Conditions: Solid Organ Malignancies Adenoidcystic Carcinoma Neuroendocrine Tumors
Keywords: kidney cancer adenoidcystic cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 44
Healthy volunteers: no

Brief summary:
The purpose of this study is to study the combination of two anticancer drugs, everolimus (RAD001) and lenalidomide in patients whose cancer is no longer responding to standard treatment or patients who are unable to tolerate the standard treatment for their cancer.

Detailed description:
The purpose of this study is to study the combination of two anticancer drugs, everolimus (RAD001) and lenalidomide in patients whose cancer is no longer responding to standard treatment or patients who are unable to tolerate the standard treatment for their cancer. The investigators seek to establish the safety of taking these two medications together and to determine the appropriate doses of the two drugs when given together as well as identify potential side effects when the drugs are administered together.

Another purpose of this study is to find out if the medication works for the patient's kind of cancer and side effects of the combination of RAD001 and lenalidomide by looking at the patient's response to the treatment. The investigators want to find out what effects, good or bad, the drugs have on the patient's cancer.

This study will also look at specific substances called biomarkers in the patient's blood and in the tumor tissue which are involved in the growth of tumor cells and determine if the levels of these biomarkers are related to the patient's response to treatment or development of side effects.

An expansion cohort is currently enrolling patients with adenoidcystic carcinoma, neuroendocrine and kidney cancer.

Arms:
arm 1: Non-randomized study of escalating doses of daily, orally administered lenalidomide in combination with standard doses of everolimus, an orally available mammalian target of rapamycin (mTOR) inhibitor.

Interventions: intervention 1: Lenalidomide intervention 2: Everolimus
Intervention descriptions: intervention 1: Lenalidomide (10mg, 15mg, 20mg or 25mg) once daily by mouth, every day of each 28-day cycle. intervention 2: 5mg or 10mg of everolimus administered once daily by mouth on a once daily continuous dosing schedule for 28 days.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Version 6: 10 June 2014 
Protocol Title: Phase I Study of Everolimus (RAD001) in Combination with 
Lenalidomide in Patients with Advanced Solid Malignancies Enriched for Renal 
Cell Carcinoma 
 
SPONSOR 
 
Emory 
University 
Winship 
Cancer Institute 
Sponsor Protocol #:  
Institution Protocol # WCI-
1717 
Celgene Tracking #:  
RV-ST-PI-0558 
Novartis Tracking #:  
CRAD001LUS141T 
DRAFT VERSION: 
DATE FINAL: 
 
July 13, 2009 
January 4, 2010 
AMENDMENT:   
June 10, 2014 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 
 
 
 


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Version 6: June 10, 2014 
 
 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Principal Investigator: 
 
 
 
 
June 10, 2014 
Signature of Investigator 
Taofeek K. Owonikoko, MD, PhD 
 
Date 
Printed Name of Investigator 
 
 
By my signature, I agree to personally supervise the conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, IRB/EC procedures, instructions from Celgene 
representatives, the Declaration of Helsinki, ICH Good Clinical Practices guidelines, and the applicable 
parts of the United States Code of Federal Regulations or local regulations governing the conduct of 
clinical studies. 
 
STUDY PERSONNEL 
Principal Investigator 
Taofeek K. Owonikoko, MD, PhD 
Co-Investigators 
Donald Harvey, PharmD  
Suresh Ramalingam, MD 
Sagar Lonial, MD 
Bassel El-Rayes, MD  
David Lawson, MD  
Wayne Harris, MD  
Omer Kucuk, MD 
Fadlo Khuri, MD  
Bradley Carthon, MD  
Shi-Yong Sun, PhD 
Edmund Waller, MD, PhD 
 
Biostatistician Research  
Nelson Zhengjia Chen, PhD 
Regulatory Specialist  
Tomekia Ndubisi 


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Version 6: June 10, 2014 
Research Coordinator 
Meredith Renfroe 
Rijalda Deovic 
Supporters 
1. Celgene Corporation  
86 Morris Ave, 
Summit, NJ 07901 
Tel: 1-800-742-3107  
 
2. Novartis Pharmaceuticals Corporation 
One Health Plaza 
East Hanover, NJ 07936 
Fax: 1-888-299-4565 
Study Location 
Emory University Winship Cancer Institute, 1365C Clifton 
Road, NE Atlanta GA 30322 
 


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Version 6: June 10, 2014 
List of Changes to Amended protocol from 06/10/2014 
Pages 2 -3: Update the list of investigators and study staff 
Page 9: Update the study synopsis to include adenoidcystic carcinoma and neuroendocrine 
tumors as eligible for treatment at the defined MTD. 
Page 12: Update footnote 11 to specify the correct time points to collect samples for correlative 
analysis 
Page 22: Update the overall study design to include adenoidcystic carcinoma and neuroendocrine 
tumors as eligible for treatment at the defined MTD 
Page 23: Update the dose escalation schema table to include adenoidcystic carcinoma and 
neuroendocrine tumors as eligible for expansion cohort treated at MTD 
Page 24: Delete Kevin Kim who is no longer a co-investigator on the study and update shipping 
instruction for collected tissue samples. 
Page 29: Update the prescribing information for lenalidomide 
Page 37: correct typographical error regarding the total number of patients to be enrolled from 39 
to 45 
Page 39: Update the inclusion criteria related to registration in the REMS program and adherence 
to pregnancy testing using the mandatory language by pharmaceutical supporter, Celgene. 
Page 45: Clarification for treatment discontinuation or resumption of therapy following delayed 
recovery from toxicity. 
Page 46: Update dose modification criteria for thrombocytopenia in line with updated guidelines 
from Celgene 
Page 58: Update the guidleines for managing occurrence of pregnancy or suspected pregnancy in 
patients on lenalidomide 
Page 59: Update Celgene drug safety contact information  
 
List of Changes to Amended protocol from 06/11/2012 
Page 40, line 22 – update the disease free interval exclusion period from previously treated 
malignancy to 3 years instead of 5 years. 


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Version 6: June 10, 2014 
TABLE OF CONTENTS 
1 
PROTOCOL SYNOPSIS ............................................................................................................................ 7 
2 
SCHEDULE OF STUDY ASSESSMENTS * ........................................................................................... 11 
3 
BACKGROUND AND RATIONALE ........................................................................................................ 13 
3.1 
INTRODUCTION ........................................................................................................................................... 13 
3.2 
LENALIDOMIDE ........................................................................................................................................... 13 
3.3 
EVEROLIMUS: ............................................................................................................................................. 13 
3.4 
RATIONALE FOR TREATMENT IN THIS SETTING ........................................................................................ 14 
3.5 
ADVERSE EVENTS ..................................................................................................................................... 19 
4 
STUDY OBJECTIVES AND ENDPOINTS .............................................................................................. 20 
4.1 
OBJECTIVES ............................................................................................................................................... 20 
4.2 
ENDPOINTS ................................................................................................................................................ 21 
5 
INVESTIGATIONAL PLAN ...................................................................................................................... 22 
5.1 
OVERALL DESIGN ....................................................................................................................................... 22 
5.2 
PROTOCOL THERAPY ........................................................................................................................................ 25 
5.3 
EVEROLIMUS DESCRIPTION ............................................................................................................................... 30 
5.4 
SCREENING AND ELIGIBILITY ..................................................................................................................... 37 
5.5 
VISIT SCHEDULE AND ASSESSMENTS ........................................................................................................ 41 
5.6 
DRUG ADMINISTRATION ............................................................................................................................. 42 
5.7 
DOSE CONTINUATION, MODIFICATION AND INTERRUPTION ..................................................................................... 43 
DAILY DOSING - 28 OF EACH 28 DAY CYCLE   UNLESS OTHERWISE STATED ................................. 43 
5.8 
TREATMENT COMPLIANCE ................................................................................................................................. 53 
5.9 
CONCOMITANT THERAPY-LENALIDOMIDE ................................................................................................. 54 
5.10 
CONCOMITANT THERAPY – EVEROLIMUS (RAD001) ............................................................................................. 54 
5.11 
DISCONTINUATION OF STUDY TREATMENT ........................................................................................................... 57 
5.12 
FOLLOW-UP ................................................................................................................................................... 57 
6 
ADVERSE EVENTS ........................................................................................................................................ 57 
6.1 
SERIOUS ADVERSE EVENT (SAE) DEFINITION ........................................................................................................ 57 
6.2 
ADVERSE DRUG REACTION REPORTING - LENALIDOMIDE......................................................................................... 58 
6.3 
ADVERSE EVENTS – RAD001 ............................................................................................................................ 59 
6.4 
INVESTIGATOR REPORTING RESPONSIBILITIES ........................................................................................ 62 
6.5 
ADVERSE EVENT UPDATES/IND SAFETY REPORTS ................................................................................................. 64 
7 
RESPONSE CRITERIA ............................................................................................................................ 64 
8 
PROTOCOL AMENDMENTS/DEVIATIONS .......................................................................................... 67 
8.1 
PROTOCOL AMENDMENTS ......................................................................................................................... 67 
8.2 
PROTOCOL DEVIATIONS ............................................................................................................................. 67 
9 
DATA MANAGEMENT ............................................................................................................................. 67 
9.1 
ANALYSES AND REPORTING...................................................................................................................... 67 
9.2 
PUBLICATION OF RESULTS ................................................................................................................................. 67 
9.3 
DATA MONITORING COMMITTEE ....................................................................................................................... 68 
9.4 
STUDY AUDITING ............................................................................................................................................. 68 
10 
BIOSTATISTICAL ANALYSIS ........................................................................................................................... 69 
10.1 
OVERVIEW ..................................................................................................................................................... 69 


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10.2 
DATASETS TO BE ANALYZED ............................................................................................................................... 69 
10.3 
STATISTICAL METHODOLOGY ............................................................................................................................. 70 
10.4 
SAFETY EVALUATION ........................................................................................................................................ 70 
10.5 
INTERIM ANALYSES .......................................................................................................................................... 71 
10.6 
SAMPLE SIZE AND POWER CONSIDERATIONS .......................................................................................................... 71 
11 
REGULATORY CONSIDERATIONS.................................................................................................................. 72 
11.1 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE APPROVAL ............................................................................... 72 
11.2 
INFORMED CONSENT ........................................................................................................................................ 72 
11.3 
SUBJECT CONFIDENTIALITY ................................................................................................................................ 72 
11.4 
STUDY RECORDS REQUIREMENTS ........................................................................................................................ 73 
11.5 
PREMATURE DISCONTINUATION OF STUDY ............................................................................................................ 73 
12 
REFERENCES ................................................................................................................................................ 74 
13 
APPENDICES ................................................................................................................................................ 76 
13.1 
APPENDIX A – ECOG PERFORMANCE STATUS SCALE ............................................................................................. 76 
13.2 
APPENDIX B: RISKS OF FETAL EXPOSURE, PREGNANCY TESTING GUIDELINES AND ACCEPTABLE BIRTH CONTROL METHODS . 77 
13.3 
APPENDIX C NCI CTC VERSION 4.0 ................................................................................................................... 79 
13.4 
APPENDIX D – BLOOD SAMPLE COLLECTION AND PROCESSING ................................................................................. 80 
13.5 
APPENDIX E – LIST OF CYP450 AND PGP INTERACTING DRUGS ............................................................................... 81 
13.6 
APPENDIX F: ESTIMATED CREATININE CLEARANCE RATE (ECCR) USING COCKCROFT-GAULT FORMULA ............................... 83 
13.7 
APPENDIX X - REVASSIST PROGRAM ................................................................................................................... 84 
13.8 
APPENDIX Y – PILL DIARY ................................................................................................................................. 85 


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1  Protocol Synopsis 
PROTOCOL TITLE: Phase I Study of Everolimus (RAD001) in Combination with Lenalidomide in 
Patients with Advanced Solid Malignancies Enriched for Renal Cell Carcinoma 
DATE PROTOCOL FINAL: 
June 11, 2012 (Version 5) 
INDICATION:  
Advanced Refractory Solid Malignancies 
STUDY PHASE:  
I 
BACKGROUND AND RATIONALE:   
The mammalian target of rapamycin (mTOR) signaling pathway is a clinically relevant 
target in many solid and hematologic malignancies. Preclinical studies showed that the 
abrogation of mTOR signaling leads to tumor growth inhibition due to the involvement 
of mTOR pathway in myriad cellular processes including cell growth, cell survival, 
protein synthesis and angiogenesis. Many investigational agents targeting the mTOR 
pathway are in advanced stage of clinical evaluation for cancer therapy. Clinical 
significance of mTOR signaling inhibition was validated by temsirolimus, a derivative of 
rapamycin, which, produced improved survival outcome and is now approved for the 
treatment of poor risk renal cell carcinoma patients. Although the combination of 
temsirolimus and interferon achieved better response rate than the comparative single 
agent arms (4.6% vs. 8.6% vs. 8.1% for interferon, temsirolimus and the combination 
respectively), this did not result in survival advantage due to the additive toxicities 
leading to overall reduced dose intensity for temsirolimus in the combination arm. 
Everolimus is an orally bioavailable derivative of rapamycin with significant anti-tumor 
activity in refractory renal cell carcinoma and with improved toxicity profile compared to 
temsirolimus. When administered at 10mg daily continuous dosing in a phase II trial 
enrolling patients either previously untreated or treaed with no more than 1 prior regimen, 
everolimus achieved a 14% response rate. This promising clinical activity and its 
tolerable toxicity profile make everolimus a preferred mTOR inhibitor to combine with 
potentially synergistic agents in early phase clinical trial.  
Lenalidomide is a second generation immunomodulatory agent with better toxicity 
profile and greater cytotoxicity than the original compound, thalidomide. Although the 
exact mechanism of action of lenalidomide remains to be fully elucidated, studies using 
multiple myeloma cell lines have shown that lenalidomide action on cancer cell-stromal 
interaction and its modulation of angiogenesis and tumor directed immunity are central to 
its cytotoxicity. Lenalidomide induces cell cycle arrest and apoptosis and also stimulates 
T cell specific immune response and promotes expansion and enhanced cytotoxicity of 
natural killer (NK) cells. Lenalidomide has been tested in phase II clinical trial enrolling 
patients with refractory renal cell carcinoma. It achieved a complete response of 3%, 
partial response of 8% and stable disease in 53% of patients when administered at the 
standard approved dose of 25mg. 
In preclinical studies, cell exposure to mTOR inhibitor results in increased expression of 
AKT protein, which in turn activates downstream signaling through alternative pathways 


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including forkhead transcription factor (FKHR) and glycogen synthase kinase (GSK)-3 
that can bypass the mTOR complex. Immunomodulatory agents such as lenalidomide can 
overcome cellular tolerance of mTOR inhibition through as yet poorly understood 
mechanism. It is however, plausible that this results from their pleiotropic effects on 
these alternative signaling molecules. In fact, the combination of lenalidomide and 
rapamycin was synergistic in in vitro experiments using multiple myeloma cell lines. We 
hypothesize that the combination of lenalidomide and everolimus will produce improved 
clinical outcome in renal cell carcinoma as well as in many other solid tumor  types 
where these agents have demonstrable clinical activity as single agents. The two drugs 
are well tolerated individually and would therefore be safe and tolerable in combination 
due to their non-overlapping toxicities. 
 
STUDY OBJECTIVES: 
Primary:   
• Determine the maximum tolerated dose (MTD) and define the phase II 
recommended dose (P2RD) for the combination 
• Assess the safety and tolerability of the combination of everolimus and 
lenalidomide in patients with advanced solid malignancies  
 
Secondary:   
• Assess for drug-drug interaction through pharmacokinetic analysis for everolimus 
and lenalidomide 
• Identify preliminary evidence of efficacy by assessing the clinical benefit rate 
(CR+PR+SD) achieved in an expanded cohort of renal cell carcinoma patients  
• Assess preliminary efficacy in an expanded cohort of patients with adenoid cystic 
carcinoma 
 
Correlative Objectives 
• Assess for the predictive ability of mTOR pathway protein expression in archival 
diagnostic tissue for the clinical activity of everolimus 
• Determine the predictive ability of changes in inflammatory and immunologic 
markers in paired blood samples as pharmacodynamic evidence of target 
modulation by escalating doses of lenalidomide 
• Correlate changes in level of cathepsin G in plasma with escalating doses of 
lenalidomide and with incidence of venous thromboembolism  
• Correlate myb protein expression with the efficacy of the combination of 
everolimus and lenalidomide in patients with adenoidcystic carcinoma. 
• Assess the predictive value of myb gene alteration in patients with adenoidcystic 
cancer 


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STUDY DESIGN: 
This is a phase I, open-label, single institution, non-randomized study of escalating doses 
of daily, orally administered lenalidomide in combination with standard doses of 
everolimus, an orally available mTOR inhibitor. The trial is open to patients with 
advanced solid malignancies who have failed or are intolerant of available standard 
treatment options for their disease. Dose escalation will proceed in a modified Fibonacci 
3+3 fashion with the requirement that dose escalation to the next level can only proceed 
if 0 of 3 or ≤1 of 6 patients experience a dose limiting toxicity (DLT). Five escalating 
dose cohorts and three deescalating dose cohorts (if DLT is encountered with the starting 
dose) will be used to evaluate different doses of lenalidomide and everolimus starting 
with the approved and or clinically relevant doses of both agents. The proposed starting 
dose level 1 is 10mg of lenalidomide in combination with 5mg of everolimus both 
administered on a once daily continuous dosing schedule for 28 days respectively in a 28-
day cycle. A serial de-escalation to 10mg of lenalidomide (21 of 28 days) and 5mg of 
everolimus every other day will be carried out if DLT is observed in ≥ 33% of patients 
enrolled to the starting dose cohort. The MTD is the highest dose level of lenalidomide 
and everolimus (up to a maximum dose of 25mg and 10mg respectively) at which <33% 
of the dose cohort experiences DLT after 1 cycle (28 days) of therapy. The established 
MTD will be the recommended dose for follow-up phase II study. To obtain preliminary 
evidence of potential clinical benefit of this combination, an expanded cohort of 15 
patients with clear cell renal cell carcinoma, adenoidcystic carcinoma and neuroendocrine 
tumors will be treated at the defined MTD. 
A parallel expansion cohort of 9 patients with adenoidcystic cancer will be treated at the 
RP2D  
STUDY ENDPOINTS 
Primary: 
• The MTD is the maximum doses of both drugs that can be administered without 
inducing DLT in ≥33% of the treated patient cohort. 
• Safety will be assessed according to NCI CTCAE 4.0v 
• Assessment of DLT will be performed during the first cycle only and the 
following will constitute DLT in this study: 
o Grade 4 hematological toxicity lasting more than 7 days 
o Grade 4 Neutropenia of any duration in the presence of fever ≥ 38.5 c 
o Grade ≥3 nausea and or vomiting in spite of standard supportive therapy 
o Grade ≥3 non-hematologic toxicity  (excluding alopecia) 
o Inability to re-treat patient within 2 wks of scheduled treatment due to 
treatment-related adverse event  
o Inability to deliver all doses of Lenalidomide and or Everolimus during 
the first cycle due to an unexpected drug-related toxicity (if toxicity is an 


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expected toxicity as per current package insert, then it will not be 
considered a DLT).  These subjects should be discontinued from the study  
In the event of study discontinuation prior to completing the entire first treatment cycle 
for reasons other than DLT, the affected subject will be considered inevaluable for 
toxicity and will be replaced by another subject to be treated at the same dose-level. 
 
