categories of patients listed in Section 4.1 should be tested for hepatitis 
B serologic markers and viral load (local results are acceptable for screening only): 
 
HBV-DNA, HBsAg, HBc Ab, and HBs Ab. 
 
During the treatment period, HBV DNA monitoring should be done depending on results from 
serologic markers and viral load as listed in Table 6-5. 


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7.2.2.2 
HCV testing for patients with hepatitis C 
Patients with hepatitis C risk factors and at the discretion of the investigator should be tested for HCV 
RNA prior to treatment (local results are acceptable for screening only). For a list of hepatitis C risk 
factors, refer to Section  
 
7.2.3 
Drug levels and pharmacokinetic assessments N/A 
 
8 
Safety monitoring and reporting 
Information about all adverse events, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be collected and 
recorded and followed as appropriate. 
 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse Events CRF. 
Conditions that were already present at the time of informed consent should be recorded in the Medical 
History page of the patient’s CRF. Adverse event monitoring should be continued for at least 30 days (or 5 
half-lives, whichever is longer) following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, rather than 
individual underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate Adverse Event. 
The occurrence of adverse events should be sought by non-directive questioning of the patient at each visit 
during the study. Adverse events also may be detected when they are volunteered by the patient during or 
between visits or through physical examination, laboratory test, or other assessments. As far as possible, 
each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates or if continuing at the Safety Follow-up Visit) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)  
4. Action taken with respect to study or investigational treatment (none, dose adjusted, temporarily 
interrupted, permanently discontinued, hospitalized, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, concomitant 
medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, recovered/resolved with 
sequalae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
All adverse events should be treated appropriately. Such treatment may include changes in study drug 
treatment including possible interruption or discontinuation, starting or stopping concomitant treatments, 
changes in the frequency or nature of assessments, hospitalization, or any other medically required 
intervention. Once an adverse event is detected, it should be followed until its resolution, and assessment 
should be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the study drug, the interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be found in the 
[Investigators’ Brochure]. This information should be included in the patient informed consent and should be 
discussed with the patient during the study as needed. 
Adverse event monitoring should be continued for at least 30 days following the last dose of study treatment 
 
 


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8.1.2 
Laboratory test abnormalities 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes in study 
treatment), should be recorded on the Adverse Events CRF. Whenever possible, a diagnosis, rather than a 
symptom should be provided (e.g. anemia instead of low hemoglobin). Laboratory abnormalities that meet 
the criteria for Adverse Events should be followed until they have returned to normal or an adequate 
explanation of the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the lab/test 
result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be reported as 
adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE unless 
it meets the definition of serious as defined below and/or as per investigator’s discretion. A dose hold or 
medication for the lab abnormality may be required by the protocol and is still, by definition, an adverse 
event. 
  
8.1.3 
Adverse events of special interest (optional) 
In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal 
outcome. Reactivation of infections is an expected event during periods of immunosuppression. 
In clinical trials and post-marketing spontaneous reports, everolimus has been associated with renal failure 
events (including fatal ones) and proteinuria. Renal function will be monitored throughout the study. In 
clinical trials Everolimus has been associated with certain adverse events. 
Clinically 
Notable 
AE 
grouping 
Risk Definition in 
RMP 
Comment 
Amenorrhea 
Amenorrhea 
Included under potential risk in RMP 
Cytopenia 
N/A 
Included under clinically notable AEs 
Hemorrhages 
Hemorrhages 
Included as important identified risk in the RMP 
Hyperglycemia/ new onset 
of diabetes mellitus 
N/A 
Included under clinically notable AEs 
Hypersensitivity reactions 
(anaphylactic reaction) 
N/A  
Included under clinically notable AEs 
Infections and infestations 
N/A 
Included under clinically notable AEs 
Intestinal obstruction/ileus 
Intestinal 
obstruction/ileus 
Included under potential risk 
N/A 
Cardiac Failure 
Not reported in the MAP. (important identified risk- RMP specific 
N/A 
Increased 
creatinine 
Please note that this RMP specific identified risk is based on lab data 
and is defined as newly occurring or worsening increase to CTC grade 
3 or 4 
Non infectious pneumonitis 
Non 
infectious 
pneumonitis 
Name changed from pulmonary events to non infectious pneumonitis in 
the MAP. Included under important identified risk in RMP 
Rash and similar events 
N/A 
Not included in the RMP 
Renal events 
Renal 
failure/proteinuria 
The names in RMP and MAP are different but the search terms are the 
same. It is included important identified risk in RMP 
Stomatitis/oral 
mucositis/ulcers 
N/A 
Included under clinically notable AEs 
Thromboembolism 
Thromboembolism 
Included as important identified risk in the RMP 


