Clinical trial NCT01076543
Conditions: AIDS-Related Hodgkin Lymphoma Recurrent Adult Hodgkin Lymphoma Recurrent Follicular Lymphoma Recurrent Lymphoplasmacytic Lymphoma Recurrent Marginal Zone Lymphoma Recurrent Non-Hodgkin Lymphoma Recurrent T-Cell Non-Hodgkin Lymphoma Waldenstrom Macroglobulinemia
Sponsor: National Cancer Institute (NCI)
Start date: 2010-04-15; Completion date: 2018-09-30
Enrollment: 110 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects and the best dose of lenalidomide when given together with temsirolimus and to see how well it works in treating patients with Hodgkin lymphoma or non-Hodgkin lymphoma that has come back after a period of improvement or is not responding to treatment. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Lenalidomide may also stop the growth of Hodgkin lymphoma or non-Hodgkin lymphoma by blocking blood flow to the cancer. Temsirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide together with temsirolimus may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety, toxicity, and maximum tolerated dose of lenalidomide when combined with temsirolimus in patients with relapsed lymphomas. (Phase I) II. To determine complete and overall response rate of lenalidomide plus temsirolimus in patients with relapsed lymphomas as stratified by histology: follicular lymphoma, diffuse large B-cell lymphoma, and lymphoma not otherwise specified (NOS) (including Hodgkin lymphoma, T-cell non-Hodgkin lymphoma \[T-NHL\], lymphoplasmacytic lymphoma, and mantle cell lymphoma). (Phase II) III. To determine duration of response, progression-free survival, and overall survival of lenalidomide plus temsirolimus in patients with relapsed lymphomas as stratified by histology: diffuse large B-cell lymphoma, follicular lymphoma, and lymphoma NOS (including Hodgkin lymphoma, T-NHL, lymphoplasmacytic lymphoma, mantle cell lymphoma). (Phase II)

SECONDARY OBJECTIVES:

I. To determine mammalian target of rapamycin (mTOR) pathway activation in pre-treatment tumor tissue.

II. To determine angiogenic and microenvironmental status of pre-treatment tissue and peripheral blood samples, and to evaluate changes following treatment with temsirolimus and lenalidomide.

III. To determine differentially expressed genes associated with differences in clinical response and in progression-free survival (PFS) in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) (Groups A and B, respectively).

IV. To determine a methylation signature predictive of clinical response and PFS in patients with DLBCL and FL (Groups A and B, respectively).

OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II study.

Patients receive lenalidomide orally (PO) on days 1-21 and temsirolimus intravenously (IV) over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease after 2 courses may continue therapy for up to 52 weeks.

After completion of study treatment, patients are followed up for 1 year.

Arms: arm 1: Patients receive lenalidomide PO on days 1-21 and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease after 2 courses may continue therapy for up to 52 weeks.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Lenalidomide intervention 3: Temsirolimus
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
i 
SUMMARY OF CHANGES 
 
For Protocol Amendment #16 to: 
 
Phase I/II Investigation of Temsirolimus Plus Lenalidomide in Relapsed Non-Hodgkin 
Lymphomas 
 
NCI Protocol #: 8309 
Local Protocol #: 09-443-A 
 
NCI Version Date:  12/20/2015 (last NCI approved version)  
Protocol Date:  6/8/2016 (current version) 
 
 
# 
Section 
Page 
Change 
1. n/a 
4 
Updated protocol version date to 6/8/2016 and the protocol 
history section. 
2. n/a 
1-2 
Updated PI information for Northwestern. 
3. CAEPR for 
Lenalidomide 
36-38 
 
  
Under section 7.1.2: Updated CAEPR for Lenalidomide (CC-5013, 
NSC 703813) with version 2.6, December 24, 2015  
 


 
1 
NCI PROTOCOL #:8309 
 
 
 
 
 
 
 
 
 
 
 
Version #16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version Date:  6/8/2016 
Local Protocol #: 09-443-A  
 
TITLE:  Phase I/II Investigation of Temsirolimus Plus Lenalidomide in Relapsed Non-Hodgkin 
Lymphomas 
 
Coordinating Center: 
 
 
University of Chicago Phase II Consortium 
 
*Principal Investigator: 
Sonali M. Smith, M.D. 
 
The University of Chicago, Section of Hematology/Oncology 
 
5841 S. Maryland Avenue MC2115 
 
Chicago, IL 60637 
 
TEL: 773-834-2895 
 
FAX: 773-702-0963 
 
smsmith@medicine.bsd.uchicago.edu  
Co-Investigators: 
 
Kenneth Cohen, M.D. 
The University of Chicago, Section of 
Hematology/Oncology 
5841 S. Maryland Avenue MC2115 
Chicago, IL 60637 
TEL: 773-834-4043 
FAX: 773-702-3163 
kcohen@medicine.bsd.uchicago.edu 
 
Edem Agamah, M.D.  
Central Illinois Hem/Onc Center 
319 E. Madison Suite F 
Springfield, IL 62701 
(217) 525-2500                              
ihdn@aol.com 
James L. Wade III, M.D.  
Decatur Memorial Hospital 
2300 N. Edward St. 
Decatur, IL 62526 
 (217) 876-6600 
Jlwade3@aol.com      
 
Krishna Rao, M.D., PhD   
 krao@siumed.edu    
 Southern Illinois University School of Medicine 
 315 West Carpenter Street 
 Springfield, IL  62794-9678 
 (217) 545-7969 
Sreenivasa Nattam, M.D. 
 
Fort Wayne Medical Oncology/Hematology, 
Inc.  
11143 Parkview Plaza Drive, Suite 100  
Fort Wayne, IN 46845  
(260) 484-8830 
ledgar@fwmoh.com  
Dr. Sunil Babu, MD 
Fort Wayne Medical Oncology/Hematology, 
Inc. 
7910 West Jefferson Blvd. Suite 108 
Fort Wayne, IN 46804 
Ph: 260-436-0800 
sunilbabumail@yahoo.com 
Mark Kozloff, M.D. 
mfkozloff@aol.com 
S. Yalavarthi, M.D. 
sulochana2001@hotmail.com 
Arnob Banerjee, M.D., Ph.D 
abannerjee@som.umaryland.edu 
 
University of Maryland Greenebaum Cancer 


NCI Protocol #:8309 
Version Date: 6/8/2016 
 
2 
Ingalls Hospital  
1 Ingalls Dr. Harvey, IL 60430-1144 
(708) 339-4800 
Center 
22 S. Greene Street, Baltimore, MD 21201-
1595 
(410) 328-8708 
 
Paul A.S. Fishkin, M.D. 
pfishkin@illinoiscancercare.com 
Illinois CancerCare, P.C. 
8940 N. Wood Sage Road, Peoria, IL  61615-
7828 
(309) 243-3000 
Bethany G. Sleckman, M.D. 
slecbg@stlo.mercy.net 
Saint John's Mercy Medical Center 
607 S. New Ballas Road,  
Ste 3425, St. Louis, MO 63141 
(314) 251-7057 
Jason B. Kaplan, M.D. 
Jason.kaplan@northwestern.eduNorthwestern 
University 
645 N. Michigan Ave Suite 1006 
Chicago, IL 60611 
312-926-9636 
Noah M. Hahn, MD  
nhahn@iupui.edu  
Indiana University Simon Cancer Center  
535 Barnhill Drive, RT473  
Indianapolis, IN 46202  
317-278-6871 
 
 
 
Statistician: 
Theodore Karrison, PhD 
5841 S. Maryland Ave., MC 2007, R-314 
Chicago, Illinois 60637 
Phone: 773-702-9326  
Fax: 773-702-1979 
 
tkarrison@health.bsd.uchicago.edu 
Phase II Regulatory Manager: 
Gabriel Pugel 
University of Chicago 
5841 S. Maryland Ave., MC 1140, Chicago, IL 
60637 
Phone:773-702-5928 
Fax:773-702-1561 
gpugel@bsd.uchicago.edu 
Responsible Research Nurse: 
Kathy Conner, RN 
The University of Chicago, Section of 
Hematology/Oncology 
5841 S. Maryland Avenue MC2115 
Chicago, IL 60637 
TEL: 773-702-2034 
FAX: 773-834-4993 
kconner@medicine.bsd.uchicago.edu  
 
Responsible Data Manager: 
Jaclyn PetersonThe University of Chicago 
Section of Hematology/Oncology 
5841 S. Maryland Ave. MC2115 
Chicago, IL 60637 
Phone:773-834-1746; Fax: 773-702-4889 
 
jdpeterson@medicine.bsd.uchicago.edu 
 
 
 
Contract #  
  
NCI Supplied Agents: 
 
 
 
Temsirolimus (NSC#683864), IND#61010 
Lenalidomide(NSC#703813), IND#70116 
NCI Approval: 
8309 / Approved 


NCI Protocol #:8309 
Version Date: 6/8/2016 
 
3 
UC Protocol Approval: 
09-443-A /Approved 
Protocol History: 
 
Version Date Description of Action 
07/27/09 
First Submission to NCI 
10/05/09 
Consensus Review Response 
11/12/09 
Follow Up Review Response 
2/16/10 
Amendment # 1 Cover Page: Version Date changed to 2/16/10. Protocol History updated.  
Section 6.1 updated in accordance with revised CAEPR for Temsirolimus v. 2.2 January 22, 
2010. Section 6.2 updated in accordance with revised CAEPR for Lenalidomide v. 2.2 January 
15, 2010. Consent Form:  Version Date changed to 2/16/10.  “What are the Risks” Section 
updated in accordance with revised CAEPR for Lenalidomide v. 2.2 January 15, 2010 and for 
Temsirolimus v. 2.2 January 22, 2010. 
03/15/2010 
NCI Approved version 02/16/10 of Protocol and consent. 
10/28/2010 
Protocol amended to expand the phase II cohort, update correlative collection process and 
procedures. Add Appendices F, G and H for data collection and update to staff.  
12/15/2010 
Protocol amendment to address recommendations from NCI received on 11/02/10. 
4/20/2011 
Protocol updated to include Secondary Malignancy reporting in section 10.1.5. 
5/04/2011 
Amendment 4/20/11 was disapproved; 5/04/2011 is a resubmission of this version correcting 
section 10.1.5. 
5/16/2011 
This amendment is in response to Dr. Johnson’s May 3, 2011 request for change in reproductive risk 
language and lenalidomide bottle counts. 
9/20/2011 
Protocol amendment submitted in response to RRA for lenalidomide received from CTEP 8/24/11.  
Updated CAEPR for lenalidomide to version 2.3, June 27, 2011. 
02/27/2012 
Protocol amendment submitted in response to RRA for temsirolimus received from CTEP 1/12/12.  
Updated CAEPR for temsirolimus to version 2.3, December 15, 2011. Updated participating sites on 
facesheet. 
06/20/2012 
Changes made with faculty and staff on face sheet of protocol and changes made throughout the 
protocol, major change includes: adding mantle cell lymphoma as a subtype in Group C and an 
expansion of correlative objectives and methods. 
02/15/2013 
Added new sites, made administrative and formatting changes throughout protocol to fit the new e-
protocol requirements. 
10/24/2013 
Updated lenalidomide dispensing language and agent ordering information in section 8.2. Updated 
CAEPR for Temsirolimus in section 7.1. 
11/4/2013 
Updated the lenalidomide CAEPR version and cleaned up the agent ordering information section for 
lenalidomide per CTEP request. 
04/30/14 
Added a Ft Wayne PI and also updated the safety event reporting mechanism from AdEERs to 
CTEP-AERS. 
10/9/14 
Protocol amendment submitted in response to RRA for lenalidomide received from CTEP 9/17/14.  
Updated CAEPR for lenalidomide to version 2.5, July 16, 2014. 
 
12/20/2015 
Protocol amendment submitted to change PI for two sites and update contact information. 
 
6/8/2016 
CAEPR for Lenalidomide and update to Northwestern PI information. 
 
 
 
 


NCI Protocol #:8309 
Version Date: 6/8/2016 
 
4 
 
 
 
 
SCHEMA 
 
Eligibility Criteria 
Phase II:  
Previously treated, histologically confirmed mature NHL stratified by histology:  
 
Group A: Diffuse large B-cell lymphoma 
 
Group B: Follicular lymphoma 
       Group C: Lymphoma NOS (including Hodgkin lymphoma, T-NHL, marginal zone 
lymphoma, lymphoplasmacytic lymphoma, mantle cell lymphoma) 
Phase I and Phase II:  
No limit to number of prior therapies as long as other entry criteria are met. Prior autologous 
stem cell transplant is allowed.  
Age > 18 years.  
ECOG Performance Status 0-2. 
Measurable disease (see Section 3.1.7). 
No known CNS involvement by lymphoma.  
Non-pregnant and non-nursing.  
No “currently active” second malignancy (see Section 3.2.6). 
No history (within 3 months of study entry) of DVT/PE (see Section 3.2.7).  
Required Initial Laboratory Values 
ANC  
 
 
> 1000  
platelets   
 
> 75K/mL 
total bilirubin  
 
< 1.5 X ULN  AST/ALT  
 
< 2.5 X ULN 
CrCl  
  
 
> 60 mL/min** 
fasting serum cholesterol  < 350 mg/dL 
fasting serum triglyceride <2.5 X ULN 
 
**Creatinine clearance must be calculated using the Cockcroft-Gault equation.  
 
Dose Escalation Schedule 
Dose Level 
Dose 
Temsirolimus     (flat dose in 
mg) 
Lenalidomide      (flat dose in 
mg) 
 
Level -2 
 
15 mg 
 
10 mg 
 
Level -1 
 
25 mg 
 
10 mg 
 
Level 1 
 
25 mg 
 
15 mg 
 
Level 2 
 
25 mg 
 
20 mg 
 
Level 3 
 
25 mg 
 
25 mg 
 
For the phase II portion of the study: Temsirolimus will be administered at 25 mg IV weekly for at least 2 consecutive 4 week cycles. Oral 
lenalidomide 20mg daily will be given on Days 1-21 of each 28 day cycle Patients showing at least stable disease after 2 cycles may continue 
treatment up to 52 weeks of therapy. Missed doses will not be made up. 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................6 
1. 
OBJECTIVES ......................................................................................................................9 
1.1 
Primary Objectives...................................................................................................9 
2.0 
BACKGROUND .....................................................................................................9 
2.1 
 Non-Hodgkin lymphoma (NHL) ............................................................................9 
2.2  Temsirolimus ..........................................................................................................................13 
2.3  Lenalidomide ..........................................................................................................................15 
2.4  Rationale .................................................................................................................................16 
2.5  Correlative Studies Background .............................................................................................17 
3.0 
PATIENT SELECTION ....................................................................................................17 
3.1 
Eligibility Criteria ..................................................................................................18 
3.2 
Exclusion Criteria ..................................................................................................20 
3.3 
Inclusion of Women and Minorities ......................................................................21 
4.0 
REGISTRATION PROCEDURES ...................................................................................21 
4.1 
General Guidelines.................................................................................................21 
4.2 
Registration Process ...............................................................................................22 
5.0 
TREATMENT PLAN ........................................................................................................23 
5.1 
Agent Administration.............................................................................................23 
5.2 
Definition of Dose-Limiting Toxicity (Phase I Portion Completed) .....................24 
5.3 
Supportive Care Guidelines ...................................................................................27 
5.4 
Duration of Therapy ...............................................................................................28 
5.5 
Duration of Follow Up ...........................................................................................28 
5.6 
Criteria for Removal from Study ...........................................................................28 
6.0 
DOSING DELAYS/DOSE MODIFICATIONS FOR PHASE II PORTION ...................28 
6.1 
Hematologic toxicity ..............................................................................................29 
6.1.3-Dermatologic Toxicity ..........................................................................................................30 
7.0 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..................................32 
7.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) for ..............................32 
7.2  Adverse Event Characteristics ................................................................................................42 
7.3  Expedited Adverse Event Reporting ...........................................................................42 
7.4  Routine Adverse Event Reporting ..............................................................................46 
7.5  Secondary Malignancy ................................................................................................46 


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7.6-Second Malignancy .....................................................................................................47 
8.0- Pharmaceutical Information ...................................................................................................47 
8.1-Temsirolimus (Torisel®, NSC 683864) ..................................................................................47 
8.2-Lenalidomide (CC-5013, NSC # 703813) ...................................................................50 
8.3-Commercial Agent(s) ...................................................................................................54 
9.0-BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ..............................................54 
9.1-Biomarker Studies .......................................................................................................54 
9.2-Laboratory Correlative Studies ....................................................................................54 
9.3-Special Studies .............................................................................................................60 
10 
STUDY CALENDAR .......................................................................................................61 
11.0  MEASUREMENT OF EFFECT...........................................................................................62 
11.1-Definition of Response ..............................................................................................62 
11.2-Guidelines for Evaluation of Measureable Disease ...................................................64 
Duration of Response .........................................................................................................64 
Definition of Survival ........................................................................................................64 
Response Criteria for Waldenstrom’s Macroglobulinemia ...............................................64 
11.3-Other Response Parameters .......................................................................................64 
12.0-DATA REPORTING / REGULATORY REQUIREMENTS...............................................65 
12.1-Data Reporting ...........................................................................................................65 
12.2-CTEP Multicenter Guidelines ...................................................................................65 
12.3-Collaborative Agreements Language ........................................................................65 
13.0-STATISTICAL CONSIDERATIONS ..................................................................................67 
13.1-Study Design/Endpoints ............................................................................................67 
13.2-Sample Size/Accrual Rate .........................................................................................68 
13.3-Stratification Factors..................................................................................................68 
13.4-Analysis of Secondary Endpoints ..............................................................................68 
13.5-Reporting and Exclusions ..........................................................................................68 
REFERENCES ..............................................................................................................................70 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................74 
APPENDIX B 
CTEP MULTICENTER GUIDELINES ....................................................75 
APPENDIX C 
Patient’s medication diary- lenalidomide ..................................................77 
APPENDIX D 
Baseline Lymphoma Data Form ................................................................78 
APPENDIX E: LYMPHOMA RESPONSE ASSESSMENT FORM ...........................................79 
Appendix F.....................................................................................................................................80 


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Appendix G ....................................................................................................................................81 
Appendix H ....................................................................................................................................82 
Shipping Instructions .....................................................................................................................82 
Appendix I: Lenalidomide Packet (4 documents) .........................................................................84 
 


NCI Protocol #:8309 
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9 
 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
Phase I portion:  
1.1. 
To determine the safety, toxicity, and maximum tolerated dose of lenalidomide when 
combined with temsirolimus in patients with relapsed lymphomas.  
Phase II Portion:  
1.2. 
To determine complete and overall response rate of lenalidomide plus temsirolimus in 
patients with relapsed lymphomas as stratified by histology: follicular lymphoma, 
diffuse large B-cell lymphoma, and lymphoma NOS (including Hodgkin 
lymphoma, T-NHL, lymphoplasmacytic lymphoma, mantle cell lymphoma) 
1.3. 
To determine duration of response, progression-free survival, and overall survival of 
lenalidomide plus temsirolimus in patients with relapsed lymphomas as stratified 
by histology: diffuse large B-cell lymphoma, follicular lymphoma, and lymphoma 
NOS (including Hodgkin lymphoma, T-NHL, lymphoplasmacytic lymphoma, 
mantle cell lymphoma).  
Primary correlative objectives for both phase I and phase II portion:  
1.4. 
To determine mTOR pathway activation in pre-treatment tumor tissue. 
1.5. 
To determine angiogenic and microenvironmental status of pre-treatment tissue and 
peripheral blood samples, and to evaluate changes following treatment with 
temsirolimus and lenalidomide.   
1.6. 
To determine differentially expressed genes associated with differences in clinical 
response and in progression-free survival (PFS) in patients with DLBCL and FL 
(Groups A and B, respectively)  
1.7. 
To determine a methylation signature predictive of clinical response and PFS in 
patients with DLBCL and FL (Groups A and B, respectively)  
 
2.0 
BACKGROUND 
 
2.1 
 Non-Hodgkin lymphoma (NHL)  
 
Nearly 70,000 new cases of non-Hodgkin lymphomas were diagnosed in 2008, making NHL the 
5th most common cause of cancer in women and the 6th most common cause of cancer in men. 
New treatments have improved the clinical outcome for many patients, but NHL remains among 
the top 10 causes of cancer mortality with nearly 20,000 annual deaths, and much work remains 
to be done in terms of understanding the biology and treatment of various subtypes.  
 
A major challenge in NHL is the heterogeneity of the disease, which now includes more than 
several dozen subtypes. The two most common NHL subtypes are diffuse large B-cell lymphoma 
(DLBCL) and follicular lymphoma (FL), each respectively being the prototype of aggressive and 
indolent lymphomas. Although the biology of unique lymphoma subtypes may differ, aberrations 
of both the mTOR pathway and of the lymphoma microenvironment appear to be shared features 
and thus represent rational targets for treatment.  
2.1.1 mTOR (mammalian target of rapamycin in NHL) 
Mammalian target of rapamycin (mTOR): mTOR is a central transducer of growth signals in 


NCI Protocol #:8309 
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10 
normal and neoplastic cells via translational modulation. Under normal conditions, mTOR 
utilizes various companion proteins and upstream signals from PI3K/Akt to sense favorable 
environments for growth and cell cycle progression; conversely, unfavorable conditions lead to a  
halt in mTOR-mediated cellular protein production and induction of cell cycle arrest. 
 
