Clinical trial NCT01665768
Conditions: CD20+, B-cell Lymphomas Mantle Cell Lymphoma Non-Mantle Cell Low Grade B Cell Lymphomas (SLL/CLL) Transformed Lymphoma/DLBCL/PMBCL Hodgkin's Disease Gray Zone Lymphoma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2012-09-01; Completion date: 2020-08-01
Enrollment: 56 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research is being done to determine if combining an investigational drug called Everolimus with Rituximab can reduce the risk of your cancer from returning after high dose chemotherapy.

Detailed description:
Everolimus is a pill that interferes with lymphoma cell growth by blocking a cellular pathway important in causing cancer cells to grow, called mTor. Rituximab is an intravenous medication that specifically attacks a protein commonly found on lymphoma cells called CD20.

Rituximab is already widely used to treat multiple forms of lymphoma. Moreover, continuing rituximab after the completion of chemotherapy is already commonly used to help patients stay in remission longer. Everolimus has been shown in many types of relapsed lymphoma to decrease the size of lymph nodes by itself. Everolimus is approved by the Food and Drug Administration (FDA) for the treatment of advanced kidney cancer and subependymal giant cell astocytoma. It is not approved for use in lymphoma. The use of everolimus in this research study is investigational. The word "investigational" means that everolimus is not approved for marketing by the Food and Drug Administration (FDA). The FDA is allowing the use of everolimus in this study.

The combination of everolimus and rituximab for 1 year after high dose therapy is also new. We believe the combination of these medications right after your chemotherapy will be more effective in attacking your remaining cancer before they have time to re-grow.

The usual treatment of lymphoma after high-dose chemotherapy is observation. After your body has fully recovered from the effects of the chemotherapy, you will receive everolimus daily for one year and IV rituximab four times during that year.

Arms: arm 1: Everolimus daily for one year and IV rituximab four times during that year.
Interventions: intervention 1: Everolimus intervention 2: Rituximab
Intervention descriptions: intervention 1: The initial dose of everolimus will be 2.5mg orally daily for a total of one year to maintain a target trough concentration between 3-15 ng/mL. intervention 2: 375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions)

Protocol documents:
Prot_SAP_000.pdf: 
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A Trial of maintenance Rituximab with mTor inhibition after High-dose 
Consolidative Therapy in CD20+, B-cell Lymphomas, Gray Zone Lymphoma, 
and Hodgkin’s Lymphoma 
 
Principal Investigator:   
Douglas E. Gladstone, MD 
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
1650 Orleans Street, CRBI-287 
Baltimore, MD 21287 
Phone: 410-955-8781 
     Fax: 410-614-1005 
Email:  dgladst1@jhmi.edu 
 
IRB Protocol Number:  NA_00067315 
Study Number:  J1228 
IND Number:  EXEMPT 
Novartis Protocol Number: CRAD001NUS157T 
 
Version:  May 7, 2018 
 
Co-Investigators: 
 
 
Jonathan Powell 
 
1650 Orleans Street, CRBI-443 
 
Phone:  410-502-7887 
 
Fax:  443-287-4653 
 
Email:  poweljo@jhmi.edu 
 
 
 
Richard Jones 
 
1650 Orleans Street, CRBI-244 
 
Phone:  410-955-2006 
 
Fax:  410-614-7279 
 
Email:  rjjones@jhmi.edu 
 
 


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Satish Shanbhag 
Johns Hopkins Bayview Medical Center  
301 Building, Suite 4500  
4940 Eastern Ave  
Phone: 410-550-4061  
Fax: 410-550-5445  
Email:  shanbhag@jhmi.edu 
 
Statisticians: 
 
Gary Rosner 
 
Phone:  410-955-4884 
 
Email:  grosner1@jhmi.edu 
 
 
Marianna Zahurak 
 
Phone:  410-955-4219 
 
Email:  zahurma@jhmi.edu 
 


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Table of contents 
Table of contents ......................................................................................................................... 3 
List of abbreviations ................................................................................................................... 5 
Schema ........................................................................................................................................ 7 
1 
Introduction ................................................................................................................... 8 
1.1 
Everolimus ...................................................................................................................... 8  
 
1.1.1.....mTOR pathway and mechanism of action ......................................................... 8 
 
1.1.2….Preclinical studies ............................................................................................ 12 
 
1.1.3….Clinical experience with Everolimus ............................................................... 15 
1.2 
Hopkins Experience of High-dose consolidative therapy for low grade B cell and 
Hodgkin's lymphoma .................................................................................................... 16 
2 
PrimaryStudy Objective ............................................................................................. 17 
2.1 
Secondary Objectives .................................................................................................... 17 
3 
Investigational plan ..................................................................................................... 18 
3.1 
Overall study design ..................................................................................................... 18 
3.2 
Study population ........................................................................................................... 18 
 
3.2.1....Patient population ............................................................................................. 19 
 
3.2.2....Inclusion and exclusion criteria ........................................................................ 19 
 
3.2.3....Study Interruption or Study Withdrawal ........................................................... 20 
 
3.2.4....Monitoring of everolimus suspected toxicities ................................................. 20 
 
3.2.5....Known Undesirable Side Effects of everolimus ............................................... 20 
3.3 
Treatments..................................................................................................................... 22 
 
3.3.1....Everolimus Administration ............................................................................... 22 
            3.3.2....Concomitant therapy ......................................................................................... 23 
 
3.3.3....Treatment compliance ....................................................................................... 23 
3.4 
Visit schedule and assessments ..................................................................................... 24 
 
3.4.1....Visit schedule:  Examination and Laboratory Evaluations ............................... 24 
 
3.4.2...Study Calendar...................................................................................................24 
 
3.4.3...Efficacy assessments .......................................................................................... 28 
 
3.4.4....Safety assessments ............................................................................................ 29 
 
            3.4.4.1....Adverse Events .................................................................................. 29 
 
            3.4.4.2....Serious Adverse Events ..................................................................... 30 
 
3.4.5....Novartis instructions for rapid notification of serious adverse events .............. 32 
 
3.4.6....Pregnancy Risks for Everolimus ....................................................................... 32 
4 
Protocol amendments, or changes in study conduct ................................................ 33 


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5 
Data management ....................................................................................................... 33 
5.1 
Data collection .............................................................................................................. 33 
5.2 
Data Safety and Monitoring Plan .................................................................................. 33 
6 
Statistical Considerations ........................................................................................... 34 
7 
References .................................................................................................................... 38 
Addendum 1: Inhibitors of CYP3A4 and/or PgP ..................................................................... 41 
Addendum 2: Inducers of CYP3A4 and/or PgP ....................................................................... 42 
Addendum 3: Clinically relevant drug interactions .................................................................. 43 
Addendum 4: Dose Modifications  ........................................................................................... 46 
Addendum 5: Management of stomatitis .................................................................................. 47 
Addendum 6: Management of hyperlipidemia and hyperglycemia .......................................... 48 
Addendum 7: Management of non-infectious pneumonitis ...................................................... 49 
Addendum 8: Action to be taken for positive baseline hepatitis B results............................. .. 50 
Addendum 9: Guidelines for management of hepatitis B...................................................... ... 51   
 
 
 
 
 


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List of abbreviations  
4E-BP1 
4E-binding protein 
Ab 
Antibodies 
ADR 
Adverse Drug Reaction 
AE 
adverse event 
ALT/SGPT 
1 
alanine aminotransferase/glutamic pyruvic 
transaminase/Serum glutamic-pyruvic transaminase 
AST/SGOT 
aspartate aminotransferase/glutamic oxaloacetic 
transaminase/Serum glutamic-oxaloacetic transaminase 
ATC 
Anatomical Therapeutic Chemical classification system 
AUC 
Area under the plasma-concentration time curve 
BAC 
Bronchoalveolar carcinoma 
Cmax 
Maximum plasma concentration 
CR 
Clinical research 
CRF 
Case report/Record form 
CRO 
Contract Research Organization 
CT 
Computer tomography 
CTC 
Common toxicity criteria 
CV 
Coefficient of Variation 
CYP3A4 
CytochromeP450 3A4 isoenzyme 
DNA 
DLT 
Deoxyribonucleic Acid 
Dose limiting toxicity 
ECG 
Electrocardiogram 
EGF 
Epidermal growth factor 
EGFR 
Epidermal growth factor receptor 
eIF-4E 
Eucariotic Initiation Factor 4E 
EPR 
Early progression rate 
FDG-PET 
Fluorine-18-2-fluoro-Deoxy-D-Glucose Positron Emission Tomography 
FKBP-12 
FK506-binding protein 12 
GF 
Growth factor 
HBV 
hepatitis B virus 
HBcAb 
hepatitis B core antibodies 
HBs Ab 
hepatitis B surface antibodies 
HbsAg 
hepatitis B surface antigen 
HCV 
INR 
hepatitis C virus 
International Normalized Ratio 
 


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LDL 
Low-density lypoproteins 
LFTs 
liver function tests 
LLOQ 
Lower limit of quantification 
MAPK 
Mitogen Activated Protein Kinase 
mRNA 
messenger Ribonucleic acid 
mTOR 
mammalian Target of Rapamycin 
NIH/NCI 
National Institutes of Health/National Cancer Institute 
nM 
nano-molar 
NSCLC 
Non-small cell lung cancer 
OS 
overall survival 
P-AKT 
phosphor-AKT 
PCR 
Polymerase Chain Reaction  
PD 
Pharmacodynamics 
PET 
Proton emission tomography 
PFS 
progression free survival 
P-gp 
P-glycoprotein 
PI3K 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetics 
PK/PD 
Pharmacokinetic/pharmacodynamic  
PT/PTT 
prothrombin time 
PTEN 
QOD 
Phosphatase and Tensin homolog deleted on chromosome 10 
Every other day 
RBC 
red blood cell count 
REB 
Research Ethics Board 
RNA 
Ribonucleic acid 
RR 
response rate 
S6K1 
S6 kinase 1 
SAE 
serious adverse event 
SCLC 
Small cell lung cancer 
STAT3 
Signal Transducer and Activator of Transcription 3 
TK 
Tyrosine kinase 
TSC2 
Tuberous Sclerosis Complex 2 
TUNNEL 
Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin 
Nick End Labeling 
ULN 
Upper limit of normal 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
total white blood cell count 


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WHO 
World Health Organization 
 
 
SCHEMA 
 
Diagnosis of CD20+, B cell Lymphoma, Gray Zone Lymphoma, 
or Hodgkin’s Lymphoma 
 
 
Standard Therapy 
 
 
High-dose Consolidation Therapy 
 
 
Registration for This Protocol 
 
 
 
Evaluation of Eligibility for Protocol Participation 
 
 
6 to 10 weeks after Initiation of High-dose Consolidation 
Therapy for Maintenance Rituximab and Everolimus for 1 year 
 
 
Treatment Evaluations with Radiographs, standard laboratories 
and examination for 3 years/correlative peripheral blood 
studies for 3 years 


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Follow-Up for 2 additional years to assess survival/disease status 
only 
 
1.0 
Introduction 
1.1 
Everolimus (RAD001) 
Everolimus (RAD001) is a novel oral derivative of rapamycin. Everolimus has been in 
clinical development since 1996 as an immunosuppressant in solid organ transplantation and 
has obtained marketing authorization (Certican®) for prophylaxis of rejection in renal and 
cardiac transplantation in a number of countries, including the majority of the European 
Union. Everolimus has been in development for patients with various malignancies since 
2002. Everolimus 2.5mg, 5mg and 10mg tablets were  approved under the trade name 
Afinitor® for patients with advanced renal cell carcinoma (RCC) after failure of treatment 
with Sutent® (sunitinib) or Nexavar® (sorafenib) in the US, EU and several other countries 
and is undergoing registration in other regions worldwide.   Afinitor® was also approved in 
2010 for the treatment of patients with subependymal giant cell astrocytoma (SEGA) 
associated with tuberous sclerosis (TS) who require therapeutic intervention but are not 
candidates for curative surgical resection.  Affinitor ® received approval for the treatment of 
postmenopausal women with advance hormone receptor-positive, HER2-negative breast 
cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with 
letrolzole or ansastrozole. 
 