Secondary: 
• Significant drug-drug interaction will be determined through pharmacokinetic 
analysis for parent drug and metabolites (the following PK parameters will be 
estimated and reported for each agent according to dose level – (AUC0→t) Area 
under the concentration-time curve from the time of dosing to the time of the last 
observation; (AUC0→∞) Area under the concentration-time curve from the time of 
dosing extrapolated to infinity; (Cmax) Maximum serum concentration observed 
postdose; (Tmax) Time point at which the Cmax occurs; (t½) Elimination half-life, 
determined as 0.693/λz) 
• The frequency of achieving a complete plus partial response to the 2 drug 
combination by dose cohort. Response will be assessed by cross sectional imaging 
after every 2 cycles and will be categorized according to RECIST 1.1 criteria.  
 
Correlative: 
• Mean change in immunological biomarkers at baseline, after 1 cycle of protocol 
directed therapy and at disease progression by dose cohort 
• Mean change in plasma levels of inflammatory markers at baseline, after 1 
completed cycle of therapy and at disease progression 
• Plasma level of cathepsin G at baseline, after 1 cycle of therapy and following the 
first diagnosis of venous thromboembolic disease 
STUDY DURATION: 18-24 months 
TOTAL SAMPLE SIZE: 45 
DOSING REGIMEN(S): 
According to dose cohort: 
Lenalidomide once daily days 1-28 of a 28 
day cycle  
Everolimus once daily continuously (day 1-
28) 
DRUG SUPPLIES: 
For 
study 
participants, 
Celgene 
Corporation will provide lenalidomide at 
no 
charge 
through 
the 
RevAssist® 
program.  
Everolimus will be supplied by Novartis 
Pharmaceuticals Corporation and dispensed 
through the Investigational Drug Pharmacy 
 
 
 


 
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2 Schedule of Study Assessments *  
 
 
Procedure 
Screening 
 28 days from 
Baseline (First day 
drug administration) 
Cycle 1 
Cycles  
2, 4, 6, 8 
Cycles  
3, 5, 7, 9 
 
Discontinuation 
From Protocol 
Therapy 
Follow-Up 
Phase 
Day  
1 
 
Day  
8 
Day  
15 
Day   
22 
Day   
1 
Day 
1 
Not 
indicated 
Record prior medications, treatments 
X 
 
 
 
 
 
 
 
 
Record prior anti-cancer therapies 
X 
 
 
 
 
 
 
 
 
Physical examination, vital signs, weight 
X 
X9 
 
 
 
X 
X 
X 
 
ECOG performance status 
X 
X9 
 
 
 
X 
X 
X 
 
CT or MRI of the chest & abdomen / pelvis 
X 
 
 
 
 
X7 
 
X 
 
Chest x-ray 1 
X 1 
 
 
 
 
X1 
 
X1 
 
Bone scan 2 
X 2 
 
 
 
 
X2 
 
X2 
 
CT or MRI of the brain  
X 3 
 
 
 
 
X3 
 
X3 
 
ECG 
X 
 
 
 
 
 
 
X 
 
Hematology 
X 
X9 
 
X 
 
X 
X 
X 
 
Serum chemistry 4 
X 
X9 
 
X 
 
X4 
X4 
X 
 
Pregnancy testing5 
X6 
X 
X 
X 
X 
X6 
X6 
X6 
 
Register patient into RevAssist® program 
X 
 
 
 
 
 
 
 
 
Baseline lesion assessment 
X 
 
 
 
 
 
 
 
 
Dispense everolimus via IDS 
Prescribe lenalidomide via RevAssist®  10 
 
X10 
 
 
 
X10 
X10 
 
 
Response assessment 7 
 
 
 
 
 
X7 
 
X 
 
Record adverse events8 
 
 
X 
 
X 
X 
X 
X8 
 
Record concomitant therapies/procedures 
 
 
X 
 
X 
X 
X 
X 
 
Obtain Follow-Up anti-cancer treatments 
 
 
 
 
 
 
 
 
X 
Obtain Follow-Up survival information 
 
 
 
 
 
 
 
 
X 
Obtain Archival Tissue Block 
X 
 
 
 
 
 
 
 
 
Collect Blood Sample for Correlative Assay   
X11 
X11 
 
 
 
X11 
 
X11,12 
 
Fresh Tumor Biopsy13 
X13 
 
 
 
 
X13 
 
 
 
 
* Variations of ± 3 days of the scheduled visit are permitted.  
If Physical examination, vital signs, weight and ECOG performance status were done within 7 days of Day 1, they do not need to be repeated at Study Day 1. 


 
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An unscheduled visit can occur at any time during the study. Source must be maintained for these unscheduled visits. The date for the visit and any data 
generated must be recorded on the appropriate CRF. Source documents for these unscheduled visits must also be maintained.  
1 Not needed if Chest CT scan has been obtained. 
2 May repeat as clinically indicated if subject had previously positive bone scan or if symptoms suggest metastases. 
3 If symptoms raise suspicion of CNS lesions. 
4 To include Thyroid Stimulating Hormone (TSH) at Screening, every 16 weeks and at treatment discontinuation. T3 and T4 levels may be assessed as clinically 
indicated. 
5 Pregnancy tests for females of childbearing potential. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
6 Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled within 7 days). FCBP with 
regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on therapy (including breaks in therapy); at 
discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide. Females with irregular menstruation must have a pregnancy test weekly for the 
first 28 days and then every 14 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose 
of lenalidomide (see Appendix B: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).  
7 Based on RECIST 1.1 criteria, PRs and CRs do not require separate confirmatory scans.  Duration of response will be determined with the results of the regular 
restaging scans  to be obtained after every 2 cycles. 
8 An additional safety assessment will be done 28 days (+/- 2 days) following the last dose of protocol therapy. 
9 If screening assessments were done within 7 days of Day 1, they do not need to be repeated at Study Day 1. 
10 Lenalidomide must be prescribed through and in compliance with the RevAssist® program of Celgene Corporation (Appendix X). Prescriptions must be filled 
within 7 days. Consideration should be given to prescribing lenalidomide 5 to 7 days in advance of Day 1 of each cycle to allow time for required patient and 
prescriber surveys, and drug shipment to patient. Any unused Revlimid® (lenalidomide) should be returned to the patient for disposition in accordance with the 
RevAssist® program. 
11Baseline samples for correlative assays may be collected up to 3 days prior to dosing. See Appendix D for directions on blood collection and preparation. 
Samples for inflammatory and immunologic markes will be collected with the first 2 restaging scans i.e. end of cycle 2 (samples should be collected on day 1 cycle 
3 ± 2days) and at the time of disease progression if different than any of the afore-listed time points. 
12 Collect at the time of documented disease progression 
13 Fresh tumor biopsy to be obtained at baseline and at the end of cycle 1. This is optional and will be limited to patients enrolled in the expansion cohort after 
obtaining a separate informed consent for the procedures.  
 
 
 


 
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3 Background and Rationale 
3.1 Introduction 
3.2 Lenalidomide 
Lenalidomide is a proprietary IMiD™ compound of Celgene Corporation. IMiD™ compounds 
have both immunomodulatory and anti-angiogenic properties which could confer antitumor and 
antimetastatic effects. Lenalidomide has been demonstrated to possess anti-angiogenic activity 
through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell migration, due at 
least in part to inhibition of Akt phosphorylation response to bFGF.1 In addition, lenalidomide 
has a variety of immunomodulatory effects. Lenalidomide stimulates T cell proliferation, and the 
production of IL-2, IL-10 and IFN-gamma, inhibits IL-1-beta and IL-6 and modulates IL-12 
production.2 Up regulation of T cell derived IL-2 production is achieved at least in part through 
increased AP-1 activity.3 Although the exact antitumor mechanism of action of lenalidomide is 
unknown, a number of mechanisms are postulated to be responsible for lenalidomide’s activity 
against multiple myeloma. Lenalidomide has been shown to increase T cell proliferation, which 
leads to an increase in IL-2 and IFN-gamma secretion. The increased level of these circulating 
cytokines augment natural killer cell number and function, and enhance natural killer cell activity 
to yield an increase in multiple myeloma cell lysis.4 In addition, lenalidomide has direct activity 
against multiple myeloma and induces apoptosis or G1 growth arrest in multiple myeloma cell 
lines and in multiple myeloma cells of patients resistant to melphalan, doxorubicin and 
dexamethasone.5  
 
3.3 Everolimus: 
Everolimus is a derivative of rapamycin, which acts as a signal transduction inhibitor. Its target 
is mammalian target of rapamycin (mTOR), a key serine-threonine kinase regulating protein 
synthesis and ultimately cell growth, cell proliferation, angiogenesis and survival.6 Downstream 
of PI3/AKT, mTOR is a component of the PI3K/AKT/mTOR pathway known to be dysregulated 
in numerous human malignancies. Molecular epidemiological studies demonstrate that, in 
addition to a high frequency in specific cancers, activation of the PI3K/AKT/mTOR pathway is 
frequently a characteristic of worsening prognoses (through increased aggressiveness), resistance 
to treatment, extension of disease and progression. Preclinical studies have confirmed the role of 
this pathway in tumor development. Gain of function models demonstrate that constitutive 
activation of kinases such as AKT can lead to the inexorable development of malignancies 
resembling those seen in patients characterized by frequent activation of the same kinase. This 
complemented the demonstration of the antitumor activity of kinase inhibitors acting in vitro and 
in vivo. 
Experiments carried out in Novartis laboratories, as well as elsewhere, show that everolimus is 
capable of inhibiting the proliferation and growth of a wide spectrum of tumor cell lines and 
tumors, respectively. The antiproliferative effects of everolimus are achieved at nanomolar 
concentrations; which is easily achieved in patients treated at the doses used in clinical trials. An 


 
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important aspect of the antitumor effect of everolimus is its potential to act on tumor cells by 
directly inhibiting growth and indirectly by inhibiting angiogenesis.6 The observation of in vivo 
sensitivity of xenografts raised from cells demonstrating resistance to everolimus in vitro is 
attributable to the drug’s potential to act on the vascular component of the supporting 
peritumoral stroma.6 The antiangiogenic property of everolimus was confirmed through 
experiments demonstrating the effect of everolimus in countering VEGF-induced proliferation of 
human umbilical endothelial cells (HUVEC) in vitro,7 VEGF-driven angiogenesis in a chamber 
implant murine model and revascularization in a murine orthotopic melanoma model.  
Although everolimus shows antitumor activity by itself, objective responses are quite modest. 
There is therefore an increasing focus on the potential for increased anti tumor activity when 
combined with other antitumor therapies. The PI3K/AKT pathway is downstream of numerous 
other effectors known to play a role in cancer cell proliferation and or survival, most notably 
growth factor receptor protein tyrosine kinase and hormone receptors. Therefore, there is great 
potential that everolimus may be combined with antibody-based therapy such as trastuzumab 
(Herceptin®) blocking HER2/ErbB2, bevacizumab (Avastin®) sequestering vascular endothelial 
growth factor, and rituximab (Rituxan®/MabThera®) directed against CD20, a B lymphocyte-
specific antigen); and small molecule inhibitors such as erlotinib (Tarceva®) and gefitinib 
(Iressa®) inhibiting EGFR/ErbB1, PTK787 inhibiting the VEGF receptor (VEGFr), bortezomib 
(Velcade®) an inhibitor of the proteosome, and vorinostat (SAHA) a histone deacetylase 
inhibitor. 
 
3.4 Rationale for Treatment in this Setting 
The mammalian target of rapamycin (mTOR) signaling pathway is a clinically relevant target in 
many solid malignancies. Preclinical studies showed that the abrogation of signaling through this 
pathway leads to tumor growth inhibition. Clinical significance of mTOR signaling inhibition 
was validated by temsirolimus, a derivative of rapamycin which produced improved survival 
outcome leading to its approval for the treatment of poor risk renal cell carcinoma patients.8 
Although the combination of temsirolimus and interferon combination achieved better response 
rate than the comparative single agent arms (4.6% vs. 8.6% vs. 8.1% for interferon, temsirolimus 
and the combination respectively), this did not result in survival advantage due to the reduced 
dose intensity necessitated by the additive toxicity observed with temsirolimus in the 
combination arm.8 Everolimus is an orally bioavailable derivative of rapamycin with significant 
anti-tumor activity in various solid malignancies, most notably refractory renal cell carcinoma. It 
has an improved toxicity profile over temsirolimus. When administered at 10mg daily 
continuous dosing in a phase II study of patients previously untreated or treated with only one 
prior regimen, everolimus achieved a 14% response rate and a 57% disease stability rate.9 A 
phase III study in previously treatedrenal cell carcinoma patients produced a 1% response rate 
and 63% stable disease rate10 suggesting that prior therapy with other targeted agents may lead to 
acquired resistance to mTOR targeting agents. Nonetheless, on the basis of the superior 
progression free survival compared to placebo treatment, everolimus received FDA approval for 
the treatment of patients with clear cell renal cell carcinoma. The demonstrated clinical activity 
of everolimus in solid malignancies and its tolerable toxicity profile recommend it as the 


 
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preferred mTOR inhibitor in early phase clinical trial of potentially synergistic combination 
regimen in solid tumors. 
Lenalidomide is a second generation immunomodulatory agent with better toxicity profile and 
greater cytotoxicity than the original compound, thalidomide. Although the exact mechanism of 
action of lenalidomide remains to be fully elucidated, studies using multiple myeloma and NHL 
cell lines have shown that lenalidomide action on cancer-stroma interaction and its modulation of 
angiogenesis and tumor directed immunity are central to its cytotoxicity.11-13 Lenalidomide 
induces cell cycle arrest and apoptosis and also stimulates T cell specific immune response and 
promotes expansion and enhanced cytotoxicity of natural killer (NK) cells.11 In preclinical 
studies, exposure of cells to mTOR inhibitor resulted in a compensatory escape reaction with 
increased expression of AKT protein,14 which in turn activates downstream signaling through 
alternative pathways including forkhead transcription factor (FKHR) and glycogen synthase 
kinase (GSK)-3 that can bypass the mTOR complex. Immunomodulatory agents such as 
lenalidomide can overcome mTOR inhibitor resistance through as yet poorly understood 
mechanism probably through their pleiotropic effects on multiple alternative signaling 
molecules. In preclinical studies with multiple myeloma cell lines, the combination of 
lenalidomide and rapamycin was capable of overcoming the protective effect of IGF1 and IL-6 
against the cytotoxic effect of rapamycin (Figure 1). This interaction was associated with 
increased apoptosis (Figure 2) and resulted in a synergistic cytotoxic effect (Figure 3).15 
Lenalidomide has been tested in phase II clinical trial enrolling patients with refractory renal cell 
carcinoma. It achieved a complete response of 3%, partial response of 8% and stable disease in 
53% of patients when administered at the standard approved dose of 25mg. 
Cytotoxicity and acquired resistance following single agent therapy with lenalidomide and 
everolimus may occur through a shared mechanism involving modulation of tumor directed 
immunity and tumor associated angiogenesis. The co-administration of both agents may 
therefore result in maximal pathway modulation leading to increased efficacy and delayed 
acquisition of the resistance phenotype by the tumor cells. Because the two drugs are well 
tolerated individually and have non-overlapping toxicities we anticipate that they would be safe 
and tolerable in combination. We therefore hypothesize that the combination of lenalidomide and 
everolimus will be safe, tolerable and will produce synergistic clinical outcome in solid 
malignancies such as renal cell carcinoma as well as other solid malignancies where these agents 
have shown single agent clinical activity.  
 
 
 
 
 
 
 
 
 


 
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Supplemental figure S1: MRI of the brain showing dramatic 
reduction in intracranial tumor growth following 6 cycles of treatment 
with lenalidomide and everolimus in a patients with salivary gland 
adenoidcystic carcinoma 
Adenoidcystic carcinoma: 
Adenoidcystic carcinoma is the second most common type of salivary gland neoplasm. It 
presents as a locally aggressive type of cancer that arise commonly in minor and major salivary 
glands. This cancer has a very poor long-term prognosis with no established FDA-approved 
therapeutic intervention. Recent research work showed that a chromosomal translocation 
involving the genes encoding the transcription factors, MYB and NFIB, is frequently observed in 
this tumor type. A balanced translocation between MYB and NFIB is present in 49% of adenoid 
cystic carcinomas but is not identified in other salivary gland tumors or nonsalivary gland 
neoplasms. Strong Myb immunostaining is detected in upto 65% of all cases and is very specific 
for adenoid cystic carcinomas (West et al. PMID:21164292 and Brill et al. 2011; 
PMID:21572406). Adenoidcystic cancer with MYB translocation tend to have poorer prognosis 
with higher local relapse rates. While it is very likely that this translocation may mediate a key 
driver event in the development of this type of cancer, there is as yet no specific therapeutic 
agent that is specific for this putative oncogenic aberration. It is also unclear whether this 
chromosomal aberration will predict for response to novel targeted therapy; however, it is 
worthwhile correlating the presence of this translocation with the clinical outcome of patients 
especially in the early drug development phase where we observe very intriguing signs of 
efficacy. . 
We enrolled five patients with salivary gland tumor in the escalation phase of this study. Four of 
the 
five 
patients 
completed at least 2 
cycles of therapy 
and all of them 
obtained meaningful 
clinical benefit. A 
heavily 
pretreated 
patient 
with 
adenoidcystic 
carcinoma 
has 
achieved near partial 
response 
(>25% 
tumor shrinkage by 
RECIST 
criteria; 
supplemental figure 
S1). She remains on protocol treatment after completing 7 cycles of treatment. This intriguing 
observation justifies a more focused evaluation of the combination of lenalidomide and 
everolimus in this patient population. 
  