 Other functions include mediating cellular adaptability to external stress signals, such as 
hypoxia, by translating a group of proteins known as hypoxia-inducible factors (HIF-).1 In 
addition, mTOR is emerging as a regulator of neoangiogenesis via translational control of 
vascular endothelial derived growth factor (VEGF), and mTOR inhibition may have 
antiangiogenic effects.2,3 Cancer cells use mTOR’s control over protein translation to their 
advantage, making mTOR inhibition an appropriate target for anti-cancer therapies.  
 
PI3K/Akt/mTOR axis: The PI3K/Akt pathway connects multiple extracellular signals to the 
translational machinery and is summarized below (Figure 1). In the case of mTOR, Akt 
activation releases the negative control of two tumor suppressor proteins (tuberous sclerosis 
proteins 1 and 2, or TSC1 and TSC2) on mTOR, which is then free to phosphorylate its own 
downstream effectors, p70 S6K1 and 4EBP1, discussed in more detail below. Several excellent 
and more detailed reviews are also available.4-7 The entire pathway is under constitutive negative 
regulation by PTEN (phosphatase and tensin homolog deleted on chromosome 10), which thus 
has a critical tumor suppressor function.8 Loss of the tumor suppressor gene, PTEN, allows for 
uncontrolled PI3K signaling and has been observed in many tumors including lymphomas. The 
loss of even a single PTEN allele in mice leads to lymphomas resistant to standard cytotoxics but 
sensitive to rapamycin with or without chemotherapy.9 
 
Downstream of mTOR: The key oncogenic potential of mTOR lies in its control over the 
initiation of translation and protein biosynthesis via two downstream targets: S6K1 (40S 
ribosomal protein S6) and 4EBP1 (eIF4E binding protein). Sequential S6K1 phosphorylation 
initiates translation of an important subset of mRNA possessing a TOP (terminal oligopyrimidine 
tract in the 5’ untranslated region) region. Although accounting for fewer than 200 genes, TOP-
Figure 1. 
PI3K/Akt/mTOR 
pathway. (from Smith 
SM, Reviews on Recent 


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dependent mRNA’s comprise up to one-third of total cellular mRNA.10 TOP-dependent mRNA 
include many ribosome biogenesis factors, ribosomal proteins, and elongation factors important 
in ribosome synthesis, as well as proteins that upregulate synthesis of other proteins.11 S6K1 (and 
its homolog S6K2) may be an important marker of PI3K/Akt/mTOR pathway activation, and is 
overexpressed in tumors with PTEN deletions. It is important to note, however, that there are 
several parallel pathways capable of phosphorylating S6K1, including direct activation from 
PDK1 and indirectly from Akt/PKB (phosphokinase B).10 Despite these caveats, S6K1 
phosphorylation status has become a commonly used marker to assess the pharmacodynamic 
effects of mTOR inhibitors. 
 
The second major downstream effector, 4EBP1, controls translation of another group of mRNA, 
all of which contain a 7-methylguanosine residue capping the 5’ end (cap-dependent mRNA). 
This group of mRNA includes essential components of the cell cycle machinery, including 
mRNAs encoding cyclin D1 and c-MYC, both of which are important in lymphomagenesis. 
Other cap-containing mRNA’s include fibroblast growth factor and VEGF. 4EBP1 is normally 
tightly bound in an inhibitory manner to eIF4E (elongation initiation factor). 4EBP1 
phosphorylation by mTOR releases eIF4E to interface with its family members, such as eIF4G 
and eIF3, and recruits the 40S ribosomal subunit to the 5’ ends of capped mRNAs, thus allowing 
translation initiation.(reviewed in 12) The initiation of translation is an important regulatory and 
rate-limiting checkpoint, and highlights the significance of inhibitory control over eIF4E.  
 
mTORC1 and mTORC2: A potentially relevant aspect of the PI3K/Akt/mTOR pathway for 
clinical applications is that the mTOR protein can exist as part of two distinct and mutually 
exclusive intracellular pools: mTORC1 and mTORC2. mTORC1, which includes the scaffold 
protein, raptor, and GL, was first identified as a rapamycin-sensitive complex that dissociates in 
the presence of rapamycin-FKBP12. Raptor is a stabilizing protein that facilitates and enhances 
mTOR’s activation of downstream targets, and its loss leads to near-absence of mTOR’s control 
over S6K1 and 4EBP1.13,14 mTORC2 contains another scaffold protein, rictor (rapamycin 
insensitive companion), which has an important role in maintaining the actin cytoskeleton and 
does not participate in mTORC1 tasks such as protein biosynthesis.15 As the name implies, 
mTORC2 is not a substrate for rapamycin and remains intact with exposure to mTOR 
inhibitors.15 However, mTORC2 has a recently identified second function, which is to 
paradoxically phosphorylate Akt at Ser473.16 Since mTOR exists in an equilibrium between these 
two complexes, rapamycin’s dissolution of the mTORC1 complex allows free mTOR to 
associate with rictor and increases the amount of intracellular mTORC2 which is then capable of 
activating Akt. mTORC2 mediated Akt activation could potentially reverse the effects of mTOR 
inhibitors.  
 
mTOR abnormalities in NHL: Many lymphoma subtypes possess abnormalities of the mTOR 
pathway, suggesting a role in lymphomagenesis. The PI3K/Akt/mTOR axis may have 
transforming capability. Wlodarski and colleagues found constitutive mTOR activation in 
multiple transformed lymphoma cell lines irrespective of EBV status; they further demonstrated 
that mTOR is required for cell proliferation in transformed B-cells.17 Akt overexpression leads to 
an aggressive lymphoma phenotype in murine models, similar to bcl-2 overexpressing 
lymphomas in the same series.18 In this study, rapamycin induced apoptosis, and the combination 
of chemotherapy plus mTOR inhibition led to dramatic lymphoma regression in the Akt 


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overexpressing but not Bcl-2 overexpressing tumors. Furthermore, eIF4E and the proto-
oncogene c-myc (frequently deregulated in lymphomas) may cooperate in promoting 
lymphomagenesis since the introduction of both eIF4E and c-myc decreases the latency of 
lymphoma formation in mice from16 months to 1 month19, suggesting a joint effect. The specific 
interaction between eIF4E and c-myc remains to be elucidated, but it is clear that eIF4E directly 
inhibits apoptosis and allows the malignant lymphomatous phenotype to be expressed.18-20. 
Finally, the mTOR inhibitor everolimus (RAD001) was shown to restore normal B-cell 
differentiation and prevent c-MYC induced malignant transformation in E-myc mice as 
compared to placebo.21  
 
Preclinical models have shown important relevance of the PI3K/Akt/mTOR pathway in mantle 
cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and alk-positive anaplastic 
large cell lymphoma. Mantle cell lymphoma has been a paradigm disease highlighting the central 
role of mTOR activation in lymphomagenesis. Although an uncommon disease accounting for 
approximately 5% of all lymphomas, mantle cell lymphoma is an incurable subtype with a 
median survival of only 3-5 years. The t(11;14)(q13;q32) translocation and consequent cyclin D1 
overexpression is a pathognomonic and pathogenetic feature of mantle cell lymphoma. Cyclin 
D1 is a cap-dependent mRNA and is therefore potentially amenable to mTOR translational 
control. Several groups have demonstrated that inhibition of PI3K, Akt, or mTOR results in 
downregulation of cyclin D1 levels. The rapamycin analog, everolimus, downregulated mTOR 
and 4EBP1 in several MCL cell lines concomitant with G1 arrest.22 Peponi and colleagues used 
mTOR-specific siRNA and this was associated with downregulation of both cyclin D1 and anti-
apoptotic proteins.23 Rudelius and colleagues confirmed the central role of Akt in the 
pathogenesis of MCL, particularly in the more aggressive blastoid variant, and conclude that the 
extent to which MCL relies on PI3K/Akt/mTOR for survival correlates with biologic 
aggressiveness.24 Inhibition of Akt signaling in all models tested led to apoptosis, concurrent 
with decreased mTOR activity. Clinical trials of mTOR inhibitors in MCL are encouraging and 
discussed below. Evidence for pathway activation is also observed in patient samples and cell 
lines of the two most common NHL histologies: follicular lymphoma and diffuse large B-cell 
lymphoma. Lesaux and colleagues compared follicular lymphoma cells to normal tonsils and 
demonstrated substantially increased S6K1 phosphorylation that was rapamycin- and 
everolimus-sensitive.25  Activated mTOR was critical for follicular lymphoma survival. This is 
consistent with proteomic data in which constitutive Akt activation was characteristic of 
follicular lymphoma samples.26 Finally, both rapamycin and everolimus induce G1 cell cycle 
arrest in diffuse large B-cell lymphoma cell lines, with both mTOR inhibitors augmenting 
rituximab (anti-CD20) cytotoxicity.27 Certainly, the optimal development of mTOR inhibitors is 
predicated on identifying tumors reliant on activation of mTOR and its pathway members, and 
the discussion above supports lymphomas as being an appropriate tumor type in which to test 
mTOR inhibitors.  
 
2.1.2 Role of microenvironment in NHL 
Although less well understood than solid tumor counterparts, it is increasingly clear that the 
lymphoma microenvironment plays an important role in sustaining the malignant phenotype. 
There are several entities comprising the lymphoma microenvironment, including normal and 
transforming features of the germinal center, pro-angiogenic proteins, the immune response to 
lymphoma cells, and the cytokine milieu. In follicular lymphoma, features of the non-malignant 


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background cells have demonstrated an effect on overall survival, and targeting these cells and/or 
interaction between the microenvironment and lymphoma represents a valid therapeutic 
strategy.28  This is underscored by the inability to sustain ex vivo follicular lymphoma cell 
populations without cytokine or stromal support.29-31 Furthermore, gene-expression profiling of 
patient samples surprisingly shows that the genetic signature of the non-malignant infiltrating 
immune cells, and not the gene-expression profile of FL cells themselves, determines survival.28 
Patients with a predominant monocytic or dendritic cell infiltrate had a 9.35-fold increased 
relative risk of death compared to patients with a predominant T-cell infiltrate. Similarly, 
increased numbers of FOXP3 positive T regulatory cells portends a good prognosis. Varying 
lymphocyte subpopulations, including FOXP3+ cells, CD57+ cells, and CD8+ cells all play a 
critical role in FL clinical outcome.32-34In terms of angiogenesis, we now know that increased 
microvessel density (MVD) is a poor prognostic marker in DLBCL, that increased MVD 
corresponds to the activated B-cell phenotype in DLBCL, that vascularization predicts both 
overall survival and transformation risk in FL, and that the intensity of VEGF-D corresponds to 
increased IPI.35-38   
 
Immunomodulatory agents, such as thalidomide and lenalidomide, have pleiotropic effects on 
the lymphoma microenvironment. The two major mechanisms of action appear to involve 
changing the cytokine milieu (and thus interrupting lymphoma-ME crosstalk) and inhibition of 
angiogenesis.  Proof of concept is provided by preliminary clinical studies showing single-agent 
activity of lenalidomide in patients (see discussion below) with both relapsed indolent and 
aggressive NHL, ranging from 26% to 34%.39,40  The oral availability and acceptable toxicity 
profile of lenalidomide makes it an attractive agent to study in combination settings.  
 
 
2.2  TEMSIROLIMUS 
Temsirolimus (sirolimus 42-ester with 2,2-bis(hydroxymethyl propionic-acid) is a water soluble 
ester of rapamycin, currently in development by Wyeth Research (Collegeville, PA). 
Temsirolimus (also called cell cycle inhibitor 779, CCI-779, ToriselTM) is a prodrug of 
rapamycin, and differs in structure by virtue of a semisynthetic substitution in the lactone ring.5,41 
After intravenous injection, temsirolimus is rapidly converted to rapamycin. Four single agent 
phase I trials and two randomized phase II trials have characterized temsirolimus 
pharmacokinetics in humans. Hidalgo and colleagues tested a unique schedule of temsirolimus 
administered daily for five days every other week.42 This schedule was based on preclinical data 
in mice demonstrating antitumor activity without permanent T-cell dysfunction, and is the sole 
published temsirolimus study not utilizing a weekly schedule. The starting dose was 0.75 
mg/m2/day with 20% dose escalations per cohort, and a final maximum tolerated dose of 19 
mg/m2/day. A total of 63 patients with advanced solid tumors were enrolled, and 
pharmacokinetic analysis demonstrated a Cmax and AUC that increased with dose in a less than 
proportional manner. Temsirolimus was converted to sirolimus within 15 minutes, and had a 
terminal half-life ranging form 13 to 25 hours.  Although generally well-tolerated, the most 
common toxicities included asthenia, mucositis, nausea, rash, thrombocytopenia, and leucopenia, 
with the severity of side effects somewhat related to the dose of temsirolimus as well as the 
intensity and number of prior therapies.  Of interest, although some of the toxicity (i.e. 
thrombocytopenia requiring dose reductions) appeared to be dose related, hints of activity were 
observed at several dose levels. These findings support the use of a flat dose of temsirolimus in 
future studies and highlight the limitations of toxicity-based phase I trials for many newer 
agents.42  


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Two other phase 1 trials have also been completed and published in final form. The study by 
Raymond and colleagues evaluated weekly temsirolimus at doses ranging from 7.5 mg/m2 to 
220 mg/m2 in 24 patients with advanced solid cancers.43 In the weekly dosing schedule, AUC 
increased proportionally with doses up to 150 mg, but this disappeared with doses greater than 
300 mg. Temsirolimus concentration declined polyexponentially, and sirolimus could be 
detected within 15 minutes with a peak at 0.5 to 2 hours following drug administration. The 
terminal half-life of sirolimus was 61-69 hours. The authors also evaluated BSA-based dosing 
and flat dosing, and found comparable pharmacokinetic profiles, again supporting the use of flat 
dosing for future studies.  
 
As mentioned above, mantle cell lymphoma is emerging as a paradigm for mTOR inhibitor 
activity in lymphoma; the pathologic expression of cyclin D1 resulting from the t(11;14) 
translocation is enhanced by mTOR translational effects and provides a direct rational for testing 
MTI in this setting. The Mayo Clinic Consortium performed a pilot phase 2 study of 
temsirolimus 250 mg weekly in 35 patients with relapsed mantle cell lymphoma.44 This was a 
poor prognosis group of patients with a median age of 70 and a median of 3 prior treatment 
regimens; 54% of patients were deemed refractory to their most recent treatment regimen prior to 
temsirolimus. The investigators observed an encouraging 38% overall response rate, with 1 (3%) 
patient achieving a complete remission. The median duration of response was 6.9 months. 
However, very few of the patients could tolerate the dose of 250 mg weekly, and all but 4 
patients required substantial dose reductions, mainly due to reversible thrombocytopenia or other 
cytopenias. Other adverse effects of temsirolimus include stomatitis, hyperglycemia, 
hypertriglyceridemia, infection without neutropenia, and rash. Although the authors evaluated 
mTOR activity via S6 phosphorylation status, they could not identify a correlation with response 
in a limited sample set. Several conclusions can be drawn from this study. First, the response rate 
to single agent temsirolimus is encouraging in such a heavily pretreated and elderly population 
with acceptable and reversible toxicity. Second, the optimal biologic dose of temsirolimus may 
be much lower than 250 mg weekly. Indeed, a parallel study in patients with renal cancer 
suggests that activity can be observed with one-tenth this dose, and ongoing trials have 
incorporated lower doses.  
 
The North Central Cancer Treatment Group used the lower 25 mg flat dose, and readdressed the 
issue of efficacy in relapsed MCL.45 In a group of 27 evaluable patients, they demonstrated an 
impressive overall response rate of 41%, although all but one was a partial response. Similar to 
the higher dose, they observed a median duration of response of 6.2 months in responding 
patients. The incidence of grade 3 and 4 thrombocytopenia decreased dramatically (12% and 0%, 
respectively) although dose reductions were still required in over half of the patients for 
unspecified reasons. Regardless, the equivalent response rate with one-tenth the original dose is 
proof of principle that future studies can justifiably be based on biologic parameters and not 
necessarily pharmacologic or toxicity-based features. In contrast to phase II studies suggesting 
preserved efficacy with lower doses, results of an international phase III trial evaluating “high 
dose” and “low dose” temsirolimus versus investigator’s choice suggests that the temsirolimus 
dose may impact results. In this study, Hess and colleagues compared three treatment arms: 
temsirolimus 175 mg weekly x 3 weeks followed by either 75 mg weekly (“high dose”) or 25 mg 
weekly (“low dose”), and investigator’s choice of single agent therapy (i.e. gemcitabine, 
fludarabine, and others). The ORR was highest for the high dose arm (22%), and only 6% and a 


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surprising 2% for the low dose and investigator’s choice arms, respectively. The median duration 
of response was also improved in the high dose arm (7.1 months) versus 3.2 months for the low 
dose. The high dose arm met the statistical endpoint of improved PFS (4.8 months) as compared 
to the control arm (1.9 months); the low dose arm had a median PFS of 3.4 months. Toxicity 
appeared similar across all arms, although the high dose arm had approximately 90% of patients 
with grade 3 or 4 adverse events, compared to approximately 80% in the low dose arm and 68% 
in the investigator’s choice arm. It is unknown if there is a similar dose response in other 
lymphoma subtypes. 
 
Although much of the clinical interest in MTI in NHL has focused on MCL based on the 
rationale stated above, The University of Chicago Phase II Consortium initiated a CTEP-
sponsored phase II study of temsirolimus in non-mantle cell lymphoma histologies, with results 
presented at ASCO 2008.46 Patients were accrued into one of three cohorts: diffuse large B-cell 
lymphoma (DLBCL), follicular lymphoma (FL), or other indolent lymphomas including 
CLL/SLL. Data on 82 evaluable patients revealed an intent-to-treat ORR 40%, and ORR of 46% 
in patients completing at least 2 cycles.47 Efficacy was strongest in follicular lymphoma, with an 
overall response rate over 50% and a median PFS of 9 months in heavily pretreated patients. Of 
interest, none of the patients with small lymphocytic lymphoma/chronic lymphocytic leukemia 
(1/15, 6%) met criteria for response; response rate when excluding patients with CLL/SLL was 
49%, with 20% complete remission rate.  Toxicities were generally mild, with metabolic changes 
(hyperglycemia, hypertriglyceridemia, hypercholesterolemia) and transient myelosuppression 
(thrombocytopenia) being most common.  The significant single agent activity observed in this 
multicenter phase II trial prompts the current trial, which aims to combine temsirolimus with 
another active agent, lenalidomide, that should have complementary effects. 
 
 
2.3  LENALIDOMIDE 
Lenalidomide and its predecessor, thalidomide, are proprietary IMiD™ compounds of Celgene 
Corporation. Thalidomide gained notoriety in the 1960s due to profound limb deformities 
observed in offspring of pregnant women who used thalidomide as a sedative. A re-evaluation of 
the agent several decades later showed important antiangiogenic, anti-inflammatory, and 
antineoplastic effects. Lenalidomide (Revlimid®, CC-5013) is an orally available and more 
potent thalidomide derivative that has a more favorable side effect profile, including lower rates 
of sedation and neuropathy. Lenalidomide has both immunomodulatory and anti-angiogenic 
effects, but the precise mechanism of action remains unknown. In general, its effects include 
inhibition of regulatory T-cells, co-stimulation of other T-cell subsets, VEGF inhibition, Akt 
inhibition, inhibition of cell cycle regulatory proteins (i.e. p21), and downregulation of a variety 
of cytokines including IL-6 and TNF Preclinical studies have shown that lenalidomide inhibits 
neovascularization, most likely via VEGF inhibition. In addition, lenalidomide decreases blood 
vessel sprouting in hypoxic conditions, possibly by downregulating HIF1 induced 
angiogenesis.48 The interaction between lenalidomide and the Akt axis is particularly relevant for 
the current clinical study, since Akt is upstream of mTOR and is often paradoxically activated 
with mTOR inhibitor therapy. Lenalidomide has been shown to inhibit Akt phosphorylation, 
allowing multiple potential “hits” to the PI3K/Akt/mTOR axis when combined with an mTOR 
inhibitor.49 In addition, in vitro data shows synergy between rapamycin and lenalidomide in 


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multiple myeloma cell lines, forming the basis for an ongoing clinical trial in multiple 
myeloma.50 
Phase I trials with lenalidomide were prompted by preclinical data suggesting anti-tumor 
effects.51-54 Doses up to 50 mg daily have been evaluated in both hematologic and solid tumor 
populations. Lenalidomide has less myelosuppression when a 7-day break is introduced, and the 
most common schedule selected for further development is 25 mg daily on Days 1-21, followed 
by a 7-day rest period. The vast majority of side effects are mild, and include rash, pruritus, 
diarrhea, and fatigue. Grade 3 and 4 toxicities observed in these trials include neutropenia and 
thrombocytopenia in approximately 10% of patients. Importantly, severe constipation, 
neuropathy and somnolence that characterize thalidomide effects were not seen.   
There are several trials investigating lenalidomide monotherapy in patients with relapsed 
lymphomas. Wiernik and colleagues recently published a final analysis of lenalidomide 25 mg 
daily on Days 1-21 repeated every 28 days in 49 patients with relapsed aggressive lymphomas.55 
Approximately half of patients had DLBCL, with the remaining patients comprised of grade 3 
follicular lymphoma, mantle cell lymphoma, and transformed follicular lymphoma. The overall 
response rate was 35%, with a median duration of response 6.2 months and median PFS 4.0 
months. This was a heavily pretreated population of patients, with a median of 4 prior regimens, 
and 30% of patients having failed a prior autologous stem cell transplant. A subsequent 
international trial of single agent lenalidomide (NHL-003) at the identical dose found an ORR of 
29% in heavily pretreated DLBCL patients; accrual to this study is ongoing.56 Witzig and 
colleagues reported on the same schedule of lenalidomide in patients with relapsed indolent 
lymphomas;57 again, the patient population was very heavily pretreated with 50% being 
refractory to their most recent regimen and near universal prior rituximab exposure. In this study, 
the ORR was 23% in all patients, and 27% in relapsed FL patients. What is interesting, however, 
is that although the median PFS is 4.4 months, the median duration of response for responding 
patients has not yet been reached and is greater than 16.5 months. Lenalidomide monotherapy 
appears particularly active in mantle cell lymphoma, with an ORR of 53% and a median duration 
of response 13.7 months.58 An ongoing international phase II trial of lenalidomide monotherapy 
(NHL-003) updated findings in patients with MCL.59 The authors report an ORR of 43% in 54 
elderly and heavily pretreated patients; when evaluating subsets of patients with prior bortezomib 
exposure and/or stem cell transplant, the response rates were 53% and 57%, respectively. This 
suggests a non-overlapping mechanism of action from other therapies, and is encouraging in this 
patient population. These single agent studies as well as preclinical studies of potential synergy 
have prompted an intense development agenda for lenalidomide in NHL, with many trials 
currently underway.  
 