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 HIF-1 activity, VEGF production and VEGF-induced proliferation 
of endothelial cells). The role of angiogenesis in the maintenance of solid tumor growth is 
well established, and the mTOR pathway has been implicated in the regulation of tumor 
production of proangiogenic factors as well as modulation of VEGFR signaling in 
endothelial cells. 
At weekly and daily schedules and at various doses explored, RAD0001 is generally well 
tolerated. The most frequent adverse events (rash, mucositis, fatigue and headache) 
associated with everolimus therapy are manageable. Non-infectious pneumonitis has been 
reported with mTOR inhibitors but is commonly low-grade and reversible. 
 
1.1.1 mTOR pathway and mechanism of action 


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The mammalian target of rapamycin (mTor): The mammalian target of rapamycin 
(mTOR) has emerged as a critical regulator of the malignant phenotype in human cancers.1  
“The mTOR protein is a serine-threonine kinase…central to a complex intracellular 
signaling pathway and is involved in a number of important processes such as cell growth 
and proliferation, cellular metabolism, autophagy, and angiogenesis. It responds to signals 
from the extracellular environment such as nutrient and growth factor supply, energy, and 
stress. Signaling through the pathway is promoted when there is an abundance of nutrients 
or energy and is down regulated in states of depletion and stress.”2  “mTOR exists within 
the cell complexed to the proteins involved in either raptor [TORC1 pathway] or rictor 
[TORC2 pathway]. The mTOR/rictor protein complex is [less] responsive to inhibition by 
rapalogs and will not be discussed in detail except to mention its interaction with 
mTOR/raptor.”2  The TORC1 pathway “can be activated by various stimuli through 
different upstream molecules. After stimulation, PI3K initiates a cascade that ultimately 
results in the phosphorylation and activation of Akt [T308]. Akt then acts via the tuberous 
sclerosis complex (TSC), consisting of the proteins TSC1 and TSC2, to exert its effect on 
mTOR. Phosphorylation of TSC2 by Akt inhibits TSC2, thereby releasing the inhibition that 
TSC2 otherwise exerts on mTOR via inhibition of Rheb, an activator of mTOR.”2 
Downstream of [TORC1 pathway] are two main effectors, S6K1 and 4E-BP1, both of which 
control the translation of specific mRNAs and the synthesis of particular proteins.2 
Phosphorylation of 4E-BP1 by mTOR ultimately results in the initiation of translation of 
certain mRNAs that have regulatory subunits in the 5'-untranslated terminal regions, 
including those that are needed for cell cycle progression and are involved in cell cycle 
regulation. Phosphorylation and activation of S6K1 are also involved in cell growth and 
proliferation, possibly via translation of mRNAs that have a terminal 5'-oligopyrimidine 
tract such as those that encode ribosomal proteins and elongation factors.  Importantly, 
S6K1 also has an inhibitory feedback function on the pathway by phosphorylating and 
inhibiting insulin receptor substrate-1, thus reducing growth factor–stimulated signaling 
through PI3K/Akt/mTOR. It also phosphorylates and inactivates BCL2 antagonist of cell 
death (BAD), a proapoptotic molecule. The numerous proteins whose translation is 
regulated through mTOR and its downstream targets include cyclin D1, MYC avian 
myelocytomatosis viral oncogene homolog (c-MYC), and hypoxia-inducible factor-l  (HIF-
1 ).”2 
 


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2 
 
 
 
Inhibitors of the mTor Pathway: “Inhibitors of the [mTORC1] pathway include sirolimus, 
temsirolimus, everolimus, and deferolimus. Sirolimus and the rapalogs exert their effects by 
the same mechanism. Each drug binds to the intracellular binding protein FK506-binding 
protein (FKBP12) to form a complex, which then binds to mTOR at the FKBP12–
rapamycin binding domain, interfering with its ability to signal adequately to its 
downstream effectors. Exactly how the sirolimus–FKBP12 complex interrupts mTOR 
signaling is not known, but it may involve a destabilization of the interaction between 
mTOR and raptor.”2   
 
Rituximab can act synergistically with mTOR inhibition: The SP49 cell line (a cell line 
established from MCL) which is sensitive to rituximab showed the combination of 
rituximab with Everolimus to produce a very strong synergistic effect on proliferation 
inhibition.3  In NHL mTORCH1 inhibitors have in-vitro synergy with rituximab.4  
 
Cancer Stem Cells: “Increasing data from several human cancers suggest that neoplastic 
cells within individual tumors are functionally heterogeneous cells despite their clonal 


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origins. In particular, the potential for long-term proliferation appears to be restricted to 
subpopulations of “cancer stem cells” functionally defined by their capacity to undergo self-
renewal and give rise to differentiated cells that phenotypically recapitulate the original 
tumor.”5  Although most low grade B cell and MCL patients respond to initial treatment, 
disease relapse is virtually universal even after autologous stem cell transplantation.6-11  The 
precise factors involved in tumor re-growth are unknown, but we have recently found that 
tumorogenic potential is restricted to distinct populations of MCL cells or MCL cancer stem 
cells.12  We contest that novel agents should be introduced that focus on the cancer stem 
cell. 
 
mTor and Mantle Cell Lymphoma (MCL): MCL cells have a distinct cytogenetic 
translocation t(11;14) which juxtaposes the cyclin D1 gene under the control of the 
immunoglobulin enhancer.  The cyclins in general promote proliferation by interacting with 
the cyclin-dependent kinases and cyclin D1 appears to play a role in enhancing the 
proliferative capacity of MCL cells.  Dysregulation of the cell cycle inhibitor p27 has also 
been implicated in MCL.  In addition, MCL cells demonstrate defects in apoptosis further 
contributing to the growth advantage of this cancer. From a cell signaling perspective, the 
PI3-kinase/AKT/mTOR pathway has been implicated in driving gene expression in MCL.  
 
Furthermore, our preliminary data suggest that this pathway is important for growth and 
survival of Aldehyde high MCL stem cells. Not surprisingly, these pathways play a role in 
promoting the expression of the cyclins, degrading p27 and promoting survival over 
apoptosis.  In this regard there have been several clinical trials demonstrating activity of 
mTOR inhibitors in MCL.  Data on the efficacy and safety of temsirolimus an intravenous 
mTOR inhibitor, as a single agent in patients with relapsed or refractory MCL have been 
published.13   
 
Thirty-five patients were treated with temsirolimus 250mg intravenously every week as a 
single agent. Patients had previously received a median of 3 prior therapies and 54% had 
been refractory to the last therapy. The overall response rate was 38% (95% CI: 22% to 
56%), with one complete response and 12 partial responses. Median time to progression was 
6.5 months (95% CI: 2.9 to 8.3 months). Hematologic toxicities were the most common: 
Grade 3 for 71% of the patients (25/35) and Grade 4 for 11% of the patients (4/35). 
Thrombocytopenia was the most frequent reason for dose reductions but typically resolved 
within 1 week. Non-hematologic toxicities of all grades included hyperglycemia (91%), 
increased triglycerides (77%), mucositis (71%), fatigue (66%), infections without 
concomitant neutropenia (63%), rash (51%), nausea (49%), AST elevations (43%), 
hypercholesterolemia (40%) and sensory neuropathy (37%). The authors concluded that 
“single-agent temsirolimus has substantial antitumor activity in relapsed MCL.”   
mTor and follicular cell lymphoma and CLL: Preclinical models demonstrate that the 
mTOR pathway is aberrant in many lymphoma subtypes, including follicular lymphoma. In 
follicular lymphoma, activated mTOR was necessary for malignant cell survival in contrast 
to normal cells derived from activated tonsillar tissue.14 In murine models, Akt 
overexpression confers an aggressive and drug-resistant phenotype that is reversed by 


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mTOR inhibition.15  54 patients with relapsed aggressive follicular and CLL received 
temsirolimus 25mg weekly for 2 months.  Three (5%) had grade III/IV pulmonary toxicity 
with temsirolimus pneumonitis.  Follicular cell patients had a complete response rate of 
25.6% and CLL patients had a partial response rate of 11%.16 
 
Possible Class effect of mTOR inhibition during ablative BMT: Sirolimus during 
ablative allogeneic bone marrow transplant increases the risk of veno-occlusive disease of 
the liver from 7.4% to 15.8%.17 
 
1.1.2 Pre-clinical studies: Everolimus acts as an inhibitor of interleukin and growth-factor-
dependent proliferation of cells. The only currently known target of everolimus is mTOR, a 
key regulatory protein affecting cell growth.18 Everolimus exerts its activity through high 
affinity interaction with an intracellular receptor protein, the immunophilin FKBP12. The 
FKBP12/everolimus complex subsequently interacts with the mTOR protein kinase, 
inhibiting downstream signaling events involved in regulation of the G1 to S-phase 
transition.  
The main known functions of mTOR include: 
• Function as a sensor of mitogens, growth factors, energy and nutrient levels, facilitating 
cell-cycle progression from G1 - S phase in appropriate growth conditions. 
• Regulation of protein synthesis important for tumor cell proliferation and angiogenesis 
through inactivating eukaryotic initiation factor 4E binding proteins and activating the 40S 
ribosomal S6 kinases (e.g. p70S6K1). For example, activation of the mTOR pathway leads 
to a) increased production of pro-angiogenic factors (e.g. VEGF) in tumors b) tumor, 
endothelial and smooth muscle cell growth and proliferation. 
The PI3K-mTOR pathway itself is frequently activated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors. The regulation of 
mTOR signaling is complex and involves positive regulators such as AKT that 
phosphorylate and inactivate negative regulators such as the Tuberous Sclerosis Complex 
(TSC1/TSC2). In summary, mTOR has pleiotropic functions; hence, the activities of 
everolimus may vary depending upon cell type. 
The mTOR inhibitory activities presumably contribute to the antiproliferative activity of 
everolimus against tumor cell lines. However, everolimus may also exert an antitumor effect 
through the inhibition of angiogenesis. Indeed, both rapamycin and everolimus potently 
inhibit proliferation of endothelial cells19 and have antiangiogenic activity in vivo.19,20 
Exactly which molecular determinants predict responsiveness of tumor cells to everolimus 
is still unclear. Currently, the activation status of the PI3K/AKT/mTOR/p70 S6K pathway 
may be indicative of responsiveness to rapamycins. For example, pre-clinically, loss of 
PTEN or constitutive/hyper-activation of AKT has been suggested to sensitize tumors to the 
effects of inhibition of mTOR20. Also, clinically, it has been suggested that high p70S6K 
activation in baseline GBM tumor samples may predict a patient population more likely to 
derive benefit from mTOR inhibition.21 
 


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The antiproliferative effects of everolimus were investigated in a mixed panel of 48 
different tumor cell lines (including breast, colon, epidermoid, glioblastoma, lung, 
melanoma, prostate and renal). The majority of tumor cell lines were highly sensitive to the 
anti-proliferative effects of everolimus while a few others appeared intrinsically insensitive, 
or ‘resistant’ (IC50 range 0.2 to 4125 nM).22 The median IC50 value of the 48 cell lines was 
0.5 nM. Similar findings have been observed for rapamycin.23 Everolimus was also shown 
to have activity in in acute myeloid leukemia cells,24 mantle cell lymphoma cells,3 adult T-
cell leukemia cells,25 diffuse large B cell lymphoma cells.4  
Everolimus was also evaluated in a clonogenic assay using cells derived from 81 patient 
derived tumor xenografts never cultured in vitro (11 human tumor types with 3 to 24 tumors 
each: bladder, colon, gastric, NSCLC, SCLC, breast, ovary, pancreatic, renal, melanoma, 
and pleuramesothelioma). Everolimus inhibited colony formation in a concentration-
dependent manner (mean IC50: 175 nM). In addition, normal hematopoietic stem cells were 
found to be relatively insensitive to everolimus, with an IC50 about 15 fold higher than the 
tumor lines. 
Everolimus is a highly specific inhibitor of mTOR, which is afforded by high-affinity 
binding to the protein FKBP-12 (IC50 of 5.3 nM) similar to that of rapamycin. Similar 
potency of rapamycin and everolimus was also demonstrated at forming the mTOR / FKBP-
12 tertiary complex in vitro. Specificity was demonstrated by a lack of inhibitory activity 
against 10 other protein kinases at concentrations up to 10 μM. The antiproliferative effects 
of everolimus were investigated in a mixed panel of 48 different tumor cell lines (including 
breast, colon, epidermoid, glioblastoma, lung, melanoma, prostate and renal).  
Everolimus was also shown to have activity in human pancreatic neuroendocrine cells, 
where induction of apoptosis was reported,26 as well as in acute myeloid leukemia cells,24 
mantle cell lymphoma cells,3 adult T-cell leukemia cells,25 diffuse large B cell lymphoma 
cells,4 pancreatic tumor cells,27 ovarian cancer cells20,28 and hepatocellular carcinoma 
cells.29 Everolimus was also evaluated in a clonogenic assay using cells derived from 81 
patient derived tumor xenografts never cultured in vitro (11 human tumor types with 3 to 24 
tumors each: bladder, colon, gastric, NSCLC, SCLC, breast, ovary, pancreatic, renal, 
melanoma, and pleuramesothelioma). Everolimus inhibited colony formation in a 
concentration-dependent manner (mean IC50: 175 nM). In addition, normal hematopoietic 
stem cells were found to be relatively insensitive to everolimus, with an IC50 about 15 fold 
higher than the tumor lines. 
 