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8.2 
Serious Adverse Events 
8.2.1 
Definitions 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
 
is fatal or life-threatening 
 
results in persistent or significant disability/incapacity 
 
constitutes a congenital anomaly/birth defect 
 
requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition (specify what this includes) 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under 
study and has not worsened since the start of study drug 
 treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE 
given above and not resulting in hospital admission 
 social reasons and respite care in the absence of any deterioration in the patient’s general condition 
 
is medically significant, i.e., defined as an event that jeopardizes the patient or may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
8.2.2 
Reporting 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, and 
Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A (MedWatch 
Form).  
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
 
after the patient has provided informed consent and until atleast 30 days after the patient has stopped 
study treatment/participation 
 
after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-blind treatment, 
etc.) and 30 days after the patient has stopped study treatment 
 
after the start of any period in which the study protocol interferes with the standard medical treatment 
given to a patient (e.g., treatment withdrawal during washout period, change in treatment to a fixed dose 
of concomitant medication) and until 30 days after the patient has stopped study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence (fax: 877-778-9739). This includes 
serious, related, labeled (expected) and serious, related, unlabeled (unexpected) adverse experiences. All 
deaths during treatment or within 30 days following completion of active protocol therapy must be reported 
within 5 working days. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the investigator 
suspects a causal relationship to the study drug. Recurrent episodes, complications, or progression of the 
initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator receiving 
the follow-up information. A SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event.  The end date of the 
first event must be provided. 
The original copy of the SAE Report and the fax confirmation sheet must be kept within the Trial Master File 
at the study site. 
Follow-up information is sent to the same fax number as the original SAE Report Form was sent, using a 
new fax cover sheet, stating that this is a follow-up to the previously reported SAE, and giving the date of the 
original report. Each re-occurrence, complication, or progression of the original event should be reported as 
a follow-up to that event regardless of when it occurs. The follow-up information should describe whether the 


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event has resolved or continues, if and how it was treated, whether the blind was broken or not (if 
applicable), and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Everolimus Investigator Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study drug, a DS&E associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study with the same drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse experiences will 
be forwarded to the comapartor drug company by the investigator. 
 
8.3 
 Emergency unblinding of treatment assignment 
N/A 
 
8.4 
Pregnancy 
Preclinical data regarding reproductive toxicity is described in the most recent Investigator Brochure. The 
potential reproductive risk for humans is unknown.  Women of childbearing potential should be advised to 
use highly effective contraception methods while they are receiving everolimus and up to 8 weeks after 
treatment has been stopped.   
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be reported 
to Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of 
any birth defects, congenital abnormalities, or maternal and/or newborn complications. The newborn will be 
followed for at least 12 months. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to the 
oncology Novartis Drug Safety and Epidemiology Department (DS&E). Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to the study 
treatment and any pregnancy outcome. Any SAE experienced during pregnancy must be reported on the 
SAE Report Form. 
 
9 
Statistical methods 
9.1 
Sample Size. 
Demographics and pre-treatment characteristics will be summarized for all patients using descriptive 
statistics.   TNBC patients will be eligible if they are at high risk of recurrence (residual disease after neo-
adjuvant treatment). 
 
An overall sample size of 32 subjects achieves 81% power, using a one-sided binomial test (alpha=0.05), 
will give us a 5% increase in the pCR rate.   
The study lasts for 30 days after the last dose of the study drug.  
The primary endpoint of this trial is pCR.  
Patients who do not exhibit recurrence or death will be censored at their last tumor assessment.  
The safety profiles of the study will be assessed through summaries of adverse events (AEs), serious 
adverse events (SAEs), AEs leading to treatment discontinuation, and treatment-related death. All patients 
who receive at least 1 dose of treatment will be included in the analysis for safety. The safety analysis will 
report the frequency of all AEs and laboratory abnormalities, as well as the frequency of dose interruptions, 
dose reductions, and treatment discontinuation for toxicity. Toxicity rates will be presented using the worst 
NCI CTCAE grade per patient. 