 
2.4  RATIONALE 
 
The current trial proposes to combine lenalidomide with temsirolimus in patients with relapsed 
lymphomas due to a variety of observations suggesting potential additive and/or synergistic 
effects. Aberrations of both the mTOR pathway and the lymphoma microenvironment contribute 
to lymphomagenesis and lymphoma progression, and the current proposal aims to inhibit both of 
these components. Potential points of overlap between these two agents are as follows. First, a 
downstream mRNA target of mTOR is VEGF, and pre-clinical studies support the ability of 
mTOR inhibitors to downregulate VEGF through indirect and direct mechanisms.60,61 The 


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mRNA for VEGF is under mTOR translational control. Second, lenalidomide has been shown to 
inhibit Akt phosphorylation, allowing multiple “hits” to the PI3K/Akt/mTOR axis when 
combined with an mTOR inhibitor.49 Akt phosphorlyation can be paradoxically increased in 
patients treated with mTOR inhibitors, most likely via an undesired increase in mTORC2 
formation, and Akt activation is known to mediate resistance to mTOR inhibitors. In addition, 
mTORC1 inhibition acting through S6 kinase phosphorylation of insulin receptor substrate 1 
(IRS1) has also been shown to activate Akt.62   In vitro data shows synergy between rapamycin 
and lenalidomide in multiple myeloma cell lines, forming the basis for an ongoing clinical trial in 
multiple myeloma.50 Finally, as discussed above, HIF1, which stimulates neovascularization, 
can be inhibited by both mTOR inhibitors (which controls mRNA translation) and lenalidomide 
(unknown mechanism).48,63 Clinical trials have established single agent efficacy for both of the 
agents to be tested, and a combination should be at least additive and perhaps synergistic.  
 
Building upon The University of Chicago Phase II Consortium’s prior experience with single 
agent temsirolimus, this protocol will determine the safe combined dose of lenalidomide when 
added to temsirolimus in patients with relapsed lymphomas. Temsirolimus dosing will be 
identical to the recently completed trial (25 mg weekly with 4 week cycles), and oral 
lenalidomide will be added in a phase I dose escalation design. Once the dosing regimen has 
been determined in the phase I portion of the study, a phase II component stratified by histology 
will determine the efficacy of the combination in patients with follicular lymphoma and diffuse 
large B-cell lymphoma. A third exploratory cohort will determine the efficacy of the 
combination in other indolent relapsed lymphomas.  
 
 
2.5  CORRELATIVE STUDIES BACKGROUND 
 
N/A 
 
 
3.0 PATIENT SELECTION 
On-study guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for the trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy and therefore only enroll patients for whom the agents administered 
are appropriate. Although they will not be considered as formal eligibility (exclusion) criteria, as 
part of the decision-making process physicians should recognize that the following may increase 
the risk to the patient entering this protocol:  
 
• Serious medical illness of psychiatric condition which would prevent 
compliance with treatment or informed consent. 
• Medical condition such as uncontrolled infection, uncontrolled diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, 
would make this protocol unreasonable hazardous for the patient.  
• Patients considered to be at high risk of developing DVT/PE or arterial 
thromboses are to receive prophylactic aspirin or low molecular weight 
heparin unless contraindicated. High risk will be defined as a history of 


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DVT/PE, significant family history, performance status > 2, smoking history, 
use of oral contraceptives, and concurrent use of epoetin. Patients with 
diabetes mellitus or coronary artery disease are considered to be at high risk 
for arterial thromboembolic events.  
 
 
3.1 Eligibility Criteria  
 
3.1.1 Histology: Bone marrow biopsies (with the exception of lymphoplasmacytic 
lymphoma) as the sole means of diagnosis are not acceptable. Fine needle 
aspirates are not acceptable.  
 
3.1.1.1 Phase I: Previously treated, histologically confirmed Hodgkin and non-
Hodgkin lymphomas.  The only exception to a requirement for a lymph 
node biopsy is lymphoplasmacytic lymphoma, which can be diagnosed 
based on morphologic evidence in the bone marrow plus the appropriate 
paraprotein. 
3.1.1.2 Phase II: Previously treated, histologically confirmed mature NHL 
stratified by histology:   
3.1.1.2.1 Group A: Diffuse large B-cell lymphoma (NOTE: all patients 
with DLBCL must have germinal center vs. non-germinal 
center phenotype established via immunohistochemistry—See 
Appendix D)64 
3.1.1.2.2 Group B: Follicular lymphoma 
Group C: Lymphoma NOS (including Hodgkin lymphoma, T-NHL, marginal zone 
lymphoma, lymphoplasmacytic 3.1.2 No limit to number of prior therapies. 
Prior autologous transplantation is allowed. 
 
3.1.2 Age >18 years.   
 
3.1.3 ECOG performance status <2 (see Appendix A). 
 
3.1.4 Patients must have normal organ and marrow function as defined below: 
 
 absolute neutrophil count  
>1000/μl 
 platelets  
 
 
 
 
 
>75,000/μl 
 total bilirubin 
 
 
 
 
<1.5 X ULN (unless due to Gilbert’s) 
 AST(SGOT)/ALT(SGPT)  
<2.5 X ULN 
 creatinine clearance  
 
 
>60 mL/min as determined by calculated 
Cockcroft-Gault equation. 
 Fasting serum cholesterol  
< 350 mg/dL 
 Fasting serum triglycerides   
< 2.5 X ULN 
 
3.1.5 All patients are required to have measurable disease. Non-measurable disease 
alone is not acceptable. Any tumor mass > 1 cm is acceptable.  
 
 
 
 
 
 


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Lesions that are considered non-measurable include the following:  
• Bone lesions (lesions if present should be noted) 
• Ascites 
• Pleural/pericardial effusion 
• Lymphangitis cutis/pulmonis 
• Bone marrow (involvement by lymphoma should be noted) 
• For Waldenstrom’s macroglobulinemia, Measurable disease is defined 
as at least one lesion with a single diameter of greater than 2 cm by 
computed tomography or bone marrow involvement with greater than 
10% malignant cells and quantitative monoclonal protein (IgM, IgG, 
IgA) greater than 1,000 mg/dL. 
 
3.1.6  Females of childbearing potential (FCBP) must have a negative serum or 
urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 – 14 days 
and again within 24 hours prior to starting Cycle 1 of lenalidomide. Further, they 
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 
starting 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.  A FCBP 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).  All patients must be 
counseled at a minimum of every 28 days about pregnancy precautions and risks 
of fetal exposure.  (See Appendix I: Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods, and also Appendix J: 
Education and Counseling Guidance Document). 
 
 
3.1.7 
Ability to understand and the willingness to sign a written informed 
consent document. 
 
3.1.8 Patients who are HIV positive are allowed to participate BUT must meet the 
following criteria (see also Appendix D):  
3.1.8.1 No AIDS-defining illness, AND                                                                   
(see http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2.htm)  
3.1.8.2 CD4 count > 400 cells/mm3, AND  
3.1.8.3 No anti-retroviral therapy (including HAART) within 7 days of starting 
protocol therapy, AND  
3.1.8.4 Patient may not take concurrent anti-retroviral therapy (including 
HAART) while on protocol (See also Section 10) 
3.1.8.5 NOTE: It is not generally recommended to suspend anti-retroviral 
therapy (including HAART). The medical team enrolling a patient 
who suspends anti-retroviral therapy for the purpose of study 
participation must have a documented note reviewing the potential 


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risks/benefits with the patient in the medical chart 
 
3.2 Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 
weeks for nitrosoureas or mitomycin C) prior to entering the study or 
those who have not recovered from adverse events due to agents 
administered more than 4 weeks earlier. 
 
3.2.2 Patients who are receiving any other investigational agents. 
 
3.2.3 Patients with known brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often 
develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical 
or biologic composition to temsirolimus or lenalidomide used in study. 
 
3.2.5 Because of the high potential for drug-drug interaction, patients requiring 
active anti-retroviral therapy for HIV are excluded.  
 
3.2.6 No “currently active” second malignancy, other than non-melanoma skin 
cancers. Patients are not considered to have a “currently active” second 
malignancy if they have completed anti-cancer therapy and are considered 
by their physicians to be at less than 30% risk of relapse.  
 
3.2.7 
No history (within 3 months of study entry) of DVT/PE. Patients with a distant history 
(greater than 3 months before study entry) of DVT/PE are eligible, but should receive 
prophylactic aspirin or low molecular weight heparin.  
 
3.2.8 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. 
 
3.2.9 Patients with relapsed/refractory DLBCL or HL who are eligible and 
willing to undergo potentially curative stem cell transplant.  
 
3.2.10 Patients with CLL/SLL are excluded. 
 
3.2.11 No corticosteroids within 14 days prior to study, except for maintenance 
therapy for a non-malignant disease. Maintenance therapy dose may not 
exceed 10 mg/day prednisone or equivalent. Any patient on steroid 
therapy must receive thromboembolic prophylaxis. 
 


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3.3 Inclusion of Women and Minorities 
 
Both men and women and members of all ethnic groups are eligible for this trial.  Based 
on the nature of our study population at the University of Chicago and the Phase II 
Consortium, we expect at least 50% of our enrollment to be women and 30% to be non-
white. 
study. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
38 
+ 
37 
= 
75 
Not Hispanic or Latino 
37 
+ 
38 
= 
75 
Ethnic Category: Total of all subjects 
75 
(A1) + 
75 
(B1) = 
150 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
5 
+ 
5 
= 
10 
Asian 
5 
+ 
5 
= 
10 
Black or African American 
10 
+ 
10 
= 
20 
Native Hawaiian or other Pacific 
Islander 
5 
+ 
5 
= 
10 
White 
50 
+ 
50 
= 
100 
Racial Category: Total of all subjects 
75 
(A2) + 
75 
(B2) = 
150 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
 
4.0 REGISTRATION PROCEDURES 
 
 
4.1 General Guidelines 
 
All patients must be registered on study centrally with the University of Chicago Study 
Coordinator/ Registrar (see face page) via email and phone: PhaseIICRA@bsd.uchicago.edu, (773) 
834-5368 at least 7 days prior to the commencement of treatment to allow for sufficient time for 
supplies to arrive from the PMB. Confirm all the selection criteria listed in Section 3.0 are met and 
then call the appropriate study coordinator/registrar (contact info above or see face page) with the 
following information: 
• Provider of information 
• Study # and Institution 
• Treating Physician 
• Patient name and hospital ID number 
• Patient's zip code of residence 
• Date of signed informed consent 
• Race, gender, date of birth of patient 
• Diagnosis and date of initial diagnosis 


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The UC Registrar/Study Coordinator will issue a confirmation of registration as follows: The 
research nurse or data manager at the participating site will initiate contact with the UC 
Registrar/Study Coordinator to verify eligibility.  To complete the registration process, the study 
coordinator/registrar will 
• assign a patient study number 
• register the patient on the study 
• assign the patient a dose 
• fax or e-mail the patient study number and dose to the participating site 
• call the research nurse or data manager at the participating site and verbally confirm 
registration. 
 
Following registration, patients should begin protocol treatment within 7-days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for group studies. 
 
Each site must have two trained counselors available for counseling all patients receiving 
lenalidomide supplied by the Division of Cancer Treatment and Diagnosis.  Trained counselors 
must complete training using the online program provided free by Celgene, the Lenalidomide 
Counseling Program (LCP). Registration for LCP is done by completing the form found in 
Appendix L and following the directions provided in the email notification. After the training is 
complete, the counselors must generate a training certificate and provide it to the University of  
coordinating office/PMB) for documentation. Sites may not order lenalidomide until documentation 
for two trained counselors is provided to the appropriate office.  
 
4.2 Registration Process 
 
Registration 
 
 
 
Submit the Phase II Consortium Affiliate Clinical Trial Patient Registration Form and all 
source documentation for the protocol required eligibility criteria and pre-study procedures. 
 
Weekly 
 
 
 
Submit the Phase II Consortium Affiliate Clinical Trial Patient Weekly Treatment Summary 
Form with supporting source documentation by noon on Friday of each week, for review at the 
weekly Phase II Conference.  All other source documentation for protocol required procedures 
should be submitted within a week after it is created or modified. 
 
Evaluations 
At each response evaluation as specified in the protocol, submit supporting source 
documentation for the response. 


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Off-study 
Submit the Phase II Consortium Affiliate Clinical Trial Patient Off Treatment Form with 
appropriate source documentation. 
 
Follow-up  
Submit the Phase II Consortium Affiliate Clinical Trial Patient Follow-Up Form with 
appropriate source documentation. 
 
Please contact the study coordinator for the appropriate CRF’s for this study. 
 
All required forms and source documentation should either be faxed to  
(773) 702-4889 or mailed to: 
Phase II Program Data Managers 
 
5841 S. Maryland Avenue MC 2115 Chicago, IL 60637 
 
Data Safety and Monitoring will occur at the weekly University of Chicago Phase II Consortium 
meetings, which are lead by senior level medical oncologists.  At each meeting, all active Phase 
II Consortium studies will be reviewed for safety and progress toward completion. Toxicities and 
adverse events will be reviewed at each meeting and a Data Safety and Monitoring form will be 
filled out for each protocol and signed by either the principal investigator, the Chairman of the 
Phase II Consortium or by his designate if the chairman is not available.   
 
5.0 TREATMENT PLAN 
 
Agent Administration (Phase I portion is completed) 
 
5.1 Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks for temsirolimus and lenalidomide are described in Section 6.  Appropriate dose 
modifications for temsirolimus and lenalidomide are described in Section 5.  No investigational 
or commercial agents or therapies other than those described below may be administered with 
the intent to treat the patient's malignancy. 
 
 
 
Dose Escalation Schedule 
Dose Level 
Dose* 
Temsirolimus    
(flat dose in mg) 
Lenalidomide     
(flat dose in mg) 
 
 
 
Level -2 
 
15 mg 
 
10 mg 
 
 
 
Level -1 
 
25 mg 
 
10 mg 
 
 
 
Level 1 
 
25 mg 
 
15 mg 
 
 
 
Level 2 
 
25 mg 
 
20 mg 
 
 
 
 
 
 


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24 
Level 3 
25 mg 
25 mg 
 
 
5.1.1 Temsirolimus 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 6.  Appropriate dose modifications for CCI-779 are described in 
Section 5.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient’s malignancy. 
 
Patients will receive 25 mg of CCI-779 administered over 30 minutes IV weekly continuously 
(i.e. without interruption between cycles).  For the purposes of evaluation, a cycle will be defined 
as 4 weeks (28 days).  It is expected that CCI-779 administration will continue on the same day 
of the week throughout the treatment period.  However, it may be given up to 2 days early or late 
due to holiday or scheduling reasons.  Missed doses should not be made up.  
 
Because of the idiosyncratic hypersensitivity reactions, patients receiving IV CCI-779 should be 
premedicated with diphenhydramine 25 – 50 mg IV (or a similar antihistamine) approximately 
30 minutes before the start of the CCI-779 infusion.   
 
CCI-779 will be administered over approximately 30 minutes as an IV infusion, via an automatic 
dispensing pump (e.g. IMED, Harvard, Travenol), using non-polyvinyl chloride (PVC) tubing 
with the appropriate filter.  See section 6.0 (Incompatibilities subsection) for list of appropriate 
tubings and filters. 
 
5.1.2 Lenalidomide 
 
Lenalidomide is administered orally once daily for 21 days every 28 days. Clinical studies have 
shown that administering lenalidomide with food intake appears to delay absorption to some 
degree, although the extent of absorption is not altered. Lenalidomide can be taken with or 
without food. Patients will be requested to maintain a medication calendar recording the dates 
and times of each dose of lenalidomide.  A copy of the medication diary/calendar has been 
included as  Appendix C to the protocol. 
 
Lenalidomide capsules should be swallowed whole, and should not be broken, chewed, or 
opened. If a dose of lenalidomide is missed, it should be taken as soon as possible on the same 
day. If a dose of lenalidomide 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. 
 
 
5.2 Definition of Dose-Limiting Toxicity (Phase I Portion Completed) 
 
DLT evaluation for purposes of dose escalation will occur at the end of cycle 1, although toxicity 
data will continue to be collected for the duration of treatment. There will be no intra-patient 
dose escalation.  The definition of DLT will be as follows:  


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• any grade 3 or 4 non-hematologic toxicity with the exception of the following:  
o grade 3 or 4 hypokalemia and/or hypomagnesemia that responds to oral or 
IV repletion. Persistent grade 3 or 4 hypokalemia and/or hypomagnesemia 
that does not respond to oral or IV repletion after 2 weeks will lead to a 
reduction by one dose level.  
o Grade 3 or 4 hypertriglyceredemia, hypercholesterolemia, and/or 
hyperglycemia that responds to appropriate diet and/or medical 
intervention. Persistent grade 3 or 4 hypertriglyceridemia, 
hypercholesterolemia, and/or hyperglycemia that does not respond to 
appropriate diet and/or medical intervention after 2 weeks will lead to a 
reduction by one dose level.  
o Grade 3 or 4 nausea, vomiting, diarrhea without optimal intervention 
• grade 4 thrombocytopenia lasting greater than 7 days OR associated with 
clinically significant bleeding OR requiring > 1 platelet transfusion in one week 
• ANC < 500/L lasting greater than 7 days despite the use of growth factors  
• Any thromboembolic event (irrespective of prophylaxis) 
 
Management and dose modifications associated with the above adverse events for the 
phase II portion of the trial are outlined in Section 5. Management and dose 
modifications for the phase I portion of the trial are in Section 4.2.1.  
 
Dose escalation for the phase I portion of the trial will proceed according to a “3+3” 
design (see section 11). Dose-limiting toxicity (DLT) is defined above.  
 
5.2.1 Dose modifications for the phase I portion of the trial. For purposes of dose 
escalation, DLT evaluation will occur at the end of Cycle 1, but toxicity information will 
continue to be collected for the duration of treatment. For patients on the phase I portion of 
the trial, treatment modifications are as follows:  
 
 
Neutropenia 
• 
For ≥ grade 3 neutropenia on day 1 of a cycle, hold both temsirolimus and 
lenalidomide, and monitor CBC weekly. Resume therapy at next lower dose 
level when neutropenia resolves to ≤ grade 2. Hence, for neutropenia occurring 
on day 1 of a cycle, the cycle may be delayed. 
• 
For ≥ grade 3 neutropenia during a cycle, hold both temsirolimus and 
lenalidomide. and monitor CBC weekly. Resume therapy at next lower dose 
level when neutropenia resolves to ≤ grade 2. 
 •If treatment is delayed for more than 6 weeks, discontinue all protocol therapy 
and remove patient from study. 
Thrombocytopenia 


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26 
• 
For ≥ grade 3 thrombocytopenia on day 1 of a cycle, hold both temsirolimus 
and lenalidomide and monitor CBC weekly. Resume therapy at the next lower 
dose level for the next cycle when thrombocytopenia resolves to ≤ grade 2. 
• 
For ≥ grade 3 thrombocytopenia during a cycle, hold both temsirolimus and 
lenalidomide for remainder of the cycle. Resume therapy at the next lower dose 
level for the next cycle, provided thrombocytopenia has resolved to 
≤ grade 2. 
• 
If treatment is delayed for more than 6 weeks, discontinue all protocol therapy 
and and remove patient from study.  
Anemia 
• 
In the instance of drug-related anemia based on hemoglobin on day 1 that has 
worsened by one or more grade levels from previous cycle, reduce 
temsirolimus and lenalidomide by one dose level. 
• 
In the instance of drug-related grade 4 hemoglobin at any time during a cycle, 
discontinue temsirolimus and lenalidomide. 
• 
Epoetin may be used to treat drug-related anemia. If epoetin is used, patients 
should receive either prophylactic aspirin or low molecular weight heparin 
unless contraindicated.  
Dermatologic Toxicity 
In the instance of any grade desquamating rash, lenalidomide must be stopped. In the 
instance of grade 3 non-desquamating rash, the rash must resolve to grade 1 or less 
prior to restarting lenalidomide. Lenalidomide should be restarted 5mg less than prior 
dose. 
Other Non-Hematologic Toxicity 
In the instance of grade 3 other non-hematologic toxicity, hold protocol therapy, notify 
the Principal Investigator, and monitor toxicity at least weekly. If toxicity resolves to ≤ 
grade 2, then resume therapy at next lower dose level with the following exceptions:  
• 
Grade 3 non-desquamating rash must resolve to grade 1 prior to restarting 
lenalidomide.  
• 
Grade 3 neuropathy must resolve to grade 1 prior to restarting 
lenalidomide.  
• 
Grade 3 or 4 hypokalemia and/or hypomagnesemia can be pre-emptively 
treated with oral or IV repletion. Persistent grade 3 or 4 hypokalemia 
and/or hypomagnesemia that does not respond to oral or IV repletion after 
2 weeks will lead to a reduction by one dose level.  
• 
Grade 3 or 4 hypertriglyceredemia, hypercholesterolemia, and/or 
hyperglycemia can be pre-emptively treated with appropriate diet and/or 
medical intervention. Persistent grade 3 or 4 hypertriglyceridemia, 
hypercholesterolemia, and/or hyperglycemia that does not respond to 
appropriate diet and/or medical intervention after 2 weeks will lead to a 
reduction by one dose level.  