Everolimus was effective and well tolerated against subcutaneous (s.c.) tumors established 
from a variety of tumor cell lines of diverse histotypes (NSCLC, pancreatic, colon, 
melanoma, epidermoid), including a PgP170-overexpressing, multi-drug resistant tumor 
line. Typically, the antitumor activity of everolimus was that of reduction of tumor growth 
rates rather than producing regressions or stable disease although, in the case of A549 and 
NCI-H596 lung and ARJ42 pancreatic tumors, regressions could be obtained. These effects 
occurred within the dose range of 2.5 to 10 mg/kg, p.o., once per day. The change in tumor 
volume of the treated mice divided by the change in tumor volume of control mice (T/C) 


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typically ranged from approximately 15 to 50% at optimal doses. A marked loss of 
antitumor activity occurred when tumor-bearing mice were treated with everolimus once per 
week, but improved moderately with twice per week dosing. Antitumor activity of 
everolimus has also been demonstrated in mouse models of ovarian,20 breast30 and 
gastrointestinal stromal tumors.31 
 
Pre-clinical safety: In safety pharmacology studies, everolimus was devoid of relevant 
effects on vital organ functions including the cardiovascular, respiratory and nervous 
systems. Everolimus had no effects on QT interval. Furthermore, everolimus showed no 
antigenic potential. Although everolimus passes the blood-brain barrier, there was no 
indication of relevant changes in the behavior of rodents, even after single oral doses up to 
2000 mg/kg or after repeated administration at up to 40 mg/kg/day. 
The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys, 
and rabbits. The major target organs were male and female reproductive systems (testicular 
tubular degeneration, reduced sperm content in epididymides and uterine atrophy) in several 
species; lungs (increased alveolar macrophages) in rats and mice; and eyes (lenticular 
anterior suture line opacities) in rats only. Minor kidney changes were seen in the rat 
(exacerbation of age-related lipofuscin in tubular epithelium, increases in hydronephrosis) 
and mouse (exacerbation of background lesions). There was no indication of kidney toxicity 
in monkeys or minipigs. 
Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of 
clastogenic or mutagenic activity. Administration of everolimus for up to 2 years did not 
indicate any oncogenic potential in mice and rats up to the highest doses, corresponding 
respectively to 4.2 and 0.2 times the estimated clinical exposure. In reproduction studies, 
everolimus was toxic to the conceptus in rats and rabbits, and was considered potentially 
teratogenic in rats. It is therefore recommended that women of childbearing potential should 
use highly effective contraceptive measures during the entire treatment period and for 8 
weeks thereafter.  It is not known whether everolimus is excreted in human milk. In animal 
studies, everolimus and/or its metabolites were readily transferred into the milk of lactating 
rats. Therefore women who are taking everolimus should not breastfeed. 
 
Everolimus Pharmacokinetics: Everolimus is rapidly absorbed with a median tmax of 1-2 
hours. The steady-state AUC0-τ is dose-proportional over the dose range between 5 to 70 
mg in the weekly regimen and 5 and 10 mg in the daily regimen. Steady-state was achieved 
within two weeks with the daily dosing regimen. Cmax is dose-proportional between 5 and 
10 mg for both the weekly and daily regimens. At doses of 20 mg/week and higher, the 
increase in Cmax is less than dose proportional. In healthy subjects, high fat meals reduced 
systemic exposure to everolimus 10 mg (as measured by AUC) by 22% and the peak plasma 
concentration Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax by 42%. 
Food, however, had no apparent effect on the post absorption phase concentration-time 
profile. 
 


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The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range 
of 5 to 5,000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is 
approximately 20% at blood concentrations observed in cancer patients given everolimus 10 
mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in 
patients with moderate hepatic impairment.  
 
Everolimus is a substrate of CYP3A4 and a substrate and moderate inhibitor of PgP. 
Following oral administration, everolimus is the main circulating component in human 
blood and is considered to contribute the majority of the overall pharmacologic activity.  No 
specific excretion studies have been undertaken in cancer patients; however, data available 
from the transplantation setting found the drug to be mainly eliminated through the feces. 
There was a significant correlation between AUC0-τ and pre-dose trough concentration at 
steady-state on the daily regimen. The mean elimination half-life of everolimus is 
approximately 30 hours. 
 
1.1.3 Clinical Experience with Everolimus: Everolimus has been in clinical development 
since 1996 as an immunosuppressant in solid organ transplantation and was approved in 
Europe in 2003 under the trade name Certican®, for the prevention of organ rejection in 
patients with renal and cardiac transplantation. Additional non-oncologic indications 
currently being explored are wet age-related macular degeneration (AMD) and autosomal 
dominant polycystic kidney disease (ADPKD).  
In oncology, everolimus has been in clinical development since 2002 for patients with 
various hematologic and non-hematologic malignancies as a single agent or in combination 
with antitumor agents. Malignancies that are currently being evaluated in Novartis 
sponsored studies include the following: metastatic renal cell carcinoma (mRCC), breast 
cancer, gastroenteropancreatic neuroendocrine tumors (GEP-NET), mantle cell lymphoma 
and diffuse large B cell lymphoma (DLBCL), hepatocellular cancer (HCC), gastric cancer, 
and lung cancer. In addition, treatment of patients with Tuberous Sclerosis Complex (TSC) 
associated subependymal giant cell astrocytoma (SEGA) and Angiomyolypoma is also 
being evaluated. 
Everolimus 2.5 mg, 5mg and 10mg tablets were approved under the trade name Afinitor® 
for patients with advanced renal cell carcinoma (RCC) after failure of treatment with 
Sutent® (sunitinib) or Nexavar® (sorafenib)  in the US, EU and several other countries and 
is undergoing registration in other regions worldwide.  Afinitor®® was also recently 
approved in the US for the treatment of patients with subependymal giant cell astrocytoma 
(SEGA) associated with tuberous sclerosis (TS) who require therapeutic intervention but are 
not candidates for curative surgical resection.   Affinitor ® received approval for the 
treatment of postmenopausal women with advance hormone receptor-positive, HER2-
negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of 
treatment with letrolzole or ansastrozole. 
 


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Phase I dose escalating studies, exploratory Phase I/II studies with everolimus as single 
agent or in combination with other anti-cancer agents, Phase II/III studies of everolimus in 
indications, and Phase III double-blind studies are contributing to the extensive database. 
Approximately 35,982  cancer patients have been treated with everolimus as of 31-March-
2014: 
 
19,668 patients in Novartis-sponsored clinical trials 
 
2,394 patients in the individual patient supply program 
 
More than 13,930 patients in investigator-sponsored studies 
 
In addition, healthy volunteers have participated in the clinical pharmacology studies 
as described in Section 7.2 of the Investigator’s Brochure 
 
Clinical Experience of Everolimus in lymphoma: everolimus, an oral mTOR inhibitor, 
was tested at 10 mg qd in a Phase II study for patients with a number of different types of 
relapsed or refractory lymphomas – including aggressive, indolent and uncommon 
lymphomas32,33 . Thirty-seven (37) patients were treated in the aggressive lymphoma group 
- 20 (54%) with diffuse large B-cell (DLBC), 14 (38%) with MCL, 2 high grade, and 1 
follicular grade III. Patients were eligible to enter if they had measurable disease and had 
met the following hematologic parameters: ANC ≥ 1.0 x 109/L, platelets ≥ 75.0 x 109/L and 
hemoglobin ≥ 8 g/L. The median age was 72 years (range, 45-92). Patients had previously 
received a median of 4 prior therapies (range, 1-15). Prior stem cell transplant was allowed. 
The median treatment duration with Everolimus was 2 cycles (range 1-16+). The overall 
response rate was 32% (12/37; 95% CI: 20-49%) with 1 complete response and 11 partial 
responses. The overall response rate in the MCL patients was 29% (4/14); including one 
who received Everolimus for more than 14 cycles, while maintaining PR. The median time 
to progression for all 37 patients was 3.7 months (95% CI: 2.1 - 8.7). The median duration 
of response for the 12 responders was 5.5 months (95% CI: 2.3 - 9.2). Three patients are 
currently maintaining a response with a median of 10.5 months (2.9-15.6+ months). 
Everolimus was well tolerated. The incidence of grade 3 anemia, neutropenia, and 
thrombocytopenia in this heavily pretreated patient population was 11%, 16%, and 30%, 
respectively. Two patients developed grade 4 neutropenia. Grade 2 hypercholesterolemia 
occurred in 11%; grade 2 hyperglycemia in 16%; grade 3 hyperglycemia in 11% of the 
patients. One patient had grade 4 hypertriglyceridemia.  
 
In the treatment of relapsed Hodgkin’s disease, everolimus dosed at 10mg daily on a 
monthly cycle, the ORR was 47%.  Ten of 19 patients had dose reductions or treatment 
delays.  The median number of cycles at 10mg daily was five (range 1-20). 
 
Everolimus serum levels are commercially available 
 Quest Diagnostics (18883X) CPT code 80299, Mon-Fri 
 Target trough concentrations 3-15 ng/mL 
 
1.2 Hopkins experience of high-dose consolidative therapy with low grade B cell and 
Hodgkin’s lymphoma. 


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The Sidney Kimmel Comprehensive Cancer center has pioneered the concept of high-dose 
cyclophosphamide without stem cell rescue for over a decade.  This high-dose consolidative 
treatment was developed for two main reasons. 
 
It does not require stem cell rescue: it eliminates the potential of cancer re-
introduction at time of stem cell rescue.  Moreover, as this high-dose therapy does 
not require stem cell rescue all the components of autologous stem cell transplant: 
collection, preservation and re-infusion are eliminated making this therapy a more 
widely available treatment modality.  
 
Tolerability: not only are the majority of the patients treated with this modality 
served in the outpatient setting, many have had a performance status or advanced 
age not otherwise well suited for an autologous stem cell transplant.   
 
We put forward that the cytoreduction achieved by high-dose consolidative 
cyclophosphamide represents the ideal foundation for the integration of novel molecularly 
targeted compounds for these lymphomas. 
 
81 adults received, as outpatients, rituximab [375mg/m2 days 1, 4, 8, 11, 45, 52] and 
cyclophosphamide [50mg/kg days 15-18 with concurrent mesna] and pegfilgrastim 
(day +20).  Forty-two participants had low grade B cell lymphoma [grade I/II 
follicular (69%), transformed lymphoma (17%), other (15%)]: 45% were treated 
without measurable disease.  Thirty-nine had mantle cell lymphoma: 82% were 
treated without measurable disease.  All achieved hematopoietic recovery; 46% 
required brief hospitalizations.  The EFS for low grade B cell patients at 3 and 5 
years was 49% and 40% with an overall survival (OS) at 3 and 5 years of 86% and 
72%.   The 3 and 5 year EFS for MCL patients was 57% and 39% with a 3 and 5 
year OS 92% and 62%. 
 