 
 


 
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Figure 1 
Combination 
of 
lenalidomide 
(CC-
5013) and rapamycin 
overcomes 
the 
protective effect of IL-6, IGF-1, and adherence to the bone marrow microenvironment. 
Rapamycin-induced cytotoxicity is abrogated in the presence of cytokines, but the combination of 
CC-5013 with rapamycin overcomes the protective effects of (A) IL-6 and (B) IGF-1. (C) 
Combined therapy was also effective at inhibiting DNA synthesis in MM1.S cells adherent to 
BMSCs. Raje et al. Blood, 104 (13): 4188-4193, 200415  
 


 
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Figure 2 
Combination CC-5013 and rapamycin induces apoptosis in MM1.S cells. (A) Increase in the 
apoptotic cells (Annexin+ PI-) after exposure to CC-5013 (1 µM) and rapamycin (1 nM) for 48 
hours, (B) associated with caspase 8 and PARP cleavage. Raje et al. Blood, 104 (13): 4188-
4193, 200415  
 
 
 
 
Figure 3 
 
Effect of CC-5013, rapamycin, and 
combination on patient myeloma cells. 
A dose-dependent increase in the 
percentage of apoptotic patient MM 
cells, evidenced by Apo 2.7 staining of 
bright CD38-positive cells, was noted 
after exposure to combination CC-5013 
and rapamycin treatment. Raje et al. 
Blood, 104 (13): 4188-4193, 200415  
 


 
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3.4.1 LENALIDOMIDE INDICATIONS AND USAGE: 
Revlimid® (lenalidomide) is available in 5 mg, 10 mg, 15 mg and 25 mg capsules for oral 
administration. Each capsule contains lenalidomide as the active ingredient and the following 
inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. The 5 mg capsule shell contains gelatin, titanium dioxide and black ink. The 
10 mg capsule shell contains gelatin, fd&c blue #2, yellow iron oxide, titanium dioxide and black 
ink. 
Revlimid® (lenalidomide) is indicated for the treatment of patients with transfusion-dependent 
anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 
5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Revlimid® is 
also approved in combination with dexamethasone for the treatment of patients with multiple 
myeloma that have received at least one prior therapy. All other uses are considered 
investigational. 
 
3.4.2 EVEROLIMUS INDICATIONS AND USAGE: 
AFINITOR® (everolimus) is indicated for the treatment of patients with advanced renal cell 
carcinoma after failure of treatment with sunitinib or sorafenib. The recommended dose of 
AFINITOR for treatment of advanced renal cell carcinoma is 10 mg, to be taken once daily at the 
same time every day, either with or without food. AFINITOR tablets should be swallowed whole 
with a glass of water. The tablets should not be chewed or crushed. Continue treatment as long as 
clinical benefit is observed or until unacceptable toxicity occurs.  
 
3.5 Adverse Events 
3.3.1 Lenalidomide 
Most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, 
nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, 
Upper respiratory infection, cellulites, atrial fibrillation, congestive heart failure, myocardial 
infarction, chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone 
pain, generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural 
effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, death not specified and fractures. 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters. 
 
3.3.2 Everolimus 
 


 
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The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a 
randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior 
treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-
85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment 
was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for 
those receiving placebo. The most common adverse reactions (incidence ≥30%) were stomatitis, 
infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions 
(incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, 
abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) 
were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and 
increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) 
were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. 
Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) 
were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-
emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 
14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common 
adverse reactions (irrespective of causality) leading to treatment discontinuation were 
pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common 
reasons for treatment delay or dose reduction. The most common medical interventions required 
during AFINITOR treatment were for infections, anemia, and stomatitis. 
 
4 Study Objectives and Endpoints 
4.1 Objectives 
4.1.1 Primary objectives 
• Determine the maximum tolerated dose (MTD) and define the phase II recommended 
dose (P2RD) for the combination of lenalidomide and everolimus in patients with 
advanced solid malignancies 
• Assess the safety and tolerability of the combination of everolimus and lenalidomide in 
patients with advanced solid malignancies  
4.1.2 Secondary study objectives 
• Assess for drug-drug interaction through pharmacokinetic analysis for everolimus and 
lenalidomide 
• Identify preliminary evidence of efficacy by assessing the clinical benefit rate 
(CR+PR+SD) achieved in an expanded cohort of renal cell carcinoma patients 
• Assess preliminary efficacy in an expanded cohort of patients with adenoid cystic 
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4.1.3 Correlative Objectives 
• Correlate mTOR pathway protein expression in archival diagnostic tumor tissue with the 
clinical activity of everolimus 
• Determine the predictive ability of changes in inflammatory and immunologic markers in 
paired blood samples as pharmacodynamic evidence of target modulation by escalating 
doses of lenalidomide 
• Correlate changes in level of cathepsin G in plasma with escalating doses of lenalidomide 
and with incidence of venous thromboembolism  
• Correlate myb protein expression with the efficacy of the combination of everolimus and 
lenalidomide in patients with adenoidcystic carcinoma. 
• Assess the predictive value of myb gene alteration in patients with adenoidcystic cancer 
4.2 Endpoints 
4.2.1 Primary Endpoint 
Maximum tolerated dose (MTD) of the combination of lenalidomide and everolimus  
Safety will be assessed according to NCI CTCAE 4.0 (Appendix C)  
Assessment of DLT will be performed during the first cycle only and the following will 
constitute DLT in this study:  
• 
Grade 4 hematologic toxicity lasting more than 7 days  
• 
Grade 4 Neutropenia of any duration with fever ≥ 38.5c 
• 
Grade ≥3 nausea and or vomiting in spite of standard supportive therapy  
• 
Grade ≥3 non-hematologic toxicity (exclude alopecia) 
• 
Inability to re-treat patient within 2 wks of scheduled treatment due to treatment-related 
toxicity  
• 
Inability to deliver all doses of  Everolimus during the first cycle due to an unexpected drug-
related toxicity (if everolimus related toxicity is an expected toxicity as per current package 
insert, then it will not be considered a DLT).  These subjects should be discontinued from the 
study. 
• 
Discontinuation of  the study prior to completing the entire first treatment cycle for reasons 
other than DLT, a subject will be added to that dose-level cohort. 
• 
The occurrence of one of the above drug-related toxicities will result in a clinical and/or 
laboratory assessment to be performed within 7 days following the initial finding to examine 
the subject for resolution of the toxicity.  Lack of resolution of any of these toxicities 
according to the guidelines above will be considered a DLT and result in discontinuation of 
that subject 
4.2.2 Secondary Endpoints 
• The frequency of achieving a complete plus partial response or disease stabilization with 
the 2 drug combination by dose cohort. (Response will be assessed by cross sectional 
imaging after every 2 cycles and will be categorized according to RECIST 1.1 criteria)  


 
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4.2.3 Correlative Endpoints 
• Immunoscore of mTOR pathway protein expression (S6, pS6, 4E-BP1, p-4E-BP1, eI4F, 
Akt, pAkt, raptor, rictor, PRAS40, mSin1, FKBP38, and IRS-1 and HIF1-α) in archival 
biopsy sample for all patients and in paired fresh tumor biopsy specimens in up to 15 
patients treated at P2RD if a separate informed consent is obtained. 
• Immunoscore of myb protein expression in archival tissue samples in patients with 
adenoidcystic cancer. 
• Serum level of inflammatory and immunologic markers (IL-6, IL-8, IL-12, IFN-γ, TNF-
α, sIL-2R-α, CD4+ and CD8+ T-cell, NK cell and Treg cells); markers of angiogenesis 
(circulating VEGF and soluble VEGFR) and level of the potent platelet aggregator, 
cathepsin G, will be performed in serial blood samples collected at baseline, at the end of 
cycle 1 and at the time of disease progression or first diagnosis of venous 
thromboembolism (in the case of cathepsin G) and correlated with lenalidomide therapy 
by dose cohort.  
 
5 Investigational Plan 
5.1 Overall design 
This is a phase I, open-label, single institution, non-randomized study of escalating doses of 
daily, orally administered lenalidomide in combination with standard doses of everolimus, an 
orally available mTOR inhibitor. The trial is open to patients with advanced solid malignancies 
who have failed or are intolerant of available standard treatment options for their disease. Dose 
escalation will proceed in a modified Fibonacci 3+3 fashion with the requirement that dose 
escalation to the next level can only proceed if 0 of 3 or ≤1 of 6 patients experience a dose 
limiting toxicity (DLT). Four escalating dose cohorts and three deescalating dose cohorts will be 
used to evaluate different doses of lenalidomide and everolimus starting with the approved and 
or clinically relevant doses of both agents. The proposed starting dose level 1 is 10mg of 
lenalidomide (days 1 – 28) in combination with 10mg of everolimus (days 1 - 28) in a 28-day 
cycle. A serial de-escalation to 10mg of lenalidomide (days 1-21 of a 28 day cycle) and 5mg of 
everolimus will be carried out if DLT is observed in ≥ 33% of patients enrolled to the starting 
dose cohort. The MTD is the highest dose level of lenalidomide and everolimus (up to a 
maximum dose of 25mg and 10mg respectively) at which <33% of the dose cohort experiences 
DLT after 1 cycle (28 days) of therapy. The established MTD will be the recommended dose for 
follow-up phase II study. To obtain preliminary clinical benefit of this combination, an expanded 
cohort of 15 patients with clear cell renal cell carcinoma, adenoidcystic carcinoma and 
neuroendocrine tumors will be treated at the define MTD. To allow for assessment of drug-drug 
interaction using PK analysis, lenalidomide will be administered alone on day 1 of the first cycle 
followed by both agents on day 2 cycle 1. Both drugs will be started simultaneously on day 1 of 
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In addition, a parallel cohort of 9 additional patients with adenoidcystic cancer will be treated at 
the RP2D. This is to enable us to obtain further evidence in support of the efficacy of this 
regimen in patients with adenoidcystic cancer as observed in the limited number of patients with 
this cancer type who were enrolled in the escalation phase of the study. 
Table 1 
Dose Level 
Lenalidomide  
( day 1 to 28) 
Everolimus 
(day 1-28) 
Patient 
Enrolment  
Remarks 
-2 
10mg Days 1-
21 
5mg every 
other day 
3 + 3 
 If DLT, study will close without defining a 
MTD 
-1 
10mg Days 1-
21 
5mg 
3 + 3 
Deescalate to level -2 if ≥ 1 of 6 patients 
experience DLT, otherwise declare as MTD 
and expand the cohort 
Starting 
Dose  
1 
10mg 
5mg 
3 + 3 
Escalate to level 2 if 0 of 3 or 1 of  6 
patients experience DLT, otherwise 
deescalate 1 level 
2 
15mg 
5mg 
3 + 3 
Escalate to level 3 if 0 of 3 or 1 of 6 patients 
experience DLT, otherwise deescalate 1 
level 
3 
20mg 
5mg 
3 + 3 
Escalate to level 4 if 0 of 3 or 1 of 6 patients 
experience DLT, otherwise deescalate 1 
level 
4 
25mg 
5mg 
3 + 3 
if  ≥ 1 of 6 patients experience deescalate 1 
level, otherwise declare as MTD 
5 
25mg 
10 
3 + 3 
if  ≥ 1 of 6 patients experience deescalate 1 
level, otherwise declare as MTD 
MTD 
TBD 
TBD 
15 
Expanded cohort of 15 patients restricted to 
patients with renal cell carcinoma, 
adenoidcystic carcinoma and 
neuroendocrine tumors 
 
5.1.1 Blood Sample Collection: 
Blood samples will be collected in heparinized green top tubes (3 mls for PK samples and 7 mls 
for PBMC collection), red top tube (7 mls to obtain serum sample for cytokine assay). PBMC 
will be purified using standard Ficoll-Paque gradient centrifugation according to the instructions 
of the manufacturer (Amersham Pharmacia, Uppsala, Sweden). All samples must be stored away 
within 1 hour of collection by refrigeration at -80oC until ready for assay.  
 
5.1.2 PK Analysis –  
PK Analysis will not be performed in this study. This information will be obtained in a separate 
ongoing phase I study of this combination in patients with hematologic malignancies where  
everolimus and lenalidomide concentrations will be assayed in blood with a liquid 
chromatography/mass spectroscopy assay as previously described.18,19.  
 


 
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5.1.3 Immunohistochemistry for mTOR pathway protein –  
Archival paraffin embedded tissue collected at the time of patient screening will be shipped to 
the lab of the PI, Taofeek K. Owonikoko, MD, PhD at the Winship Cancer Institute. After 
obtaining a separate informed consent from trial subjects, CT -guided biopsy will be performed 
using either fine-needle aspiration for lung metastases or a 17 gauge biopsy gun for all other 
organ sites. Biopsies will be directed by a specialist from the Interventional Radiology 
department. Accessible lesions may also be biopsied by a preferred surgeon or other specialist as 
appropriate for the site. Submitted material obtained by various biopsy methods will be 
embedded in paraffin. Archival and fresh tumor biopsies will be stored until the end of the trial 
when all samples will be analyzed in a single batch. Immunohistochemical detection of the 
mTOR pathway proteins will be carried out with the avidin-biotin technique using specific 
monoclonal antibodies in the laboratory of the principal investigator, Dr. Taofeek Owonikoko in 
collaboration with Shi-Yong Sun, PhD. Paired fresh tumor biopsy will be limited to patients 
enrolled in the expansion cohort. The final decision to proceed with fresh biopsy will however, 
be based on the experience in the escalation phase of the study and will require express approval 
of celgene. 
Assess for myb protein expression by IHC in patients with adenoidcystic cancer and correlate 
with response to therapy. 
 
5.1.4 Flow Cytometry for Detection and Quantification of T-cell Subsets -  
At the appropriate time points as specified in the treatment schema (baseline, with the first 2 
restaging assessment and at disease progression), 7 mls of anticoagulated whole blood sample 
will be collected and sent to the lab of Dr. Edmund Waller, a collaborator at the Winship Cancer 
Institute, who will perform flow cytometry for the detection of different subsets of circulating T 
and B lymphocytes. 
 
5.1.5 ELISA Assay for Circulating Cytokine and Angiogenesis Mediators -  
ELISA detection and quantification of the cytokines of interest will be performed using 
previously published methods. Samples will be collected at baseline, with the first 2 restaging 
assessment and at disease progression. Samples will be loaded onto a 96-well microtiter plate 
coated with monoclonal antibody specific for the cytokine of interest. After a blocking step, 
samples will be diluted into a buffer and incubated with the primary antibody. After a washing 
step, antisera specific for the cytokine is added followed by additional incubation. Another 
washing step will be performed to be followed by the addition of peroxidase-conjugated 
secondary antibody. The concentrations of the respective cytokines will be determined in 
triplicate for each serum samples using an ELISA plate reader. A set of calibrators and assay 
controls will be run with each assay. The ELISA assays will be performed by Dr. Owonikoko’s 
lab. 
 


 
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5.2 Protocol Therapy  
5.2.1 Lenalidomide Description 
REVLIMID®  (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti-
angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) 
piperidine-2,6-dione and it has the following chemical structure:  
Chemical Structure of Lenalidomide 
 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.  
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 
0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically 
active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero. 
 
5.2.2 Clinical pharmacology 
Mechanism of action:  
Lenalidomide is a proprietary IMiD™ compound of Celgene Corporation. IMiD™ compounds 
have both immunomodulatory and anti-angiogenic properties which could confer antitumor and 
antimetastatic effects. Lenalidomide has been demonstrated to possess anti-angiogenic activity 
through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell migration, due at 
least in part to inhibition of Akt phosphorylation response to bFGF. In addition, lenalidomide has 
a variety of immunomodulatory effects. Lenalidomide stimulates T cell proliferation, and the 
production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates IL-12 
production. Upregulation of T cell derived IL-2 production is achieved at least in part through 
increased AP-1 activity.  
Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of 
mechanisms are postulated to be responsible for lenalidomide’s activity against multiple 
myeloma. Lenalidomide has been shown to increase T cell proliferation, which leads to an 
increase in IL-2 and IFN-gamma secretion. The increased level of these circulating cytokines 
augment natural killer cell number and function, and enhance natural killer cell activity to yield 
an increase in multiple myeloma cell lysis. In addition, lenalidomide has direct activity against 


 
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multiple myeloma and induces apoptosis or G1 growth arrest in multiple myeloma cell lines and 
in multiple myeloma cells of patients resistant to melphalan, doxorubicin and dexamethasone.  
Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the secretion 
of anti-inflammatory cytokines from peripheral blood mononuclear cells. Lenalidomide inhibited 
cell proliferation with varying effectiveness (IC50s) in some but not all cell lines.  Of cell lines 
tested, lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell 
lymphoma cell line with a deletion of one chromosome 5) but was much less effective in 
inhibiting growth of KG-1 cells (human myeloblastic cell line, also with a deletion of one 
chromosome 5) and other cell lines without chromosome 5 deletions.  Lenalidomide inhibited the 
expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro.   
 
Clinical Pharmacokinetics and Pharmacodynamics 
Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with 
maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. Co-
administration with food does not alter the extent of absorption (AUC) but does reduce the 
maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of 
lenalidomide is linear. Cmax and AUC increase proportionately with increases in dose. Multiple 
dosing at the recommended dose-regimen does not result in drug accumulation. 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the phase I 
studies.  Absorption was found to be rapid on both Day 1 and Day 28 with time to maximum 
blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, and 50mg).  No 
plasma accumulation was observed with multiple daily dosing.  Plasma lenalidomide declined in 
a monophasic manner with elimination half-life ranging from 2.8 to 6.1 hours on both Day 1 and 
28 at all 4 doses.  Peak and overall plasma concentrations were dose proportional over the dosing 
range of 5mg to 50mg.  Exposure (AUC) in multiple myeloma patients is 57% higher than in 
healthy male volunteers.  
 
Distribution: 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
Metabolism and excretion: 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. 
The process exceeds the glomerular filtration rate and therefore is partially or entirely active. 
Half-life of elimination is approximately 3 hours.  
 