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27 
In the instance of grade 4 other non-hematologic toxicity, remove patient from 
protocol therapy. 
If a patient’s creatinine clearance (CrCl) decreases to 30-59 cc/min, the dose of 
lenalidomide should be decreased by one dose level.  
Venous or Arterial Thrombosis 
See Appendix D. Patients who develop signs or symptoms suggestive of thrombosis 
should be evaluated and treated as clinically indicated. Lenalidomide should be held 
for patients with grade 3 thrombosis or asymptomatic pulmonary embolism. 
Lenalidomide may resume when patient is adequately anticoagulated. Patients with 
recurrent thrombosis despite adequate anticoagulation should be removed from 
protocol therapy. For grade 4 thrombosis or symptomatic pulmonary embolism, 
discontinue protocol therapy. If lenalidomide is held for thrombosis, continue 
temsirolimus. 
Abnormal Menstruation or Pregnancy Test 
If a female misses a period, or for abnormal menstrual bleeding or abnormal 
pregnancy test, obtain a pregnancy test and counseling as appropriate. Hold all 
protocol therapy until pregnancy is ruled out. Discontinue protocol therapy if 
pregnancy test is positive. 
 
5.3 Supportive Care Guidelines 
 
Temsirolimus-specific guidelines 
Because of the idiosyncratic hypersensitivity reactions, subjects receiving IV temsirolimus 
should be premedicated with diphenhydramine 25 – 50 mg IV (or a similar antihistamine) 
approximately 30 minutes before the start of the temsirolimus infusion.  If the subject begins to 
develop a hypersensitivity reaction despite pretreatment with diphenhydramine, the infusion 
should be stopped for at least 30 – 60 minutes, depending upon the severity of the reaction.   The 
infusion may be resumed by administering a histamine H2-receptor antagonist approximately 30 
minutes before restarting the CCI-779 infusion. Famotidine 20 mg IV or ranitidine 50 mg IV are 
recommended rather than cimetidine, because of the lack of likely metabolic/pharmacologic 
interactions with the former drugs.  The rate of the CCI-779 infusion may also be slowed from 
30 minutes to over an hour.  All subjects should be monitored while receiving the CCI-779 
infusion and emergency medical equipment and health care personnel must be readily available 
to respond to hypersensitivity reactions or other medical emergencies. 
 
Although drug interaction studies have not been reported, a potential drug interaction 
involving CCI-779 and warfarin/Coumadin™ (with an increase in INR) was reported. 
Patients on warfarin should have PT/INR monitored frequently after starting and 
discontinuing CCI-779 to determine whether the warfarin dose needs to be adjusted.  
 
Lenalidomide-specific guidelines  
Patients considered to be at high risk of developing DVT/PE or arterial thromboses are to receive 
either prophylactic aspirin or low molecular weight heparin unless contraindicated (See 


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28 
Appendix D). High risk will be defined as a history of DVT/PE, significant family history, 
performance status ≥ 2, smoking history, use of oral contraceptives, chronic steroid use, and 
concurrent use of epoetin. Patients with diabetes mellitus or coronary artery disease are 
considered to be at high risk for arterial thromboembolic events. 
Other supportive care (including growth factor use) 
 
Treatment with hormones used as chemotherapy or other chemotherapeutic agents may not be 
administered except for steroids given for adrenal failure; hormones administered for non-
disease related conditions (e.g., insulin for diabetes; birth control pills). The use of 
dexamethasone and other steroidal antiemetics is prohibited.  Routine supportive measures for 
cancer patients such as erythropoietin, analgesics, blood transfusions, antibiotics, 
bisphosphonates, hematopoetic colony stimulating factors for treatment of cytopenias are 
permitted as per ASCO guidelines but must be clearly documented. Due to the weekly schedule 
of administration, the use of pegfilgrastim will not be allowed. 
 
5.4 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 52 or until 
one of the following criteria applies: 
 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
• 
The patient becomes eligible for an autologous or allogeneic stem cell transplant 
 
5.5 Duration of Follow Up 
 
Patients will be followed for one year after removal from study or until death, whichever occurs 
first.  Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
5.6 Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
6.0 DOSING DELAYS/DOSE MODIFICATIONS FOR PHASE II PORTION 
 
Dose Levels for the phase I portion of the study are as per the Section 5.0.  During the phase 
II portion of the trial, dose delays/modifications are per the table below. Once the dose of an 
agent has been reduced, no dose re-escalation is permitted. If a scheduled dose is delayed for 
more than 6 weeks due to treatment-related toxicity, remove the patient from protocol 


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29 
therapy. No dose reductions below Dose Level -3 are permitted. A missed dose should not be 
made up, so that cycle lengths are always 28 days irrespective of the number of doses 
delivered in that cycle. NOTE: Dose delays/dose reductions for the phase II portion of the 
study will be re-evaluated at the conclusion of the phase I portion of the study, and the 
following section is subject to revision.  
 
Temsirolimus (T)/Lenalidomide (L) Dose Levels for Phase II Portion Only 
 
INDUCTION THERAPY 
Starting Dose 
T:  25mg IV weekly, repeated every 28 days 
L:  20mg PO daily on Days 1-21, repeated every 28 days 
Dose Level –1 
T:  25mg IV weekly, repeated every 28 days 
L:  15mg PO daily on Days 1-21, repeated every 28 days  
Dose Level –2 
T:  20mg IV weekly, repeated every 28 days 
L:  15mg PO daily on Days 1-21, repeated every 28 days 
Dose Level –3 
T:  20mg IV weekly, repeated every 28 days 
L:  10mg PO daily on Days 1-21, repeated every 28 days 
 
6.1 Hematologic toxicity 
 
6.1.1 Neutropenia and thrombocytopenia  
Observation 
Action 
Comments 
Neutropenia > gr 3 
• Hold both agents 
• Resume therapy at 
same dose level once 
neutropenia resolves to 
< grade 2 
• If recurs, reduce by one 
dose level.  
• If recurs again, reduce 
by one additional dose 
level.  
• If recurs again, discuss 
with PI 
Monitor CBC 
weekly.  
 
Consider use of 
growth factor 
support.  
 
If treatment is 
delayed by more 
than 6 weeks due 
to treatment-
related toxicity, 
remove patient 
from study 
 
Thrombocytopenia > 
gr 3 
• Hold both agents 
• Resume therapy at 
same dose level once 
neutropenia resolves to 
< grade 2 
• If recurs, reduce by one 
dose level.  
Monitor CBC 
weekly.  
 
If treatment is 
delayed by more 
than 6 weeks due 
to treatment-


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• If recurs again, reduce 
by one additional dose 
level.  
• If recurs again, discuss 
with PI 
related toxicity, 
remove patient 
from study 
 
 
 
 
6.1.2 Anemia 
• 
In the instance of drug-related anemia based on hemoglobin on day 1 that has 
worsened by one or more grade levels from previous cycle, reduce 
temsirolimus and lenalidomide by one dose level. 
• 
In the instance of drug-related grade 4 hemoglobin at any time during a cycle, 
discontinue temsirolimus and lenalidomide. 
• 
Epoetin may be used to treat drug-related anemia. If epoetin is used, patients 
should receive either prophylactic aspirin or low molecular weight heparin 
unless contraindicated.  
6.1.3-DERMATOLOGIC TOXICITY 
In the instance of any grade desquamating rash, lenalidomide must be stopped. In the 
instance of grade 3 non-desquamating rash, the rash must resolve to grade 1 or less 
prior to restarting lenalidomide. Lenalidomide should be restarted 5mg less than prior 
dose.  
6.1.4-Other Non-Hematologic Toxicity 
Observation 
Action 
Comments 
AE resolves promptly 
with supportive care 
Maintain dose level 
 
Grade 3 or higher non-
hematologic AE (except 
for those listed below) 
related to 
temsirolimus or 
lenalidomide that does not 
resolve to grade 2 or 
below despite maximum 
supportive care 
  
  
• Hold both agents 
• Resume therapy at 
same dose level once 
AE resolves to < grade 
2 
• If recurs, reduce by one 
dose level.  
• If recurs again, reduce 
by one additional dose 
level.  
• If recurs again, discuss 
with PI 
Monitor CBC and 
CMP weekly.  
 
If treatment is 
delayed by more 
than 6 weeks due 
to treatment-
related toxicity, 
remove patient 
from study 
 
Grade 3 or 4 non-
desquamating rash 
• Hold lenalidomide 
• Resume lenalidomide 
at 5mg less than prior 
dose once rash is < 
grade 1  
 


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31 
• If recurs, discuss with 
PI 
Grade 3 or 4 neuropathy 
• Hold lenalidomide 
• Resume lenalidomide 
at 5mg less than prior 
dose once neuropathy 
is < grade 1  
Provide optimal 
supportive care  
 
If treatment is 
delayed by more 
than 6 weeks due 
to treatment-
related toxicity, 
remove patient 
from study 
 
Grade 3 or 4 hypokalemia, 
hypomagnesemia, 
hypertriglyceridemia, 
hypercholesterolemia, 
and/or hyperglycemia 
• Provide optimal 
supportive care 
• If AE does not resolve 
after 2 weeks of 
optimal intervention, 
reduce by one dose 
level.  
• If AE recurs, reduce by 
one additional dose 
level 
• If AE recurs, discuss 
with PI  
 
Decrease in CrCl to 30-59 
cc/min 
• Decrease lenalidomide 
by one dose level 
• If recurs, decrease 
lenalidomide by one 
additional dose level 
• If recurs, discuss with 
PI 
 
 
 
6.1.5-Venous or Arterial Thrombosis 
See Appendix D. Patients who develop signs or symptoms suggestive of thrombosis 
should be evaluated and treated as clinically indicated. Lenalidomide should be held 
for patients with grade 3 thrombosis or asymptomatic pulmonary embolism. 
Lenalidomide may resume when patient is adequately anticoagulated. Patients with 
recurrent thrombosis despite adequate anticoagulation should be removed from 
protocol therapy. For grade 4 thrombosis or symptomatic pulmonary embolism, 
discontinue protocol therapy. If lenalidomide is held for thrombosis, continue 
temsirolimus. 
 


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32 
6.1.6- Abnormal Menstruation or Pregnancy Test 
If a female misses a period, or for abnormal menstrual bleeding or abnormal 
pregnancy test, obtain a pregnancy test and counseling as appropriate. Hold all 
protocol therapy until pregnancy is ruled out. Discontinue protocol therapy if 
pregnancy test is positive. 
 
7.0 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting. 
 
 
 
7.1 COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) 
FOR 
Temsirolimus (CCI-779, NSC 683864) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI via CTEP-AERS  (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. Frequency is provided based on 1927 patients. Below is the CAEPR for temsirolimus (CCI-
779, Torisel). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
 
Version 2.4, July 2, 20131 
 
 Adverse Events with Possible  
 Relationship to Temsirolimus (CCI-779, Torisel) 
 (CTCAE 4.0 Term) 
[n= 1927] 
 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
ENDOCRINE DISORDERS 
  
 
Endocrine disorders - Other 
(decreased testosterone) 
 
 Endocrine disorders - Other 
(decreased testosterone) (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension (Gr 2) 


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Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Anal mucositis2 
 
 Anal mucositis2 (Gr 2) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
 
Gastrointestinal fistula3 
  
 
 
Gastrointestingal perforation4 
 Gastrointestinal perforation4 (Gr 2) 
Mucositis oral2 
 
 
 Mucositis oral2 (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Rectal mucositis2 
 
 Rectal mucositis2 (Gr 2) 
 
Small intestinal mucositis2 
 
 Small intestinal mucositis2 (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema face 
 
 Edema face (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Flu like symptoms 
 
 Flu like symptoms (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 2) 
 
Pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction5 
 
 Allergic reaction5 (Gr 2) 
INFECTIONS AND INFESTATIONS6 
  
 
Infection7 
 
 Infection7 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Wound dehiscence8 
 
 Wound dehiscence8 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 3) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 3) 
Cholesterol high9 
 
 
 Cholesterol high9 (Gr 4) 
 
Creatinine increased 
 
 Creatinine increased (Gr 3) 
 
Fibrinogen decreased 
 
 Fibrinogen decreased (Gr 2) 
 
GGT increased 
 
 GGT increased (Gr 2) 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 4) 
 
Neutrophil count decreased10 
 
 Neutrophil count decreased10 (Gr 4) 
Platelet count 
decreased10 
 
 
 Platelet count decreased10 (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 3) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Acidosis 
 
 Acidosis (Gr 2) 
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Glucose intolerance11 
 
 Glucose intolerance11 (Gr 2) 
 
Hyperglycemia11 
 
 Hyperglycemia11 (Gr 3) 
 
Hypertriglyceridemia9 
 
 Hypertriglyceridemia9 (Gr 4) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 3) 
 
Hypokalemia 
 
 Hypokalemia (Gr 4) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
 
Metabolism and nutrition 
disorders - Other 
 
 Metabolism and nutrition disorders - 
Other (hyperlipidemia)9 (Gr 4) 


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34 
(hyperlipidemia)9 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Depressed level of 
consciousness 
 
 Depressed level of consciousness 
(Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
 Depression (Gr 2) 
 
Insomnia 
 
 Insomnia (Gr 2) 
 
Libido decreased 
 
 Libido decreased (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury12 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
Erectile dysfunction 
 
 Erectile dysfunction (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
 Epistaxis (Gr 2) 
 
Laryngeal mucositis2 
 
 Laryngeal mucositis2 (Gr 2) 
 
Pharyngeal mucositis2 
 
 Pharyngeal mucositis2 (Gr 2) 
 
Pleural effusion 
 
 Pleural effusion (Gr 3) 
 
Pneumonitis13 
 
 Pneumonitis13 (Gr 3) 
 
Sinus disorder 
 
 Sinus disorder (Gr 2) 
 
Tracheal mucositis2 
 
 Tracheal mucositis2 (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform (Gr 2) 
Rash maculo-papular  
 
 Rash maculo-papular (Gr 3) 
 
Skin and subcutaneous tissue 
disorders – Other (nail 
disorder/nail changes)15 
 
 Skin and subcutaneous tissue 
disorders – Other (nail disorder/nail 
changes)15 (Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
Hypotension 
 
 Hypotension (Gr 3) 
 
 
Thromboembolic event 
 Thromboembolic event (Gr 4) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Mucositis/stomatitis:  Gingivitis, mucositis/stomatitis, ulcers in mouth and throat, pharyngitis, and 
dysphagia have been reported in subjects receiving temsirolimus. 
 
3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 


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4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC.  GI perforation (including fatal outcome) 
has been observed in subjects who received temsirolimus. 
 
5Hypersensitivity /infusion reactions (including some life threatening and rare fatal reactions), including 
and not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, 
hypersensitivity, and anaphylaxis, have been associated with the administration of temsirolimus.  These 
reactions can occur very early in the first infusion, but may also occur with subsequent infusions.  Patients 
should be monitored early during infusion and appropriate supportive care should be available.  
Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate 
medical care administered.  A risk-benefit assessment should be done prior to the continuation of 
temsirolimus therapy in patients with severe life-threatening reactions. 
 
6Infections:  Bacterial and viral infections including opportunistic infections have been reported in 
subjects. Infections may originate in a variety of organ systems/body regions and may be associated with 
normal or grade 3-4 neutropenia. Bacterial and viral infections have included cellulitis, herpes zoster, 
herpes simplex, bronchitis, abscess, pharyngitis, urinary tract infection (including dysuria hematuria, 
cystitis, and urinary frequency), rhinitis folliculitis, pneumonia, and upper respiratory tract infection. 
 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.  
 
8Wound Dehiscence:  The use of temsirolimus has been associated with abnormal wound healing. 
Therefore, caution should be exercised with the use of temsirolimus in the perisurgical period. 
 
9Cholesterol High: The use of temsirolimus in subjects has been associated with increases in serum 
levels of triglycerides and cholesterol. This may require initiation of or increase in the dose of lipid-
lowering agents. 
 
10Thrombocytopenia and Neutropenia: Grades 3 and 4 thrombocytopenia and/or neutropenia have been 
observed at higher frequency in subjects with mantle cell lymphoma (MCL). 
 
11Hyperglycemia/Glucose Intolerance: The use of temsirolimus in subjects was associated with increases 
in serum glucose level. This may result in the need for an increase in the dose of, or initiation of, insulin 
and/or oral hypoglycemic agent therapy.  
 
12Acute Kidney Injury: Renal failure (including fatal outcome) has been observed in subjects receiving 
temsirolimus for advanced RCC and/or with pre-existing renal insufficiency. 
 
13Interstitial Lung Disease: There have been cases of nonspecific interstitial pneumonitis, including rare 
fatal reports. Some subjects were asymptomatic with pneumonitis detected on computed tomography 
scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, and fever. Some 
subjects required discontinuation of temsirolimus or treatment with corticosteroids and/or antibiotics, while 
some subjects continued treatment without additional intervention. 
 
14Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
15Nail Disorder/Nail Changes includes Nail discoloration, Nail loss, and Nail ridging under the SKIN AND 
SUBCUTANEOUS TISSUE DISORDERS SOC. 
 


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Also reported on temsirolimus (CCI-779, Torisel) trials but with the relationship to temsirolimus 
(CCI-779, Torisel) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(coagulopathy); Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Chest pain - cardiac; Heart failure; 
Left ventricular systolic dysfunction; Myocardial infarction; Pericardial effusion; Right ventricular 
dysfunction; Sinus tachycardia; Supraventricular tachycardia; Ventricular fibrillation; Ventricular 
tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (Cushing's syndrome); Endocrine disorders - 
Other (diabetes mellitus) 
EYE DISORDERS - Blurred vision; Cataract; Conjunctivitis; Dry eye; Eye disorders - Other (diplopia); Eye 
pain; Flashing lights; Photophobia; Retinopathy 
GASTROINTESTINAL DISORDERS - Anal pain; Anal ulcer; Ascites; Bloating; Colitis; Colonic 
obstruction; Colonic ulcer; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophageal 
pain; Esophageal ulcer; Esophagitis; Flatulence; Gastritis; Gastrointestinal disorders - Other (anal 
fissure); Gastrointestinal disorders - Other (gastroenteritis); Gastrointestinal disorders - Other (mouth 
ulceration); Gastrointestinal hemorrhage14, Hemorrhoids; Ileus; Oral pain; Pancreatitis; Periodontal 
disease; Proctitis; Rectal pain; Small intestinal obstruction; Stomach pain; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; Facial pain; Gait 
disturbance; Injection site reaction; Localized edema; Malaise; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatic failure 
IMMUNE SYSTEM DISORDERS - Anaphylaxis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fracture; Postoperative 
hemorrhage; Vascular access complication; Wound complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; CD4 
lymphocytes decreased; INR increased (potential interaction with Coumadin); Investigations - Other (BUN 
increased); Investigations - Other (lactic dehydrogenase increased); Lipase increased; Lymphocyte count 
increased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hyperuricemia; Hypoalbuminemia; Hypoglycemia; Hypomagnesemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (albuminuria) ; Metabolism and nutrition 
disorders - Other (blood urea increased); 
Metabolism and nutrition disorders - Other (hypoproteinemia)  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular necrosis; Bone 
pain; Chest wall pain; Generalized muscle weakness; Joint effusion; Muscle weakness lower limb; 
Musculoskeletal and connective tissue disorder - Other (muscle cramps); Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (carcinoma of the lung); Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (lymphoma); Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dizziness; Dysesthesia; 
Hydrocephalus; Intracranial hemorrhage; Lethargy; Neuralgia; Paresthesia; Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy syndrome; Seizure; 
Somnolence; Spasticity; Stroke; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Mania; Psychiatric disorders - Other (bipolar 
disorder); Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Cystitis noninfective; Hematuria; 
Hemoglobinuria; Proteinuria; Renal hemorrhage; Urinary frequency; Urinary retention; Urinary tract pain; 
Urinary urgency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Female genital tract fistula; Hematosalpinx; 
Irregular menstruation; Menorrhagia; Ovarian hemorrhage; Prostatic hemorrhage; Spermatic cord 
hemorrhage; Testicular disorder; Testicular hemorrhage; Testicular pain; Uterine hemorrhage; Vaginal 
discharge; Vaginal dryness; Vaginal fistula; Vaginal hemorrhage; Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 


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Allergic rhinitis; Bronchopulmonary hemorrhage; Bronchospasm; Hiccups; Hypoxia; Nasal congestion; 
Pharyngolaryngeal pain; Pleuritic pain; Productive cough; Pulmonary edema; Pulmonary fibrosis; 
Pulmonary hypertension; Respiratory failure; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Hyperhidrosis; 
Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Skin and subcutaneous 
tissue disorders - Other (angioneurotic edema); Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Phlebitis; Superficial thrombophlebitis; Visceral arterial ischemia 
 
 
Note:  Intracerebral Bleeding: Subjects with central nervous system (CNS) tumors (primary CNS tumors 
or metastases) and/or receiving anticoagulation therapy may be at an increased risk of intracerebral 
bleeding (including fatal outcomes) while receiving therapy with temsirolimus (CCI-779, Torisel). 
 