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10 
Protocol amendments, or changes in study conduct 
Any change or addition (excluding administrative) to this protocol requires a written protocol amendment that 
must be reviewed by Novartis and the investigator before implementation. Amendments significantly 
affecting the safety of subjects, the scope of the investigation or the scientific quality of the study require 
additional approval by the IRB at each study center.  A copy of the written approval of the IRB must be 
provided to Novartis. Examples of amendments requiring such approval are: 
1. increases in drug dose or duration of exposure of subjects, 
2. significant changes in the study design (e.g. addition or deletion of a control group), 
3. increases in the number of invasive procedures, 
4. addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being taken by the 
investigator or by Novartis in the interests of preserving the safety of all patients included in the trial.  If an 
immediate change to the protocol is felt to be necessary by the investigator and is implemented for safety 
reasons Novartis must be notified and the IRB at the center must be informed immediately.   Amendments 
affecting only administrative aspects of the study do not require formal protocol amendments or IRB approval 
but the IRB must be kept informed of such administrative changes. Examples of administrative changes not 
requiring formal protocol amendments and IRB approval include: 
1. 
changes in the staff used to monitor trials  
2. 
minor changes in the packaging or labeling of study drug. 
 


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11 
References: 
1. Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an adjuvant 
treatment in operable breast cancer. New England J Med, 294:405-10, 1976. 
 
2. Henderson C, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential paclitaxel 
but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with 
node-positive primary breast cancer. J of Clinical Oncology. 21:976-83, 2003. 
 
3. Roche H, Fumoleau P, Spielman M, et al. Five years analysis of the PAC01 trial: 6 cycles of FEC 
100 vs. 3 cycles of FEC 100 followed by 3 cycles of docetaxel for the adjuvant treatment of node 
positive breast cancer. J Clinical Oncology, 24:564-71, 2006. 
 
4. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. 
New England J Med, 358:1663-71, 2008. 
 
5. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern 
chemotherapy for patients with node-positive breast cancer. JAMA, 295:1658-67, 2006. 
 
6. Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: A critical review. J Clinical Oncology, 
26:2568-81, 2008. 
 
7. Boulay A, Lane HA (2007) The mammalian target of rapamycin kinase and tumor growth inhibition. 
Recent Results Cancer Res. 2007;172:99-124. 
 
8. Cohen HT, McGovern FJ (2005) Renal Cell Carcinoma. N Engl J Med; 353(23):2477-90. 
 
9. Bjornsti MA, Houghton PJ (2004) The TOR Pathway: A target for Cancer therapy. Nat Rev Cancer; 
4(5):335-48. 
 
10. Frattini M, Signoroni S, Pilotti S (2005) Phosphatase protein homologue to tensin expression and 
phosphatidylinositol-3 phosphate kinase mutations in colorectal cancer. Cancer Res; 65(23):11227. 
 
11. 11 Goel A, Arnold CN, Niedzwiecki D, et al (2004) Frequent inactivation of PTEN by promoter 
hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res; 
64(9):3014-21. 
 
12. Cisplatin Package Insert 
 
13. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in 
independent gene expression data sets. Proc Natl Acad Sci U S A, 100:8418-23, 2003. 
 
14. Matros E, Wang ZC, Lodeiro G, Miron A, Iglehart JD, Richardson AL. BRCA1 promoter methylation 
in sporadic breast tumors: relationship to gene expression profiles. Breast Cancer Research and 
Treatment, 91:179-86, 2005. 
 
15. Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer, 
4:814-9, 2004. 
 


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16. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish 
tumor subclasses with clinical implications. Proc Natl Acad Sci U S A, 98:10869-74, 2001. 
 