 
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Clinical experience 
A phase I study in subjects with refractory or relapsed multiple myeloma was conducted to 
identify the maximum tolerated dose (MTD) and to evaluate the safety of lenalidomide given 
orally for up to 4 weeks at 5 mg/day, 10 mg/day, 25 mg/day and 50 mg/day. Secondary 
objectives included evaluation of response to lenalidomide, as well as pharmacokinetics and 
identification of surrogate markers to aid in defining mechanisms of action. Subjects who 
tolerated study drug with acceptable toxicity and were without disease progression were 
permitted to continue on therapy beyond 28 days as part of an extension phase for over 1 year. 
Twenty-seven subjects were enrolled, of whom 15 had undergone prior autologous stem cell 
transplantation and 16 had received prior thalidomide, with a median of 3 prior regimens (range 
2-6). All subjects had relapsed MM and 18 (72%) were refractory to salvage therapy. Two 
subjects were removed from study on the first day of treatment due to rapid disease progression, 
which resulted in renal dysfunction and rendered them ineligible. The first group of 3 subjects 
were treated for 28 d at 5 mg/d without any dose limiting toxicity (DLT). The second cohort of 3 
subjects commenced therapy at 10 mg/day. In one subject, DLT was encountered with grade 2 
fever as well as grade 3 leukopenia and neutropenia, resulting in removal from study before day 
28. Two subjects tolerated drug. Three additional subjects were treated at 10 mg/day with no 
attributable toxicity within the first 28 days. In the third cohort of 3 subjects at 25mg/day, drug 
was well tolerated within the first 28 days but grade 3 thrombocytopenia and grade 3 and 4 
neutropenia occurred during the second month, resulting in 2 subjects being removed from study. 
In the fourth cohort at 50mg/day, the first 3 subjects tolerated treatment without DLT in the first 
28 days and a subsequent 10 subjects also tolerated drug without DLT within the first 28 days. 
However, subsequent grade 3 thrombocytopenia and grade 3/4 neutropenia in the extension 
phase has prompted dose reduction and GCSF support in all subjects. No significant somnolence, 
constipation or neuropathy has been seen in any cohort. Median duration of therapy is currently 4 
months [range 2 weeks – 14 months] and 11 subjects continue on treatment. Maximal protein 
reductions seen during therapy in subjects who have received > 28d of treatment are summarized 
below: 
Table 2: Monoclonal protein reductions in a phase I study with lenalidomide 
  dose 
      pts  
      [n] 
    < 25% 
> 25%  <50% 
    >50% 
Progression 
      5 
    3 
         - 
          2 
        1 
         - 
      10 
    5 
         - 
          - 
        1 
         4 
      25 
    3 
         1 
          2 
        - 
         - 
      50 
   13 
         3 
          5 
        4 
         1 
Subtotals 
   24 
4 (17%) 
         9 (37%) 
6 (25%) 
5 (21%) 
 
Thus, best responses in protein of > 25% have been seen in 15 of 24 evaluable pts (63%), and a 
<25% reduction has been seen in 4 subjects to achieve stable disease or better in 19 of 24 (79%). 
Pharmacokinetics [days 1-4, and 28] have been completed in 24 subjects and reveal rapid 
absorption (t max: 1-1.5 h); monophasic elimination (t ½: 3.1-4.2 h), and low to moderate inter-
subject variability for AUC (11-52%) and Cmax (3-33%). Furthermore, there was no significant 
accumulation by day 28. In conclusion, these studies suggest lenalidomide at the dose levels 


 
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studied has anti-tumor activity, Continuous pharmacokinetics with convenient daily oral dosing 
and acceptable toxicity in subjects with relapsed and refractory multiple myeloma. Given the 
myelosuppression beyond day 28 seen in all subjects at 50 mg/day, this dose was considered to 
be the DLT, and thus the 25 mg/day dose level as a continuous daily schedule of administration 
was considered MTD. Given the activity of the drug seen at lower dose levels and the PK 
characteristics observed, 30 mg/day in divided or single daily dose was assessed for activity and 
safety, and to determine whether a divided dose schedule is superior. In addition, a 3-week on 
and one-week off schedule was assessed to determine if a cycling schedule would decrease the 
myelosuppression that was observed in earlier trials with daily dosing. In this phase II study, 70 
subjects with relapsed and refractory myeloma were enrolled at several centers in the U.S. 
Richardson et al reported that 26% of subjects required dose reduction due to myelosuppression 
in this study. Responses that were observed included 4% of subjects with complete responses, 
17% with partial responses and 33% with minimal responses. Progressive disease occurred in 
15% of subjects.17 It was concluded that daily dosing was better tolerated than twice daily dosing 
because of a lower incidence and severity of myelosuppression.  
Data from two phase III trials comparing lenalidomide + dexamethasone to single agent 
dexamethasone in patients with relapsed and/or refractory multiple myeloma were presented at 
the 10th international multiple myeloma workshop in Sydney Australia (Weber et al., 2005; 
Dimopoulos et al., 2005). Patients who had received 1-3 prior therapies, and progressing on their 
last therapy were randomized to receive lenalidomide, 25 mg/d x 21 d, placebo d22-28 plus 
dexamethasone, 40 mg, d 1-4, 9-12, 17-20, q 28d or placebo daily x 28 d plus dexamethasone, 40 
mg, d 1-4, 9-12, 17-20, q28d. Anemia, thrombocytopenia, neutropenia, fatigue, neuropathy, and 
constipation were also observed more often in lenalidomide + dexamethasone group compared to 
dexamethasone only group, however these events were generally manageable. 
 
Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through the RevAssist® program.   
Dosage form 
Lenalidomide will be supplied as capsules for oral administration.   
Packaging 
Lenalidomide will be shipped directly to patients.   Bottles will contain a sufficient number of 
capsules for one cycle of dosing.    
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold.     


 
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5.2.3 Prescribing Information  
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide will be 
provided in accordance with the  Celgene Corporation’s Revlimid REMS® program.  Per 
standard Revlimid REMS® program requirements,  all physicians who prescribe lenalidomide 
for research subjects enrolled into this trial, and all research subjects enrolled into this trial, must 
be registered in, and must comply with, all requirements of the Revlimid REMS® program.   
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site for IND 
studies. Only enough lenalidomide for one cycle of therapy will be supplied to the patient 
each cycle. 
Pregnancy Testing    
Must follow pregnancy testing requirements as outlined in the Revlimid REMS® program 
material. 
 
Special populations: 
Patients with renal insufficiency: the pharmacokinetics of lenalidomide in solid tumor patients 
with renal dysfunction has not been determined. In multiple myeloma patients, those with mild 
renal impairment had an AUC 56% greater than those with normal renal function. (see 
precautions: renal impairment). 
Patients with hepatic disease: the pharmacokinetics of lenalidomide in patients with hepatic 
impairment has not been studied. 
Age: the effects of age on the pharmacokinetics of lenalidomide have not been studied. 
Pediatric: no pharmacokinetic data are available in patients below the age of 18 years. 
Gender: the effects of gender on the pharmacokinetics of lenalidomide have not been studied. 
Race: pharmacokinetic differences due to race have not been studied. 
 
Deep Venous Thrombosis and Pulmonary Embolism 
Lenalidomide has demonstrated a significantly increased risk of DVT and PE in patients with multiple 
myeloma who were treated with Revlimid® (lenalidomide) combination therapy. Patients and physicians 
are advised to be observant for the signs and symptoms of thromboembolism. Patients should be 
instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm 
or leg swelling. Prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with 
Revlimid® (lenalidomide) may be required for patients enrolled in this current trial.  
 


 
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Other adverse events 
Most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, 
nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, uti, 
upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, 
chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, 
generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural 
effusion, pulmonary embolism, deep vein thrombosis, cva, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, death not specified and fractures. 
Complete and updated adverse events are available in the investigational drug brochure and the 
IND safety letters. 
 
5.3 Everolimus Description 
AFINITOR (everolimus), an inhibitor of mTOR, is an antineoplastic agent. The chemical name 
of 
everolimus 
is 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- 
dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-
methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-
tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-pentaone. 
The molecular formula is C53H83NO14 and the molecular weight is 958.2.  
The structural formula is  


 
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AFINITOR is supplied as tablets for oral administration containing 5 mg and 10 mg of 
everolimus together with butylated hydroxytoluene, magnesium stearate, lactose monohydrate, 
hypromellose, crospovidone and lactose anhydrous as inactive ingredients.  
 
5.3.1 Indication and Administration 
AFINITOR is a kinase inhibitor indicated for the treatment of patients with advanced renal cell 
carcinoma after failure of treatment with sunitinib or sorafenib. The recommended dose of 
AFINITOR for treatment of advanced renal cell carcinoma is 10 mg, to be taken once daily at the 
same time every day, either with or without food. AFINITOR tablets should be swallowed whole 
with a glass of water. The tablets should not be chewed or crushed. 
 
5.3.2 CLINICAL PHARMACOLOGY 
Mechanism of Action 
Everolimus is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, 
downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human 
cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory 
complex formation and inhibition of mTOR kinase activity. Everolimus reduced the activity of 


 
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S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-
BP), downstream effectors of mTOR, involved in protein synthesis. In addition, everolimus 
inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of 
vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown 
to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.  
 
Pharmacodynamics 
QT/QTc Prolongation Potential - In a randomized, placebo-controlled, crossover study, 59 
healthy subjects were administered a single oral dose of AFINITOR (20 mg and 50 mg) and 
placebo. There is no indication of a QT/QTc prolonging effect of AFINITOR in single doses up 
to 50 mg. Markers of protein synthesis show that inhibition of mTOR is complete after a 10 mg 
daily dose. 
Pharmacokinetics 
Everolimus is rapidly absorbed with a median Tmax of 1-2 hours. The bioavailability of the drug 
is believed to be 11% or greater. 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. 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. The coefficient of 
variation between patients is approximately 50%. Trough levels (24 hour post-dose) correlate 
well with AUC0-τ at steady-state during daily administration. About 20% of the drug in blood is 
in plasma, the remainder being sequestered in blood cells. The unbound fraction in plasma is 
about 26%. Everolimus is extensively metabolized in the liver, and eliminated in the bile. Major 
metabolites are inactive. Everolimus is a substrate of CYP3A4 and a substrate and moderate 
inhibitor of P-glycoprotein and so its metabolism is sensitive to drugs which modify these 
enzymes. Competitive inhibition could occur when everolimus is combined with drugs which are 
also CYP3A4 or P-glycoprotein substrates. The elimination half-life is approximately 30 hours.  
 
Absorption 
In patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours 
after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is 
dose-proportional between 5 mg and 10 mg. At doses of 20 mg and higher, the increase in Cmax 
is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg 
dose range. Steady-state was achieved within two weeks following once-daily dosing. 
Food effect: Based on data in healthy subjects taking 1 mg everolimus tablets, a high-fat meal 
reduced Cmax and AUC by 60% and 16%, respectively. No data are available with AFINITOR 5 
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Distribution 
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 
to 5000 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 AFINITOR 10 
mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients 
with moderate hepatic impairment. 
 
5.3.3 Metabolism 
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the 
main circulating component in human blood. Six main metabolites of everolimus have been 
detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-
opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were 
also identified in animal species used in toxicity studies, and showed approximately 100-times 
less activity than everolimus itself. In vitro, everolimus competitively inhibited the metabolism 
of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. The mean 
steady state Cmax following an oral dose of 10 mg daily is more than 12-fold below the Ki-
values of the in vitro inhibition. Therefore, an effect of everolimus on the metabolism of 
CYP3A4 and CYP2D6 substrates is unlikely. 
 
5.3.4 Excretion 
No specific excretion studies have been undertaken in cancer patients. Following the 
administration of a 3 mg single dose of radiolabelled everolimus in patients who were receiving 
cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in 
the urine. The parent substance was not detected in urine or feces. The mean elimination half-life 
of everolimus is approximately 30 hours. 
Patients with Renal Impairment 
Approximately 5% of total radioactivity was excreted in the urine following a 3 mg dose of 
[14C]-labeled everolimus. In a population pharmacokinetic analysis which included 170 patients 
with advanced cancer, no significant influence of creatinine clearance (25 – 178 mL/min) was 
detected on oral clearance (CL/F) of everolimus  
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The average AUC of everolimus in eight subjects with moderate hepatic impairment (Child-Pugh 
class B) was twice that found in eight subjects with normal hepatic function. AUC was positively 
correlated with serum bilirubin concentration and with prolongation of prothrombin time and 
negatively correlated with serum albumin concentration. A dose reduction for patients with 
Child-Pugh class B hepatic impairment is recommended. AFINITOR should not be used in 
patients with severe (Child-Pugh class C) hepatic impairment as the impact of severe hepatic 
impairment on everolimus exposure has not been assessed. 
Effects of Age and Gender 
In a population pharmacokinetic evaluation in cancer patients, no relationship was apparent 
between oral clearance and patient age or gender. 
Ethnicity 
Based on a cross-study comparison, Japanese patients (n = 6) had on average exposures that were 
higher than non-Japanese patients receiving the same dose. Based on analysis of population 
pharmacokinetics, oral clearance (CL/F) is on average 20% higher in Black patients than in 
Caucasians. The significance of these differences on the safety and efficacy of everolimus in 
Japanese or Black patients has not been established. 
 
5.3.5 Non Clinical Toxicology 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Administration of everolimus for up to 2 years did not indicate oncogenic potential in mice and 
rats up to the highest doses tested (0.9 mg/kg) corresponding respectively to 4.3 and 0.2 times 
the estimated clinical exposure (AUC0-24h) at the recommended human dose of 10 mg daily. 
Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, 
mutation test in L5178Y mouse lymphoma cells, and chromosome aberration assay in V79 
Chinese hamster cells). Everolimus was not genotoxic in an in vivo mouse bone marrow 
micronucleus test at doses up to 500 mg/kg/day (1500 mg/m2/day, approximately 255-fold the 
recommended human dose, based on the body surface area), administered as two doses, 24 hours 
apart. Based on non-clinical findings, male fertility may be compromised by treatment with 
AFINITOR. In a 13-week male fertility study in rats, testicular morphology was affected at 0.5 
mg/kg and above, and sperm motility, sperm count, and plasma testosterone levels were 
diminished at 5 mg/kg, which resulted in infertility at 5 mg/kg. Effects on male fertility occurred 
at the AUC0-24h values below that of therapeutic exposure (approximately 10%-81% of the 
AUC0-24h in patients receiving the recommended dose of 10 mg daily). After a 10-13 week 
non-treatment period, the fertility index increased from zero (infertility) to 60% (12/20 mated 


 
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females were pregnant). Oral doses of everolimus in female rats at ≥ 0.1 mg/kg (approximately 
4% the AUC0-24h in patients receiving the recommended dose of 10 mg daily) resulted in 
increases in pre-implantation loss, suggesting that the drug may reduce female fertility. 
Everolimus crossed the placenta and was toxic to the conceptus. 
In safety pharmacology studies, everolimus was devoid of relevant effects on vital functions 
including the cardiovascular, respiratory and nervous systems. Everolimus had no influence on 
QT interval prolongation. 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. Based on these findings, the potential of everolimus to 
affect vital functions in patients is low. 
Everolimus has no genotoxicity or carcinogenicity potential. All significant adverse events 
observed in preclinical toxicology studies with everolimus in mice, rats, monkeys and minipigs 
were consistent with the anticipated pharmacological action as an antiproliferative and 
immunosuppressant and at least in part reversible after a two or four week recovery period, with 
the exception of the changes in male reproductive organs, most notably testes. Ocular effects 
(lenticular disorders) observed in rats were not observed in any other species and are considered 
to be a species-specific disorder. The known pharmacokinetic half-life of 30 hours in patients, 
and the prolonged pharmacodynamic effect of several days demonstrated preclinically, justified 
initial use of a weekly regimen in patients as a means of investigating safety at doses higher than 
those used in previous transplant studies. At the same time, analysis of changes in a non-tumoral, 
blood borne biomarker of activity in patients permitted pharmacokinetic-pharmacodynamic 
modeling with extrapolation from preclinical findings to predict the likely effect of everolimus 
on its intracellular target in tumors, at different doses for both the weekly and daily regimens. 
 
5.3.6 Clinical Studies 
Everolimus has been investigated in various indications, including solid organ transplantation, 
hematologic and non-hematologic malignancies, and rheumatoid arthritis. Efforts to evaluate 
everolimus in the setting of rheumatoid arthritis have since been discontinued. Everolimus has 
been in clinical development for solid organ transplantation since 1996 and obtained marketing 
authorization in 2003 under the trade name Certican®. Certican® is indicated for prophylaxis of 
rejection in renal and cardiac transplantation in over 60 countries, including the majority of the 
European Union. Certican® is commercially available in tablets strengths of .25, .5, .75 and 1 
mg. In the United States Certican® is an investigational new drug in development for the 
indication of transplantation. Everolimus has been in development for patients with various 


 
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hematologic and nonhematologic malignancies since 2002, and has been evaluated either as a 
single agent or in combination with other antitumor agents, tyrosine kinase inhibitors, antibodies 
and aromatase inhibitors. Patients with metastatic renal cell carcinoma (mRCC) who failed a 
previous vascular endothelial growth factor receptor (VEGFr) tyrosine kinase inhibitor (TKI), 
advanced breast cancer patients, carcinoid neuroendocrine tumors, pancreatic islet cell tumors 
(pNET), hematologic malignancies including chronic myelogenous leukemia (CML) non-
Hodgkin’s and mantle cell lymphoma, hepatocellular, gastric, colorectal, gastrointestinal stromal 
tumors (GIST), prostate and other indications including sarcoma, head, neck, lung and 
glioblastoma multiforme conducted in investigator sponsored studies have or are being 
conducted. A Phase III, randomized, double blind, placebo controlled study in patients with 
mRCC who progressed on a VEGFr TKI recently demonstrated that everolimus, administered 
daily at an oral dose of 10 mg administered provides positive clinical benefit.10 Median 
progression free survival (PFS) was prolonged from 1.87 months for patients receiving placebo 
to 4.01 months for everolimus treated patients, assessed by central independent review blinded to 
clinical data (hazard ratio 0.30, 95% CI 0.22-0.40, p<0·0001). Median PFS was prolonged from 
1.87 months for patients receiving placebo to 4.9 months for everolimus treated patients, 
assessed by central independent review blinded to clinical data (hazard ratio 0.33, 95% CI 0.25-
0.43, p<0.001). Additionally, two Phase III combination studies are ongoing for patients with 
advanced pNET receiving best supportive care, and one in carcinoid tumors with Sandostatin 
LAR® Depot.  
An international, multicenter, randomized, double-blind trial comparing AFINITOR 10 mg daily 
and placebo, both in conjunction with best supportive care, was conducted in patients with 
metastatic renal cell carcinoma whose disease had progressed despite prior treatment with 
sunitinib, sorafenib, or both sequentially. Prior therapy with bevacizumab, interleukin 2, or 
interferon-α was also permitted. Randomization was stratified according to prognostic score1 
and prior anticancer therapy. 
Progression-free survival (PFS), documented using RECIST (Response Evaluation Criteria in 
Solid Tumors) was assessed via a blinded, independent, central radiologic review. After 
documented radiological progression, patients could be unblinded by the investigator: those 
randomized to placebo were then able to receive open-label AFINITOR 10 mg daily. In total, 
416 patients were randomized 2:1 to receive AFINITOR (n=277) or placebo (n=139). 
Demographics were well balanced between the two arms (median age 61 years; 77% male, 88% 


 
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Caucasian, 74% received prior sunitinib or sorafenib, and 26% received both sequentially). 
AFINITOR was superior to placebo for progression-free survival. The treatment effect was 
similar across prognostic scores and prior sorafenib and/or sunitinib. The overall survival (OS) 
results were not mature and 32% of patients had died by the time of cut-off. 
Supplier(s) 
Novartis Pharmaceuticals Corporation will supply everolimus (AfinitorR) to study participants at 
no charge. 
Drug Handling 
Procedures for proper handling and disposal of anticancer drugs should be considered. 
AFINITOR tablets should not be crushed. Direct contact of crushed tablets with the skin or 
mucous membranes should be avoided. If such contact occurs, wash thoroughly as outlined in 
the references. Personnel should avoid exposure to crushed tablets. 
Dosage form 
Everolimus will be supplied as tablets for oral administration.  
Packaging 
Everolimus will be provided to patients through the Investigational Drug Supply Pharmacy at the 
Winship Cancer Institute at the beginning of each cycle. Blister packets will contain sufficient 
number of capsules for one cycle of dosing.    
Storage 
Store AFINITOR (everolimus) tablets at 25° C (77°F); excursions permitted between 15°–30°C 
(59°–86°F). Store in the original container, protect from light and moisture. Keep this and all 
drugs out of the reach of children. 
 