Note: Temsirolimus (CCI-779, Torisel) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Lenalidomide (CC-5013, NSC 703813) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential 
adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate 
column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 4081 patients. Below is the CAEPR for lenalidomide (CC-5013). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in 
the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an 
AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.6, December 24, 20151 
 
 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 4.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 Anemia 
 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Myocardial infarction2 
  
ENDOCRINE DISORDERS 
  
 
 Hypothyroidism 
 
 Hypothyroidism (Gr 3) 
GASTROINTESTINAL DISORDERS 
  
Constipation 
 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  


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38 
 
 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 4.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
 
 
Immune system disorders - 
Other (graft vs. host disease)3  
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
 Infection (Gr 3)4  
INVESTIGATIONS 
  
 
 
Lipase increased 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 3) 
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 3) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 3) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 
 
Musculoskeletal and connective 
tissue disorders - Other (muscle 
cramp/muscle spasm) 
 
 Musculoskeletal and connective tissue 
disorders - Other (Muscle cramp/muscle 
spasm) (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
 
Leukemia secondary to 
oncology chemotherapy5 
  
 
 
Myelodysplastic syndrome5 
  
 
 
Neoplasms benign, malignant 
and unspecified (incl cysts 
and polyps) - Other (tumor 
flare)6  
  
 
 
Treatment related secondary 
malignancy5 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
  
 
 
Stroke2 
  
 
 
Leukoencephalopathy 
  
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RENAL AND URINARY DISORDERS 
  


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39 
 
 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 4.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme 
  
 
Hyperhidrosis 
 
 Hyperhidrosis (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Skin and subcutaneous tissue 
disorders - Other (pyoderma 
gangrenosum) 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
SURGICAL AND MEDICAL PROCEDURES 
  
 
 
Surgical and medical 
procedures - Other (impaired 
stem cell mobilization)7 
  
VASCULAR DISORDERS 
  
 
Thromboembolic event8 
 
 Thromboembolic event8 (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. 
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Myocardial infarction and cerebrovascular accident (stroke) have been observed in multiple myeloma patients 
treated with lenalidomde and dexamethasone. 
 
3Graft vs. host disease has been observed in subjects who have received lenalidomide in the setting of allo-
transplantation. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5There has been an increased frequency of secondary malignancies (including AML/MDS) in multiple myeloma 
patients being treated with melphalan, prednisone, and lenalidomide post bone marrow transplant. 
 
6Serious tumor flare reactions have been observed in patients with chronic lymphocytic leukemia (CLL) and 
lymphoma. 
 
7A decrease in the number of stem cells (CD34+ cells) collected from patients treated with >4 cycles of 
lenalidomide has been reported. 
 
8Significantly increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis has 
been observed in patients with multiple myeloma receiving lenalidomide with dexamethasone. 
 
9Gastrointestinal hemorrhage includes:  Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 


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40 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
10Gastrointestinal obstruction includes:  Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal 
obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small intestinal obstruction under the 
GASTROINTESTINAL DISORDERS SOC. 
 
11Osteonecrosis of the jaw has been seen with increased frequency when lenalidomide is used in combination with 
bevacizumab, docetaxel (Taxotere®), prednisone, and zolendronic acid (Zometa®). 
 
 
NOTE:  While not observed in human subjects, lenalidomide, a thalidomide analogue, caused limb abnormalities in 
a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used 
during pregnancy, it may cause birth defects or embryo-fetal death. Pregnancy must be excluded before start of 
treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. 
 
Adverse events reported on Lenalidomide (CC-5013) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Lenalidomide (CC-5013) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(eosinophilia); Blood and lymphatic system disorders - Other (monocytosis); Blood and lymphatic system disorders 
- Other (pancytopenia); Disseminated intravascular coagulation; Febrile neutropenia; Hemolysis; Spleen disorder 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Atrial flutter; Atrioventricular block first 
degree; Cardiac arrest; Cardiac disorders - Other (cardiovascular edema); Cardiac disorders - Other (ECG 
abnormalities); Chest pain - cardiac; Heart failure; Left ventricular systolic dysfunction; Palpitations; Pericarditis; 
Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Cushingoid; Hyperthyroidism 
EYE DISORDERS - Blurred vision; Conjunctivitis; Dry eye; Flashing lights; Retinopathy 
GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal pain; Anal mucositis; Ascites; 
Colonic perforation; Dry mouth; Dyspepsia; Dysphagia; Flatulence; Gastritis; Gastroesophageal reflux disease; 
Gastrointestinal disorders - Other (Crohn's disease aggravated); Gastrointestinal disorders - Other (diverticulitis); 
Gastrointestinal disorders - Other (pale feces); Gastrointestinal hemorrhage9; Gastrointestinal obstruction10; Ileus; 
Mucositis oral; Rectal mucositis; Small intestinal mucositis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - General disorders and 
administration site conditions - Other (edema NOS); Malaise; Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Immune system disorders - Other (angioedema) 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (Opportunistic infection associated 
with >=grade 2 lymphopenia) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fall; Fracture; Hip fracture; 
Vascular access complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine aminotransferase increased; 
Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin increased; Cholesterol high; 
Creatinine increased; Electrocardiogram QT corrected interval prolonged; INR increased; Investigations - Other 
(hemochromatosis) 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Bone pain; Chest wall pain; 
Generalized muscle weakness; Joint effusion; Muscle weakness lower limb; Musculoskeletal and connective tissue 
disorders - Other (rhabdomyolysis); Neck pain; Osteonecrosis of jaw11; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of consciousness; 
Dysgeusia; Dysphasia; Edema cerebral; Encephalopathy; Intracranial hemorrhage; Ischemia cerebrovascular; 
Memory impairment; Myelitis; Nervous system disorders - Other (hyporeflexia); Nervous system disorders - Other 
(spinal cord compression); Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; 


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Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Psychosis 
RENAL AND URINARY DISORDERS - Urinary frequency; Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - Other 
(hypogonadism); Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Atelectasis; Bronchopulmonary hemorrhage; Epistaxis; Hypoxia; Laryngeal mucositis; Pharyngeal 
mucositis; Pleural effusion; Pneumonitis; Pulmonary hypertension; Respiratory failure; Tracheal mucositis; Voice 
alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Nail loss; Photosensitivity; Rash 
acneiform; Skin and subcutaneous tissue disorders - Other (Sweet’s syndrome); Urticaria 
VASCULAR DISORDERS - Hot flashes; Hypertension; Hypotension; Phlebitis; Vascular disorders - Other 
(hemorrhage NOS) 
 
Note: Lenalidomide (CC-5013) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 


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7.2  ADVERSE EVENT CHARACTERISTICS  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
NOTE: HIV-positive patients will be carefully monitored. Once 5 patients with HIV-positive 
disease have been accrued, CTEP and the PI will discuss toxicity and efficacy, with a 
consideration of reintroducing anti-retroviral therapy.  
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3  Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (Cancer Therapy Evaluation Program Adverse 
Event Reporting SystemCTEP-AERS accessed via the CTEP Web site (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: Adverse Event 
Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded 
from the CTEP Web site (http://ctep.cancer.gov).  These requirements are briefly outlined in the tables 
below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 The following text is required for multi-institutional studies only and may be deleted for single institution 
studies. 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature for 


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other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting regardless of causality, unless 
as noted below.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) - Other (Progressive Disease)” under the system organ class (SOC) 
of the same name.  Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a disease process) 
should be submitted.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS  within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS  within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 


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agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS  within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS  within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 


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45 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
• For Hospitalization only – Any medical event equivalent to CTC Grade 3, 4, 
or 5 which precipitated hospitalization (or prolongation of existing 
hospitalization) must be reported regardless of designation as expected or 
unexpected and attribution. 
 
• Telephone reports to the Investigational Drug Branch at 301-230-2330 
available 24 hours daily (recorder between 5 P.M. and 9 A.M. EST). 
 
• In the rare event when Internet connectivity is disrupted a 24-hour notification 
is to be made to NCI by telephone at: 301-897-7497, or 301-897-7402 for CIP 
studies. An electronic report MUST be submitted immediately upon re-
establishment of internet connection”, for the reason that all paper CTEP-
AERS  forms have been removed from the CTEP website and will no longer 
be accepted. 
 
Pregnancy Reporting Requirements 
Females of Childbearing Potential: 
• Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject or the partner of a male 
subject occurring while the subject is on lenalidomide or within 28 days after 
the subject’s last dose, are considered immediately reportable events. 
Lenalidomide is to be discontinued immediately. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported via CTEP-AERS  as a 
grade 4 event under: SOC pregnancy, puerperium and perinatal conditions; 
adverse event: pregnancy, puerperium and perinatal conditions-other, 
fetal exposure. 
o 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 make an amendment to the initial pregnancy report 
immediately regarding the outcome of the pregnancy and neonatal status 
(either normal or abnormal outcome). 
• If the outcome of the pregnancy was abnormal (including spontaneous or 
therapeutic abortion, fetal demise and congenital abnormalities), the 


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46 
Investigator should report the abnormal outcome as an amendment to the 
initial pregnancy report as soon as the as the Investigator has knowledge of the 
outcome.  
• All neonatal deaths and neonatal complications that occur within 28 days of 
birth should be reported, without regard to causality, as an amendment to the 
initial pregnancy report. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the lenalidomide 
should also be reported as an amendment within 24 hours of the Investigator’s 
knowledge of the event. 
 
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 her healthcare 
provider immediately. 
 
 
CTEP-AERS  provides a copy feature for other e-mail recipients. AE notification must be sent 
to:  
The Cancer Clinical Trials Office to:  
Quality Assurance Operations Manager 
University of Chicago 
Cancer Clinical Trials Office 
5841 S. Maryland, MC1140 
Chicago, IL 60637 
qaccto@bsd.uchicago.edu  
 
The UC Principal Investigator, if UC is not the lead institution.   
 
Use the NCI Protocol Number on all reports. 
 
 
7.4  Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
7.5  Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). Investigators are 
required to report cases of secondary malignancies, including AML/MDS occurring on or 
following treatment on NCI-sponsored chemotherapy protocols via CTEP-AERS  with CTCAE 
4.0. Refer to the “CTEP website http://ctep.cancer.gov) for additional information about 
secondary AML/MDS reporting.   


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47 
• 
All new malignant tumors must be reported through CTEP-AERS  whether or not they 
are thought to be related to either previous or current treatment.  All new malignancies should 
be reported including solid tumors (including non-melanoma skin 
malignancies), hematologic malignancies, Myelodysplastic Syndrome (MDS)/Acute 
Myelogenous Leukemia (AML), and in situ tumors.  
• 
Using CTCAE v4.0, the event(s) may be reported as one of the following:  (1) 
Leukemia secondary to oncology chemotherapy; (2) Myelodysplastic syndrome; (3) 
Treatment-related secondary malignancy; or (4) Neoplasm other, malignant (grade 3 or 
4).   
• 
These events should be reported for the duration of the study treatment and during 
any protocol-specified follow-up periods.   
 
7.6-Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 
 
 
 
8.0- PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
 
8.1-TEMSIROLIMUS (TORISEL®, NSC 683864) 
 
 
Chemical Name:  Sirolimus 42-ester with 2,2-bis (hydroxymethyl)-propionic acid 
 
 
Other Names: 
CCI-779, Torisel®, Rapamycin analog, WAY-130779 
 
Classification:   
Cell cycle inhibitor 
 
Molecular Formula:  C56H87NO16 
 
 
M.W.: 1030.30 daltons 
 
Mode of Action:  Temsirolimus [an ester of the immunosuppressive compound sirolimus, 
(rapamycin, Rapamune®)] blocks cell cycle progression from the G1 to the S phase by binding 
to the intracellular cytoplasmic protein, FK506 binding protein (FKBP)12.  This complex 
inhibits activity of the enzyme mTOR (mammalian target of rapamycin), inhibiting translation of 
several key proteins that regulate progression through the G1 phase in response to growth 
factors.  Sirolimus, temsirolimus's major metabolite, also binds to FKBP12.  
 
How Supplied:  TORISEL (temsirolimus) is supplied as a commercially labeled kit consisting 


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48 
of the following:   
 
• TORISEL (temsirolimus) injection (25 mg/mL).  The TORISEL vial includes an overfill 
of 0.2 mL.   Inert ingredients in the drug vial include dehydrated alcohol, d,l-alpha-
tocopherol, propylene glycol, and anhydrous citric acid.  
 
• DILUENT for TORISEL.  The DILUENT vial includes a deliverable volume of 1.8 mL.  
The diluent vial contains polysorbate 80 NF, polyethylene glycol 400 NF, and absolute 
alcohol USP. 
 
Preparation:   
 
 
Protect from excessive room light and sunlight during preparation. 
 
Follow this two step dilution process (TORISEL should only be diluted with the supplied 
diluent): 
 
Step 1 
Inject 1.8 mL of DILUENT for temsirolimus into the vial of temsirolimusconcentrate for 
injection (25 mg/mL).  A total volume of 3 mL (10mg/mL) will be obtained.  Mix well by gentle 
inversion of the vial.  DO NOT SHAKE. Allow sufficient time for air bubbles to subside. The 
solution should be clear to slightly turbid, colorless to light-yellow in color and free from visual 
particulates. 
 
Step 2 
Withdraw the required amount of temsirolimus from the 10 mg/mL concentrate/diluent mixture 
prepared in Step 1. For doses less than 10mg, filter the concentrate/diluents mixture using a 
syringe filter unit before measuring required volume. Further dilute with 0.9% sodium chloride 
injection in glass or polyolefin containers to a final concentration between 0.04 mg/mL and 
1mg/mL. Mix by inversion of the bag and avoid excessive shaking. Inspect for visual particulates 
and discoloration prior to administration.   
 
Storage: 
Refrigerate intact temsirolimus kit at 2º-8ºC and protect from light. 
 
Stability: 
The 10 mg/mL drug solution/diluent mixture is stable for 24 hours at room 
temperature.  
 
Administer within 6 hours of the final dilution in 0.9% NaCl.  Store at room 
temperature (20º-25ºC) and protect from light.    
 
Route of Administration: 
Intravenous with an appropriate in-line filter (i.e. 0.2 to 5 
micron) for all temsirolimus doses equal to or greater than 10 mg.  To avoid drug 
loss, prepare doses less than 10mg by filtering the concentrate/diluents mixture as 
noted previously between steps 1 and 2 using a syringe filter unit. 
 


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49 
Incompatibilities: Avoid contact of the diluted product with polyvinyl chloride (PVC) 
equipment or devices that are plasticized with di- (2-ethylhexyl)pthalate (DEHP) to prevent 
DEHP leaching.  Store diluted temsirolimus solutions in bottles (glass) or plastic bags 
(polyolefin or polypropylene).   
 
Temsirolimus is compatible with most infusion sets that are acceptable with paclitaxel.  
 
Infusion sets which have been qualified for use with temsirolimus include the following:  
•Baxter vented paclitaxel set 
•Baxter unvented paclitaxel set 
•Abbott #11947 tubing set   
•Alaris #72953 tubing set   
 
Other non-PVC tubings can be used with the following in-line filters: 
•IV 6200 Disposable I.V. Filter 0.2 micron by EPS®, Inc  
•IV 6120 Disposable I.V. Filter 1.2 micron by EPS®, Inc  
•LV 5000 Large Volume 5 micron Conical Filter by B.Braun  
•Baxter Paclitaxel IV 0.2 micron filter set (2C7555) 
•Codan 5 micron monofilter 
•Alaris extension filter set #20350E 
Other polyethersulfone filters may be used.  
  
Potential Drug Interactions:  
Temsirolimus is a CYP3A4 substrate.  Avoid concomitant treatment of temsirolimus with potent 
CYP3A4 inhibitors and agents that have CYP3A4 induction potential.  
 
The combination of temsirolimus and sunitinib resulted in dose limiting toxicity at low doses of 
both agents.  Avoid concomitant sunitinib during temsirolimus treatment.   
 
Temsirolimus and warfarin may interact to increase INR. Monitor warfarin patient’s PT/INR 
after starting and stopping temsirolimus. 
 
The combination of temsirolimus and ACE inhibitors resulted in angioedema-type reactions 
(including delayed reactions occurring up to 2 months after initiation of therapy).  
 
Patient Care Implications:  For hypersensitivity prophylaxis, give diphenhydramine 25-50 mg 
I.V. (or comparable antihistamine) approximately 30 minutes before starting temsirolimus 
infusion.  Infuse over 30 minutes. 
 
If a patient develops a hypersensitivity reaction despite diphenhydramine pretreatment, stop the 
infusion and wait 30 to 60 minutes (depending upon the reaction severity).  At the physician’s 
discretion, it may be possible to resume treatment by administering an H2 blocker approximately 
30 minutes before restarting the infusion.  The manufacturer recommends famotidine 20 mg IV, 
rather than cimetidine, because it lacks reported drug interactions.  If famotidine is unavailable, 
administer ranitidine 50 mg IV. Re-attempt infusion at a slower rate, possibly over one hour.  
 


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50 
Vaccinations:  Avoid the use of live vaccines during temsirolimus treatment. 
 
Agent Accountability and Ordering 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the patient is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained).  The CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial 
Disclosure Form (FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status and a 
“current” password.  For questions about drug orders, transfers, returns, or accountability, call 
(240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
 
8.2-Lenalidomide (CC-5013, NSC # 703813) 
 
Black Box warning 
NOTE: 
Before lenalidomide is dispensed, patients must 1) have a negative pregnancy test (if 
applicable) and 2) be counseled by a trained counselor. Pharmacists may be trained 
counselors (see Lenalidomide Counselor Program Site Counselor Identification Form in the 
protocol). The counseling requirements for investigational-use lenalidomide are separate 
from the RevAssist program. Only a 28-day supply may be dispensed to a patient at one time. 
Lenalidomide (-[3-aminophthalimido] glucaride, Revlimid™ “(formerly known as Revimid™, 
CC-5013) (NSC # 703813) 
 
Chemical Name:   
3-(4’-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione 
 
Other Names:        
CC-5013, Revlimid™, CDC-501 
 
Classification:      
 Immunomodulatory Agent  
 
CAS Registry Number:       191732-72-6 


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51 
 
Molecular Formula:   C13H13N303 
 
 
M.W.:   259.25 
 
Mode of Action:  Lenalidomide, a thalidomide analog, is an immunomodulatory agent with a 
spectrum of activity that is still under investigation.  Some of its effects include inhibition of 
inflammation, inhibition of angiogenesis, inhibition of hematopoetic tumor cell proliferation, 
modulation of stem cell differentiation and upregulating responses of T cells and NK cells.  
 
How Supplied: Celgene supplies and CTEP, NCI, DCTD distributes lenalidomide 2.5 mg (size 4), 
5 mg (size 2) and 25 mg (size 0) hard gelatin capsules in tamper-evident, child-resistant, opaque, 
high density polyethylene (HDPE) bottles with HDPE caps Bottles contain 100 capsules per 
container. The capsules also contain anhydrous lactose, microcrystalline cellulose, croscarmellose 
sodium, and magnesium stearate. 
 
Storage:  Store capsules at room temperature (25°C). Excursions are permitted (to 15-30°C). 
 
Stability:  Refer to the package labeling for expiration date. Lenalidomide stability is adequate for 
at least 28 days after transferring to a pharmacy vial. 
 
Route of Administration:  Take lenalidomide by mouth with or without food. Do not crush, chew 
or open capsules.  
 
Dispensing: Only a 28-day supply may be dispensed at one time. Sites may not mail lenalidomide 
to patients. 
 
Patient Care Implications and Counseling 
Risks Associated with Pregnancy 
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic 
active substance that causes severe life-threatening birth defects.  An embryofetal development 
study in animals indicates that lenalidomide produced malformations in the offspring of female 
monkeys who received the drug during pregnancy.  The teratogenic effect of lenalidomide in 
humans cannot be ruled out.  Therefore, a risk minimization plan to prevent pregnancy must be 
observed. 
 