Hodgkin’s data: Rituximab, high dose cy, and GM-CSF based immunotherapy for 
relapsed Hodgkin's lymphoma:  This phase I/II, single-institution trial for relapsed 
classical Hodgkin lymphoma has just completed accrual of its planned 30 
patients.  Clinical outcomes of this platform, which was developed as a potentially 
less toxic alternative to autologous BMT, are encouraging.  In the first 25 patients, 
whose median time between first-line therapy completion and relapse was 12 
months, actuarial event-free survival is 79% at 1 year and 63% at 2 and 3 years 
following high-dose cyclophosphamide; overall survival is 100% at 2 years and 92% 
at 3 years.  These early results are comparable to what is seen with autologous 
BMT.  The toxicity profile has been manageable, and there has been no treatment-
related mortality.  Median time to neutrophil recovery after high dose 
cyclophosphamide was 17 days, and 21 days for platelet recovery with 5 patients not 


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requiring platelet transfusion. The trial was presented in a poster session at the 52nd 
American Society of Hematology annual meeting (Kasamon Y et al, Blood 2010, 
abstract 3954).   
 
2.0       Primary Study Objective:   
To determine the safety of maintenance rituximab and prolonged mTOR inhibition with 
everolimus in CD20+, B cell lymphomas, Gray Zone Lymphoma, and Hodgkin’s 
Lymphoma after high-dose consolidative therapy.  
 
 Safety will be determined by the extent of avoidance of ≥ grade III common 
toxicities (CTCAE version 4.0) 
 
2.1  
Secondary Objectives: 
1) The secondary endpoint of this study is to evaluate event free survival (EFS) at three 
years based on histology. 
 EFS will be histology grade specific: Mantle cell lymphoma group, low-grade 
lymphoma group, high-grade lymphoma group 
2) To determine whether maintenance rituximab with everolimus treatment reduces the 
frequency of circulating cancer cells. 
3) To determine if relapsed disease is sensitive, in-vivo, to mTor kinase inhibition. 
 
3 
Investigational plan 
 
3.1 
Overall study design: After high dose consolidative therapy, patient will receive one 
year of adjuvant rituximab and everolimus.  Treatment evaluation with radiographs, 
standard laboratories and examination will follow for the next three years.  
Survival/disease status will also be assessed for an additional two years, for up to 5 years 
total of follow-up. 
 
3.2 
Study population 
 
Lymphoma histologies: 
 
Mantle cell lymphoma 
 Biopsy-proven diagnosis of Mantle Cell Lymphoma per the World Health 
Organization classification criteria 
 The diagnosis is to be based on histologic and immunophenotypic criteria 
and include either immunohistochemical analysis for cyclin D1, 
cytogenetic analysis be either conventional karyotyping of fluorescence in 
situ hybridization (FISH) for 9(11;14)(q13;32), or both. 
 Patient had met institutional standards for having high-dose consolidative 
therapy 
 


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Non-Mantle cell low grade B cell lymphomas (including SLL/CLL) 
 Biopsy-proven diagnosis of lymphoma per the World Health Organization 
classification criteria 
 Patient had met institutional standards for having high-dose consolidative 
therapy and relapsed disease despite the use of at least on 
chemotherapeutic agent (single agent Rituximab does not qualify for these 
histologies) 
 Exception for mantle cell lymphoma and high risk SLL/CLL [defined as: 
del(17p), del (11q), or del(13q) concurrent with an unmutated IGVH 
status] who received high-dose consolidative therapy in first response are 
eligible for this protocol. 
 
Transformed lymphoma/DLBCL/High risk DLBCL in first response/PMBCL 
 Biopsy-proven diagnosis of lymphoma per the World Health Organization 
classification criteria 
 Patient had met institutional standards for having high-dose consolidative 
therapy. 
 
Gray Zone Lymphoma in first CR 
 Biopsy-proven diagnosis of lymphoma per the World Health Organization 
classification criteria 
 Patient had met institutional standards for having high-dose consolidative 
therapy. 
 
Hodgkin’s Disease 
 Biopsy-proven diagnosis of lymphoma per the World Health Organization 
classification criteria 
 Patient had met institutional standards for having high-dose consolidative therapy. 
 
3.2.1 Patient population Patients must have had chemotherapy responsive disease 
(Partial response or better) before high-dose consolidative therapy.  The accrual rate 
for this study is expected to be 20 patients per year.  Assuming a three year 
recruitment period with a minimum follow-up of one year, 60 patients will give us 
85% power to detect a 20% increase in EFS: 49% to 69%.Inclusion and exclusion 
criteria 
Patients must have baseline evaluations performed prior to the first dose of study 
drug and must meets 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 regulatory requirements for informed consent.  The written informed 
consent must be obtained from the patient prior to enrollment. 


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3.2.2.     Inclusion Criteria 
•      Age >18 years of age  
•      ECOG performance status ≤ 2 
•     INR ≤ 2 
•    Adequate renal and hepatic function defined as a serum creatinine <2.0mg/dL, total       
  bilirubin <5mg/dL, and AST and ALT ˂ 2.5 ULN.•    Platelet count >75 x 109/L 
•    Hemoglobin >10mg/dL 
 •    ANC >3.0x109/L 
 •    Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L and fasting   
 
  triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are   
         exceeded, the patient can only be included after initiation of appropriate lipid  
 
  lowering medication. 
 
  A willingness to use an accepted and effective method of birth control for   
 sexually active women of childbearing potential during the study and for 8 weeks  
 after the end of study drug treatment. 
 •   Ability to sign informed consent. 
 
 
Exclusion Criteria 
    •    Patient who have previously received an mTor inhibitor 
    •    Patients who are pre-terminal or moribund  
 Patients currently receiving anticancer therapies or who have received anticancer 
therapies within 4 weeks of the start of Everolimus (including chemotherapy, 
radiation therapy, antibody based therapy, etc.) 
 Uncontrolled diabetes mellitus as defined by HbA1c>8% despite adequate therapy. 
Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) 
may be included, however blood glucose and antidiabetic treatment must be 
monitored closely throughout the trial and adjusted as necessary 
 Chronic treatment with corticosteroids or other immunosuppressive agents. Topical 
or inhaled cortosteroids are allowed 
 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 


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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; 
 Patients who have a history of another primary solild malignancy, with the exceptions of: 
non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from 
which the patient has been disease free for ≥3 years; 
 Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will not be able to complete the entire study; 
 Patients with active bacterial or fungal infections requiring oral or intravenous 
antimicrobials are not eligible until resolution of the infection 
 Female patients who are pregnant or breast feeding, or of reproductive potential 
whoe are not using effective birth control methods.  Adequate contraception must be 
used throughout the trial and for 8 weeks after the last dose of study drug. 
. 
 Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate 
contraception, during the study and for 8 weeks after the end of treatment 
 •  Patients with known intolerance to rituximab 
 •  Known history of HIV or Hepatitis C 
 Active Hepatitis B as defined by seropositivity for hepatitis B surface antigen.  
Subjects with positive hepatitis B core antibody titers and normal liver transaminases 
are allowed provided that prophylaxis is administered per institutional guidelines. 
Please see Addendum 8 for the action to be taken for patients with positive baseline 
hepatitis B results. 
 
3.2.3 Study Interruption or Study Withdrawal 
A patient may be taken off this study early or may discontinue participation in this 
clinical study due to the following factors: 
 •  Serious or intolerable adverse reaction to treatment 
 •  Progression of disease 
 •  Protocol violation  
 •  Withdrawal of consent 
 •  Withdrawal of sponsor support 
 
There is no limit to how long a patient can have their treatment on hold.  Prolonged 
holds are not considered “serious or intolerable adverse reactions to treatment.”  


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3.2.4    Monitoring of everolimus suspected toxicities: Patients whose treatment is 
interrupted or permanently discontinued due to an adverse event or abnormal 
laboratory value suspected to be related to everolimus must be followed at least 
weekly until the adverse event or abnormal laboratory completely resolves or returns 
to baseline as clinically appropriate.  For patients whose treatment is on hold, labs 
will be monitored every two weeks while on hold.  
 
3.2.5  Known Undesirable Side Effects of everolimus 
 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 stomatitis, rash, 
diarrhea, fatigue, infections, asthenia, nausea, peripheral edema, decreased 
appetite, headache,dysgeusia, epistaxis, mucosal inflammation, pneumonitis, 
weight decreased, vomiting,pruritus, cough, dyspnea, dry skin, nail disorder, and 
pyrexia. Overall, the most frequently observed laboratory abnormalities include 
decreased hematology parameters including hemoglobin, lymphocytes, platelets, 
and neutrophils (or collectively as pancytopenia); increased clinical chemistry 
parameters including cholesterol, triglycerides, glucose, aspartate transaminases, 
creatinine, alanine transaminases, and bilirubin; and decreased clinical chemistry 
parameters including phosphate and potassium.  The majority of these AEs have 
been of mild to moderate severity (NCI CTC grade 1-2).  
Everolimus has immunosuppressive properties and may predispose patients to 
bacterial, fungal, viral or protozoan 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 sepsis, 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 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. 
 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer 
receiving chemotherapy (Yeo 2004). Sporadic cases of Hepatitis B reactivation have 
also been seen in this setting with everolimus. Use of antivirals during anti-cancer 


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therapy has been shown to reduce the risk of Hepatitis B virus reactivation and 
associated morbidity and mortality (Loomba 2008). 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. Addendum 8 
details the action to be taken for a patient with a positive baseline hepatitis B result.  
For hepatitis B reactivation, definition, and management guidelines, please see 
Addendum 9.  For patients who have already received study drug prior to the 
approval of Protocol Version date February 18, 2014, HBV-DNA testing will be 
performed at the patient’s next visit, and the result will be regarded as baseline.   
 
Hypersensitivity reactions manifested by symptoms including, but not limited to, 
anaphylaxis, dyspnea, flushing, chest pain or angioedema (e.g. swelling of the 
airways or tongue, with or without respiratory impairment) have been observed with 
everolimus. 
 
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is 
recommended prior to the start of everolimus therapy and periodically thereafter. Optimal 
glycemic control should be achieved before starting a patient on everolimus. Mouth ulcers, 
stomatitis and oral mucositis have been seen in patients treated with everolimus. In such 
cases topical treatments are recommended, but alcohol- or peroxide-containing 
mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents 
should not be used unless fungal infection has been diagnosed. 
Cases of renal failure (including acute renal failure), some with fatal outcome, 
occurred in patients treated with everolimus.  Renal function of patients should be 
monitored particularly where patients have additional risk factors that may further 
impair renal function.  Elevations of serum creatinine, usually mild, have been 
reported in clinical trials. Monitoring of renal function, including measurement of 
blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended 
prior to the start of everolimus therapy and periodically thereafter. 
Decreased hemoglobin, lymphocytes, platelets and neutrophils have been reported in 
clinical trials. Monitoring of complete blood count is recommended prior to the start 
of everolimus therapy and periodically thereafter. 
Everolimus is not recommended in patients with severe hepatic impairment, (Child-
Pugh class C). 
The use of live vaccines and close contact with those who have received live 
vaccines should be avoided during treatment with everolimus. 
Hypophosphatemia, hypomagnesemia, hyponatremia and hypocalcemia have been 
reported as serious adverse reactions. Electrolytes should be monitored in patients 
treated with everolimus. 
Addendums 4-7 provide recommendations for the management of patients, with 
suspected drug toxicities while on treatment with everolimus. 


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More detailed information regarding everolimus reported suspected toxicities and 
individual cases is provided in the Investigator’s Brochure.  Management of non-
infectious pneumonitis is described in Addendum 7. 
  