5.4 Screening and Eligibility 
The Investigator is responsible for keeping a record of all subjects who sign an Informed 
Consent Form for entry into the study. All subjects will be screened for eligibility. Screening 
procedures are outlined in Section 2, Schedule of Study Assessments and unless otherwise 
specified, must take place within 28 days prior to initiation of therapy.  
Approximately 45 subjects with advanced refractory solid malignancies will be screened for 
enrollment and must meet the eligibility criteria below.  
Subjects must meet the following inclusion/exclusion criteria to be eligible for the study. 


 
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5.4.1 Inclusion Criteria 
• Subjects must meet the following inclusion/exclusion criteria to be eligible for the study. 
• Ability to understand and willingness to voluntarily sign an informed consent form.  
• Histologic or cytologic confirmation of a solid malignancy  
• Age ≥18 years at the time of signing the informed consent form. Because no dosing or 
adverse event data are currently available on the use of everolimus in combination with 
lenalidomide in patients <18 years of age, children are excluded from this study. 
• Able to adhere to the study visit schedule and other protocol requirements. 
• Patients must have at least one measurable site of disease according to RECIST 1.1 
criteria that has not been previously irradiated. If the patient has had previous radiation to 
the marker lesion(s), there must be evidence of progression since the radiation. 
• Diagnosed with advanced refractory solid malignancies or intolerant of standard therapy 
for the stage of the disease (because there is currently no standard approved therapy for 
adenoidcystic carcinoma, therefore there is no requirement of prior therapy for this 
patient population). 
• All previous cancer therapy, including radiation, hormonal therapy and surgery, must 
have been discontinued at least 4 weeks prior to treatment in this study. A minimum of 6 
weeks treatment break is required in case of nitrosoureas or mitomycin C.  
• ECOG performance status of 0 - 2 at study entry (see Appendix A).  
• Able to receive prophylactic anticoagulation with aspirin, warfarin or low molecular 
weight heparin when required for lenalidomide administration  
• 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. 
 
• Laboratory test results within these ranges:  
o Absolute neutrophil count 1500 ≥ /mm³  
o Platelet count ≥ 100,000/mm³  
o Hb ≥9 g/dL 
o Creatinine within  institutional limits of normal or Creatinine clearance ≥ 60 
ml/min/m2 if elevated creatinine (see Appendix F: Cockcroft-Gault estimation of CrCl): 


 
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o Total bilirubin < 2.0 mg/dL or < 1.5.0 x ULN for the institution whichever is 
higher  
o AST (SGOT) and ALT (SGPT) < 2.x ULN or < 5 x ULN if hepatic metastases are 
present.  
• All study participants must be registered into the mandatory Revlimid REMS® program, 
and be willing and able to comply with the requirements of the REMS® program. 
• Females of reproductive potential must adhere to the scheduled pregnancy testing as 
required in the Revlimid REMS® program.  
• Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to and 
again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 
days) and must either commit to continued abstinence from heterosexual intercourse or 
begin TWO acceptable methods of birth control, one highly effective method and one 
additional effective method AT THE SAME TIME, at least 28 days before she starts 
taking lenalidomide.  FCBP must also agree to ongoing pregnancy testing.  Men must 
agree to use a latex condom during sexual contact with a FCBP even if they have had a 
successful vasectomy.  See Appendix B: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods. 
 
5.4.2 Exclusion criteria 
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements 
including signing the informed consent form.  
• Pregnant or breast feeding females. (Lactating females must agree not to breast feed 
while taking lenalidomide).  
 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy 
or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has 
had menses at any time in the preceding 24 consecutive months). 
 
 


 
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• Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study or confounds the 
ability to interpret data from the study.  
• Use of any other experimental drug or therapy within 28 days of baseline.  
• Known hypersensitivity to thalidomide or everolimus (including other rapamycins, 
sirolimus and temsirolimus).  
• The development of erythema nodosum if characterized by a desquamating rash while 
taking thalidomide or similar drugs.  
• Prior treatment with lenalidomide or everolimus  
• Concurrent use of other anti-cancer agents or treatments. 
• Patients known to be positive for HIV or infectious hepatitis, type B or C requiring active 
therapy (hepatitis B seropositivity due to Hep B virus vaccine is not an exclusion). Patients on 
combination antiviral therapy are ineligible because of the potential for pharmacokinetic 
interactions with everolimus and or lenalidomide. In addition, these patients are at 
increased risk of lethal infections when treated with marrow-suppressive therapy. 
Appropriate studies will be undertaken in this patient population.  
• Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).  
o History of liver disease, such as cirrhosis or chronic active hepatitis B and C.  
o Presence of Hepatitis B surface antigen (HbsAg) 
o Presence of Hepatitis C antibody test (anti-HCV)  
o Note: A detailed assessment of Hepatitis B/C medical history and risk factors 
must be done at screening for all patients.  HBV DNA and HCV RNA PCR 
testing are required at screening for all patients with a positive medical history 
based on risk factors and/or confirmation of prior HBV/HCV infection. 
• Symptomatic brain metastasis. Patients with treated brain metastasis must be completely 
weaned off of steroid therapy for at least 14 days prior to starting protocol therapy  
• Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent. (Topical or inhaled corticosteroids are allowed). 
• Patients should not receive immunization with attenuated live vaccines within one week 
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• Diagnosed venous thromboembolic disease within the preceding 6 months (patient on full 
dose or prophylactic anticoagulation are eligible)  
• Patients receiving any medications or substances that are inhibitors or inducers of 
CYP450 enzyme(s) are ineligible. Lists of excluded medications and substances known 
or with the potential to interact with theCYP450 enzyme(s) are provided in Appendix E. 
• History of other malignancies except: (i) adequately treated basal or squamous cell 
carcinoma of the skin; (ii) curatively treated, a) in situ carcinoma of the uterine cervix, b) 
prostate cancer, or c) superficial bladder cancer; or (iii) other curatively treated solid 
tumor with no evidence of disease for ≥ 3 years 
• Patients, who have had a major surgery or significant traumatic injury within 4 weeks of 
start of study drug, patients who have not recovered from the side effects of any major 
surgery (defined as requiring general anesthesia) or patients that may require major 
surgery during the course of the study 
• Patients with an active, bleeding diathesis 
 
5.4.3 Inclusion of Women and Patients of Ethnic Minority Background  
Both men and women of all races and ethnic groups are eligible for this trial.  
 
5.5 Visit schedule and assessments 
Screening Assessments and all on study scheduled visits and assessments are outlined in Section 
2 Table of Study Assessments.  
At treatment discontinuation, subjects will undergo off study evaluations per the Schedule of 
Assessments, Section 2. In addition, a safety assessment will be done approximately 30 days post 
the last dose of protocol therapy.  


 
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5.6 Drug Administration 
5.6.1 Treatment assignments 
Patient will be assigned to dose cohort in the order they enter the study using the modified 
Fibonacci dose escalation schema as detailed in Table 1, section 5.1. 
5.6.2 Dosing regimen 
The planned starting dose of lenalidomide for investigation is 10 mg/day, orally on days 1 - 28 
(28 day cycle). Dosing will be in the morning at approximately the same time each day. 
Prescriptions must be filled within 7 days. Subjects deemed by the Principal Investigator to be at 
heightened risk of venous thromboembolism will receive prophylaxis with daily aspirin (81mg or 
325 mg) or low molecular weight heparin if intolerant to ASA. Coumadin should be used with 
caution and close monitoring of INR required. 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day.  If it 
is missed for the entire day, it should not be made up. Patients who take more than the prescribed 
dose of lenalidomide should be instructed to seek emergency medical care if needed and contact 
study staff immediately. 
The planned starting dose of everolimus (RAD001) is an approved dose of 5 mg/day on a 
continuous basis, days 1- 28. RAD001 will be self-administered (by the patients themselves). 
The investigator will instruct the patient to take the study drug exactly as specified in the 
protocol. RAD001 will be administered orally as once daily dose of 5 mg or 10 mg (one or two 5 
mg tablets) starting from study day 2, cycle 1 until progression of disease or unacceptable 
toxicity. Patients will be instructed to take RAD001 in the morning, at the same time each day.  
RAD001 may be taken with or without food.  
If vomiting occurs, no attempt should be made to replace the vomited dose.  
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded. 
Medication labels will comply with US legal requirements and be printed in English. They will 
supply no information about the patient. The storage conditions for study drug will be described 
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RAD001 will be provided by Novartis. RAD001 is formulated as tablets for oral administration 
of 5mg strength. Tablets are blister-packed under aluminum foil in units of 10 tablets, which 
should be opened only at the time of administration as drug is both hygroscopic and light-
sensitive. 
 
 
Subjects experiencing adverse events may need study treatment modifications (See section 5.7). 
5.6.3 Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide or everolimus 
unless they are wearing gloves. 
5.6.4 Record of administration 
Accurate records will be kept in the source documents of all drug administration (including 
prescribing and dosing).  
5.7 Dose Continuation, Modification and Interruption    
Subjects will be evaluated for adverse events (AEs) at each visit with the NCI CTCAE v4.0 
(Appendix C: NCI CTCAE v4.0) used as a guide for the grading of severity. Sections below 
describe dose reduction steps, instructions for initiation of a new cycle of therapy and dose 
modifications during a cycle of therapy.  
5.7.1 Dose Reduction Steps 
This dose reduction steps will guide dose modification for Lenalidomide and Everolimus in 
patients who either experienced a DLT or who develop  treatment related toxicity beyond cycle 1 
of therapy. The decision for dose escalation or deesclation for dose cohorts will however proceed 
according to the dose escalation schema (Table 1, Section 5.1). 
 
Table 3: LENALIDOMIDE Dose Reduction Steps 
 
If toxicity occurred at
  
Reduce dose to


 
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25 mg  
20 mg daily  
20 mg  
15 mg daily  
15 mg  
10 mg daily  
10 mg  
10  mg daily on Days 1-21 every 28 days 
10 mg daily on Days 1 – 21 of 28 
5 mg daily on Days 1-21 every 28 days 
 
 
 
Table 4: Everolimus Dose Reduction Steps 
If the Toxicity occurred at 
 --- (MG/DOSE): 
Reduce dose to 
--- (MG/DOSE): 
 
0 (starting dose) 
10 mg daily 
-1 
5 mg daily 
-2 
5 mg every other day 
 
5.7.2 Instructions for initiation of a New Cycle  
A new course of treatment may begin on the scheduled Day 1 of a new cycle if:: 
• The ANC is ≥ 1500/mm³;  
• The platelet count is 100,000≥ /mm³; (If held during the previous cycle for low platelet 
count, prophylactic anti-coagulation should be re-started when platelet count is ≥75,000) 
• Any drug-related rash or neuropathy that may have occurred has resolved to ≤ grade 1 
severity;  
• Any other drug-related adverse events that may have occurred have resolved to ≤ grade 2 
severity.  
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly and 
a new cycle of treatment will not be initiated until the toxicity has resolved as described above. If 
a lenalidomide or everolimus dose reduction was taken during the previous cycle, and the cycle 
was completed without requiring further dose modification, then the next cycle will start at the 
same reduced dose. If drug dosing was omitted for the remainder of the previous cycle or if 
the new cycle is delayed due to toxicity newly encountered on the scheduled Day 1, then the 


 
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new cycle will be started with a one-level dose reduction of the drug to which the toxicity was 
attributed. 
5.7.3 Instructions for dose modifications or interruption during a cycle 
This information is meant to assist in dose modification for individual study participant who 
experienced a treatment-related toxicity. The dose escalation schema for the study cohort will 
proceed as described under the escalation schema (refer Table 1, Section 5.1). 
In the event of treatment interruption due to study-drug related toxicity, both agents will be held 
until the patient is able to resume further therapy. At the time of dosing resumption, alternate 
dose reduction strategy will be employed if the dose reduction is necessitated by hematologic 
toxicity. This alternate dose reduction will always start with Lenalidomide (not required if 
already at the minimum dose of 5mg) followed by Everolimus if further reduction is still 
necessary. In the case of non-hematological toxicity, dose reduction will be limited to the drug 
with the highest likelihood of attribution. In case of equal likelihood of attribution or where clear 
attribution is impossible, simultaneous reduction of both drugs will be effected at resumption of 
therapy.  
NB: Patients unable to resume treatment within the allotted time period for recovery from 
treatment-related toxicities detailed in Table 5  and Table 6 may be allowed to resume treatment 
with express approval of the study sponsor provided they have evidence of clinical benefit from 
treatment and the toxicity has resolved to a level considered safe for further treatment with 
everolimus or lenalidomide. Also, patient may be allowed to continue on only one study drug if a 
permanent discontinuation of the other study drug is mandated by a unique treatment-related 
toxicity e.g. discontinuation of lenalidomide for desquamating rash. 
 
 
 


 
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Table 5: Dose Modifications NOTE: Please consider altering threshold hematologic toxicity criteria for 
dose modifications depending on specific disease and patient population involved in study, and with 
consideration given to the Inclusion Criteria and the Instructions for Initiation of a New Cycle.  Also consider 
whether the use of G-CSF is permitted as outlined in the neutropenia row.  For combination therapy trials, 
please consider the following recommendations/issues: 1) it is highly recommended that appropriate dose 
modifications (holding and reductions as needed) for other drugs in the regimen are incorporated into this 
table, 2) whether the holding of 1 drug requires other drugs to be held, 3) for drugs with overlapping 
toxicities (hematologic toxicities, for example) please consider, if appropriate, alternating dose reductions 
by episode (reduce 1 drug for the first episode and then another drug for the second episode and 
continuing to alternate which drug is reduced for subsequent reductions as needed, and 4) whether dose 
modifications for the category ”other non-hematologic toxicities ≥ grade 3” should be based on attribution 
(this is recommended). 
 
NCI CTC Toxicity Grade 
Dose Modification Instructions 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia 
• 
Hold (interrupt) lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If neutropenia has resolved to ≤ grade 2 within 14 days, restart 
lenalidomide at next lower dose level and continue through the 
scheduled end of the cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at the start of the 
next cycle.  Omitted doses are not made up.  If neutropenia is the 
only toxicity for which a dose reduction is required, G-CSF may be 
used and the lenalidomide dose maintained prior to considering dose 
reduction for Everolimus. 
Thrombocytopenia 
≥Grade 3 (platelet count 
< 50,000/mm³) 
• 
Hold (interrupt) lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If thrombocytopenia resolves to ≤ grade 2 prior to Day 21 of the 
current cycle, restart lenalidomide at next lower dose level and 
continue through the scheduled Day 21 of the current cycle.  
Otherwise, omit for remainder of cycle and reduce the dose of 
lenalidomide by 1 dose level at the start of the next cycle.  Omitted 
doses are not made up. 
Platelet count < 
50,000/mm³ 
• 
Hold prophylactic anti-coagulation, if applicable. 
• 
Restart prophylactic anti-coagulation when platelet count is ≥ 
75,000/mm³. 
Non-blistering rash 
 
Grade 3 
 
 
 
 
             Grade 4 
 
• 
If Grade 3, hold (interrupt) lenalidomide dose.  Follow weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to Day 28, restart 
lenalidomide at next lower dose level and continue through the 
scheduled end of the cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at the start of the 
next cycle.  Omitted doses are not made up. 
 
 
• 
If Grade 4, discontinue lenalidomide.  Remove patient from study. 
Desquamating 
(blistering) rash- any 
Grade  
• 
Discontinue lenalidomide.  Remove patient from study. 


 
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Table 5: Dose Modifications NOTE: Please consider altering threshold hematologic toxicity criteria for 
dose modifications depending on specific disease and patient population involved in study, and with 
consideration given to the Inclusion Criteria and the Instructions for Initiation of a New Cycle.  Also consider 
whether the use of G-CSF is permitted as outlined in the neutropenia row.  For combination therapy trials, 
please consider the following recommendations/issues: 1) it is highly recommended that appropriate dose 
modifications (holding and reductions as needed) for other drugs in the regimen are incorporated into this 
table, 2) whether the holding of 1 drug requires other drugs to be held, 3) for drugs with overlapping 
toxicities (hematologic toxicities, for example) please consider, if appropriate, alternating dose reductions 
by episode (reduce 1 drug for the first episode and then another drug for the second episode and 
continuing to alternate which drug is reduced for subsequent reductions as needed, and 4) whether dose 
modifications for the category ”other non-hematologic toxicities ≥ grade 3” should be based on attribution 
(this is recommended). 
 
NCI CTC Toxicity Grade 
Dose Modification Instructions 
Neuropathy 
 
Grade 3 
 
 
 
 
Grade 4 
 
• 
If Grade 3, hold (interrupt) lenalidomide dose.  Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to Day 28, restart 
lenalidomide at next lower dose level and continue through the 
scheduled end of the cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at the start of the 
next cycle.  Omitted doses are not made up. 
 
 
• 
If Grade 4, discontinue lenalidomide.  Remove patient from study. 
Venous 
thrombosis/embolism 
≥ Grade 3 
• 
Hold (interrupt) lenalidomide and start anticoagulation; restart 
lenalidomide at investigator’s discretion (maintain dose level). 
• 
Omit lenalidomide for remainder of cycle. See Anticoagulation 
Consideration (Section 5.7.2) 
Hyperthyroidism or 
hypothyroidism 
• 
Omit lenalidomide for remainder of cycle, evaluate etiology, and 
initiate appropriate therapy.  
• 
Resume lenalidomide at the same dose for 1st occurrence 
• 
Reduce dose of lenalidomide with 2nd occurrence 
• 
See Instructions for Initiation of a New Cycle   
other non-hematologic 
toxicity ≥ Grade 3 
• 
Hold (interrupt) lenalidomide dose.  Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 2 prior to Day 28, restart 
lenalidomide and continue through the scheduled end of the cycle.  
Otherwise, omit for remainder of cycle.  Omitted doses are not made 
up.  For toxicity attributed to lenalidomide, reduce the lenalidomide 
dose by 1 dose level when restarting lenalidomide. 