Definition of female of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman who: 1) has 
not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) 
for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 
consecutive months). 
 
Before starting study drug:   
Female Subjects:   
• FCBP must have two negative pregnancy tests (minimum sensitivity of 25 
mIU/mL) prior to starting study drug.  The first pregnancy test must be performed 
within 10-14 days prior to the start of study drug and the second pregnancy test 


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52 
must be performed within 24 hours prior to the start of study drug.  The subject 
may not receive study drug 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.  
 
All Subjects: 
• Only enough lenalidomide for one cycle of therapy may be dispensed with each 
cycle of therapy.  
 
• 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. 
 
Counseling 
• In investigational studies where lenalidomide is supplied by the NCI, patients will 
be counseled by a qualified healthcare professional (including but not limited to, 
nurses, pharmacists and physicians).  Two healthcare professionals at each site 
will be trained by Celgene in requirements specific to counseling of subjects 
(investigators cannot counsel patients as part of this requirement). Refer to 
specific protocol sections for more information about training requirements. 
• Once trained, these healthcare staff will counsel subjects prior to medication 
being dispensed to ensure that the subject has complied with all requirements 
including use of birth control and pregnancy testing (FCBP) and that the subject 
understands the risks associated with lenalidomide.  This step will be documented 
with a completed Lenalidomide Education and Counseling Guidance Document 
(Appendix J) and no drug will be dispensed until this step occurs. Counseling 
includes verification with the female patient that required pregnancy testing was 
performed and results were negative. A Lenalidomide Information 
Sheet (Appendix K) will be supplied with each medication dispense. 
• 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.    
 
TOXICITY 
The most common toxicity reported with lenalidomide to date is myelosuppression. In a phase I 
dose-finding trial, grade 3 neutropenia was seen in 60% and grade 4 in 15% of 25 patients. Grade 
3 thrombocytopenia occurred in 20%. Myelosuppression frequently occurred after the first 28 
days of single daily dose treatment. It has been suggested that myelosuppression may not be 
completely reversible in heavily pretreated patients. No other grade 3 or 4 toxicities were noted 


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53 
in this trial. Mild (grade 1) lightheadedness, fatigue, rash, and leg cramps were reported in as 
many as 40% of patients. Abnormal kidney function and thyroid function tests have been noted. 
In contrast to thalidomide, lenalidomide is thought not to cause significant somnolence, 
constipation, or neuropathy. Rarely, tumor lysis syndrome (TLS) has been seen. In trials with 
lenalidomide, in a small number of patients, cardiac arrhythmias have been described. 
Preliminary data also indicate that anemia may occur, in addition to thrombocytopenia and 
neutropenia, and may be severe. In addition, a small increase in the risk of arterial thrombosis 
(e.g., myocardial infarction, CNS thromboembolic events) has been reported. Lenalidomide is a 
derivative of thalidomide, however, studies in animal models have not as yet demonstrated that 
lenalidomide is a teratogen. 
 
Recent data indicate that like thalidomide, lenalidomide may be associated with an increased risk 
of venous thrombosis and pulmonary embolism. It appears that this risk is increased when 
lenalidomide is used concurrently with dexamethasone or epoetin. Prophylactic aspirin or low 
molecular weight heparin are to be given for patients with a high risk of developing DVT/PE or 
arterial thromboses unless contraindicated. High risk will be defined as a history of DVT/PE, 
significant family history, performance status  2, smoking history, use of oral contraceptives, 
and concurrent use of epoetin. Patients with diabetes mellitus or coronary artery disease are 
considered to be at high risk for arterial thromboembolic events. 
Agent Ordering 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designees) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that the agent be shipped directly to the institution where the patient is to 
be treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Note that mailed and faxed Clinical Drug Requests (CDRs) are no longer accepted. Active 
CTEP-registered investigators and investigator-designated shipping designees and ordering 
designees can submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account  https://eapps-
ctep.nci.nih.gov/iam/  and the maintenance of an “active” account status and a “current” 
password.   For questions about drug orders, transfers, returns, or accountability, call (240) 276-
6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
Agent Accountability 
 
 
 
Agent Inventory Records – The investigator, or a responsible party designated by the 


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54 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See the CTEP 
home page at http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage and 
to obtain a copy of the DARF and Clinical Drug Request form.).   
 
8.3-Commercial Agent(s) 
 
N/A 
 
9.0-BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
 
9.1-Biomarker Studies 
 
N/A 
 
9.2-Laboratory Correlative Studies 
 
 
A critical component of this trial is the collection and analysis of primary tumor and 
surrogate tissue patient samples. Our prior experience with these agents suggests a 
heterogeneity of response that may be explained by biologic features. The overarching 
hypothesis is that baseline biologic features of these pathways influence response rate and 
progression-free survival, and that genetic, epigenetic and pharmacodynamic changes in 
specific drug targets correlate with outcome in patients treated with temsirolimus plus 
lenalidomide.  Specifically, we propose to evaluate the mTOR pathway, angiogenic 
processes, and immune status in patients treated in this phase I/II clinical trial of 
temsirolimus plus lenalidomide.  A summary of sample collection is in the table below. The 
pre-treatment/diagnostic tissue block collection is required unless there is insufficient 
material; all other correlative studies are optional.  
Sample type 
Sample Collection Time Points 
Prior to 
initiation of 
therapy 
(Baseline) 
Cycle 1 Day 1 
Cycle 1 Day 
15 
Cycle 
2 Day 
1 
Day 1 of 
all 
subsequent 
cycles 
Prior to 
infusion 
(Hour 
0) 
After 
infusion 
(Hour 
4) 
Tissue block for 
TMA 
X* 
 
 
 
 
 
Plasma for cytokine 
analysis (red and 
green tops) 
 
X 
X 
X 
X 
X 
Peripheral blood for 
flow cytometry and 
lymphocyte subsets 
(purple top)  
 
X 
 
X 
X 
X 
Peripheral blood for 
methylation, DNA 
 
X 
 
 
 
 


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55 
  
 
* Consenting patients may also opt for a second tumor biopsy just prior to Cycle 2 Day 1.  
 
Evaluation of mTOR pathway activation in pre-treatment tumor tissue and target 
inhibition in peripheral blood. 
 
Background: The heterogeneity of clinical response to single agent temsirolimus suggests 
biologic features that are potentially predictive of outcome. Identification of these biologic 
features and correlation with outcome will aid future applications of temsirolimus plus 
lenalidomide on specific patient populations with a higher likelihood of response. Response to 
temsirolimus plus lenalidomide therapy should correlate with baseline activation status of mTOR 
pathway, i.e.  PTEN, pAkt, p70 S6K/S6K1, 4E-BP1, pmTOR and rpS6 as assessed by 
immunohistochemistry (IHC) in tissue microarray (TMA) of pre-treatment paraffin embedded 
tumor specimens.  
 
Methods: mTOR pathway analysis will be performed on primary tissue via a TMA of pre-
treatment lymphoma tissue. The TMA will be constructed from paraffin tissue blocks of 
diagnostic biopsies in all patients enrolled to study. Paraffin embedded tumor blocks will be 
obtained in collaboration with the department of pathology at the University of Chicago medical 
center.  In cases where fresh biopsies are not available, archived samples will be used and noted.  
Tumor tissue arrays will be generated using all available samples. TMA or paraffin tissue 
sections (when blocks are not available for punching cores) will be analyzed for the following 
target proteins: PTEN/phospo-PTEN (Ser380), AKT (pan)/phospho-AKT(Ser473), mTOR 
(pan)/phospho- mTOR (Ser2448), p70 S6 Kinase(total)/phospho-p70 S6 Kinase (Thr389), S6 
ribosomal protein (total)/phospho-S6 ribosomal protein (Ser 235/236) and phospho-S6 ribosomal 
protein (Ser 240/244), 4E-BP1 (total)/phospho-4E-BP1 (Th37/46), (Cell Signalling Technology).  
Analysis:.Analysis will be descriptive in nature. 
 
Primary tumor sample vascular phenotype assessment (angiogenesis)  
 
Background. Both mTOR inhibitors and immune modulatory drugs have anti-angiogenic 
activity.  Angiogenic cytokine mediators such as VEGF and HIF1 are downstream of the 
mTOR pathway.  Inhibition of mTOR, then, results in the downregulation of angiogenic 
cytokines.  Immune modulatory drugs such as lenalidomide impact tumor microenvironments as 
well as angiogenesis.  Therefore, combination therapy with these novel anti-lymphoma agents 
are expected to have potent anti-angiogenic activity.  In order to understand the potential anti-
vascular activity of these agents, a detailed analysis of the vascular structures of primary tumor 
samples will be performed. 
  
Methods:  1. Tissue microarray of primary tumor samples. Paraffin embedded tumor blocks will 
be obtained in collaboration with the department of pathology at the University of Chicago 
medical center.  In cases where fresh biopsies are not available, archived samples will be used 
and noted.  Tumor tissue arrays will be generated using all available samples.  Microvessel 
density will be analyzed by staining samples with an anti-CD34 antibody.  Hypervascular 
analysis (purple 
top) 


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interfollicular areas and hypovascular follicular areas will be analyzed separately.  Anti-
podoplannin antibodies will be used to assess lymphatic vascular density.  An anti-CD68 
antibody will be used to assess for macrophage infiltration.  Antibody staining will be visualized 
with a secondary detection system.  Staining intensity will be quantitated by blinded pathological 
assessment as well as digital image analysis using an Acid Chromavision system. 
2. Plasma and serum samples for assessment of circulating levels of pro-angiogenic 
cytokines.  
Peripheral blood samples will be drawn from patients as per the table above.  Samples will be 
analyzed by ELISA.  Please see section 7.5 for sampling handling detais.  Commercial ELISA 
assays will be used and supplied protocols followed.  The following ELISA assays from R&D 
Systems will be used: anti-VEGF, anti-CXCL12/SDF-1, anti-PDGF-beta, and anti-bFGF. 
Samples will be run in duplicate.  Cytokine concentration data will be correlated with pre-
treatment disease state and vascular density, and will in addition be correlated with response to 
therapy during and after completion of therapy. 
3. Flow cytometry to assess the effect of therapy on circulating angiogenic cells 
Peripheral blood samples will be drawn from patients as per the table above. One purple top tube 
(EDTA) will be drawn and transferred on wet ice to Dr. Cohen’s laboratory for processing.  
Samples will be stained with antibody cocktails and analyzed by flow cytometry as previously 
described.65 except with the following modifications.  Blood will be diluted 1:1 with PBS.  
Diluted blood will be layered on top of 5mls ficoll  (Amersham Pharmacia Biotech).  Specimens 
will be spun at 350g  for 20 minutes at room temperature.  The buffy coat layer containing 
mononuclear cells will be collected and washed two times with PBS.  Mononuclear cells will 
then be frozen in 90% fetal calf serum/10% DMSO and stored in liquid nitrogen.  For flow 
cytometric analysis, cells will be thawed, washed, and resuspended in  5mLs of 
PBS/0.5%BSA/1mM EDTA.  500ul aliquots will be delivered to flow cytometry tubes.  Samples 
will undergo FcR blocking with anti-CD16/32 (Fc  block, Pharmingen) for 10 minutes at room 
temperature.  Samples will then be stained with the following antibodies: CD31-FITC/CD133-
PE/CD45-PerCP/CD34-APC or CD31-FITC/KDR-PE/CD45-PerCP/CD34-APC.  After staining 
samples will be fixed in 2% paraformaldehyde.  Stained samples will be analyzed by flow 
cytometry using a FacsCanto (BD) and data analyzed using FlowJo software (Treestar).   
Circulating endothelial cell phenotypes will be defined as CD31+bright/CD34+dim/CD45-.  
Circulating progenitor cells will be defined as CD34+bright/CD31+dim/CD45+dim.  Circulating 
endothelial progenitor cells will be defined as CD34+/KDR+.  Circulating cell population data 
will be correlated with pre-treatment disease state and vascular density, and will in addition be 
correlated with response to therapy during and after completion of therapy. 
 
Evaluation of immune components of the lymphoma microenvironment.  
 
Background. Microenvironmental immune components in pre-tumor tissue biopsies and 
changes in these populations in peripheral blood may correlate with response to combination 
therapy. It is expected that patients with increased macrophage infiltration and decreased T-cell 
infiltration will respond best to microenvironmental targeted therapy.   
 
Methods: IHC will be performed on pre-treatment (and post-treatment when available) samples 
using a panel of antibodies.  T-cell subsets and Tregs will be analyzed using CD3, CD4, CD8, 
CD25, and FoxP3.  Infiltrating macrophages will be marked with CD68 while follicular dendritic 


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cells will be marked with CD21.  NK subpopulations will be marked with CD16, CD56, and 
CD57.  Given the expected paucity of post-treatment tissue biopsies, peripheral blood samples 
will be collected as above to assess changes in these populations over time.   
 
Analysis: Differences in pre- and post-treatment levels, as well as comparisons between tissue 
and blood samples, will be compared using a paired t-test.  Changes in levels of responders 
versus non-responders will be analyzed using a non-parametric Wilcoxon rank-sum test.  
 
Evaluation of gene expression profile and methylation patterns in DLBCL and FL patients 
(groups A and B, respectively) 
 
Background: differences in gene expression profiles (GEP) may help predict resistance to 
agents that inhibit the Mammalian Target of Rapamycin (mTOR), and may help to identify 
combinations of drugs capable of overcoming this resistance66,67_In addition, there are profound 
changes in distribution of DNA methylation across the genome in NHLs, including DLBCL68 
and FL69,70.  The genes affected by changes in methylation involve critical intracellular processes 
like transcription, cell cycle and cell survival.  Integrated analysis of genome-wide methylation 
and expression can yield biological insights and identify patient subgroups that are not apparent 
from either GEP or methylation analyses alone. We therefore hypothesize that integrated high-
resolution analysis of DNA methylation and gene expression can identify key epigenomic 
determinants of clinical outcomes in patients with relapsed and refractory NHL. If this is 
successful in developing a predictive model for response, this information will be applied to pre-
treatment tumor specimens for patients enrolled in group C.  
 
Methods: Pre-treatment FFPE tumor biopsies will be used for RNA extraction and for DNA 
analysis. This will allow analysis of miRNA promoter regions and differentially methylated sites 
identified in tumor versus normal tissue.    
 
Analysis: To determine association between gene expression or methylation and clinical 
response, patients will be divided based on response to combination mTORi and IMID therapy: 
responders (those with partial response [PR] or complete response [CR]), versus non-responders 
(those with stable disease [SD] or progressive disease [PD]). The differences will be assessed 
using a conventional T-test, followed by a modified T-test employed using the eBayes function 
in limma (R version 9.2).71,72    
 
Handling of Specimens 
All tumor specimens must be accompanied by a specimen transmission (Appendix H) form that 
includes: 
• Patient name 
• Hospital record number 
• NCI protocol number 
• Sample type (aspirate, surgical specimen, core biopsy, etc) 
• Date when biopsy was obtained; site of tumor tissue (e.g. primary tumor, metastatic site) 
 
Shipping of Specimens (see also Appendix H) 
 


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The shipment of all human tissue samples (for blood samples see 7.6) must comply with 
appropriate regulations as specified by the carrier. Samples should be frozen and sent on dry ice 
except for one lavender top tube which will be sent on wet ice.  At a minimum, all samples must 
be packaged within two containers with absorbent material between containers to control any 
spill or leakage. The outer container must be puncture resistant (e.g., cardboard mail tube, 
corrugated cardboard box). A biohazard sticker must be affixed to both the inner and outer 
containers. 
 
All tumor blocks must be accompanied by a pathology report and a sample transmission form 
(appendix H) and shipped the following address: 
 
Jose Zavala 
University of Chicago 
5841 S. Maryland Ave. 
M/C 2115 
Chicago, IL 60637 
Phone: 773-834-5358 
Fa x :  773-702-4889 
 
jzavala@bsd.uchicago.edu  
 
 
***Prior to shipment (serum, plasma, tissue and purple tops/DNA) please email Sara Chung to 
notify that the samples have been sent, and email the FedEX bill number to him. 
 
Blood Draws (Appendix F): Serum and Plasma and DNA Preparation: 
 
All patients consenting to phlebotomy for correlative studies will have samples as described by 
the chart above (Section 9.0) and in Appendices F, G, and H.  Samples will be drawn by an 
experienced phlebotomist: One 6ml red top (serum) tube processed into two 1ml aliquots, one 
6ml green top (plasma) tube processed into two 1ml aliquots, and TWO 10ml purple tops (whole 
blood).  Serum (red tops) will be used to assess for cytokine levels by ELISA assay.   
 
Red top (Serum):  The specimen will be allowed to clot for one hour after collection time in the 
refrigerator.  The collection time should be written on the tube or accompanying paperwork.  It 
will then be placed, along with a balancing falcon tube (15 ml) containing water, in holders 
inside the centrifuge.  They will be spun for 10 minutes at 3000 rpm.  The red top tube will be 
removed.  Using a plastic pipette, 1 ml of supernatant (serum) will be siphoned individually into 
clear, plastic 1.8 ml vials, and labeled as serum, patient ID  number, Cycle number/Day and 
date in indelible ink.  
 
Green top (Plasma): The specimen will be allowed to clot for one hour after collection time in 
the refrigerator.  The collection time should be written on the tube or accompanying paperwork.  
It will then be placed, along with a balancing falcon tube (15 ml) containing water, in holders 
inside the centrifuge.  They will be spun for 10 minutes at 3000 rpm.  The green top tube will be 
removed.  Using a plastic pipette, 1 ml of supernatant (plasma) will be siphoned individually into 
clear, plastic 1.8 ml vials and labeled as plasma, patient ID  number, Cycle number/Day and 
date in indelible ink.  


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Purple Tops (Whole Blood): Two purple tops will be collected.  One purple top tube will be 
aliquoted into 4 separate 1.8mL plastic vials and labeled as “Whole Blood, Patient ID number, 
cycle number/Day, date” in indelible ink and frozen at -80C after appropriate labeling. These 
tubes should be transferred to Dr. Cohen’s lab on dry ice.  
 
The second purple top tube will be collected and transferred to Dr. Cohen’s lab on wet ice.  This 
second tube should not be frozen on dry ice as doing so will lyse both red and white blood cells.  
In Dr. Cohen’s lab, blood will be diluted 1:1 with PBS.  Diluted blood will be layered on top of 
5mls ficoll  (Amersham Pharmacia Biotech).  Specimens will be spun at 350g for 20 minutes at 
room temperature.  The buffy coat layer containing mononuclear cells will be collected and 
washed two times with PBS.  Mononuclear cells will then be frozen in 90% fetal calf serum/10% 
DMSO and stored in liquid nitrogen.   
 
Storage/Batching: The blood samples will be stored and batched over time throughout the 
patient’s treatment as in Appendices G and I at -80C.  When samples are drawn, the appendix G 
will be filled out and faxed to study coordinator listed on face sheet of protocol for EACH 
BLOOD DRAW at 773-702-4889, to document that each blood draw is collected. 
 
Shipping: They will be batch shipped by overnight carrier on dry ice to the address noted in 
Appendices G and H. (only on Mondays, Tuesdays, or Wednesdays – to ensure receipt before the 
weekend at the University of Chicago by study coordinator). Each vial must be labeled with 
patient ID number, Cycle number/Day, sample type (serum or plasma) and date in indelible ink. 
Another ‘Master’ Appendix G form (separate from the ones faxed in real-time during therapy at 
each time point) will be included and filled out to indicate what samples are included in the 
shipment. 
 
 Handling of Specimens 
 
All blood specimens must be accompanied by a specimen transmission (Appendix G) form that 
includes: 
• 
Patient name 
• 
Hospital record number 
• 
NCI protocol number 
• 
Date/time of blood draw 
• 
Indication of the timepoint of the draw (ie C2D1) 
 
Shipping of Blood Samples (see also Appendix I) 
 
All blood samples must be accompanied by a sample transmission form (appendix G) and 
shipped to the following address: 
Jose Zavala 
University of Chicago 
5841 S. Maryland Ave. 
M/C 2115 
Chicago, IL 60637 


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Phone: 773-834-5358 
Fa x :  773-702-4889 
 
jzavala@bsd.uchicago.edu  
 
 
9.3-Special Studies 
 
See section above.


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61 
 
10 STUDY CALENDAR 
 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done 4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
   
 
Pre- 
Study 
 
Wk 
1 
 
Wk 
2 
 
Wk 
3 
 
Wk 
4 
 
Wk 
5 
 
Wk 
6 
 
Wk 
7 
 
Wk 
8 
 
Wk 
9 
 
Wk 
10 
 
Wk 
11 
 
Wk 
12 
 
Off Study 
 
Temsirolimus 
 
 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
A 
 
 
 
Lenalidomideg,j 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
X---------------------------------------------------------------------------------------------X 
 
 
 
Physical examh 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Vital signs 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Performance status 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
CBC w/diff, plts 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Serum chemistrya 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
EKG (as indicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIVf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
 
X---------------------------------------------------------------------------------------------X 
X 
 
 
Tumor measurements 
 
 
X 
 
Tumor measurements are repeated after Week 8, then every 3 cycles (i.e. every 12 
weeks).  Documentation (radiologic) must be provided for patients removed from 
study for progressive disease. 
 
X 
 
Radiologic evaluation 
 
X 
Tumor measurements are repeated after Week 8, then every 3 cycles (i.e. every 12 
weeks).  Documentation (radiologic) must be provided for patients removed from 
study for progressive disease. 
X 
 
B-HCGb,c 
 
Xb 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
Xc 
 
 
 
Bone marrow aspirate and biopsy 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative studies 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A: Temsirolimus 25 mg on D1, D8, D15, D22 of a 28 day cycle.  
B: Lenalidomide 20 daily on Days 1-21 of a 28 day cycle.  
a: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], 
SGPT [ALT], sodium, triglycerides, cholesterol panel (cholesterol, HDL, LDL),  magnesium on Day 1 of each cycle. For all subsequent days: CMP, LDH, Mg. 
b: 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 (amenorrhea following cancer therapy does not rule out childbearing potential) for 
at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).   
 
c: Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to initiation of Cycle 1 of lenalidomide.  FCBP with regular or no menstruation must 
have a pregnancy test weekly for the first 28 days and then every 28 days while on lenalidomide 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 lenalidomide therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see 
Appendix I: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods). 
 


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d: Bone marrow aspirate and biopsy should be performed within 6 weeks of starting therapy. If positive, it must be repeated to document response as per Section 9.0.  
e: See Section 7.0 for summary of correlative studies.  
f: HIV testing is NOT required for study entry. However, if a patient with known HIV disease is enrolled as per Section 3.1.10, then baseline CD4 count, viral load, and 
record of recent anti-retroviral therapy must be documented as per Appendix D.  
g: All patients must be considered for prophylaxis against thromboembolic events as per Section 4.3.2 and Appendix D.  
h: Physical exam must be documented on Day 1 of each cycle at a minimum 
i: The Lenalidomide Education and Counseling Guidance Document (Appendix _J_) must be completed and signed by a trained counselor at the participating site prior 
to each dispensing of lenalidomide treatment.   A copy of this document must be maintained in the patient records. The Lenalidomide Information Sheet (Appendix _K_) 
will be given to each patient receiving lenalidomide treatment. The patient must read this document prior to starting lenalidomide study treatment and each time they 
receive a new supply of study drug. 
j: Only enough lenalidomide for 21 days or one cycle of study treatment (whichever is shorter) may be provided to the patient each cycle. 
 
 
 
 
11.0  MEASUREMENT OF EFFECT 
 
Eligible patients with measurable disease will be assessed by revised lymphoma response 
criteria.73  For the purposes of this study, patients should be reevaluated at week 8, then every 3 
cycles (12 weeks). Confirmatory scans are recommended at least 4 weeks following initial 
documentation of an objective response.  
 
11.1-Definition of Response 
 
 
11.1.1-Complete Response (CR):  
 
• Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy. 
• In patients with no pre-treatment PET scan, or if the PET scan was positive before 
therapy, a post-treatment residual mass of any size is permitted as long as it is PET-
negative. NOTE: mTOR inhibitors are known to affect cellular metabolism and may 
confound the interpretation of post-treatment PET images. Patients who are considered 
by the treating physician to be responding but who still have a PET-avid focus should 
have the PET scan images submitted to the PI (Sonali Smith, MD) for review.  
• The spleen and/or liver, if considered enlarged prior to therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear. However, determination of splenic involvement is not always reliable because 
a spleen considered normal in size may still contain lymphoma, whereas an enlarged 
spleen may reflect variations in anatomy, blood volume, the use of hematopoietic growth 
factors, or causes other than lymphoma. 
• If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is 
made must be adequate (with a goal of > 20 mm unilateral core). If the sample is 
indeterminate by morphology, it should be negative by immunohistochemistry. A sample 
that is negative by immunohistochemistry, but that demonstrates a small population of 
clonal lymphocytes by flow cytometry, will be considered a CR until data become 
available demonstrating a clear difference in patient outcome. 


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11.1.2-Partial Response(PR):   
• At least a 50% decrease in the sum of the product of the diameters (SPD) of up to six of 
the largest dominant nodes or nodal masses. These nodes or masses should be selected 
according to all of the following: a ) they should be clearly measurable in at least two 
perpendicular dimensions; b) if possible, they should be from disparate regions of the 
body; and c) they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved. 
• No increase should be observed in the size of other nodes, liver, or spleen. 
• Splenic and hepatic nodules must regress by  50% in their SPD, or, for single nodules, 
in the greatest transverse diameter. 
• With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present. 
• Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment. However, if positive, the cell type should be specified (e.g., 
large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR by the 
above criteria, but who have persistent morphologic bone marrow involvement, will be 
considered partial responders. When the bone marrow was involved before therapy and a 
clinical CR was achieved, but with no bone marrow assessment after treatment, patients 
should be considered partial responders. 
• No new sites of disease should be observed. 
• For patients with no pre-treatment PET scan, or if the PET scan was positive before 
therapy, the post-treatment PET should be positive in at least one previously involved 
site. NOTE: mTOR inhibitors are known to affect cellular metabolism and may confound 
the interpretation of post-treatment PET images. Patients who are considered by the 
treating physician to be responding but who still have a PET-avid focus should have the 
PET scan images submitted to the PI (Sonali Smith, MD) for review. 
 
 
11.1.3-Stable Disease (SD):   
• Patient fails to attain the criteria needed for a CR or PR, but does not fulfill those for 
progressive disease (see below). The PET should be positive at prior sites of disease, with 
no new areas of involvement on the post treatment CT or PET. 
 
11.1.4-Progression (PD) or Relapse: 
• Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, regardless of 
the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be 
considered abnormal if its short axis is > 1.0. Lymph nodes ≤ 1.0 cm by ≤ 1.0 cm will not 
be considered as abnormal for relapse or progressive disease. 
• Appearance of any new lesion > 1.5 cm in any axis during or at the end of therapy, even 
if other lesions are decreasing in size. Increased FDG uptake in a previously unaffected 
site should only be considered relapsed or progressive disease after confirmation with 
other modalities. In patients with no prior history of pulmonary lymphoma, new lung 
nodules identified by CT are mostly benign. Thus, a therapeutic decision should not be 
made solely on the basis of the PET without histologic confirmation. 


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64 
• At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To be 
considered progressive disease, a lymph node with a diameter of the short axis of < 1.0 
cm must increase by  50% and to a size of 1.5 x 1.5 cm, or > 1.5 cm in the long axis. 
• At least a 50% increase in the longest diameter of any single previously identified node > 
1.0 cm in its short axis. 
• Lesions should be PET-positive if a typical FDG-avid lymphoma or the lesion was PET-
positive prior to therapy unless the lesion is too small to be detected with current PET 
systems (< 1.5 cm in its long axis by CT). 
 
 
11.2-Guidelines for Evaluation of Measureable Disease 
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
For these recommendations, the spleen is considered nodal disease. Disease that is only 
assessable (e.g., pleural effusions, bone lesions) will be recorded as present or absent only, 
unless, while an abnormality is still noted by imaging studies or physical examination, it is found 
to be histologically negative. 
Clinical Lesions will only be considered measurable when they are superficial (e.g. skin 
nodules, palpable lymph nodes). 
Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
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 the chest, abdomen, and pelvis. Head & neck and extremities usually require 
specific protocols. 
Ultrasound (US) should not be used to measure tumor lesions that are clinically not easily 
accessible when the primary endpoint of the study is objective response evaluation. It is a 
possible alternative to clinical measurements of superficial palpable nodes, subcutaneous lesions, 
and thyroid nodules. US might also be useful to confirm the complete disappearance of 
superficial lesions usually assessed by clinical examination. 
Duration of Response 
Duration of response is defined as the time interval between when criteria for response (PR or 
CR) are first met until the first documentation of relapse or progressive disease. 
Definition of Survival 
Progression-free survival (PFS) is defined as the time from study entry until disease progression 
or death from any cause. Overall survival (OS) is defined as the time from study entry until death 
from any cause. 
Response Criteria for Waldenstrom’s Macroglobulinemia 
Responses for WM will be categorized using the Consensus recommendations for response. 
Progressive disease will be measured as a confirmed 25% increase in the monoclonal protein 
from baseline 69. 
 
 
11.3-Other Response Parameters 
 
N/A 


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65 
 
 
12.0-DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1-Data Reporting 
 
12.1.1-Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis, either by FTP burst of data or via the CDS web application.  Reports are due 
January 31, April 30, July 31, and October 31.  Instructions for submitting data using the CDUS 
can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html).  
 
 
12.1.2-Responsibility for Data Submission 
 
N/A 
12.2-CTEP Multicenter Guidelines 
 
Suggested text is provided below which can be modified as necessary.  If this study is being 
performed within a single institution, this section should be marked “N/A” and the text below 
deleted. 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix B. 
• The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from CTEP to all participating institutions for 
submission to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
 
12.3-Collaborative Agreements Language 
 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 


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under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 


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studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
13.0-STATISTICAL CONSIDERATIONS 
 
13.1-Study Design/Endpoints 
 
The primary objective of the phase I portion of the trial is to determine safety and tolerability of 
the combination of temsirolimus and lenalidomide in relapsed and refractory Hodgkin and non-
Hodgkin lymphoma patients. The phase I study will utilize a traditional “3+3” design.  Groups of 
3 subjects will be treated per cohort beginning at dose level 1.  If 0 of 3 patients experience DLT, 
the dose will be escalated for the next cohort.  The definition of DLT is outlined in Section 4.2. If 
1 of 3 patients experiences a DLT, 3 more patients will be treated at the same dose level, and if 
no further DLTs are observed the dose will be escalated.  If 2 or more DLTs occur at any dose 
level the MTD will have been exceeded.   A minimum of 6 patients will be treated at the MTD 
(recommended phase II dose) before proceeding to the second phase of the study. There will be 
no intra-patient dose escalation.  Patients in the phase I portion of trial who were treated at the 
eventual phase II dose will be rolled into the phase II efficacy analysis.   
The primary objective of the phase II portion will be to evaluate the complete and overall 
response rate, and the secondary endpoints will be progression free survival and overall survival. 
Patients will be accrued in a two-stage, phase II “mini-max” design. This design, which has 
larger first-stage sample sizes than the “optimal” designs, is justified due to the high anticipated 
activity of the treatment combination. Separate analyses will be performed for each lymphoma 


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subtype, with alpha=0.1 and power=90%.  For FL subtypes: we will test the hypothesis that the 
response rate is <= 50% vs. the alternative that it is >=70%.  11 or fewer responses with the drug 
combination in the first 23 patients per subtype will result in termination of the trial due to lack 
of activity.  Otherwise, an additional 16 patients will be enrolled per subtype. If there are 24 or 
more responders (>61%) the treatment will be considered worthy of further study. Response 
criteria will be per updated international definitions.67 For DLBCL and NOS lymphoma patients: 
we will test the hypothesis that the response rate is <= 30% vs. the alternative that it is >=50%.  
Here 7 or fewer responses in the first 28 patients will result in early termination.  Otherwise, an 
additional 11 patients will be enrolled and if there are 16 or more responders (> 41%) the 
treatment will be considered sufficiently active to warrant further study.  For the two sets of 
designs, the probability of early stopping under the null hypothesis is 0.50 and 0.36, respectively.   
 
13.2-Sample Size/Accrual Rate 
 
The proposed sample size is 9-18 patients for the phase I dose-finding portion of the study. The 
proposed sample size for the phase II portion of the study (“mini-max” two-stage design) is up to 
121 patients. At an estimated 4 patients/month, the study will take approximately 34 months for 
accrual.  
 
13.3-Stratification Factors 
 
Patients will by stratified into histologically-based cohorts for the phase II portion of the study as 
described in Section 11.1. Patients with DLBCL will be further stratified based on 
immunophenotype (germinal center vs. non-germinal center), but comparison of these two 
subgroups will be descriptive in nature and will not change the total accrual goal for this 
subgroup.  
 
 
13.4-Analysis of Secondary Endpoints 
 
Kaplan-Meier curves will be generated for progression-free (PFS) and overall survival (OS) 
stratified by histology; median PFS and OS times will be determined and 90% confidence 
intervals derived as described in Brookmeyer and Crowley74.  Correlative data will be analyzed 
using paired t and nonparametric tests as described above.  Baseline levels and early changes will 
also be correlated with PFS using the Cox75 regression model.   
 
 
13.5-Reporting and Exclusions 
 
13.5.1-Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
Temsirolimus and Lenalidomide. 
 
13.5.2-Evaluation of Response 
 


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All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
• Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 
• Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 


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Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
➢ The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
➢ Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
➢ Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO.  
 
 
 


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77 
 
APPENDIX C 
PATIENT’S MEDICATION DIARY- LENALIDOMIDE 
 
Today’s date ______________________________ 
Agent ___ Lenalidomide  
Patient Name__________________ (initials acceptable) 
Patient Study ID ___________________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each 4 week-period while you take Lenalidomide. 
2. 
You will take your dose of Lenalidomide each day in the morning.  You will take 5 mg or 25 mg capsules.  You may take the 
capsules with or without food as you wish. 
3. 
Record the date, the number of capsules of each size you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please return this form to your physician when you go for your next appointment. 
 
Day 
 
Date 
Time of daily 
dose 
# of capsules taken 
Comments 
5 mg 
25 mg 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment____________________________________________________________________ 
2. 
Date patient was removed from study_____________________________________________________________________ 
3. 
Patient’s planned total daily dose________________________________________________________________________ 
4. 
Total number of capsules taken this month (each size)___________________________________________________ 
5. 
Physician/Nurse/Data Manager’s Signature ________________________________________________________________ 
 
Patient’s signature 
___________________________________________________________________________________________ 
 
CTEP-assigned Protocol 
#_______8309____ 
 


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APPENDIX D 
BASELINE LYMPHOMA DATA FORM  
 
Study: NCI# 8309 Phase I/II Trial of Temsirolimus plus Lenalidomide in relapsed lymphomas  
Local IRB#: 
 
 
 
 
 
 
Patient ID#:     
__________ 
 
Study drug start date:__________ 
 
 
Patient initials: 
__________ 
 
 
 
 
 
 
 
Assignment of germinal center (GCB) vs. non-germinal center (NGCB) phenotype for DLBCL pts (Group A)--
CIRCLE ONE 
 
 
 
 
 
 
 
 
 
GC 
NGCB 
 
 
 
 
MARKER  
POS/NEG 
not done 
 
 
 
 
CD10 
  
  
 
 
 
 
Bcl6 
  
  
 
 
 
 
MUM1 
  
  
 
 
 
 
Other______________ 
  
  
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
Inclusion of patients with HIV-associated lymphoma  
 
 
 
 
 
 
Result 
 
 
 
 
 
HIV (yes/no)  
  
 
 
 
 
 
CD4 count at study entry 
  
 
 
 
 
 
viral load at study entry 
  
 
 
 
 
 
recent anti-retroviral use 
(<14d)  
  
 
 
 
 
 
 
 
 
 
 
 
Prophylaxis for thromboembolic events 
 
 
 
**Patients with any one of the following risk factors require prophylaxis against 
thromboembolic events**  
 
 
 
 
 
 
 
 
 
 
Risk factor 
yes/no 
 
 
 
 
 
FH of DVT/PE 
  
 
 
 
 
 
Personal history of DVT/PE 
  
 
 
 
 
 
Performance status >2 
  
 
Prophylaxis 
initiated? y/n 
 
 
Smoking history 
  
 
Type of 
prophylaxis___________
__________ 
 
Oral contraceptive use 
  
 
If not, why? 
_____________________
_______ 
 
Concurrent epoietin use 
  
 
 
 
 
 
Diabetes mellitus 
  
 
 
 
 
 
Coronary artery disease  
  
 
 
 
 
 
Chronic steroid use  
  
 
 
 
 
Investigator 
signature: 
  
  
 
 
 
 
Date:  
  
 
 
 
 
 


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79 
APPENDIX E: LYMPHOMA RESPONSE ASSESSMENT FORM 
 
 
 
 
 
 
 
Study: NCI# 8309 Phase I/II Trial of Temsirolimus plus Lenalidomide in relapsed lymphomas 
 
 
 
Local IRB#: 
 
 
 
 
 
 
Patient ID#:     
__________ 
 
Study drug start date:__________ 
 
 
Patient initials: 
__________ 
 
Study drug end date: __________ 
 
 
 
 
# cycles delivered:    
__________ 
 
 
 
Response to most recent regimen prior to study 
entry (circle one) 
 
 
 
 
 
 
CR/CRu 
PR 
SD 
PD 
 
 
List all  measurable and assessable sites to be 
used for response:  
 
 
 
 
 
Measurable sites (cm) 
Date of evaluation: 
  
  
  
  
  
Site for response 
Type of Scan 
Measurement 
Measureme
nt 
Measurem
ent 
Measurem
ent 
Measurem
ent 
1. 
  
  
  
  
  
  
2. 
  
  
  
  
  
  
3. 
  
  
  
  
  
  
4. 
  
  
  
  
  
  
5. 
  
  
  
  
  
  
 
 
 
% inc/dec 
% inc/dec 
% inc/dec 
% inc/dec 
 
 
 
  
  
  
  
Total Tumor Size 
  
  
  
  
  
  
Assessable sites (e.g. liver, spleen) and Response status (present, no change, incr., decr., absent, 
or indeterminate) 
 
 
 
Date of evaluation: 
  
  
  
  
  
Site for response 
Means of evaluation 
Assessment 
Assessment 
Assessmen
t 
Assessmen
t 
Assessmen
t 
1. 
  
  
  
  
  
  
2. 
  
  
  
  
  
  
3. 
  
  
  
  
  
  
Total Tumor Size 
  
  
  
  
  
  
Bone marrow biopsy 
Date of evaluation: 
  
  
  
  
  
 
Result (pos, neg, indet) 
  
  
  
  
  
 
 
 
 
 
 
 
PET scan   
Date of evaluation: 
  
  
  
  
  
 
Result (pos, neg, incr., 
decr.) 
  
  
  
  
  
Overall Response Status   
  
  
  
  
  
(CR/CRu, PR, SD, PD) 
  
  
  
  
  
  
Investigator signature: 
  
  
 
 
 
 
Date:  
  
 
 
 
 
 
 
 


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80 
APPENDIX F 
The University of Chicago 
 
 
 
Blood Sample Collection Form 
 
 
 
Clinician/Research Nurse: Please Fill Out 
Blood Samples  
Patient Name: ___________________ 
 Cycle#            Day#_______    
Patient Protocol ID #:______________ 
 Date Blood Obtained: _________________ 
Date of Birth: _____________________      Attending Physician: ______________ 
Institution: _________________ 
 
 Cross-over samples (COS)? (circle): yes / no 
Date consent was signed: ___________           if YES Cross-over samples: label COS-CXDX 
on tubes 
Day started on clinical protocol:______      Diagnosis:__________________ 
Visit 
 Collection Tubes to 
use: 
 
Date 
Drawn 
Processing  
Please check all sent 
samples                  
C1 Day 1   
 One 6ml Red (serum) Top pretreatment 
and 4h after infusion 
One 6ml Green (plasma) Top pretreatment 
and 4h after infusion  
One 10ml Purple  (whole blood) Top  
One 10mL Purple (whole blood) top 
 
Two 1 ml aliquots 
Two 1 ml aliquots 
No processing purple tops 
 
Four 1.8mL aliquots 
No processing for second purple top 
 
 
 
 
C1 Day 15 
One 6ml Red (serum) Top 
One 6ml Green (plasma) Top 
One 10ml Purple  (whole blood) Tops  
 
Two 1 ml aliquots 
Two 1 ml aliquots 
No processing purple tops 
 
 
 
 
C2D1 
One 6ml Red (serum) Top 
One 6ml Green (plasma) Top 
One 10ml Purple  (whole blood) Tops  
 
Two 1 ml aliquots 
Two 1 ml aliquots 
No processing purple tops 
 
 
 
 
C3D1 
One 6ml Red (serum) Top 
One 6ml Green (plasma) Top 
One 10ml Purple  (whole blood) Tops  
 
Two 1 ml aliquots 
Two 1 ml aliquots 
No processing purple tops 
 
 
 
 
C4D1 
One 6ml Red (serum) Top 
One 6ml Green (plasma) Top 
One 10ml Purple  (whole blood) Tops  
 
Two 1 ml aliquots 
Two 1 ml aliquots 
No processing purple tops 
 
 
 
 
C5D1 
One 6ml Red (serum) Top 
One 6ml Green (plasma) Top 
One 10ml Purple  (whole blood) Tops  
 
Two 1 ml aliquots 
Two 1 ml aliquots 
No processing purple tops 
 
 
 
 
C6D1 
One 6ml Red (serum) Top 
One 6ml Green (plasma) Top 
One 10ml Purple  (whole blood) Tops  
 
Two 1 ml aliquots 
Two 1 ml aliquots 
No processing purple tops 
 
 
 
 
Progression 
One 6ml Red (serum) Top 
One 6ml Green (plasma) Top 
One 10ml Purple  (whole blood) Tops  
 
Two 1 ml aliquots 
Two 1 ml aliquots 
No processing purple tops 
 
 
 
 
 
 
 
 
 
 
 
Protocol 
# 8309 
  


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81 
APPENDIX G 
The University of Chicago 
Archived Tissue Acquisition Form 
 
 
 
 
Clinician/Research Nurse: Please Fill Out 
 
 
 
Lymphoma Tissue (blocks/unstained slides) 
Patient Name: ___________________ 
            
Patient Protocol ID #:______________ 
          Date Tissue Obtained: _________________ 
Date of Birth: _____________________               Attending Physician: ______________ 
Origin of Tissue: __________________                Institution: _________________ 
Date consent was signed: ___________               Diagnosis:__________________ 
Day started on clinical protocol:______ 
Researcher: Please Fill Out 
Date Samples received: _________________ 
Data entered into Database: 
Yes
 
No 
Name of Data Manager informed: _______________________ Date Informed:_________ 
Approximate size of tissue: _____________________________________________ 
Notes: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol 
#8309 


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82 
APPENDIX H 
SHIPPING INSTRUCTIONS 
 
All shipments must contain a completed Sample Identification form and Tracking form.  
 