 
3.3 
Treatment 
Pre-treatment evaluation (to be completed <30 days before treatment initiation) 
History and Physical Examination 
History should try to document the pre high dose consolidative therapy MIPI score 
(age at diagnosis, ECOG performance status, LDH and WBC) and FLIPI score (age 
of diagnosis, LDH, ECOG performance status, number of extranodal sites, Ann 
Arbor stage) for Mantle and follicular lymphoma patients, respectively. 
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.  Please see Addendum 8 for action to be taken for patients with a 
positive baseline hepatitis B result.  
CBC with platelet and reticulocyte count 
Complete metabolic panel, immunoglobulin panel (IGG, IGA, IGM), fasting 
triglycerides, glucose and total cholesterol (cholesterol and triglycerides can be 
measured on either the screening visit or the day 1 visit) 
PET/CT scans. If PET/CT is not possible a CT of the chest/abdomen/pelvis is 
required. 
Bone marrow aspirate and biopsy: if bone marrow was previously involved 
HCG urine pregnancy test for women of child bearing potential 
 
Treatment initiation: treatment is to begin between six (6) weeks and ten (10) weeks 
after high dose consolidative therapy 
 
3.3.1 Everolimus administration 
The initial dose of everolimus will be 2.5mg orally daily for a total of one year to 
maintain a target trough concentration between 3-15 ng/mL 
Everolimus should be administered orally once daily, preferably in the morning, at 
the same time every day with or without food.  
Everolimus tablets should be swallowed whole with a glass of water.  
The tablets must not be chewed or crushed.   
If vomiting occurs, no attempt should be made to replace the vomited dose 


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Everolimus will be provided by Novartis. Everolimus is formulated as tablets for 
oral administration of 2.5mg, 5mg, and 10mg strength.  
Dose modification will occur as per Addendum 4. 
 
Everolimus can still be administered per protocol even if Rituximab treatment 
is on hold. 
3.3.2 Concomitant therapy 
Rituximab will be administered concomitantly with everolimus as per the dose and 
schedule below.  Instructions for administration of Bactrim and Valtrex for PCP 
prophylaxis and herpes prophylaxis treatment, respectively, are also listed.   
 
Patients will be instructed not to take any additional medications (including over-
the-counter products) during the course of the study without prior consultation with 
the investigator.  At each visit, the patient will be asked about any new medications 
he/she is or has taken after the start of the study drug.  Additional information about 
clinically relevant drug interactions can be found in Addendums 1-3. 
 
All Concomitant medications/significant non-drug therapies taken ≤30 days prior to 
the start and after start of study drug, including physical therapy and blood 
transfusions, should be recorded. 
 
 
Rituximab administration 
Dose and schedule: 375mg/m2 day +1and then every 90 days for 1 year (a total of 4 
infusions) 
Rituximab will not be given unless the patient’s ANC is greater than 1.5. 
Administration as per institutional standard, with infusions 90 days apart, regardless 
of the study date that it was given.  For example, if Rituximab is given on day 95 
instead of 90, the next infusion will be given on day 185, not 180. 
Rituximab can still be administered per protocol even if Everolimus treatment is on 
hold. 
It is not considered a protocol deviation if Rituximab is withheld due to Rituximab-
induced cytopenias.  There is no limit to the number of Rituximab doses that can be 
held.  For example, some patients may not get any doses of Rituximab, or possibly 
only one dose, if their counts have a history of extreme sensitivity to Rituximab. 
Primary antimicrobial prophylaxis 
Bactrim SS PO qd or equivalent/suitable antimicrobial regimen for PCP prophylaxis 
during everolimus administration 


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Valtrex 500mg PO bid or acyclovir 400 mg PO tid for herpes prophylaxis in 
HSV/CMV positive individuals during everolimus administration 
 
3.3.3 Treatment compliance:  
Everolimus compliance will be monitored by serum blood analysis.  Records of 
study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be 
asked to return all unused study medication.  Rituximab will be infused at the cancer 
center. 
 
3.4 
Visit schedule and assessments  
3.4.1 Visit schedule: Examination and Laboratory evaluations 
 
Physical examination: Complete lymphomatous physical examination every ninety 
(90) days for the first two (years), then every six (6) months for the third year. 
 
CBC with platelet count every two (2) weeks for the first sixty (60) days then 
monthly for a total of one (1) year, then every 90 days for the next two (2) years. 
 
Metabolic panel every two (2) weeks for the first sixty (60) days then monthly for a 
total of one (1) year 
Imunoglobulin panel (IgG, IgA, IgM), fasting triglycerides and fasting cholesterol 
levels monthly for a total of one (1) year.   
Patients will be scheduled for an IVIG infusion if their IgG level falls below 500 
mg/dL. 
Patients with an IgG serum level of <500mg/dL will either have supplemental Ig 
administration or changes in primary oral antimicrobial prophylaxis per PI 
discretion. 
 
HCG urine pregnancy testing every 4 weeks during everolimus administration and 
for 8 weeks post everolimus administration for women of child bearing potential 
Everolimus serum trough levels every two (2) weeks for the first sixty (60) days then 
monthly for a total of one (1) year. Everolimus levels will not be drawn during a 
hold once the level is less than 1.0. 
Research peripheral blood labs (2 green top tubes) every ninety (90) days for a total 
of three (3) years. 
Bone marrow evaluation at ninety (90) days and at the end of cycle 13 (or the 365 
day appointment when patients move into the follow-up stage) at PI’s discretion.  If 
a bone marrow evaluation is performed, an additional 10 ml green top tube of 
aspirate will be drawn for research purposes. 


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Adverse events and concomitant medications will be monitored throughout the 
duration of the study. 
            Survival/disease status will be assessed at year 4 and year 5. 
 
Radiographic evaluation 
Computerized Tomography (CT) of chest/abdomen/pelvis and whole body Positron 
emission tomography (PET) scanning every ninety (90) days for two (2) years, then 
every six (6) months for the third year. 
CT scans of the neck and other structures as determined by physical examination 
 
3.4.2  Study Calendar 
            Study procedures are detailed in the study calendar, which is located on the following 
pages.


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Examination 
Screening 
<30 days 
before 
treatment 
initiation 
First 
60 
days 
Year 1 (after first 60 days) ± 3 days 
Year 
2 ± 3 
days 
Year 
3 ± 1 
month 
Year 4 
and Year 
5 
 
 
Every 
2 
weeks 
Monthly 
At 
Day 
90 
Every 
60 
days 
Every 
90 
days 
End 
of 
cycle 
13 
Every 
90 
days 
Every 
6 
months 
At 
patient’s 
routine 
visits 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
 
 
 
 
 
 
Physical 
examination1 
X 
 
 
 
 
X 
 
X 
X 
 
Medical History2 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
medication review 
X 
 
 
Continuous 
ECOG 
performance 
status 
X 
 
 
 
 
 
 
 
 
 
Urine HCG test 
for applicable 
women only 
X3 
X3 
X3 
 
 
 
 
X3 
 
 
PET/CT14 
X 
 
 
 
 
X 
 
X 
X 
 
Hematology4 
X 
X  
X  
 
 
 
 
X 
 
 
Reticulocyte 
Count 
X 
 
 
 
 
 
 
 
 
 
Chemistry5 
X 
X  
X  
 
 
 
 
 
 
 
INR  
X 
 
 
 
 
 
 
 
 
 
Fasting 
Cholesterol and 
Triglycerides 
X 
 
X 
 
 
 
 
 
 
 


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Examination 
Screening 
<30 days 
before 
treatment 
initiation 
First 
60 
days 
Year 1 (after first 60 days) ± 3 days 
Year 
2 ± 3 
days 
Year 
3 ± 1 
month 
Year 4 
and Year 
5 
Immunoglobulin 
panel (IGG, IGA, 
IGM) 
X 
 
X 
 
 
 
 
 
 
 
Hepatitis B and C 
screening6 
X6 
 
 
 
 
 
 
 
 
 
HIV screening 
X 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate and 
biopsy7 
X 
 
 
X7 
 
 
X 
 
 
 
Non-drug 
therapies and 
Blood transfusion 
record8  
X 
 
 
 
 
 
 
 
 
 
Research 
peripheral blood9 
X 
 
 
 
 
X 
 
X 
X 
 
Study Drug 
Administration10 
 
 
Daily for 1 year 
 
 
 
 
Everolimus Serum 
trough levels11 
 
X 
X 
 
 
 
 
 
 
 
Rituximab12 
 
 
 
 
 
X 
 
 
 
 
Appropriate birth 
control measures 
 
 
X13 
 
 
 
 
 
 
 
Adverse events 
 
 
Continuous 
Survival/Disease 
Status 
 
 
Continuous 
1 Should include a complete lymphomatous physical examination. 
2 History should try to document the pre high dose consolidative therapy MIPI score (age at diagnosis, ECOG performance status,     LDH and WBC) and FLIPI score 
(age of diagnosis, LDH, ECOG performance status, number of extranodal sites, Ann Arbor stage) for Mantle and follicular lymphoma patients, respectively. 


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3 Urine HCG testing for applicable women conducted pre-study, every 4 weeks during everolimus administration until 8 weeks post everolimus administration. 
4 Should include a heme 8 with differential 
5 Chemistry should include a complete metabolic panel and glucose. 
6 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. Please see section Addendums 8 and 9 for action to be taken for patients with positive baseline hepatitis B results and management of hepatitis 
reactivation. 
7 Done at PI’s discretion.  When bone marrow biopsies are being performed, an additional 10 ml green top tube of aspirate will be collected for research samples. 
8 All Concomitant medications/significant non-drug therapies taken ≤30 days prior to the start and after start of study drug, including physical therapy and blood 
transfusions, should be recorded. 
9 Collect 2-10ml green tops. 
10 Bactrim SS PO qd or equivalent/suitable antimicrobial regimen for PCP prophylaxis during everolimus administration.  Valtrex 500mg PO bid or acyclovir 400 mg 
PO tid for herpes prophylaxis in HSV/CMV positive individuals during everolimus administration.  The initial dose of everolimus will be 10mg orally daily for a 
total of one year to maintain a target trough concentration between 3-15 ng/mL.  Dose modification will occur as per Addendum 4.  Treatment is to begin between 
six (6) weeks and ten (10) weeks after high dose consolidative therapy. 
11 Everolimus compliance will be monitored by serum blood analysis.  Everolimus serum levels are commercially available through Quest Diagnostics (18883X) CPT 
code 80299, Mon-Fri.  The target trough concentrations 3-15 ng/mL. 
12 Dose and schedule of Rituximab: 375mg/m2 day +1 and then every 90 days for 1 year (a total of 4 infusions).  Administration as per institutional standard.  
Rituxumab should only be given if patient’s ANC > 1.5. 
13 Patient must agree to use TWO acceptable versions of birth control monthly during everolimus administration and for 8 weeks after everolimus has been stopped. 
14 PET/CT scans are recommended. If a PET/CT is not possible a CT of the chest, abdomen, and pelvis can suffice. 
15 Years 4 and 5 of follow-up are for survival and disease status only and will occur at the patient’s routine visits 
 
 


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3.4.3 Efficacy assessments 
Response Evaluation: Conventional response criteria are modeled after the 1999 International 
Working Group criteria for non-Hodgkin’s lymphoma.34  Disease sites that are considered non-
measurable, such as malignant effusions, ascites, or bony lesions, will be considered in the 
overall response. 
Complete Response: Complete disappearance of all detectable clinical and radiographic 
evidence of disease. 
Nonspecific laboratory measures such as LDH or ESR are not included in the response 
assessment.   
All lymph nodes and nodal masses must have regressed to normal size (< 1.5 cm in their 
greatest transverse diameter for nodes > 1.5 cm before therapy). Previously involved nodes 
that were 1.1 to 1.5 cm in greatest transverse diameter must have decreased to < 1 cm, or by 
> 75% in the sum of the products of the greatest diameters (SPD).   
The spleen, if previously enlarged due to lymphoma, must have regressed in size and must 
not be palpable. Macroscopic nodules in any organs should no longer be present. Other 
organs considered to be enlarged before therapy due to lymphoma, such as liver and 
kidneys, must have decreased in size.  
Negative bone marrow biopsy and aspirate, if bone marrow previously involved 
Partial response (PR):  
> 50% decrease in the sum of the products of greatest diameter (SPD) of the six largest (or 
fewer) dominant nodes or nodal masses. These nodes or masses should be a) clearly 
measurable in at least two perpendicular dimensions; b) be from as disparate regions of the 
body as possible; and c) include mediastinal and retroperitoneal areas of disease when 
involved.   
Regression of splenic and hepatic nodules by > 50% in SPD   
Bone marrow assessment is not relevant for determination of a PR   
No sites of new or progressive disease  
Stable disease (SD): less than a PR but is not progressive disease (see below), and must be 
maintained for a minimum of 4 weeks  
Relapsed disease (after CR) / Progressive disease (after PR or SD)   
Appearance of any new lesion or increase by > 50% in size of previously involved sites. 
50% increase in greatest diameter of any previously identified node >1 cm in short axis, or 
in the SPD of more than one node 
Standard Definitions of Disease and Survival Endpoints 
Overall survival (OS) will be measured from registration to the time of death from any 
cause or last patient contact. 


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Event-free survival (EFS) is defined as the interval from registration to the date of first 
objective disease progression, death from any cause, or last patient evaluation. Patients 
who have not progressed or died will be censored at the last date they were assessed and 
deemed relapse-free. 
Failure-free survival (FFS) is defined as the interval from registration to the date of first 
objective disease progression or last patient evaluation. Patients who have not progressed, 
or patients who have died without evidence of lymphoma progression, will be censored at 
the last date they were assessed and deemed progression- or relapse-free. 
Time to tumor progression (TTP) is defined as the interval from the date the patient 
was last found to be progression-free, to the date of first objective disease progression. 
 
3.4.4 Safety assessments 
Safety assessments will consist of monitoring and recording  adverse events that are 
grade 3 and above and all serious adverse events, the regular monitoring of hematology 
and blood chemistry values, regular measurement of vital signs and the performance of 
physical examinations.   
 
These assessments should be performed within ± 2 days of the scheduled day of assessment 
except for adverse events that will be evaluated continuously through the study.  Toxicity will be 
scored using CTCAE Version 4.0 for toxicity and adverse event reporting.  A copy of the 
CTCAE Version 4.0 can be downloaded from the CTEP homepage (http://ctep.info.nih.gov).  
All adverse clinical experiences, whether observed by the investigator or reported by the patient, 
must be recorded, with details about the duration and intensity of each episode, the action taken 
with respect to the test drug, and the patient’s outcome.  The investigator must evaluate each 
adverse experience for its relationship to the test drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical significance.  If 
any abnormal laboratory result is considered clinically significant, the investigator must provide 
details about the action taken with respect to the test drug and about the patient’s outcome. 
 
3.4.4.1 Adverse Events 
Information about adverse events that are grade 3 or above, 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. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered 
to be related to study drug. Medical conditions/diseases present before starting study drug 
are only considered adverse events if they worsen after starting study drug. Abnormal 


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laboratory values or test results constitute adverse events only if they induce clinical signs 
or symptoms, are considered clinically significant, or require therapy. 
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 (mild, moderate, severe) or (grade 1-4) its relationship to the study 
drug(s) (suspected/not suspected) 
2. its duration (start and end dates or if continuing at final exam) 
3. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
4. whether it constitutes a serious adverse event (SAE) 
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. 
 
3.4.4.2 Serious Adverse Events 
A serious adverse event is a 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   
 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 


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 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 
 
Reporting of Serious Adverse Events: 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
 after the patient has provided informed consent and until 4 weeks after the patient has 
stopped study treatment/participation 
 after the patient is randomized and until 4 weeks after the patient has stopped study 
treatment 
 after the patient begins taking study drug and until 4 weeks after the patient has stopped 
study treatment 
 after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-
blind treatment, etc.) and until 4 weeks 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 4 weeks after the 
patient has stopped study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs 
experienced after this 4-week 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. An 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 investigator must assess and record the relationship of each SAE to each specific study 
drug (if there is more than one study drug), complete the SAE Report in English, and send 
the completed, signed form by fax (877-778-9739) within 24 hours to the Novartis Drug 
Safety and Epidemiology Department.  
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 person to whom the original SAE Report Form 
was sent, using a new SAE Report Form 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 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. 


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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study drug, a Drug Safety and 
Epidemiology Department 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. 
 
3.4.5 Novartis instructions for rapid notification of serious adverse events  
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).  
All events must be reported, by FAX (877-778-9739), to Novartis Pharmaceuticals DS&E 
Department within 24 hours of learning of its occurrence. 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 serious adverse event occurring after the patient has provided informed consent and 
until 4 weeks after the patient has stopped study participation must be reported. This 
includes the 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). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only 
be reported if a relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
 
3.4.6  Pregnancy and assessments of fertility for Everolimus 
 
There are no adequate data from the use of everolimus in pregnant women. Studies 
inanimals have shown reproductive toxicity effects including embryo-toxicity and feto-
toxicity. The potential risk for humans is unknown. Everolimus should not be given to 
pregnant women unless the potential benefit outweighs the potential risk to the fetus. If a 
pregnancy occurs while on study treatment, the newborn will be followed for at least 12 
months. 


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It is not known whether everolimus is excreted in breast milk.  However, in animal studies, 
everolimus and/or its metabolites readily passed into the milk of lactating rats.  Women 
taking everolimus should therefore not breast-feed. 
 
Women of childbearing potential 
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. 
 
Male Contraception 
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. 
 
Fertility 


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The potential for everolimus to cause infertility in male and female patients is unknown. 
However, menstrual irregularities, secondary amenorrhea and associated luteinizing 
hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed.  Based on 
non-clinical findings, male and female fertility may be compromised by treatment with 
everolimus. 
 
Pregnancy Reporting 
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 everolimu 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. 
4 
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 and 
approved by the IRB 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. A copy of the written approval of the IRB must 
be provided to Novartis.  
5 
Data Management 
5.1 
Data Collection 
Investigators must record the information required by the protocol. 
5.2 
Data Safety and Monitoring Plan 
  
 
The CRO website link describing the CRO monitoring plans can be found here: 
http://cro.onc.jhmi.edu/news/SKCCC_DSMP.doc  
 


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Internal Monitoring Plan  
The PI will review data to assure the validity of data, as well as, the safety of the 
subjects.  The PI will monitor the progress of the trial, review safety reports and 
clinical trial efficacy endpoints –on an ongoing basis to confirm that the safety 
outcomes favor continuation of the study. 
 
The PI will be responsible for maintaining the clinical protocol, timely reporting of 
adverse events, assuring that consent is obtained and documented, reporting of 
unexpected outcomes, and reporting the status of the trial in the annual report 
submitted to the IRB and to the Safety Monitoring Committee per the SKCCC Data 
and Safety Monitoring Plan.  
 
External Monitoring Plan 
This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan 
(9/22/2011). The Clinical Research Office QA Group will perform an audit after the 
first subject has been treated and then periodically depending on the rate of accrual 
and prior audit results. All trial monitoring and reporting will be reviewed by the 
SKCCC Safety Monitoring Committee in accordance with the Data and Safety 
Monitoring Plan and IRB policies.  
 
6.0 
 Statistical Considerations 
This is a study of maintenance rituximab with mTor inhibition (everolimus) after 
high-dose consolidative therapy in CD20+, B-cell Lymphomas and Hodgkin’s 
Lymphoma.    It is hypothesized that the addition of new agents in patients with 
minimal residual disease will improve event free survival and that everolimus may 
act synergistically with rituximab.       
Primary Objective:  
To determine the safety of maintenance rituximab and prolonged mTOR inhibition 
with everolimus in CD20+, B cell lymphoma and Hodgkin’s Lymphoma after high-
dose consolidative therapy. 
 
Secondary Objectives: 
1. 
The secondary endpoint of this study is to evaluate event-free survival (EFS) at three 
years.  EFS is defined as the interval from registration to the date of first objective 
disease progression, death from any cause, or last patient evaluation.  Patients who 
have not progressed or died will be censored at the last date they were assessed and 
deemed relapse-free.   
2. 
To determine whether maintenance rituximab with everolimus treatment reduces the 
frequency circulating cancer cells. 
3. 
To determine if relapsed disease is sensitive, in-vivo, to mTor kinase inhibition. 


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Study Design:   
Treatment will consist of rituximab 375mg/m2 q 90 days (4 infusions) with 
everolimus 2.5 mg orally daily for one year.  There will be no drug escalation in this 
study however serum drug levels will be monitored and the level of everolimus will 
be maintained in the therapeutic window.  For patients outside the range of 3 – 
15ng/mL and not experiencing grade 3 or higher toxicity, the dose will either be 
increased or decreased by 2.5mg per day to bring patients within range, down to 2.5 
mg every 4 days. Addendum 4 provides details on dose adjustments and treatment 
holds.  For patients experiencing grade 3 or higher toxicities adjustments will be 
made as detailed in addendum 4.  The study will be monitored continuously for 
safety. 
 
Sample size/Accrual Rate:   
The accrual rate for this study is expected to be 20 patients per year.  The safety 
objective of this trial is based on the precision of estimating grade 3 or higher 
toxicities.  Sixty patients will allow us to estimate the proportion of patients 
experiencing grade 3 or higher toxicities with a precision of ± 13%. 
 
Early Stopping Guideline for Safety:   
Because dose will be managed to target a therapeutic window, toxicity evaluation in 
this study will be based on events that would indicate either the therapeutic dose was 
too toxic to maintain or that this method increased the probability of unexpected 
complications.  These events include any patient for which the minimum 2.5 mg 
everolimus every other day was not tolerable or any unexpected hospitalizations 
during protocol participation.  We will monitor the study continuously.  If it 
becomes evident that the proportion of failures convincingly exceeds 15%, the study 
will be halted for a safety consultation.  The stopping rule will hold enrollment if the 
posterior probability of failure being larger than 0.15 is 75% or higher.  The prior for 
this monitoring rule is beta(1, 6).  This means that our prior guess at the proportion 
of failures is 14.3%, and there is 90% probability that this proportion is between 
0.85% and 39%.   
 
Stop if 
 2AEs 
3AEs 
 4AEs 
 5AEs 
 6AEs 
 7AEs 
 8AEs 
 9AEs 
10AEs 
11AEs 
12AEs 
in N 
 2-5 
6-11 
12-16 
17-22 
23-28 
29-34 
35-40 
41-46 
47-52 
53-58 
59-60 
 
The next table shows the percent of the time that the stopping rule will terminate the 
study under different hypothetical risks of AEs, along with the average sample size 
(based on 5000 simulations). 
 


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Risk of AE 
0.05 
0.10 
0.15 
0.20 
0.25 
0.30 
0.35 
% of Time Study Stops 
3.2% 
18.5% 
49.7% 
79.4% 
95.2% 
99.2% 
99.9% 
Expected Sample Size 
58.3 
51.2 
38.6 
25.4 
16.1 
10.9 
8.0 
 
Early Stopping Guideline for Futility and Simulation Sample Size:   
This study will be monitored for efficacy as well as toxicity.  If the study meets the 
accrual goal of 20 patients per year, accrual would be completed by the time the first 
patients enrolled on study reach the three year efficacy endpoint.  We will therefore 
monitor the study based on one-year EFS, knowing that if the one-year EFS is 
convincingly less than our targeted EFS at three years, the study would not meet its 
efficacy objective and the trial should be halted.  Patients that have not progressed or 
died will be censored at the last date they were assessed and deemed relapse-free.  
The non-parametric Kaplan-Meier estimate will be used to estimate the EFS function 
at one year.  After 20 patients have been enrolled, the design will include interim 
analyses for futility that could halt the trial if it seems likely that the drug 
combination does not have sufficient clinical activity.      
 
 
The sample size of 60 and the study design operating characteristics assume a three-
year recruitment period with an additional follow-up of one year.  Based on a study 
of high dose cyclophosphamide and rituximab without stem cell transplantation at 
our institution [2], the one and three-year EFS for low grade B cell lympohmas was 
67 and 49% respectively.  The simulation below demonstrates how the operating 
characteristics of the design varies when the uncertainty of the one-year EFS is 
characterized with the prior: beta(3,2).  This implies that our prior guess at one-year 
EFS for these patients is 60%, and there is 90% probability that the EFS at 12 
months is between 25% and 90%.  
 
We have designed this study to stop early only if it appears that this treatment is 
associated with a lower one-year EFS than 50%.  Specifically, the stopping rule will 
hold enrollment if the posterior probability of one-year EFS being less than 50% is 
70% or higher.  Simulations were carried out with exponential survival and 
staggered patient entry.  We assumed, on average, 2 patients would enter the study 
per month.  Interim analyses began once 20 patients entered the study and occurred 
after groups of 10 patients thereafter, up to a maximum of 60 patients.  The interim 
analysis estimates of one-year EFS are based on analyses with an underlying 
Dirichlet process prior.  We approximated the posterior distribution, which is 
actually a mixture of Beta distributions, the mixture depending on the amount of 
censoring, with a single Beta distribution.  The parameters of this posterior Beta 
distribution are based on the number of failures and the effective sample size at 12 
months, combined with the parameters of the prior.  The following tables summarize 
the operating characteristics under various scenarios for the underlying exponential 
EFS, based on 1000 simulations.  The 95% posterior intervals are the quantiles of 


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the simulated one-year EFS corresponding to probabilities of .025 and .957.  The 
interpretation is that the posterior probability that the estimate of one-year PFS lies 
in this interval is 95%.   
Prior is beta(3,2) :  Mean is 0.60  
 
1-yr 
EFS 
Prob 
Stop 
for 
Futility 
Avg 
N 
Est 1-
yr 
PFS 
Lo 
95% 
Post 
Int’l 
Hi 
95% 
Post 
Int’l 
Prob H0 
Rejected 
0.45 
0.60 
40.3 
0.42 
0.25 
0.58 
0.03 
0.5 
0.37 
47.7 
0.47 
0.25 
0.62 
0.12 
0.55 
0.17 
54.1 
0.53 
0.35 
0.67 
0.28 
0.60 
0.07 
57.5 
0.59 
0.40 
0.72 
0.57 
0.65 
0.02 
59.1 
0.64 
0.50 
0.77 
0.83 
0.7.0 
0.01 
59.8 
0.70 
0.58 
0.82 
0.96 
 
Analysis of primary objective:   
The proportion of patients positive for the toxicity evaluation as define for this 
study: patients for which the minimum 2.5 mg everolimus every other day was not 
tolerable or any unexpected hospitalizations during protocol participation will be 
reported with an exact binomial calculation and 95% confidence interval.  The 
proportion of patients requiring dose adjustments down as well as the proportion 
requiring dose adjustments up will be reported separately with confidence intervals.  
All other grade 1 and 2 toxicities will be reported by type and grade, overall and 
within intervals throughout the study (0, 60], (60, 90], (90,120], (120, 180], (180, 
365] and (365, 1460].   
 
Analysis of secondary objectives:   
Standard life table methods will be used to analyze EFS.  We will report the one and 
three-year EFS with 95% confidence intervals.  The three-year EFS will be 
compared to the null EFS of 49% with a Z-score and a one-sided alpha level of 0.05. 
 
 
 


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7.0  
References 
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Haritunians T, Mori A, O'Kelly J, Luong QT, Giles FJ, Koeffler HP. Antiproliferative 
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Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative 
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Montoto S, Canals C, Rohatiner AZ, et al. Long-term follow-up of high-dose treatment with 
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Oliansky DM, Gordon LI, King J, et al. The role of cytotoxic therapy with hematopoietic 
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Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free 
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van Besien K, Loberiza FR, Jr., Bajorunaite R, et al. Comparison of autologous and 
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Brennan SK, Meade B, Wang Q, Merchant AA, Kowalski J, Matsui W. Mantle cell 
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Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus (CCI-
779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005;23:5347-5356. 
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Leseux L, Hamdi SM, Al Saati T, et al. Syk-dependent mTOR activation in follicular 
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Wendel HG, De Stanchina E, Fridman JS, et al. Survival signalling by Akt and eIF4E in 
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Smith SM, van Besien K, Karrison T, et al. Temsirolimus has activity in non-mantle cell 
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17. 
Cutler C, Stevenson K, Kim HT, et al. Sirolimus is associated with veno-occlusive disease 
of the liver after myeloablative allogeneic stem cell transplantation. Blood. 2008;112:4425-4431. 


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18. 
Boulay A, Lane HA. The mammalian target of rapamycin kinase and tumor growth 
inhibition. Recent Results Cancer Res. 2007;172:99-124. 
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Lane HA, Wood JM, McSheehy PM, et al. mTOR inhibitor RAD001 (everolimus) has 
antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer 
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Mabuchi S, Altomare DA, Cheung M, et al. RAD001 inhibits human ovarian cancer cell 
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Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus (CCI-779) in 
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22. 
O'Reilly T, McSheehy PM. Biomarker Development for the Clinical Activity of the mTOR 
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Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor 
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Zeng Z, Sarbassov dos D, Samudio IJ, et al. Rapamycin derivatives reduce mTORC2 
signaling and inhibit AKT activation in AML. Blood. 2007;109:3509-3512. 
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Ikezoe T, Nishioka C, Bandobashi K, et al. Longitudinal inhibition of PI3K/Akt/mTOR 
signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells. Leuk 
Res. 2007;31:673-682. 
26. 
Zitzmann K, De Toni EN, Brand S, et al. The novel mTOR inhibitor RAD001 (everolimus) 
induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. 
Neuroendocrinology. 2007;85:54-60. 
27. 
Tuncyurek P, Mayer JM, Klug F, et al. Everolimus and mycophenolate mofetil sensitize 
human pancreatic cancer cells to gemcitabine in vitro: a novel adjunct to standard chemotherapy? 
Eur Surg Res. 2007;39:380-387. 
28. 
Treeck O, Wackwitz B, Haus U, Ortmann O. Effects of a combined treatment with mTOR 
inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells. Gynecol 
Oncol. 2006;102:292-299. 
29. 
Sieghart W, Fuereder T, Schmid K, et al. Mammalian target of rapamycin pathway activity 
in hepatocellular carcinomas of patients undergoing liver transplantation. Transplantation. 
2007;83:425-432. 
30. 
Lu CH, Wyszomierski SL, Tseng LM, et al. Preclinical testing of clinically applicable 
strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res. 
2007;13:5883-5888. 
31. 
Rossi F, Ehlers I, Agosti V, et al. Oncogenic Kit signaling and therapeutic intervention in a 
mouse model of gastrointestinal stromal tumor. Proc Natl Acad Sci U S A. 2006;103:12843-12848. 
32. 
Johnston P, Ansell S, Colgan J. ABSTRACT: Phase II trial of the oral mTOR inhibitor 
everolimus (RAD001) for patients with relapsed or refractory lymphoma. J Clin Oncol. 
2007;25:454s.  Abstract 8055. 
33. 
Reeder C, Gornet M, Habermann T. A Phase II trial of the oral mTOR inhibitor everolimus 
(RAD001) in relapsed aggressive non-Hodgkin lymphoma (NHL). Program and abstracts of the 49th 
Annual Meeting of the American Society of Hematology. Atlanta, Georgia; 2007. 
34. 
Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to 
standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working 
Group. J Clin Oncol. 1999;17:1244. 


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35. 
Yeo W, Lam KC, Zee B, et al. Hepatitis B reactivation in patients with hepatocellular 
carcinoma undergoing systemic chemotherapy. Ann Oncol. 2004;15:1661-1666. 
36. 
Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of preventive 
lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med. 2008;148:519-528. 
37. 
Brookmeyer R and Crowley, JJ. A confidence interval for the median survival time. 
Biometrics, 38, 29-41, 1982. 
 


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Addendum 1: Inhibitors of CYP3A4 and/or PgP 
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, 
itraconazole, ritonavir) or P-glycoprotein (PgP) should be avoided. 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, 
fluconazole) or PgP inhibitors should be used with caution.  If patient requires co-
administration of moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose 
of everolimus to half the currently used dose. 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. 
Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. 
Concomitant use should be avoided. 
 
 


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Addendum 2: Inducers of CYP3A4 and/or PgP 
 
If patients require co-administration of a strong CYP3A4 inducer, consider doubling the 
daily dose of Afinitor (based on pharmacokinetic data), using increments of 5 mg or 
less. This dose of Afinitor is predicted to adjust the 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, consider a 
washout period of at least 3 to 5 days (reasonable time for significant enzyme de-
induction), before the Afinitor dose is returned to the 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. 
 
 


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Addendum 3: Clinically relevant drug interactions: substrates, inducers, and 
inhibitors of isoenzyme CYP3A 
 
SUBSTRATES 
Antibiotics: 
Clarithromycin, erythromycin, 
telithromycin 
Calcium channel blockers: 
Amlodipine, diltiazem, felodipine, 
lercanidipine, nifedipine, 
nisoldipine, nitrendipine, 
verapamil 
Anti-arrhythmics: 
Quinidine 
HMG CoA reductase inhibitors: 
Cerivastatin, lovastatin, simvastatin 
Benzodiazepines: 
Alprazolam, diazepam, midazolam, 
triazolam 
Steroid 6beta-OH: 
estradiol, hydrocortisone, 
progesterone, testosterone 
Immune modulators: 
Cyclosporine, tacrolimus (FK506) 
Miscellaneous: 
Alfentanil, aprepitant, aripirazole, 
buspirone,  cafergot, caffeine, 
cilostazol, cocaine, codeine-N-
demethylation, dapsone, 
dexamethasone, 
dextromethorphan, docetaxel 
domperidone, eplerenone, 
fentanyl, finasteride, 
Gleevec/imatinib, haloperidol, 
irinotecan, LAAM, lidocaine, 
methadone, nateglinide, 
ondansetron, pimozide, 
propranolol, quetiapine, 
quinine, risperidone, salmeterol, 
sildenafil, sirolimus, sorafenib, 
sunitinib, tamoxifen, taxol, 
terfenadine, torisel, trazodone, 
vincristine, zaleplon, 
ziprasidone, zolpidem 
HIV Antivirals: 
Indinavir, nelfinavir, ritonavir, 
saquinavir 
Prokinetic: 
Cisapride 
Antihistamines: 
Astemizole, chlorpheniramine, 
terfenadine 
INDUCERS 
Strong inducers: 
avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin  
(rifampicin), St. John's wort (hypericum perforatum) 


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Moderate inducers: 
bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, [talviraline],  
thioridazine, tipranavir 
 
Weak inducers: 
amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, clobazam, danshen,  
dexamethasone, Echinacea, garlic (allium sativum), gingko (ginkgo biloba),  
glycyrrhizin, methylprednisolone, nevirapine, oxcarbazepine, pioglitazone,  
prednisone, [pleconaril], primidone, raltegravir, rufinamide, sorafenib, telaprevir,  
terbinafine, topiramate, [troglitazone] , vinblastine 
INHIBITORS 
 
Clinically relevant drug interactions mediated by PgP 
PgP Substrates 
PgP Inhibitors and 
PgP/CYP3A 
Dual Inhibitors 
PgP Inducers 
digoxin, fexofenadine,  
indinavir, 
vincristine, 
colchicine, 
topotecan, 
paclitaxel, 
talinolol, 
everolimus 
amiodarone, 
azithromycin, 
captopril, 
carvedilol, 
clarithromycin, 
conivaptan, 
diltiazem, 
dronedarone, 
elacridar, 
erythromycin, 
felodipine, 
(GF120918), 
fexofenadine, 
fluvoxamine, 
ginko (ginko 
biloba), 
indinavir, 
itraconazole, 
lopinavir, 
(LY335979), 
mibefradil, milk 
thistle (silybum 
marianum), 
nelfinavir,  
rifampin, St John’s 
wort 


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PgP Substrates 
PgP Inhibitors and 
PgP/CYP3A 
Dual Inhibitors 
PgP Inducers 
nifedipine, 
nitrendipine, 
(PSC833), 
paroxetine, 
quercetin, 
quinidine, 
ranolazine, 
rifampin, 
ritonavir, 
saquinavir, 
Schisandra 
chinesis, St 
John’s wort 
(hypericum 
perforatum),  
talinolol, 
Telaprevir, 
telmisartan, 
ticagrelor, 
tipranavir, 
tolvaptan 
valspodar, 
verapamil 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, 
updated Oct. 2, 2011,29-Oct-2012 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. 
 
 


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Addendum 4: Dose Modifications for abnormal serum drug concentrations 
without grade III/IV toxicities, grade >III toxicities (CTCAE version 4.0) except 
for stomatitis and lipid/hyperglycemia toxicities 
 Patient will have regularly scheduled everolimus levels drawn throughout the study  
 Everolimus is available in 2.5mg, 5mg and 10mg strengths  
 The reference range for patients experiencing a <II common toxicity (CTCAE 
version 4.0) is 3-15ng/mL  
 Anytime a dose is adjusted, repeat everolimus serum trough levels will be re-drawn  
14 days (± 3 days) later. As clinically possible, all patients’ other labs will be reset to 
match this new everolimus serum trough level schedule.  
 Once everolimus is held due to high serum trough levels, everolimus should be held 
for 7 days before restarting at a lower dose level. 
 During a treatment hold, everolimus levels will not be drawn once the serum trough 
level is less than 1.0. 
 There is no limit on how long a patient can be on everolimus treatment hold.  Labs 
will be monitored every two weeks while the patient is on hold. 
 For patients >15ng/mL or <3.0ng/mL and not experiencing >II grade common 
toxicity, their dose will be adjusted by +/-2.5mg/day; lowest dose allowed is 2.5mg 
every 4 days.  The study nurse will provide a calendar to patients when the dose 
level is 2.5 mg taken every 3 or 4 days 
 If a patient on a schedule of 2.5 mg  (QOD) or lower misses a dose, that dose should 
be made up. 
 Non-hematologic grade > III CTCAE toxicities: hold drug until CTCAE toxicity is  
(I) but can be continued at grade 2 if the baseline values were within the range of 
grade 2 and restart at a dose level -2.5mg/day.  Lowest dose allowed is 2.5mg every 
4 days 
 Grade 4 or 4 clinical failure – discontinue RAD001 
 Recurrence of grade 4 toxicity after dose reduction – discontinue RAD001 
 Hematologic grade >III CTCAE toxicity 
o Anemia  
 Hgb <8.0g/dL: transfuse RBC; hold drug for 7 days or until Hgb 
>10mg/dL (untransfused): whichever is longer. Restart at a dose -
2.5mg/day. Lowest dose allowed is 2.5mg every 4 days 
o Thrombocytopenia 
 Platelets < 50,000:  hold drug until platelet count is >75,000 and 
restart at a dose level -2.5mg/day. Lowest dose allowed is 2.5mg 
every 4 days 
 


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 Platelets <10,000: transfuse PLT: when platelet count is >75,000 
(transfusion independent: at least 7 days). Restart at a dose level             
-2.5mg/day; lowest dose allowed is 2.5mg every 4 days 
o Neutropenia:  
 ANC <1,000/mm3 hold drug (and rituximab) until ANC >1,500 and 
restart at a dose level -2.5mg/day.Lowest dose allowed is 2.5mg 
every 4 days  
 No adjustments will be made for lymphopenia 
 Lowest dose allowed on protocol is 2.5mg every 4 days.  If serum concentrations on 
this dosing schedule are >15ng/mL or if on this dosing schedule greater than grade II 
toxicities are experienced the patient will be taken off study. However, patients will 
be followed until toxicities return to grade 1 or baseline as appropriate. 
 
 


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Addendum 5: Management of stomatitis/oral mucositis/mouth ulcers 
Management of stomatitis / oral mucositis / mouth ulcers 
Adverse Drug 
Reaction 
Severity 
Afinitor Dose Adjustment and Management 
Recommendations 
Stomatitis 
Grade 1 
(Minimal 
symptoms, 
normal diet) 
No dose adjustment required.  
Manage with non-alcoholic or salt water 
(0.9%) mouth wash severaltimes a day. 
 
Grade 2 
(Symptomatic 
but can eat 
and swallow 
modified diet) 
Temporary dose interruption until recovery 
to grade ≤1.  
Re-initiate Afinitor at the same dose. 
If stomatitis recurs at grade 2, interrupt dose 
until recovery to grade ≤1. Re-initiate 
Afinitor at a lower dose. 
Manage with topical analgesic mouth 
treatments (e.g. benzocaine,butyl 
aminobenzoate, tetracaine hydrocholoride, 
menthol or phenol)with or without topical 
corticosteroids (i.e. triamcinolone oral 
paste)*. 
 
Grade 3 
(Symptomatic 
and unable to 
adequately eat 
or hydrate 
orally) 
Temporary dose interruption until recovery 
to grade ≤1.  
Re-initiate Afinitor at lower dose. 
Manage with topical analgesic mouth 
treatments (i.e. benzocaine,butyl 
aminobenzoate, tetracaine hydrocholoride, 
menthol or phenol) with or without topical 
corticosteroids (i.e. triamcinolone oral 
paste)* 
 
Grade 4 
(Symptoms 
associated 
with life-
threatening 
consequences) 
Discontinue Afinitor and treat with 
appropriate medical therapy. 
* using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in 
management of stomatitis as they may worsen 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 


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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. The 
suggested paradigm for treatment of stomatitis/oral mucositis/mouth ulcers is as 
follows: 
 
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 hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents. 
4. Antifungal agents must 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, thereby leading to higher everolimus exposures. Therefore, 
topical antifungal agents are preferred if an infection is diagnosed. Similarly, 
antiviral agents such as acyclovir should be avoided unless a viral infection is 
diagnosed. 
 
 


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Addendum 6: Management of hyperlipidemia and hyperglycemia  
Treatment of hyperlipidemia should take into account the pre-treatment status and 
dietary habits. Blood tests to monitor hyperlipidemia must be taken in the fasting 
state. Hyperlipidemia and hypertriglyceridemia should be treated according to local 
best clinical practice. Patients should be monitored clinically and through serum 
chemistry for the development of rhabdomyolysis and other adverse events as 
required in the product label/data sheets for HMG-CoA reductase inhibitors. 
Management of hyperlipidemia and hyperglycemia 
Adverse Drug Reaction 
Severity 
Afinitor Dose Adjustment and 
Management Recommendations 
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia) 
Grade 1 
No dose adjustment required. 
Initiate appropriate medical therapy and 
monitor. 
 
Grade 2 
No dose adjustment required. 
Manage with appropriate medical therapy 
and monitor. 
 
Grade 3 
Temporary dose interruption. 
Re-initiate Afinitor at lower dose. 
Manage with appropriate medical therapy 
and monitor. 
 
Grade 4 
Discontinue Afinitor and treat with 
appropriate medical therapy. 
 
Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been 
reported in patients taking everolimus.  Monitoring of blood cholesterol and 
triglycerides prior to the start of everolimus therapy and periodically thereafter as 
well as management with appropriate medical therapy is recommended. 
Hyperglycemia has been reported in patients taking everolimus. Monitoring of 
fasting serum glucose is recommended prior to the start of everolimus therapy and 
periodically thereafter. More frequent monitoring is recommended when 
everolimus is co-administered with other drugs that may induce hyperglycemia.  
Optimal glycemic control should be achieved before starting trial therapy. 
 
 


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Addendum 7: 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 dyspnoea, and in whom infectious, neoplastic and other 
non-medicinal causes have been excluded by means of appropriate investigations.  
Opportunistic infections such as PJP should be ruled out in the differential 
diagnosis of non-infectious pneumonitis. 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 Afinitor therapy without 
dose alteration. 
If symptoms are moderate (grade 2), consideration should be given to interruption 
of therapy until symptoms improve.  The use of corticosteroids may be indicated.  
Afinitor may be reintroduced at a daily dose approximately 50% lower than the 
dose previously administered. 
For cases of grade 3 non-infectious pneumonitis, interrupt Afinitor until resolution 
to less than or equal to grade 1.  Afinitor may be re-initiated at a daily dose 
approximately 50% lower than the dose previously administered depending on the 
individual clinical circumstances.  If toxicity recurs at grade 3, consider 
discontinuation of Afinitor.  For cases of grade 4 non-infectious pneumonitis, 
Afinitor therapy should be discontinued.  Corticosteroids may be indicated until 
clinical symptoms resolve. 
For patients who require use of corticosteroids for treatment of non-infectious 
pneumonititis, prophylaxis for pneumocystis jirovecii pneumonia (PJP) may be 
considered. The two compounds studied most extensively for prophylaxis against 
PJP have been trimethoprim-sulfamethoxazole, given orally, and pentamidine, 
given as an aerosol. 
 
If non-infectious pneumonitis develops, the guidelines in the table below 
should be followed.  Consultation with a pulmonologist is recommended for 
any case of pneumonitis that develops during the study. 
 


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Version Date: May 7, 2018 
  
 
IRB study Number: NA_00067315  
 
Management of non-infectious pneumonitis 
Worst grade 
pneumonitis 
Suggested investigations 
Management 
of pneumonitis 
Everolimus dose adjustment 
Grade 1 
(Asymptomatic, 
radiographic 
findings only) 
CT scans with lung 
windows. 
No specific 
therapy is 
required 
No dose adjustment required.  
Initiate appropriate monitoring. 
Grade 2 
(Symptomatic, 
not interering 
with Activities 
of Daily 
Living) 
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 
(Symptomatic, 
Interfering with 
Activities of 
Daily Living. 
O2 indicated 
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 
(approximately 50% lower than 
the dose previously administered 
depending on individual clinical 
circumstances) 
Discontinue Everolimus if failure 
to recover within ≤ 28 days.If 
toxicity recurs at Grade 3, 
consider discontinuation 
Grade 4 (Life-
threatening, 
ventlatory 
support 
indicated) 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version Date: May 7, 2018 
  
 
IRB study Number: NA_00067315  
 
 
 
 
 
 
 
Addendum 8:  Action to be taken for positive baseline 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 study drug. 
 
Monitor HBV-DNA 
approximately every 4 
weeks 
No prophylaxis 
 
Monitor HBV-DNA 
approximately every 4 
weeks 
No 
specific 
action 
 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study 
drug. 
 
For patients who have already received study drug prior to the approval of Protocol Version date  
February 18, 2014, HBV-DNA testing will be performed at the patient’s next visit, and 
the result will be regarded as baseline.  Any action for positive hepatitis results will then 
proceed as detailed in the table above. 
 


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Clinical study protocol number: J1228 
  
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Version Date: May 7, 2018 
  
 
IRB study Number: NA_00067315  
 
Addendum 9:  Guidelines for management of hepatitis B 
 
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] 
AND 
ALT elevation x 5 ULN 
Treat: Start a second antiviral  
AND 
Interrupt study drug administration until 
resolution:  
 ≤ grade 1 ALT (or baseline ALT, if > grade 
1) and 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study 
drug should be re-started at one dose 
lower, if available. If the patient is 
already receiving the lowest dose of 
study drug 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 study drug.  
If resolution occurs > 28 days Patients 
should discontinue study drug but 
continue both antiviral therapies at least 
4 weeks after last dose of study drug. 
For patients with baseline 
results:  
Negative 
HBV-DNA 
and 
HBsAg  
AND  
Positive HBs Ab (with no prior 
history 
of 
vaccination 
against HBV), OR positive 
HBc Ab  
------------------------------------- 
reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat : Start first antiviral medication  
AND 
Interrupt study drug administration until 
resolution:  
  ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study 
drug should be re-started at one dose 
lower, if available. If the patient is 
already receiving the lowest dose of 
study drug 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 study drug.  


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Clinical study protocol number: J1228 
  
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Version Date: May 7, 2018 
  
 
IRB study Number: NA_00067315  
 
If resolution occurs > 28 days Patients 
should discontinue study drug but 
continue antiviral therapy at least 4 
weeks after last dose of study drug. 
 
* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 3.0 Metabolic 
Laboratory/Other: Viral Re-activation), unless considered life threatening by the 
investigator; in which case they should be recorded as grade 4 (CTCAE v 3.0 
Metabolic Laboratory/Other: Viral Re-activation). Date of viral reactivation is the 
date on which both DNA and ALT criteria were met (e.g. for a patient who was 
HBV-DNA positive on 01-JAN-10 and whose ALT reached ≥ 5 × ULN on 01-
APR-10, the date of viral reactivation is 01-APR-10).