 
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Table 6: Dose Interruption/Modification Guidelines for Everolimus 
Please note that in case of hematological toxicity, Everolimus dose reduction should be considered only if the 
dose reduction for lenalidomide has been effected as per Table 5 above and found to be ineffective or 
insufficient to allow the patient to safely resume therapy per protocol guidelines 
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2  
(except pneumonitis – refer to Table 3-2) 
If the toxicity is tolerable to the patient, maintain 
the same dose. If the toxicity is intolerable to 
patient, interrupt RAD001 until recovery to grade 
1. Then reintroduce RAD001 at same dose. 
If event returns to grade 2, then  interrupt 
RAD001 until recovery to grade 1. Then 
reintroduce RAD001 at the lower dose level. 
Grade 3 
(except hyperlipidemia*) 
(except pneumonitis – refer to Table 3-2) 
Interrupt RAD001 until recovery to grade 1. 
Then reintroduce RAD001 at the lower dose 
level. For pneumonitis consider the use of a short 
course of corticosteroids. 
Grade 4 
Discontinue RAD001. 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets <75, ≥ 50x109/L)  
Interrupt RAD001 until recovery to grade 1 (>75 
x109/L). Then reintroduce RAD001 at initial dose. 
If thrombocytopenia again returns to grade 2,  
interrupt RAD001 until recovery to grade 1. 
Then reintroduce RAD001 at the lower dose 
level.  
Grade 3 Thrombocytopenia (platelets <50, ≥ 25 x109/L)  
Interrupt RAD001 until recovery to grade ≤1 
(platelets ≥ 75 x109/L).  Then resume  RAD001 at 
one dose level lower.  If grade 3 
thrombocytopenia recurs, discontinue RAD001. 
Grade 4 Thrombocytopenia (platelets < 25 x109/L) 
Discontinue RAD001. 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L) 
Interrupt RAD001 until recovery to grade 1 ( 
neutrophils ≥ 1.5 x 109/L). Then resume RAD001 
at the initial dose.  If ANC again returns to Grade 
3, hold RAD001 until the ANC ≥ 1.5 x 109/L.  
Then resume RAD001 dosing at the lower dose 
level.  Discontinue patient from study therapy for 
a third episode of grade 3 neutropenia. 
Grade 4 Neutropenia (neutrophils < 0.5 x109/L) 
Interrupt RAD001 until recovery to grade  1  
(neutrophils ≥ 1.5 x 109/L). Then resume RAD001 
at the lower dose level. If grade 3 or grade 4 
neutropenia occurs despite this dose reduction, 
discontinue RAD001. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt RAD001 until resolution of fever and 
neutropenia to grade ≤ 1. Hold further RAD001 
until the ANC ≥ 1,500/mm3 and fever has 
resolved. Then resume RAD001 at the lower 
dose level. If febrile neutropenia recurs, 
discontinue RAD001. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue RAD001. 
Any hematological or non-hematological toxicity requiring 
interruption for ≥ 3 weeks 
Discontinue RAD001 
 


 
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Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be managed 
using medical therapies (see Sec. 3.2.5.2). 
5.7.4 Monitoring of RAD001 suspected toxicities  
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value suspected to be related to RAD001 must be followed at least weekly 
until the adverse event or abnormal laboratory resolves or returns to grade 1. If a patient requires 
a dose delay of > 21 days from the intended day of the next scheduled dose, then the patient must 
be discontinued from the study. 
5.7.5 Known Undesirable Side Effects of RAD001 
Overall, the most frequent adverse effects suspected to be related to RAD001 have been 
stomatitis, rash,  anemia, fatigue, asthenia, diarrhea, anorexia, nausea, hypercholesterolemia, 
mucosal inflammation, vomiting, hypertriglyceridemia, cough, peripheral edema, dry skin, 
epistaxis, pruritus and dyspnea. The most common Grade 3 or 4 adverse reactions suspected to 
be related to treatment were anemia, infections, hyperglycemia, stomatitis, fatigue, lymphopenia, 
hypercholesterolemia, pneumonitis, and elevated gammaglutamyltransferase concentrations. 
The principal DLT in Phase 1 trials has been Grade 3 stomatitis. For guidance on management of 
stomatitis refer to Section 5.7.6. 
Hyperlipidemia was reported as a serious adverse reaction. It is a recognized side-effect of 
rapamycins. Use of lipid-lowering drugs should be associated with dietary recommendations. 
Monitoring of blood lipid levels requires patients to be fasting so that this aspect must be verified 
when interpreting results. For guidance on management of hyperlipidemia refer to Section 5.7.7. 
Hyperglycemia was reported as a serious adverse reaction. Similarly, the fasting state of patients 
should be verified when interpreting results. For guidance on management of hyperglycemia 
refer to Section 5.7.7. 
Pneumonitis is a recognized adverse effect of rapamycins (sirolimus, temsirolimus, and 
everolimus). Numerous case reports in the literature suggest that rapamycin-associated 
pneumonitis is relatively unaggressive, limited in extent, and reversible upon drug 
discontinuation. The term ‘pneumonitis’ is used here to describe non-infectious, non-malignant 
infiltration in the lungs which is evident radiologically. More precise diagnosis should follow 
histocytological examination following lung biopsy, generally during bronchoscopy which may 
or may not be symptomatic. Advice on the management of pneumonitis has been provided in 
Table 7.  
In oncology studies with RAD001, severe pneumonitis suspected as drug-related has been 
reported as a serious adverse event on 13 occasions and additionally in the following associated 
preferred terms including acute respiratory distress syndrome (n=2), alveolitis (n=1) and allergic 
alveolitis (n=1), interstitial lung disease (n=10), lung infiltration (n=23), cryptogenic organizing 
pneumonia, lung consolidation, pulmonary alvealoar haemorrhage, pulmonary toxicity and 
pulmonary fibrosis (n=1, each). One fatal case of drug-related pneumonitis was reported for a 
patient with metastatic infiltrating ductal carcinoma of the breast treated with 10 mg/day, which 


 
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developed approximately two months after starting RAD001. Cytology for both the pleural and 
pericardial fluids were positive for malignancy.  The death was considered possibly related to the 
underlying late stage tumor and study drug. Additionally, one patient treated with 10 mg/day 
died due to severe acute respiratory distress syndrome and septic shock. Thoracic CT scan 
demonstrated condensation in the majority of the left lower lobe and frosted glass appearance in 
the left upper lobe, lingula, and right lung. 
Along with the cases of non-infectious pneumonitis, serious opportunistic infections have also 
been reported in cancer patients treated with RAD001: mycobactrium, aspergillus, and fatal 
candidal sepsis, and  fatal pneumocystis carnii in particular. Because RAD001, as other 
rapamycins, inhibits proliferation of activated lymphocytes and reduces neutrophil counts, 
treatment with RAD001 must be considered as predisposing patients to the risk of infection. This 
risk will be higher in patients severely immunocompromised because of their underlying disease 
and/or co-medications. Outcome may be fatal in case of serious infections.  
A reduction in blood cell counts is frequent when RAD001 therapy is initiated. Without clinical 
significance and infrequently, anemia and thrombocytopenia have been reported. In heavily 
pretreated patients with aggressive lymphoma, the incidence of grade 3 anemia, neutropenia, and 
thrombocytopenia was reported to be 11%, 16%, and 30%, respectively. Serious, suspected drug-
related hemorrhages have been exceptional. Nevertheless, RAD001 should be considered as 
predisposing patients to hemorrhage, potentially fatal, should they develop severe drug-related 
thrombocytopenia. 
Discrete, reversible changes in liver enzymes have been found to occur in numerous patients 
during treatment with RAD001 in oncology clinical studies, and in a study in rheumatoid 
arthritis. In oncology studies, these changes may be evident only in patients without severe 
underlying morbidity. The increase in transaminase’s (AST and ALT) generally appears after 4 
weeks of treatment. In all but a few cases it does not exceed Grade 1 (≤ 2.5 x ULN). Similarly, 
mild increases in alkaline phosphatases can coexist. Spontaneous corrections or intermittent 
correction with continued treatment can occur. Serum bilirubin is not increased.  In studies of 
patients with advanced cancers, clinically relevant changes in liver enzymes have been 
invariably associated with the presence of liver metastases and/or progression of the underlying 
cancer.  
Renal failure has been reported in five suspected cases to date. One patient with no alternative 
explanation made a complete recovery following study drug adjustment and no treatment/therapy 
for the event. The rest or the patients had concurrent morbidities, which might have contributed 
to the reported events. 
Hypophosphatemia, hypomagnesemia, hyponatremia and hypocalcemia have been reported as 
serious adverse reactions. Electrolytes should be monitored in patients treated with RAD001. 
Table 6 provides general recommendations for the management of patients, with suspected drug 
toxicities while on treatment with RAD001 as single-agent therapy. 
More detailed information regarding RAD001 reported suspected toxicities and individual cases 
is provided in the [Investigator’s Brochure]. 


 
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5.7.6 Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to RAD001 should be treated using local supportive 
care. Please note that investigators in earlier trials have described the oral toxicities associated 
with RAD001 as mouth ulcers, rather than mucositis or stomatitis. If your examination reveals 
mouth ulcers rather than a more general inflammation of the mouth, please classify the adverse 
event as such. Please follow the paradigm below for treatment of stomatitis/oral mucositis/mouth 
ulcers: 
1. For mild toxicity (Grade 1), use conservative measures such as non-alcoholic mouth wash 
or salt water (0.9%) mouth wash several times a day until resolution. 
2. For more severe toxicity (Grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or Grade 3 in which case patients cannot maintain adequate oral 
alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., local 
anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®). 
3. Agents containing 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 RAD001 metabolism, thereby 
leading to higher RAD001 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. 
Note:  Stomatitis/oral mucositis should be appropriately graded using the functional grading 
given on the NCI-CTC for adverse events, version 3.0. 
5.7.7 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. Grade 2 
hypercholesterolemia (> 300 mg/dL or 7.75 mmol/L) or Grade 2 hypertriglyceridemia (>2.5 x 
ULN) should be treated with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor 
(e.g., atorvastatin, pravastatin) or appropriate lipid-lowering medication, in addition to diet. 
Patients should be monitored clinically and through serum biochemistry for the development of 
rhabdomyolysis and other adverse events as required in the product label/data sheets for HMG-
CoA reductase inhibitors. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated with 
an increased risk of a rare but serious skeletal muscle toxicity manifested by rhabdomyolysis, 
markedly elevated creatine kinase (CPK) levels and myoglobinuria, acute renal failure and 
sometimes death. The risk versus benefit of using this therapy should be determined for 
individual patients based on their risk of cardiovascular complications of hyperlipidemia. 
Grade 3 hyperglycemia has been observed in patients receiving RAD001 therapy. In many cases 
in study RAD001 C2222, the affected patients had an abnormal fasting glucose at baseline. 


 
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Based on this finding, it is suggested that optimal glucose control should be achieved before 
starting a patient on RAD001 and should be monitored during RAD001 therapy. 
5.7.8 Management of non-infectious pneumonitis 
Both asymptomatic radiological changes (grade 1) and symptomatic non-infectious pneumonitis 
(grade 2 = not interfering with activities of daily living or grade 3 = interfering with activities of 
daily living and oxygen indicated) have been noted in patients receiving RAD001 therapy. Non-
infectious pneumonitis has been associated with RAD001 and other mTOR inhibitors (Atkins 
2004). In order to monitor for asymptomatic (grade 1) pulmonary infiltrates, a chest X-ray is 
required if a CT scan of chest is not used for bi-monthly disease evaluations. Additional chest 
CT scans may be performed, when clinically necessary. If non-infectious pneumonitis develops, 
a consultation with a pulmonologist should be considered. If the patient develops grade 3 
pneumonitis, treatment with RAD001 should be interrupted and the patient should be treated as 
medically indicated (short course corticosteroids, oxygen, etc). 
Management of non-infectious pneumonitis suspected to be associated with RAD001 and dose 
modifications instructions are provided in Table 3-2  


 
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Table 7 
Management of non-infectious pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis  
RAD001 Dose Adjustment 
Grade 1 
CT scans with lung windows 
and pulmonary function 
testing including: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat 
chest x-ray/CT scan every 2 
Cycles until return to 
baseline. 
No specific 
therapy is required 
Administer 100% of RAD001 dose. 
Grade 2 
CT scan with lung windows 
and pulmonary function 
testing including: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat 
each subsequent Cycle until 
return to baseline. Consider 
bronchoscopy *  
Symptomatic only. 
Prescribe 
corticosteroids if 
cough is 
troublesome. 
Reduce RAD001 dose until recovery 
to ≤ Grade 1. RAD001 may also be 
interrupted if symptoms are 
troublesome. Patients will be 
withdrawn from the study if they fail 
to recover to ≤ Grade 1 within 3 
weeks. 
Grade 3 
CT scan with lung windows 
and pulmonary function 
testing including: spirometry, 
DLCO, and room air O2 
saturation at rest.; Repeat 
each subsequent Cycle until 
return to baseline. 
Bronchoscopy is 
recommended * 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Hold treatment until recovery to ≤ 
Grade 1. May restart protocol 
treatment within 2 weeks at a 
reduced dose (by one level) if 
evidence of clinical benefit. 
Patients will be withdrawn from the 
study if they fail to recover to ≤ 
Grade 1 within 2 weeks.  
Grade 4 
CT scan with lung windows 
and required pulmonary 
function testing includes: 
spirometry, DLCO, and room 
air O2 saturation at rest. 
Repeat each subsequent 
Cycle until return to baseline. 
Bronchoscopy is 
recommended *. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Discontinue treatment. 
*A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 
 
All interruptions or changes to study drug administration must be recorded. 
 
 
5.8 Treatment compliance 
Research center personnel will review the dosing instructions with subjects. Subjects will be 
asked to maintain a diary to record the drug administration (Appendix Y). Subjects will be asked 
to bring any unused drug and empty drug containers to the research center at their next visit. 
Research personnel will count and record the number of used and unused drug at each visit and 
reconcile with the patient diary.  
Any unused Revlimid® (lenalidomide) should be returned to the patient for disposition in 
accordance with the RevAssist® program. 


 
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Any unused everolimus pills should be returned to the IDS pharmacy for appropriate handling 
and destruction. 
5.9 Concomitant therapy-Lenalidomide   
5.9.1 Recommended concomitant therapy   
Subjects should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, and antiemetics when appropriate 
5.9.2 Anticoagulation Consideration   
Lenalidomide increases the risk of thrombotic events in patients who are at high risk or with a 
history a thrombosis, in particular when combined with other drugs known to cause thrombosis. 
When lenalidomide is combined with other agents such as steroids (e.g. dexamethasone, 
prednisone), anthracyclines (Doxil, Adriamycin) and erythropoietin the risk of thrombosis is 
increased.  
Subjects deemed by the principal investigator at heightened risk of venous thrombosis will 
receive prophylactic anticoagulation with the use of aspirin (81 or 325 mg) or some other form of 
prophylaxis as deemed appropriate. Low molecular weight heparin may be utilized in patients 
that are intolerant to ASA. Coumadin should be used with caution and close monitoring of INR. 
Prophylactic anti-coagulation should be held for platelet counts ≤ 50,000, and then restarted 
when platelet counts are ≥ 75, 000. 
5.9.3 Prohibited concomitant therapy 
Concomitant use of other anti-cancer therapies outside of the study drugs, including radiation or 
other investigational agents is not permitted while subjects are receiving protocol therapy during 
the treatment phase of the study. 
 
5.10 Concomitant Therapy – Everolimus (RAD001) 
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 investigator will ask the patient about any new medications he/she is or has taken after 
the start of the study drug. 
All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start and 
after start of study drug, including physical therapy and blood transfusions, should be recorded. 
The following restrictions apply during the entire duration of the study: 
• No other investigational therapy should be given to patients. 
• No anticancer agents other than the study medication should be given to patients. If such 
agents are required for a patient then the patient must first be withdrawn from the study. 


 
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• Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) should be avoided 
• Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. 
Concomitant use 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 RAD001 to 5 mg daily. Additional 
dose reductions to 5 mg every other day may be required to manage toxicities. If the inhibitor 
is discontinued the RAD001 dose should be returned to the dose used prior to initiation of the 
moderate CYP3A4/PgP inhibitor. 
• Avoid the use of strong CYP3A4 inducers. If patient requires co-administration of strong 
CYP3A4 inducers (i.e., phenytoin, carbamazepine, rifampin, rifabutin, Phenobarbital, St. 
John’s wort), the patient should be monitored as per protocol and discontinued from 
study treatment if progression occurs. An increase in the dose of RAD001 from 10 mg up 
to 20 mg daily should be considered, using 5 mg increments. Enzyme induction usually 
occurs within 7-10 days, therefore RAD001 dose should be increased to 15 mg daily, 7 days 
after the start of the inducer therapy.  If no safety concerns are seen within the next 7 days, 
the dose can be increased again to 20 mg daily.  This dose of RAD001 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 RAD001 dose should be returned to the dose used prior to 
initiation of the strong CYP3A4/PgP inducer. 
• No chronic treatment with systemic steroids or another immunosuppressive agents. Topical 
or inhaled corticosteroids are allowed. 
• RAD001 may affect the response to vaccinations making the response to the vaccination less 
effective. Live vaccines should be avoided while a patient is treated with RAD001. 
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no interaction with 
RAD001 is expected. However, drug-drug interaction studies between macrolide antibiotics and 
warfarin have produced mixed outcomes and the disparity in these findings has led to the 
conclusion that multiple factors may alter the clearance of warfarin. The coadministration of 
RAD001 and oral anticoagulants is possible but should be subject to verification of coagulation 
(INR) once steady state is reached (after one week’s treatment). 
Examples are provided in Table 8. A comprehensive list of cytochrome P450 isoenzymes and 
CYP3A4 inhibitors, inducers, and substrates can be found at http://medicine.iupui.edu/flockhart.  
This website is continually revised and should be checked frequently for updates. 