17. Garber JE, Richardson AL, Harris LN, et al. Neo-adjuvant cisplatin (CDDP) in "triple-negative" 
breast cancer (BC). 29th Annual San Antonio Breast Cancer Symposium 2006; abstract 3074.  
 
18. Byrski T, Gronwald J, Huzarski T, et al. Response to neo-adjuvant chemotherapy in women with 
BRCA1-positive breast cancers. Breast Cancer Research and Treatment, 108:289- 96, 2008. 
 
19. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in 
patients with triple-negative breast cancer. Journal of Clinical Oncology, 26:1275-81, 2008. 
 
20. De Laurenzi V, Costanzo A, Barcaroli D, et al. Two new p73 splice variants, gamma and delta, with 
different transcriptional activity. J Exp Med, 188:1763-8, 1998.  
 
21. Lamb J, Crawford ED, Peck D, et al. The Connectivity Map: Using gene-expression signatures to 
connect small molecules, genes, and disease. Science, 313:1929-35, 2006. 
 
22. Yeo W, Lam KC, Zee B, et al. (2004) Hepatitis B reactivation in patients with hepatocellular 
carcinoma undergoing systemic chemotherapy. Annals of Oncology 15: 1661-1666 
 
23. Loomba R, Rowley A, Wesley R, et al (2008). Systematic review: the effect of preventive lamivudine 
on hepatitis B reactivation during chemotherapy. Ann Intern Med 148(7): 519-28. 
 
24. Krishna G, Moton A, Lei Ma L, Savant I, Martinho M, Seiberling M, McLeod J. Effects of oral 
posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: A phase I, 
randomized, open-label, crossover study in healthy volunteers. Clinical Therapeutics, 2009;  31: 
286-98 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12 
Appendices  
Appendix A: ECOG/ Karnofsky Performance Status Criteria 
 
 
 
 
 
 


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Appendix B: New York Heart Association (NYHA) Classifications 
 
This table is an excerpt from the Oxford Textbook of Medicine, 2nd ed. Oxford; New York: Oxford University Press, 1987, p. 2228. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix C: Version 4.0 (dated June-14-2010) 
 
 
13 
CTCAE Files 
NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4 data files and related documents 
are published here. The most current release files appear in this directory:  
Files: Booklet 
 
Content 
CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
Most recent release of core terminology: PDF document, 
traditional small booklet format. 
 
 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NOVARTIS, TMHRI&TMHCC                                         Everolimus Clinical Protocol                                                 Page 46 
          
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Appendix D: WOCBP & Determination of Menopausal Status 
 
WOCBP 
Women of childbearing potential and men must agree to use adequate contraception (one of the following 
listed below) prior to study entry, for the duration of study participation and up to 90 days following 
completion of therapy.  Additionally, male subjects (including those who are vasectomized) whose partners 
are pregnant or might be pregnant must agree to use condoms for the duration of the study and for 90 days 
following completion of therapy. 
● Total abstinence from sexual intercourse (minimum one complete menstrual cycle). 
● Vasectomized male subjects or vasectomized partner of female subjects. 
● Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study drug 
administration. 
● Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal 
jellies or cream). 
● Intrauterine device (IUD). 
 
 
The following criteria will be used in the NECTAR trial to define postmenopausal: 
 
Age 56 or older with no spontaneous menses for at least 12 months prior to study entry;  
Or 
 
Age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., 
spontaneous or secondary to hysterectomy) and with a documented estradiol level in the 
postmenopausal range according to local institutional/laboratory standard;  
Or 
 
Documented bilateral oophorectomy. 
 
Women failing to meet one of these criteria will be classified as pre-menopausal. 
 
 
 
 
 
 


NOVARTIS, TMHRI&TMHCC                                         Everolimus Clinical Protocol                                                 Page 47 
          
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Appendix D:  Trial Logistics 
No. of Centers:   
Key Milestones: 
FPFV / First Dose: With documented Residual Disease after Ne0-Adj standard treatment 
LPLV / Last Subject completed:   Sep/2014 
Database Lock: Nov/2014 
Final Report: Jan/2015 
 
Sponsoring Department: 
TMHCC ________TMHRI ________TMHS________ 
 
Prepared by: _________________________________ Date ___________