****Each site will be required to pay for shipping using their per patient amounts, and 
really should only batch ship once per patient.   
 
* Purple , Red, and Green top tubes should be collected and processed as per Section 7 (see 
also Appendix F). Paraffin sections can be sent at room temperature.  The blood samples 
should be labeled with the patient protocol ID#, Cycle and Day identifiers and stored throughout 
treatment at -80C at your institution, and then shipped to the below address: 
 
Jose Zavala 
University of Chicago 
5841 S. Maryland Ave. 
MC2115 
Chicago, IL 60637 
Phone: 773-834-5358 
Fa x :   773-702-4889  
jzzvala@bsd.uchicago.edu 
 
 
 
 
 
 
 
 
***Prior to shipment (serum, plasma, tissue and purple tops/DNA) please call UC study 
coordinator to notify that the samples have been sent.  
*** Please ship preferentially on Monday, Tuesday or Wednesday, to allow for arrival prior to weekends. 
Instructions for Shipping Specimens 
 
The Federal Aviation Administration (FAA) is an arm of the Department of 
Transportation (DOT). The DOT requires that anyone involved in the transport of hazardous 
materials (such as infectious substances, diagnostic specimens, genetically modified organisms, 
biological products, and dry ice) needs to comply with the Federal transportation law (49 CFR 
172.700). These regulations are applicable to anyone who handles, offers for transport, and 
transports dangerous goods or causes dangerous goods to be transported. Please comply with 
federal regulations 49 CFR and IATA 1.5. 
Helpful Hints for Shipping 
Dry Ice: Packing Instruction  
Processed plasma, serum, and whole blood aliquots 
1. Please fill cooler at least half full with dry ice and cover specimen bag with dry ice to 
prevent thawing. 
2. Enclose embedded tissue or serum/plasma vial in a sealed biohazard bag. 
3. Include an absorbent pad within primary sealed biohazard bag. 
4. Place the primary bag in a secondary bag. 
5. Box (cooler) must be able to release gas build-up. 
6. Indicate the dry ice weight in kg on both the waybill and on the box.  
7. Include the marking "Dry Ice, UN1845" on the box.  


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8. Place a Class 9 label on the box.  
*These are only a few helpful hints to aide in shipping.  Please refer to CFR 49 for exact criteria. 
 
 
 
Unprocessed whole blood (purple top tube) 
1. Enclose embedded tissue or serum/plasma vial in a sealed biohazard bag. 
2. Include an absorbent pad within primary sealed biohazard bag. 
3. Place the primary bag in a secondary bag. 
4. Fill cooler with half full with ice in a contained bag. 
 
 
 
 
 
 
 
Training courses and additional information about shipping requirements can be also found at: 
http://www.saftpak.com/ 
http://hazmat.dot.gov  
 
Whole Blood (10ml Purple Top aliquoted into four 1.8 mL plastic freezing vials) 
-Please write the study number, patient initials, cycle number, and date on tubes. 
-Store at –80C. If -80C is not available, please store at-20C. 
Whole Blood (10mL Purple Top, unprocessed) 
-Please send to Dr. Cohen’s lab as described above on wet ice. 
Serum (Red Top Tubes: Two 1ml aliquot Tubes) 
Red top (Serum):  Allow the specimen to clot for one hour after collection time in the 
refrigerator.  The collection time should be written on the tube or accompanying paperwork.  
Then place the tube, along with a balancing falcon tube (15 ml) containing water, in holders 
inside the centrifuge.  Spin them for 10 minutes at 3000 rpm.  Remove the red top tube.  Using a 
plastic pipette, siphon 0.5 ml of supernatant (serum) individually into clear, plastic 1.8 ml vials.   
 
Plasma (Green Top Tubes: Two 1ml aliquot Tubes) 
Green top (Plasma): Allow the specimen to clot for one hour after collection time in the 
refrigerator.  The collection time should be written on the tube or accompanying paperwork.  
Then place the tube, along with a balancing falcon tube (15 ml) containing water, in holders 
inside the centrifuge.  Spin them for 10 minutes at 3000 rpm.  Remove the green top tube.  Using 
a plastic pipette, siphon 0.5 ml of supernatant (plasma) individually into clear, plastic 1.8 ml 
vials.   
 
Tissue  
Preferably, whole Tissue blocks sent to University of Chicago and processed. Blocks will be returned. 
Alternatively, please process paraffin embedded tissue as follows: 
1. For IHC- Unstained formalin fixed paraffin embedded tissue sections should be cut at 4-5 micron thickness. Cut 
20 serial sections and store at room temperature. 
2a. For DNA extraction -10 micron thick sections in approximately 25 curls should be placed in a sterile eppendorf 
tube and labeled with appropriate identifiers; do this for a total of 5 tubes.  


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84 
2b) Alternatively to 2a, please cut 10 micron thick sections onto slides for a total of 20 slides. 
 
APPENDIX I: LENALIDOMIDE PACKET (4 DOCUMENTS) 
1- 
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods 
2- 
Lenalidomide Education and Counseling Guidance 
3- 
Lenalidomide Information Sheet 
4- 
Lenalidomide Counseling Program 
 
1- Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods 
 
Risks Associated with Pregnancy 
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that 
causes severe life-threatening birth defects.  An embryofetal development study in animals indicates that 
lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy.  
The teratogenic effect of lenalidomide in humans cannot be ruled out.  Therefore, a risk minimization plan to 
prevent pregnancy must be observed. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer 
therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time 
in the preceding 24 consecutive months). 
Counseling 
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following are met (i.e., all 
females of childbearing potential must be counseled concerning the following risks and requirements prior to the 
start of lenalidomide):  
• 
She understands the potential teratogenic risk to the unborn child 
• 
She understands the need for effective contraception, without interruption, 4 weeks before starting 
study treatment, throughout the entire duration of study treatment, dose interruption and 28 days 
after the end of study treatment 
• 
She should be capable of complying with effective contraceptive measures 
• 
She is informed and understands the potential consequences of pregnancy and the need to notify 
her study doctor immediately if there is a risk of pregnancy 
• 
She understands the need to commence the study treatment as soon as study drug is dispensed 
following a negative pregnancy test 
• 
She understands the need and accepts to undergo pregnancy testing based on the frequency 
outlined in this protocol 


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85 
• 
She acknowledges that she understands the hazards and necessary precautions associated with the 
use of lenalidomide 
The investigator must ensure that for females of childbearing potential: 
• 
Complies with the conditions for pregnancy risk minimization, including confirmation that she has 
an adequate level of understanding 
• 
Acknowledge the aforementioned requirements 
 
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the following are met (i.e., 
all females NOT of childbearing potential must be counseled concerning the following risks and requirements prior 
to the start of lenalidomide):  
• 
She acknowledges that she understands the hazards and necessary precautions associated with the 
use of lenalidomide 
Traces of lenalidomide have been found in semen.  Male patients taking lenalidomide must meet the following 
conditions (i.e., all males must be counseled concerning the following risks and requirements prior to the start of 
lenalidomide): 
• 
Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female or a 
female of childbearing potential 
• 
Understand the need for the use of a condom even if he has had a vasectomy, if engaged in sexual 
activity with a pregnant female or a female of childbearing potential.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable forms of 
contraception simultaneously or to practice complete abstinence from heterosexual contact during the following time 
periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; 3) 
during dose interruptions; and 4) for at least 28 days after study treatment discontinuation.  
The two methods of reliable contraception must include one highly effective method and one additional effective 
(barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following 
are examples of highly effective and additional effective methods of contraception:   
Highly effective methods: 
 
Intrauterine device (IUD) 
 
Hormonal (birth control pills, injections, implants) 
 
Tubal ligation 
 
Partner’s vasectomy 
Additional effective methods: 
 
Male condom 
 
Diaphragm 
 
Cervical Cap 


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86 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the 
time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients 
with neutropenia.  
 
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed for females of 
childbearing potential, including females of childbearing potential who commit to complete abstinence, as outlined 
below. 
Before starting study drug 
Female Patients: 
FCBP must have two negative pregnancy tests (minimum sensitivity of 25 mIU/mL) prior to starting study drug.  
The first pregnancy test must be performed within 10 to 14 days prior to the start of study drug and the second 
pregnancy test must be performed within 24 hours prior to the start of study drug.  The patient may not receive study 
drug until the study doctor has verified that the results of these pregnancy tests are negative. 
Male Patients: 
Must practice complete abstinence or  agree to use a condom during sexual contact with a pregnant female or a 
female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days 
following study drug discontinuation, even if he has undergone a successful vasectomy.   
During study participation and for 28 days following study drug discontinuation  
Female Patients: 
• 
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 study drug discontinuation. 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 study drug discontinuation.   
• 
At each visit, the Investigator must confirm with the FCBP that she is continuing to use two 
reliable methods of birth control.   
• 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days.  
• 
If pregnancy or a positive pregnancy test does occur in a study patient, study drug must be 
immediately discontinued. 
• 
Pregnancy testing and counseling must be performed if a patient misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal.  Study treatment must be discontinued 
during this evaluation. 
• 
Females must agree to abstain from breastfeeding during study participation and for at least 28 
days after study drug discontinuation. 
 
 


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87 
 
 
 
Male Patients: 
• 
Counseling about the requirement for complete abstinence or condom use during sexual contact 
with a pregnant female or a female of childbearing potential and the potential risks of fetal 
exposure to lenalidomide must be conducted at a minimum of every 28 days.   
• 
If pregnancy or a positive pregnancy test does occur in the partner of a male study patient during 
study participation, the investigator must be notified immediately. 
Additional precautions 
• 
Patients should be instructed never to give this medicinal product to another person and to return 
any unused capsules to the study doctor at the end of treatment. 
• 
Female patients should not donate blood during treatment and for at least 28 days following 
discontinuation of lenalidomide. 
• 
Male patients should not donate blood, semen or sperm during treatment or for at least 28 days 
following discontinuation of lenalidomide. 
• 
Only enough study drug for 28 days or one cycle of therapy (whichever is shorter) may be 
dispensed with each cycle of therapy.  
 
2- Lenalidomide Education and Counseling Guidance Document 
 
Protocol Number: ____________________________________________ 
Patient Name (Print): __________________ DOB: _____/_____/_____ (mm/dd/yyyy) 
Female:  
⁯ 
 
If female, check one: 
FCBP (Female of childbearing potential): sexually mature female who: 1) has not undergone a 
hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical 
removal of both ovaries) or 2) has not been naturally postmenopausal (amenorrhea following 
cancer therapy does not rule out childbearing potential) for at least 24 consecutive months 
(i.e., has had menses at any time during the preceding 24 consecutive months) 
 NOT FCBP 
Male: 
⁯ 
To be completed prior to each dispensing of lenalidomide. 
 
Do Not Dispense lenalidomide if: 
• The patient is pregnant. 
• No pregnancy tests were conducted for a FCBP. 
• The patient states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence of heterosexual intercourse) [at least 28 days prior, 
during dose interruption, and 28 days after discontinuation of lenalidomide]. 


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FCBP: 
 
1. 
I verified that the required pregnancy tests performed are negative. 
 
2. 
I counseled FCBP regarding the following: 
• Potential risks of fetal exposure to lenalidomide:  If lenalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby.  Females are advised 
to avoid pregnancy while taking lenalidomide. The teratogenic potential of lenalidomide 
in humans cannot be ruled out.  FCBP must agree not to become pregnant while taking 
lenalidomide.  
• Using TWO reliable methods of birth control at the same time or complete abstinence 
from heterosexual intercourse [at least 28 days prior, during dose interruption and 28 
days after discontinuation of lenalidomide]. 
• Continuation of TWO reliable methods of birth control or complete abstinence if therapy 
is interrupted. 
• That even if she has amenorrhea she must comply with advice on contraception   
• Use of one highly effective method and one additional method of birth control AT THE 
SAME TIME. The following are examples of highly effective and additional effective 
methods of contraception:   
o Highly effective methods: 
▪ Intrauterine device (IUD) 
▪ Hormonal (birth control pills, injections, implants) 
▪ Tubal ligation 
▪ Partner’s vasectomy 
o Additional effective methods: 
▪ Male condom 
▪ Diaphragm 
▪ Cervical Cap 
• Pregnancy tests before and during treatment, even if the patient agrees not to have 
reproductive heterosexual intercourse.  Two pregnancy tests will be performed prior to 
receiving study drug, one within 10-14 days and the second within 24 hours of the start of 
lenalidomide. 
• Frequency of pregnancy tests to be done: 
o Every week during the first 28 days of this study and a pregnancy test every 28 
days during the patient’s participation in this study if menstrual cycles are regular 
or every 14 days if cycles are irregular.   
o If the patient missed a period or has unusual menstrual bleeding.   
o When the patient is discontinued from the study and at day 28 after study drug 
discontinuation if menstrual cycles are regular.  If menstrual cycles are irregular, 
pregnancy tests will be done at discontinuation from the study and at days 14 and 
28 after study drug discontinuation. 


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89 
• Stop taking lenalidomide immediately in the event of becoming pregnant and to call their 
study doctor as soon as possible.  
• NEVER share lenalidomide with anyone else. 
• Do not donate blood while taking lenalidomide and for 28 days after stopping 
lenalidomide. 
• Do not breastfeed a baby while participating in this study and for at least 28 days after 
study drug discontinuation. 
• Do not break, chew, or open lenalidomide capsules. 
• Return unused lenalidomide to the investigator. 
3. 
Provide Lenalidomide Information Sheet to the patient. 
 
FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR AT LEAST 24 
CONSECUTIVE MONTHS, A HYSTERECTOMY, OR BILATERAL OOPHORECTOMY): 
 
1. 
I counseled the female NOT of child bearing potential regarding the following: 
• Potential fetal harm (Refer to item #2 in FCBP) 
• NEVER share lenalidomide with anyone else. 
• Do not donate blood while taking lenalidomide and for 28 days after stopping 
lenalidomide. 
• Do not break, chew, or open lenalidomide capsules 
• Return used lenalidomide capsules to the Investigator. 
2. 
Provide Lenalidomide Information Sheet to the patient. 
 
MALE: 
 
1. 
I counseled the Male patient regarding the following: 
• Potential fetal harm (Refer to item #2 in FCBP). 
• To engage in complete abstinence or use a condom when engaging in sexual intercourse 
(including those who have had a vasectomy) with a female of childbearing potential,  
while taking lenalidomide, during dose interruptions and for 28 days after stopping 
lenalidomide. 
 
• Males should notify their study doctor when their female partner becomes pregnant and 
female partners of males taking lenalidomide should be advised to call their healthcare 
provider immediately if they get pregnant 
 
• NEVER share lenalidomide with anyone else. 


NCI Protocol #:8309 
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90 
• Do not donate blood, semen or sperm while taking lenalidomide and for 28 days after 
stopping lenalidomide. 
• Do not break, chew, or open lenalidomide capsules. 
• Return unused lenalidomide capsules to the investigator. 
 
2. 
Provide Lenalidomide Information Sheet to the patient. 
 
 
Counselor Name (Print): ____________________ 
 
 
Counselor Signature: _______________________  
Date: _____/_____/_____ 
 
**Maintain a copy of the Education and Counseling Guidance Document in the patient 
records.** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3- Lenalidomide Information Sheet 
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES  
Please read this Lenalidomide Information Sheet before you start taking lenalidomide and each time you 
get a new supply, since there may be new information. This Lenalidomide Information Sheet does not take 
the place of an informed consent to participate in clinical research or talking to your study doctor or 
healthcare provider about your medical condition or your treatment.   
What is the most important information I should know about lenalidomide? 


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91 
Lenalidomide may cause birth defects (deformed babies) or death of an unborn baby. 
Lenalidomide is similar to the medicine thalidomide. It is known that thalidomide causes 
life-threatening birth defects. Lenalidomide has not been tested in pregnant women but 
may also cause birth defects. Findings from a monkey study indicate that lenalidomide 
caused birth defects in the babies of female monkeys who received the drug during 
pregnancy. 
If you are a woman who is able to become pregnant: 
Do not take study drug if you are pregnant or plan to become pregnant 
Either do not have sexual intercourse at all or use two reliable, separate forms of 
effective birth control at the same time:  
 for 28 days before starting lenalidomide 
 while taking lenalidomide 
 during dose interruptions of lenalidomide 
 for 28 days after stopping lenalidomide 
You must have pregnancy testing done at the following times: 
 within 10 to 14 days and again 24 hours prior to the first dose of lenalidomide 
 weekly for the first 28 days 
 every 28 days after the first month or every 14 days if you have irregular 
menstrual periods 
 if you miss your period or have unusual menstrual bleeding 
 28 days after the last dose of lenalidomide (14 and 28 days after the last dose if 
menstrual periods are irregular) 
Stop taking study drug if you become pregnant during treatment 
 If you suspect you are pregnant at any time during the study, you must stop 
lenalidomide immediately and immediately inform your study doctor. Your study 
doctor will report all cases of pregnancy to the National Cancer Institute and the 
pharmaceutical collaborator, Celgene Corporation.  
Do not breastfeed while taking study drug 
The study doctor will be able to advise you where to get additional advice on 
contraception. 
If you are a female not of childbearing potential: 
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor 
will confirm that you are not able to become pregnant. 
If you are a man: 


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Lenalidomide is detected in trace quantities in human semen. The risk to the fetus in 
females of child bearing potential whose male partner is receiving lenalidomide is 
unknown at this time.   
Men (including those who have had a vasectomy) must either abstain from sexual 
intercourse or use a condom during sexual contact with a pregnant female or a female 
that can become pregnant: 
 While you are taking lenalidomide 
 During dose interruptions of lenalidomide 
 For 28 days after you stop taking lenalidomide 
Men should not donate sperm or semen while taking study drug and for 28 days after 
stopping lenalidomide.  
If you suspect that your partner is pregnant any time during the study, you must 
immediately inform your study doctor. The study doctor will report all cases of 
pregnancy to the National Cancer Institute and the pharmaceutical collaborator, 
Celgene Corporation. Your partner should call their healthcare provider 
immediately if she gets pregnant. 
Restrictions in sharing lenalidomide and donating blood: 
Do not share lenalidomide with other people. It must be kept out of the reach of 
children and should never be given to any other person. 
Do not donate blood while you take lenalidomide and for 28 days after stopping study 
drug.  
Do not break, chew, or open study drug capsules. 
You will get no more than a 28-day supply of lenalidomide at one time. 
Return unused study drug capsules to your study doctor. 
Additional information is provided in the informed consent form and you can ask your 
study doctor for more information. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4-Lenalidomide Counseling Training Request Form 
 
 
• Please identify at least two (2) counselors and fax back to 888-314-2392 
• Use one form per counselor. 
• Identified counselors must be licensed healthcare professionals (e.g. RN, PA, RPh, PhD, 
LPN, CNP, or MD) and must not be the principal investigator. 
• If you have any questions, please email (coop_ma@celgene.com) 
 
General Information 
 
Principal Investigator: _____________________________   Institution Name: 
_____________________________ 
 
Celgene 
Corporation 
Celgene Pregnancy Prevention & Counseling Program 
Site Counselor Identification Form 
for NCI Studies 
NCI Protocol #: _______________________________ 
 
Counselor Information  
 
CTEPpersonID:  _______________________________    CTEPsiteID:  _________________ 
 
 
First Name: __________________________    Middle Initial:______    Last Name: ______________________________ 
 
 
License Type: (circle one)    MD        PhD        PA        CNP        RN        LPN       RPh      Other:_____________________ 
 
 
Email Address: _____________________________________________________________________________________ 
 
 
Phone: _________________________________________   Fax: _____________________________________________ 
 
 
Institution Street Address: ____________________________________________________________________________ 
 
 
City: __________________________________________ State/Region: _______________________________________ 
 
 
Zip/Post Code: ___________________________ Country: _________________________________________________ 
 
Previously approved as a Counselor? □ No □ Yes 
 
If no, please list all the protocols #(s), corresponding CTEPsiteID(s) and institution names(s) that you plan to provide 
counseling for: 
 
If yes, please list the protocols #(s), corresponding CTEPsiteID(s) and institution names(s) for protocols Celgene has 
already associated you with: 
 


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94 
 
 
 
 
 
 
 
 
Protocol#: 
CTEPsiteID  
Institution