 
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Table 8 Examples of clinically relevant drug interaction: substrates, inducers and 
inhibitors of isoenzyme CYP3A.  
Substrates (competitive inhibition) 
 
Antibiotics1: 
 
clarithromycin* 
 
erythromycin  
 
telithromycin* 
Anti-arrhythmics: 
 
quinidine 
Benzodiazepines: 
 
alprazolam 
 
diazepam 
 
midazolam 
 
triazolam 
Immune Modulators: 
 
cyclosporine 
 
tacrolimus (FK506) 
HIV Protease Inhibitors: 
 
indinavir* 
 
ritonavir* 
 
saquinavir* 
Prokinetic: 
 
cisapride 
Antihistamines: 
 
astemizole 
 
chlorpheniramine_ 
Calcium Channel Blockers: 
 
amlodipine 
 
diltiazem 
 
felodipine 
 
nifedipine 
 
nisoldipine 
 
nitrendipine 
 
verapamil 
HMG CoA Reductase Inhibitors2:  
 
atorvastatin 
 
cerivastatin 
 
lovastatin 
 
simvastatin 
Miscellaneous: 
 
aprepitant 
 
buspirone 
 
haloperidol 
 
methadone 
 
pimozide  
 
quinine 
 
sildenafil 
 
tamoxifen 
 
trazodone 
 
vincristine 
Inducers 
Carbamazepine 
Phenobarbital 
Phenytoin* 
Rifabutin* 
Rifampin* 
St John’s wort 
Troglitazone 
Inhibitors 
Amiodarone 
Cimetidine 
Clarithromycin 
Delaviridine 
Diltiazem 
Erythromycin 
Fluvoxamine* 
Grapefruit juice 
Sevilla orange 
Indinavir 
Itraconazole* 
Ketoconazole* 
Voriconazole* 
Posaconazole* 
Mibefradil 
Nefazodone* 
Nelfinavir* 
Troleandomycin 
Verapamil 
Based on: Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: properties and 
polymorphisms, Naunyn Schmiedebergs Arch Pharmacol. 2004 Jan;369(1):89-104.  and 
[http://www.medicine.iupui.edu/flockhart/clinlist.htm as of July 13, 2006] 
* asterisk denotes strong inhibition/ induction  
Please note: 
- 
strong inhibitor implies that it can cause ≥5-fold increase in AUC or ≥80% decrease in clearance of 
sensitive CYP substrates 
- 
moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values or 50-80% decrease in 
clearance  of sensitive CYP substrates. 
(Distinction is not always categorical as interaction can vary according to conditions). 
1. Macrolide antibiotics: 
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antibiotherapy with a macrolide is desirable in a patient being treated with RAD001 
2. Statins: Atorvastatin and pravastatin may be associated with RAD001, since a PK interaction study has shown 
that there is no relevant PK interaction.  
 
5.11 Discontinuation of Study Treatment  
Treatment will continue at the prescribed dose level until the occurrence of any of the following 
events.  
• Disease progression  
• Adverse event(s) that, in the judgment of the Investigator, may cause severe or permanent 
harm or which rule out continuation of the treatment regimen.  
• Intolerance of lenalidomide or everolimus for any reason.  
• Major violation of the study protocol.  
• Withdrawal of consent  
• Lost to follow up  
• Death  
o Suspected pregnancy or positive pregnancy 
5.12 Follow-Up   
Subjects who discontinue treatment for any reason, will not be followed if they have no residual 
toxicity (≥ grade 3) attributable to the study drugs at the time of the final safety assessment 
planned for approximately 30 days post the last dose of protocol therapy. If otherwise indicated 
by persistent grade ≥ 3 toxicity, patients will be followed by telephone contact every 30 days. In 
addition off study evaluations per the Schedule of Assessments, Section 2 will be done. 
6 Adverse events 
6.1 Serious Adverse Event (SAE) Definition  
A serious adverse event is one that at any dose (including overdose): 
· Results in death 
· Is life-threatening1 
Requires inpatient hospitalization or prolongation of existing hospitalization 
· Results in persistent or significant disability or incapacity2 
· Is a congenital anomaly or birth defect 
· Is an important medical event3 
· Pregnancy 


 
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 1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused death if it 
were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s 
ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred.  Important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the definition above should also 
usually be considered serious.  Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.  A new diagnosis of cancer during 
the course of a treatment should be considered as medically important.  
6.2 Adverse Drug Reaction Reporting - Lenalidomide 
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  
OR 
HTTP://CTEP.CANCER.GOV/PROTOCOLDEVELOPMENT/ELECTRONIC_APPLIC
ATIONS/DOCS/CTCAEV4.PDF ).  All appropriate treatment areas should have access to a 
copy of the CTCAE Version 4.0.  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. 
6.2.1 Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on lenalidomide, or within  28 
days of the subject’s last dose of lenalidomide, are considered immediately reportable events. 
Lenalidomide  is to be discontinued immediately. The pregnancy, suspected pregnancy, or 
positive pregnancy test must be reported to Celgene Drug Safety immediately by facsimile or 
email using the Pregnancy Initial Report Form. The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for further 
evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form.  If the outcome of the 
pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 


 
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report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, 
it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form.  
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking lenalidomide  should notify the Investigator, and the pregnant female partner 
should be advised to call their healthcare provider immediately. 
 
6.2.2 Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: 
 
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
 
6.3 Adverse events – RAD001 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
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 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: 
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2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. 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) 
5. 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. 
Serious adverse events 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
• is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 
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 


 
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• 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 (888-299-4565) within 24 hours to the Novartis Clinical 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. 
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 Clinical 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. 
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 Clinical Safety and Epidemiology Department (CS&E). 


 
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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 (888-299-4565), to Novartis Pharmaceuticals CS&E 
Department within 24 hours of learning of it’s 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. 
 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also 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. 
 
6.3.1 Novartis Drug Safety Contact Information: 
 
CS&E Department 
Novartis Pharmaceuticals Corporation 
Fax: 888-299-4565  
 
6.4 Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
 
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date. 21 CRF 312.33 


 
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provides the data elements that are to be submitted in the report. The Annual Report should be 
filed in the study's Regulatory Binder, and a copy provided to Celgene Corporation and Novartis 
Pharmaceuticals as supporters of this study as follows.  
 
 
 
Celgene Corporation 
 
Attn: Medical Affairs Operations 
 
Connell Corporate Park  
 
400 Connell Drive Suite 700 
 
Berkeley Heights, NJ  07922 
 
Tel: (908) 673-9000 
 
 And  
 
CS&E Department 
Novartis Pharmaceuticals Corporation 
180 Park Avenue 
Florham Park, NJ 07932 
Fax: 888-299-4565  
 
 
All adverse experience reports must include the patient number, age, sex, weight, severity of 
reaction (i.e. mild, moderate, severe), relationship to drug (i.e. probably related, unknown 
relationship, definitely not related), date and time of administration of test medications and all 
concomitant medications, and medical treatment provided.   The investigator is responsible for 
evaluating all adverse events to determine whether criteria for “serious” and as defined above are 
present.  The investigator is responsible for reporting adverse events to Celgene as described 
below. 
6.4.1 Expedited reporting by investigator to Celgene 
Serious adverse events (SAE) are defined above. The investigator must inform the study 
supporters, Novartis Pharmaceuticals and Celgene in writing using a Celgene SAE form or 
MEDWATCH 3500A form of any SAE within 24 hours of being aware of the event. The written 
report must be completed and supplied to Celgene by facsimile within 24 hours/1 business day. 
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s) if available. Information not 
available at the time of the initial report (e.g., an end date for the adverse event or laboratory 
values received after the report) must be documented on a follow-up report. A final report to 
document resolution of the SAE is required. The Celgene tracking number (RV-ST-PI-0558) and 
the institutional protocol number should be included on SAE reports (or on the fax cover letter) 
sent to Celgene. A copy of the fax transmission confirmation of the SAE report to Celgene 
should be attached to the SAE and retained with the patient records. 


 
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6.4.2 Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a 
serious adverse event according to institutional policy.   
6.4.3 Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly associated 
to the drug, and that have not previously been reported in the Investigators brochure, or 
reference safety information document should be reported promptly to the Food and Drug 
Administration (FDA) by telephone or by fax. Fatal or life threatening SAEs that meet the 
criteria for reporting to the FDA must be reported to the FDA within 7 calendar days after 
awareness of the event. All other SAEs that meet the criteria for reporting to the FDA must be 
reported to the FDA within 15 calendar days after awareness of the event. A clear description of 
the suspected reaction should be provided along with an assessment as to whether the event is 
drug or disease related. In accordance with 21CFR312.32, adverse events associated with the use 
of investigational use will be reported to the FDA. The PI is responsible for notifying the FDA 
and all other participating investigators in a written IND safety report of any AE that is both 
serious and unexpected. 
6.5 Adverse Event Updates/IND Safety Reports 
Celgene shall notify the Investigator via an IND Safety Report of the following information: 
 
• Any AE associated with the use of drug in this study or in other studies that is both 
serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected 
AE(s) or significant risks to subjects. 
 
The Investigator must keep copies of all AE information, including correspondence with Celgene 
and the IRB/EC, on file (see Section 11.4 for records retention information). 
7 Response Criteria 
Baseline lesion assessments must occur within  28 days of protocol therapy initiation or as 
indicated in Section 2, Schedule of Study Assessments. 
Efficacy assessments are scheduled to occur after every 2 cycles of protocol therapy or 
approximately every 8 weeks (as detailed in Schedule of Study Assessments Table). All partial 
and complete responses will be confirmed with another efficacy assessment in no less than 4 
weeks apart.  
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Measurable Disease - the presence of at least one measurable lesion at baseline is only 
mandatory for the expansion cohort. If the measurable disease is restricted to a solitary lesion, its 
neoplastic nature should be confirmed by cytology/histology.  
Measurable Lesions - lesions that can be accurately measured in at least one dimension with 
longest diameter ≥ 20 mm using conventional techniques or ≥10 mm with spiral CT scan.  
Non-measurable Lesions - all other lesions, including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed and followed by 
imaging techniques; and: 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. The same method of assessment 
and the same technique should be used to characterize each identified and reported lesion at 
baseline and during follow-up. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
7.1.1 Methods of Measurement  
• CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed with 
cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 
mm contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen and 
pelvis. Head and neck tumors and those of extremities usually require specific protocols. 
• Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable.  
• Tumor markers alone cannot be used to assess response. If markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete clinical response 
when all lesions have disappeared. 
• Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after 
treatment to differentiate between residual benign lesions and residual malignant lesions in tumor 
types such as germ cell tumors).  
Baseline Documentation of “Target” and “Non-Target” Lesions 
• All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline.  
• Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging techniques or 
clinically).  


 
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• A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 
• All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up.  
7.1.2 Response Criteria  
 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions 
Partial Response (PR) 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD 
Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment 
started or the appearance of one or more new lesions 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
 
Evaluation of Non Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor 
marker level 
Incomplete 
Response/ 
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and maintenance 
of tumor marker level above the normal limits 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
7.1.3 Confirmation 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed. In cases where confirmation of response is not feasible, it should be made clear when 
reporting the outcome of such studies that the responses are not confirmed. 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for response 
are first met. Longer intervals as determined by the study protocol may also be appropriate.  


 
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In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the 
study protocol  
 
8 Protocol Amendments/Deviations 
8.1 Protocol amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and reviewed by 
Celgene. Amendments should only be submitted to IRB/EC after consideration of Celgene 
review. Written verification of IRB/EC approval will be obtained before any amendment is 
implemented.  
8.2 Protocol deviations 
When an emergency occurs that requires a deviation from the protocol for a subject, a deviation 
will be made only for that subject. A decision will be made as soon as possible to determine 
whether or not the subject (for whom the deviation from protocol was effected) is to continue in 
the study. The subject’s medical records will completely describe the deviation from the protocol 
and state the reasons for such deviation. In addition, the Investigator will notify the IRB/EC in 
writing of such deviation from protocol. 
Non-emergency minor deviations from the protocol will be permitted with approval of the 
Principal Investigator.  
9 Data Management 
9.1 Analyses and Reporting 
Data will be analyzed and reported within 3 months of enrolment of the last patient in the 
expansion cohort.. All subsequent data collected will be analyzed and reported in a follow-up 
clinical report.  
9.2 Publication of results 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Novartis and Celgene Corporation and prior to any outside submission.  Novartis 
and Celgene Corporation must receive copies of any intended communication in advance of 
publication (at least fifteen working days for presentational materials and abstracts and thirty 
working days for manuscripts).   These requirements acknowledge Celgene Corporation and 
Novartis’ responsibility to provide peer input regarding the scientific content and conclusions of 
such publications or presentations.  Principal Investigation/Institution shall have the final 
authority to determine the scope and content of its publications, provided such authority shall be 
exercised with reasonable regard for the interests of Novartis and Celgene Corporation and, in 
accord with the trial contract and shall not permit disclosure of Novartis and Celgene 
Corporation confidential or proprietary information. 


 
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9.3 Data Monitoring Committee 
The institution data safety monitoring committee will review the outcome of the study at regular 
intervals as mandated by institutional policy or more frequently if deemed necessary by the 
Principal Investigator. The Data Monitoring Committee (DMC) will be composed of medical 
and statistical independent reviewers and will meet to review the efficacy and safety data and 
determine a risk/benefit analysis in this subject population. The purpose of the DMC is to advise 
on serious safety considerations, lack of efficacy and any other considerations within the charge 
to the Committee. The DMC may request additional meetings or safety reports as deemed 
necessary upon discussion with Celgene and its representatives. The DMC may stop the study 
following review of results from each interim analysis. Appropriate efficacy and safety data 
summaries will be provided to the DMC after each interim analysis. 
In addition, the principal investigator will review the toxicities as they occur and/or are reported. 
The approval of the principal investigator or designee is necessary for accrual of all patients. 
Toxicity information will be reviewed at the weekly Phase I meetings attended by all PIs, clinical 
coordinators and research nurses involved in all ongoing phase I clinical trials at WCI If the data 
review reveals a change in the risk/benefit ratio, the investigator will notify the IRB. The 
principal investigator and co-investigators will review the data and forward any changes or 
protocol amendments to the IRB. All serious adverse events will be immediately reported to the 
IRB as outlined in the full protocol. All study participant information will be kept in a 
confidential manner by the assigning of a random number to each study participant. All data will 
be kept confidential as per institutional guidelines and policies. Any breach of confidentiality is a 
serious matter and conflicts with institutional policies and will be reported to the IRB. A 
cumulative summary of all adverse events occurring on this study and a report of the data safety 
and monitoring plan will be submitted to the IRBs with the annual renewal reports. 
9.4 Study auditing 
9.4.1 Investigator responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) 
and in the US Code of Federal Regulations. 
Investigators must enter study data onto CRFs or other data collection system. The Investigator 
will permit study-related audits by Celgene or its representatives, IRB/EC review, and regulatory 
inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to the facilities where the study 
took place, to source documents, to CRFs, and to all other study documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during audits to review data and resolve any queries and to allow direct access to the 
subject’s records (e.g., medical records, office charts, hospital charts, and study related charts) 
for source data verification. The data collection must be completed prior to each visit and be 
made available to the Celgene representative so that the accuracy and completeness may be 
checked. 


 
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10 Biostatistical Analysis 
10.1 Overview 
 
All data will be listed individually by subject. Continuous variables will be summarized using 
descriptive statistics: mean, standard deviation, median, and minimum and maximum values. 
Categorical variables will be summarized using number of subjects and proportion expressed as 
percentage. Baseline value for any specified variable is the last valid measurement before the 
administration of the study drug. Unless otherwise indicated, statistical significance will be 
declared if the two-sided p value is ≤ 0.05. 
10.2 Datasets to be analyzed 
Demographics 
Subject demographics including age, sex, race, ethnicity, height, weight, disease information, 
and medical conditions will be summarized by cohort using descriptive statistics. 
Extent of Drug Exposure 
The total number of doses of lenalidomide and everolimus (mg), and total number of treatment 
cycles delivered will be summarized by dose level using descriptive statistics. 
Efficacy Endpoints 
The secondary endpoint of the trial is response rate. The best overall response rate as defined by 
the proportion of subjects who have had a CR or PR will be summarized by dose level. Any 
subject treated in the expansion phase with overall response assessment of partial or complete 
response will have the response confirmed by repeat assessment no less than 4 weeks after the 
criteria for response are first met. The RR will be summarized by dose level using descriptive 
statistics along with a 95% confidence interval.  
Pharmacokinetic Parameters 
Serum concentration of study drug will be determined by a validated method according to 
assessment schedules. The pharmacokinetic parameters will be summarized using descriptive 
statistics. 
The concentrations of everolimus, lenalidomide and their clinically significant metabolic product 
will be summarized by dose level using descriptive statistic. The mean concentration for each 
dose level will be plotted on scheduled sample time. The following pharmacokinetic parameters 
will be estimated and reported for each agent according to dose level. 
AUC0→t Area under the concentration-time curve from the time of dosing to the time of the last 
observation; AUC0→∞ Area under the concentration-time curve from the time of dosing 
extrapolated to infinity; Cmax Maximum serum concentration observed postdose; Tmax Time point 
at which the Cmax occurs; t½ Elimination half-life, determined as 0.693/λz. 
Pharmacodynamic Correlates 
The levels of mTOR pathway proteins, inflammatory cytokines and lymphocyte subsets at each 
specified time point will be reported in a descriptive manner for each dose schedule and analyzed 
by tumor type, when appropriate. Data will also be explored graphically. The PK and 


 
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pharmacodynamic data will be used to describe potential relationships between plasma levels of 
everolimus and or lenalidomide and changes in serum protein, toxicities, and tumor response.  
10.3 Statistical Methodology 
All data will be listed individually by subject. Continuous variables will be summarized using 
descriptive statistics: mean, standard deviation, median, and minimum and maximum values. 
Categorical variables will be summarized using number of subjects and proportion expressed as 
percentage. Baseline value for any specified variable is the last valid measurement before the 
administration of the study drug. Unless otherwise indicated, statistical significance will be 
declared if the two-sided p value is ≤ 0.05. 
The estimation of pharmacokinetic parameters will be performed using WinNonlin® Version 5.0 
or higher. All statistical analyses will be performed using SAS® Version 9.13 or higher. 
Changes in immunological markers between baseline and C2D1 samples will be compared for 
each patient and for each dose cohort. In addition, mTOR pathway protein expression in baseline 
diagnostic biopsy samples will be assessed by Immunohistochemistry (IHC) and correlated with 
response. The dynamic changes in biomarker expression before and after one cycle of treatment 
with the drug combination will be summarized using summary statistics mean and standard 
deviation. Comparisons between the two time points will be presented graphically and subjected 
to statistical analysis using the Pearson’s correlation coefficient.  
Missing Data Handling 
Unresolved missing data may be imputed when the analysis integrity is affected. The 
conservative principle will be used for data imputation. For example, if an adverse event onset 
day is missing but the adverse event onset year and month can not exclude this adverse event as a 
TEAE, the adverse event will be flagged as a TEAE. 
 
10.4 Safety evaluation 
Data from all subjects who receive any protocol therapy will be included in the safety analyses. 
Subjects who entered the study and did not receive any protocol therapy and had this confirmed, 
will not be evaluated for safety. 
The severity of the toxicities will be graded according to the NCI CTCAE v4.0 whenever 
possible. The safety analysis will be conducted on all enrolled patient population. The following 
safety parameters will be evaluated: 
Adverse Events 
A treatment-related adverse event (TRAE) is defined as a sign or symptom that emerges during 
treatment or within 30 days after the last dose of study drug, having been absent pre-treatment or 
that has worsened relative to the pretreatment state. Any adverse events deemed related to study 
drug will also be considered a TRAE regardless of the elapsed time since the last dose of study 
drug. Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) to categorize the event to a system organ class and a preferred term. The number of 
subjects who experienced at least 1 adverse event, severe (≥ Grade 3) adverse event, study drug-


 
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related adverse event, serious adverse event, and the number of subjects discontinued due to 
adverse events will be summarized by dose level. For each system organ class and preferred 
term, summaries will be made with respect to the number and proportion of subjects having at 
least 1 occurrence of an adverse event during the study. The incidence of adverse events will be 
presented overall, by system organ class and preferred term, intensity (based on CTCAE Version 
4.0), TRAEs, and additional grouping by severity and relationship to study drug. An individual 
listing of adverse events will be provided. DLTs and study drug-related ≥ Grade 2 adverse events 
will be listed individually. 
 
10.5 Interim analyses  
No interim efficacy analysis is planned. However, safety and toxicity analysis will be conducted 
on an ongoing basis by the Winship Cancer Institute DSMC. 
 
10.6 Sample size and power considerations 
The sample size of up to 30 patients is required to establish the MTD and the RP2D based on the 
proposed modified Fibonacci dose escalation schema assuming that each dose cohort requires the 
maximum of 6 subjects . Up to 6 subjects will be enrolled at each dose level. If no DLTs occur, a 
total of 15 subjects will be needed to complete the dose escalation part of the study. To further 
characterize safety and efficacy, fifteen additional subjects will be enrolled at the MTD in an 
expansion cohort. In order to perform preliminary evaluation of anti-tumor activity, the sample 
size at the MTD or highest dose level cohort is determined by a power analysis. It is assumed 
that the subjects would have no response if they would not have received any therapy and that 
response rate for subjects in the MTD or highest dose level cohort would be 10%. Based on this 
assumption, a sample size of 15 subjects in the MTD cohort will provide more than 79% power 
in a one-sample exact binomial test at the significance level of 0.05. We anticipate accrual of 2-3 
patients per month for the escalation phase and approximately 1-2 patients per month for the 
expansion phase, which is restricted to patients with clear cell renal cell carcinoma. At this 
accrual rate, we expect total accrual and study completion within 18-24 months. 
A parallel expansion cohort of 9 patients with adenoidcystic carcinoma will also be evaluated. 
An objective response in at least 3 of 9 patients will be considered sufficient evidence to explore 
the benefit of this regimen in a larger phase II efficacy trial. The expected maximum overall 
sample size of 45 patients will still be maintained with the addition of this parallel cohort 
because only 21 of the maximum expected 30 patients were required in the dose escalation of the 
study. 


 
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11 Regulatory Considerations 
11.1  Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki. The review of this protocol by the IRB/EC and the 
performance of all aspects of the study, including the methods used for obtaining informed 
consent, must also be in accordance with principles enunciated in the declaration, as well as ICH 
Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human 
Subjects and Part 56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to the relevant 
IRB/EC and obtaining written approval for this study. The approval will be obtained prior to the 
initiation of the study. 
The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by the 
Investigator to the IRB/EC for approval. The Investigator is also responsible for notifying the 
IRB/EC of any serious deviations from the protocol, or anything else that may involve added risk 
to subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved by the 
IRB/EC prior to use. 
11.2 Informed consent 
The Investigator must obtain informed consent of a subject or his/her designee prior to any study 
related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study and the 
informed consent process should be recorded in the subject’s source documents. The original 
consent form signed and dated by the subject and by the person consenting the subject prior to 
the subject’s entry into the study, must be maintained in the Investigator’s study files. 
11.3 Subject confidentiality 
Celgene affirms the subject’s right to protection against invasion of privacy. In compliance with 
United States federal regulations, Celgene requires the Investigator to permit representatives of 
Celgene Corporation and, when necessary, representatives of the FDA or other regulatory 
authorities to review and/or copy any medical records relevant to the study in accordance with 
local laws. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 


 
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11.4 Study records requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the protocol therapy, that is copies of CRFs and source documents 
(original documents, data, and records [e.g., hospital records; clinical and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; SAE reports, pharmacy 
dispensing records; recorded data from automated instruments; copies or transcriptions certified 
after verification as being accurate copies; microfiches; photographic negatives, microfilm, or 
magnetic media; x-rays; subject files; and records kept at the pharmacy, at the laboratories, and 
at medico-technical departments involved in the clinical study; documents regarding subject 
treatment and drug accountability; original signed informed consents, etc.]) be retained by the 
Investigator for as long as needed to comply with national and international regulations 
(generally 2 years after discontinuing clinical development or after the last marketing approval). 
The Investigator agrees to adhere to the document/records retention procedures by signing the 
protocol. 
11.5 Premature discontinuation of study 
The Principal Investigator, institution and Celgene have the right to discontinue this study at any 
time for reasonable medical or administrative reasons. Possible reasons for termination of the 
study could be but are not limited to: 
Unsatisfactory enrollment with respect to quantity or quality.  
Inaccurate or incomplete data collection.  
Falsification of records.  
Failure to adhere to the study protocol.  
Any possible premature discontinuation would be documented adequately with reasons being 
stated, and information would have to be issued according to local requirements (e.g., IRB/EC, 
regulatory authorities, etc.). 


 
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12 References 
 
1. Dredge K, Horsfall R, Robinson SP, et al: Orally administered lenalidomide (CC-5013) is 
anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. 
Microvasc Res 69:56-63, 2005 
2. Corral LG, Haslett PA, Muller GW, et al: Differential cytokine modulation and T cell 
activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-
alpha. J Immunol 163:380-6, 1999 
3. Schafer PH, Gandhi AK, Loveland MA, et al: Enhancement of cytokine production and AP-1 
transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J Pharmacol 
Exp Ther 305:1222-32, 2003 
4. Davies FE, Raje N, Hideshima T, et al: Thalidomide and immunomodulatory derivatives 
augment natural killer cell cytotoxicity in multiple myeloma. Blood 98:210-6, 2001 
5. Hideshima T, Chauhan D, Shima Y, et al: Thalidomide and its analogs overcome drug 
resistance of human multiple myeloma cells to conventional therapy. Blood 96:2943-50, 2000 
6. 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 
Res 15:1612-22, 2009 
7. Manegold PC, Paringer C, Kulka U, et al: Antiangiogenic therapy with mammalian target of 
rapamycin inhibitor RAD001 (Everolimus) increases radiosensitivity in solid cancer. Clin 
Cancer Res 14:892-900, 2008 
8. Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa, or both for advanced 
renal-cell carcinoma. N Engl J Med 356:2271-81, 2007 
9. Amato RJ, Jac J, Giessinger S, et al: A phase 2 study with a daily regimen of the oral mTOR 
inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 
115:2438-46, 2009 
10. Motzer RJ, Escudier B, Oudard S, et al: Efficacy of everolimus in advanced renal cell 
carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449-56, 
2008 
11. Tai YT, Li XF, Catley L, et al: Immunomodulatory drug lenalidomide (CC-5013, IMiD3) 
augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical 
implications. Cancer Res 65:11712-20, 2005 
12. Wu L, Adams M, Carter T, et al: lenalidomide enhances natural killer cell and monocyte-
mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin 
Cancer Res 14:4650-7, 2008 
13. Vallet S, Palumbo A, Raje N, et al: Thalidomide and lenalidomide: Mechanism-based 
potential drug combinations. Leuk Lymphoma 49:1238-45, 2008 


 
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14. Sun S-Y, Rosenberg LM, Wang X, et al: Activation of Akt and eIF4E Survival Pathways by 
Rapamycin-Mediated Mammalian Target of Rapamycin Inhibition. Cancer Res 65:7052-7058, 
2005 
15. Raje N, Kumar S, Hideshima T, et al: Combination of the mTOR inhibitor rapamycin and 
CC-5013 has synergistic activity in multiple myeloma. Blood 104:4188-4193, 2004 
16. Goel MS, Diamond SL: Neutrophil cathepsin G promotes prothrombinase and fibrin 
formation under flow conditions by activating fibrinogen-adherent platelets. J Biol Chem 
278:9458-63, 2003 
17. Richardson PG, Schlossman RL, Weller E, et al: Immunomodulatory drug CC-5013 
overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. 
Blood 100:3063-7, 2002 
18. Brignol N, McMahon LM, Luo S, et al: High-throughput semi-automated 96-well 
liquid/liquid extraction and liquid chromatography/mass spectrometric analysis of everolimus 
(RAD 001) and cyclosporin a (CsA) in whole blood. Rapid Commun Mass Spectrom 15:898-
907, 2001 
19. Dahut WL, Aragon-Ching JB, Woo S, et al: Phase I study of oral lenalidomide in patients 
with refractory metastatic cancer. J Clin Pharmacol 49:650-60, 2009  


 
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13 Appendices 
13.1 Appendix A – ECOG Performance Status Scale 
 
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light house 
work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
 


 
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13.2 Appendix B: Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has 
the effect of the lenalidomide on human eggs and sperm.  The risks to a fetus are not known.  
However, because lenalidomide is related to thalidomide, and thalidomide is known to cause 
severe birth defects, the following requirements must be observed. 
All study participants must be registered into the mandatory RevAssist® program, and be willing 
and able to comply with the requirements of RevAssist®. 
Females of childbearing potential (FCBP)† must agree to use two reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual intercourse during the 
following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 
2) while participating in the study; and 3) for at least 28 days after discontinuation from the 
study. The two methods of reliable contraception must include one highly effective method (i.e. 
intrauterine device (IUD), hormonal [birth control pills, injections, or implants], tubal ligation, 
partner’s vasectomy) and one additional effective (barrier) method (i.e. latex condom, 
diaphragm, cervical cap).  FCBP must be referred to a qualified provider of contraceptive 
methods if needed.   
Because of the increased risk of venous thromboembolism in patients with multiple myeloma 
taking lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended 
with regimens combining lenalidomide and dexamethasone.  If a patient is currently using 
combined oral contraception the patient should switch to one of the other highly effective 
methods listed above.  The risk of venous thromboembolism continues for 4−6 weeks after 
discontinuing combined oral contraception.  The efficacy of contraceptive steroids may be 
reduced during co-treatment with dexamethasone.  
Before starting lenalidomide:   
Female Subjects:   
• FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
prescribing lenalidomide.  The first pregnancy test must be performed within 10-14 days 
 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy 
or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has 
had menses at any time in the preceding 24 consecutive months). 
 
 


 
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prior to prescribing lenalidomide and the second pregnancy test must be performed 
within 24 hours prior to prescribing lenalidomide (prescriptions must be filled within 7 
days).  The subject may not receive lenalidomide until the Investigator has verified that 
the results of these pregnancy tests are negative. 
 
 
Male Subjects:   
• Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following 
discontinuation from the study even if he has undergone a successful vasectomy.  
During study participation and for 28 days following discontinuation from the study: 
All Subjects: 
• If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a 
male study subject during study participation, lenalidomide must be immediately 
discontinued. 
Female Subjects:   
• FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, at study 
discontinuation, and at day 28 following discontinuation from the study. If menstrual 
cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and 
then every 14 days while on study, at study discontinuation, and at days 14 and 28 
following discontinuation from the study.   
• In addition to the required pregnancy testing, the Investigator must confirm with FCBP 
that she is continuing to use two reliable methods of birth control at each visit.   
• 
Pregnancy testing and counseling must be performed if a subject misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment must 
be discontinued during this evaluation. 
Male Subjects: 
• Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following 
discontinuation from the study even if he has undergone a successful vasectomy. 
 


 
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13.3 Appendix C NCI CTC Version 4.0 
 
TOXICITY WILL BE SCORED USING NCI  CTC VERSION 4.0 FOR TOXICITY AND 
ADVERSE EVENT REPORTING.  A COPY OF THE NCI CTC VERSION 4.0 CAN BE 
DOWNLOADED FROM THE CTEP HOMEPAGE: (HTTP://CTEP.INFO.NIH.GOV) OR 
HTTP://CTEP.CANCER.GOV/PROTOCOLDEVELOPMENT/ELECTRONIC_APPLIC
ATIONS/DOCS/CTCAEV4.PDF .   
ALL APPROPRIATE TREATMENT AREAS HAVE ACCESS TO A COPY OF THE 
CTC VERSION  
 
 
 


 
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13.4 Appendix D – Blood Sample Collection and Processing  
Pharmacokinetic and Pharmacodynamic Studies 
PK samples will not be collected during this study. 
 
Flow Cytometry: 
All patients will have blood samples collected for assessment of circulating lymphocytes as a 
pharmacodynamic endpoint for lenalidomide therapy. Samples will be collected at baseline and 
with the first 2 restaging scans for response assessment (on day 1 cycle 3 ± 2days  and day 1 
cycle 5  ± 2days;) and at the time of disease progression. Collect 5mls of whole blood in purple-
topped tubes and invert gently several times to ensure appropriate mixing of blood and 
anticoagulant. Samples should be transported at room temperature to Ned Wallers lab on the 4th 
floor of the Winship Cancer Institute building (Attn: Hillary Rosenthal, MT, ASCP; Tel - 404-
727-3086). 
 
ELISA Assay for circulating cytokines: 
Samples for ELISA test should be collected in two red-topped tubes at baseline and with the first 
2 restaging scans (day 1 cycle 3 ± 2days  and day 1 cycle 5  ± 2days;) and at the time of disease 
progression if different than any of the aforelisted time points. Please transport samples on ice to 
the laboratory of Shi-Yong Sun, PhD on the 3rd floor of the Winship Cancer Institute building, 
(Attention: Guojing Zhang or Ping Yue). 
 
Tumor Biopsy 
Patients enrolled in the expansion cohort must sign a separate informed consent form for 
research tumor tissue biopsy. Surgical tumor tissue and needle biopsies (collected by 18-gauge or 
larger needles), should be collected in pre-cooled cryovials and immediately flash frozen in 
liquid nitrogen, then stored at -80 degrees C. Samples will be sent to the laboratory of Shi-Yong 
Sun, PhD (Attention: Guojing Zhang or Ping Yue) on the 3rd floor of the Winship Cancer 
Institute building.  
 


 
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13.5 Appendix E – List of CYP450 and PgP Interacting Drugs 
Agents that may Increase Everolimus Blood Concentrations 
CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to everolimus treatment 
alone there were significant increases in everolimus exposure when coadministered with: 
ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 
3.9- and 15.0-fold, respectively; erythromycin (a moderate CYP3A4 inhibitor and a PgP 
inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively; verapamil (a moderate 
CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3-and 3.5-fold, 
respectively. Concomitant strong or moderate inhibitors of CYP3A4 and PgP inhibitors should 
not be used. Due to significant increases in exposure of everolimus, co-administration with 
strong or moderate inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, 
atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, 
delavirdine, fosamprenavir, voriconazole, aprepitant, erythromycin, fluconazole, grapefruit juice, 
verapamil or diltazem) or P-glycoprotein (PgP) should be avoided.  
Agents that may Decrease Everolimus Blood Concentrations 
CYP3A4 Inducers: In healthy subjects, co-administration of everolimus with rifampin, a strong 
inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, 
compared to everolimus treatment alone. An increase in the everolimus dose is recommended 
when co-administered with a strong CYP3A4 inducer (e.g., dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital.  
Agents whose Plasma Concentrations may be Altered by Everolimus 
Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic 
interactions between everolimus and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 
substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses 
also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of everolimus  
Drug Interactions with Lenalidomide 
Results from human in vitro metabolism studies and nonclinical studies show that lenalidomide 
is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that 
lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions in 
man. Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single 
dose pharmacokinetics of R- and S-warfarin. Co-administration of single 25-mg dose warfarin 
had no effect on the pharmacokinetics of total lenalidomide. Expected changes in laboratory 
assessments of PT and INR were observed after warfarin administration, but these changes were 
not affected by concomitant lenalidomide administration. When digoxin was co-administered 
with lenalidomide the digoxin AUC was not significantly different, however, the digoxin Cmax 
was increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical 


 
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judgment and based on standard clinical practice in patients receiving this medication, is 
recommended during administration of lenalidomide. 
 


 
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13.6 Appendix F: Estimated creatinine clearance rate (eCCr) using 
Cockcroft-Gault formula 
In men, this is: GFR= (140 - age) x weight (kg) / (72 x serum creatinine)  
In women, multiply this result by .85 i.e. GFR= [(140 - age) x weight (kg) / (72 x serum 
creatinine)] x 0.85 


 
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13.7 Appendix X - RevAssist Program 
RevAssist® for Prescribers Prescribing REVLIMID® (lenalidomide) 
REVLIMID® is available only under a restricted distribution program called RevAssist®.  
Healthcare providers must register with RevAssist® to prescribe REVLIMID® for their patients.  
 
RevAssist® for Patients 
• 
To avoid fetal exposure, REVLIMID® (lenalidomide) is only available under a special restricted 
distribution program called RevAssist®.  
• 
Only prescribers registered with RevAssist® can prescribe REVLIMID®.  
• 
Only RevAssist® contract pharmacies can dispense REVLIMID®.  
• 
In order to receive REVLIMID®, patients must enroll in RevAssist® and agree to comply with the 
requirements of the RevAssist® program.  
Information about REVLIMID® and the RevAssist® program can be obtained by calling the Celgene 
Customer Care Center toll-free at 1-888-423-5436. FAX: 1-888-432-9325; 86 Morris Avenue, Summit, NJ 
07901 
 


 
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13.8 Appendix Y – Pill Diary 
Study Title 
Phase I Study of Everolimus (RAD001) in Combination with 
Lenalidomide in Patients with Advanced Solid Malignancies Enriched 
for Renal Cell Carcinoma 
Pill Diary  
 
 
 
 
Subject Initials 
 
Subject ID 
 
Cycle # 
 
Research Coordinator 
Name: 
Phone: 
Pager: 
e-mail: 
Cohort# 
Original Everolimus Dose 
…………………… 
Original 
Lenalidomide Dose 
……………………. 
# of Dose Reductions  
 
Current Daily Everolimus Dose: 
……………….. 
Current Daily 
Lenalidomide Dose: 
……………… 
Instructions:  
 
1. Please take the prescribed pills as instructed 
 
2. Please record the date and time you take your medications. On visit days, medications should 
be taken in the clinic unless otherwise instructed 
 
3. Please bring medication and pill diary to each study visit. 
Day 
Date 
Everolimus (Y/N) 
Lenalidomide (Y/N) 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 


 
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13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
Patient Signature 
 
……………………………………………… 
 
 
Date: 
This section to be completed by a Research Personnel (Investigator, Research Nurse / 
Research Coordinator) 
Dosing Cycle Start Date: 
Dosing Cycle End Date: 
Everolimus Lot 
Number: ………… 
#  of Bottles / # of Tablets Dispensed :  
 ____5mg     ____10mg 
 
 
Any 
Interruptions?  
(Yes/No) 
Lenalidomide Lot 
Number ….……… 
#  of Bottles / # of Tablets Dispensed :  
 ____5mg     ____10mg 
Any 
Interruptions?  
(Yes/No) 
Length of Dose Interruption: 
 
Reason for Interruption: 
 
Reason for Dose Reduction: 
 
Additional Comments: