Clinical trial NCT01208051
Conditions: Refractory Differentiated Thyroid Gland Carcinoma Refractory Thyroid Gland Follicular Carcinoma Refractory Thyroid Gland Hurthle Cell Carcinoma Refractory Thyroid Gland Papillary Carcinoma Unresectable Thyroid Gland Carcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2010-09-09; Completion date: 2020-02-01
Enrollment: 127 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This partially randomized phase I/II trial studies the side effects and best dose of cediranib maleate when given together with or without lenalidomide and to see how well they work in treating patients with thyroid cancer. Cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Lenalidomide may stop the growth of thyroid cancer by blocking blood flow to the tumor. It is not yet known whether cediranib maleate is more effective when given together with lenalidomide in treating thyroid cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of cediranib maleate (cediranib) plus lenalidomide. (Phase I) II. Determine the progression-free survival rates of single agent cediranib in patients with iodine refractory, unresectable differentiated thyroid cancer (DTC) who have evidence of disease progression within 12 months of study enrollment. (Phase II) III. Determine the progression-free survival rates of cediranib in combination with lenalidomide in patients with iodine refractory, unresectable DTC who have evidence of disease progression within 12 months of study enrollment. (Phase II) IV. Compare the progression-free survival curves of single agent cediranib to combination therapy with cediranib with lenalidomide. (Phase II)

SECONDARY OBJECTIVES:

I. Determine the response rate of cediranib in combination with lenalidomide in patients with iodine refractory, unresectable DTC who have evidence of disease progression within 12 months of study enrollment. (Phase I) II. Determine the toxicity, duration of response, progression free survival, and overall survival in patients with DTC treated with cediranib plus lenalidomide. (Phase I) III. Determine response rates and duration of response, early tumor size changes, the toxicity, and overall survival in patients with DTC treated with cediranib or cediranib plus lenalidomide. (Phase II) IV. Determine whether the presence of v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) or V-Ki-ras2 Kirsten rat sarcoma (K-RAS) mutations in patients with DTC predict response to cediranib or cediranib plus lenalidomide. (Phase II)

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

Phase I: Patients receive cediranib maleate orally (PO) once daily (QD) on days 1-28 and lenalidomide PO QD on days 1-21 or 1-28. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Phase II: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive cediranib maleate PO QD on days 1-28. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive cediranib maleate PO and lenalidomide PO as in Phase I. NOTE: As of April 10, 2015, patients assigned to this arm are to discontinue lenalidomide and may continue on cediranib alone.

After completion of study treatment, patients are followed up periodically.

Arms: arm 1: Patients receive cediranib maleate 30 mg PO QD on days 1-28. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive cediranib maleate 30 mg PO and lenalidomide 15 mg PO on days 1-21. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. NOTE: As of April 10, 2015, patients assigned to this arm are discontinued lenalidomide and continued on cediranib alone.
Interventions: intervention 1: Cediranib intervention 2: Cediranib Maleate intervention 3: Laboratory Biomarker Analysis intervention 4: Lenalidomide
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies intervention 4: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
i 
UC IRB # 10-182-B 
NCI # 8317 
Version Date:    09/25/2019 
 
SUMMARY OF CHANGES 
For Protocol Amendment #36 (CTEP Amd # 36) to: 
 
NCI Protocol #: 8317 
Local Protocol #: 10-182-B 
 
Protocol Date:  09/25/2019  
 
    Per CTEP recommendations the following changes were made: 
 
# 
Section 
Page 
Change 
1.  Title Page 
1 
Updated the protocol version date from 03.14.2019 to 09.25.2019 
 
 
2. Protocol 
history 
5 
Updated protocol history section to change Regulatory Manager 
from Supriya Perambakam to Mary Harris and updated RM 
contact information  
 
3. 
CAEPR 
Lenalidomi
de 
60 
Updated CAEPR for Lenalidomide from Version 2.6, December 
24, 2015 to Version 2.8, June 27, 2019 
 


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UC IRB # 10-182-B 
NCI # 8317 
Version Date:    09/25/2019 
 
NCI Protocol #:  
8317 
Local Protocol #:  
10-182-B  
 
TITLE:  Phase I/II trial of Cediranib alone or Cediranib and Lenalidomide in iodine 
131-refractory differentiated thyroid cancer 
 
 
Coordinating Center: 
 
 
The University of Chicago for the University of Chicago Phase 
II Consortium 
 
Principal Investigator: 
 
Chih-Yi Liao, M.D. 
The University of Chicago Medical Center 
5841 S. Maryland Ave., MC 2115 
Chicago, IL- 60637 
Tel: (773) 702 6241 
Fax: (773) 702 3163 
e-mail: andyliao@medicine.bsd.uchicago.edu 
 
 
Lenalidomide training: Any new site has to have two trained counselors for lenalidomide 
dispensing. Training documentation must be kept on file at PMB per section 4 of the protocol. 
Sites cannot register patients or order agents until this is done. Recommend that two counselors 
at each site be identified and trained as early as possible. Please note as of April 10, 2015, 
patients on Arm B are no longer receiving lenalidomide. For further details refer to section 
5.1.2.  
 
Participating Sites: 
James L. Wade III, M.D.  
Decatur Memorial Hospital  
2300 N. Edward St. 
Decatur, IL 62526  
Ph: (217) 876-6600 
JLWADE3@sbcgloab.net      
 
Krishna Rao, M.D. , PhD   
krao@siumed.edu                  
Springfield, IL; (217) 545-5817 or (217) 545-
7089  
Sreenivasa Nattam, M.D. 
Fort Wayne Medical Oncology/Hematology, Inc. 
Research Department 
11143 Parkview Plaza Drive, Suite 100  
Ft. Wayne, IN 46815 
Ph: (260) 484-8830 
snattam@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 
 


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Mark Kozloff, M.D. 
S. Yalavarthi, M.D. 
Ingalls Hospital  
1 Ingalls Dr.  
Harvey, IL 60430-1144  
Ph: (708) 339-4800 
mfkozloff@aol.com 
sulochana2001@hotmail.com 
Mark Agulnik, M.D. 
Northwestern Memorial Hospital 
676 N St. Clair St Suite 850 
Chicago, IL 60611 
(312) 695-1222 
m-algulnik@northwestern.edu 
 
  
 Bethany G. Sleckman, M.D. 
Saint John's Mercy Medical Center  
607 S. New Ballas Road, Ste 3425 
St. Louis, MO 63141 
Ph: (314) 251-7057 
slecbg@stlo.mercy.net 
   
Stephanie Wagner, MD 
Hematology/Oncology Department 
IU Simon Cancer Center 
535 Barnhill Drive, RT 449 
Indianapolis, IN 46202 
Phone: 317-962-9000 
E-mail: wagnerst@iupui.edu 
 
FrancisWorden M. D. 
University of Michigan  
Comprehensive Cancer Center 
C361 MIB 0848 
1500 E Medical Center Drive 
Ann Arbor, MI  48109-0848 
Ph: (734) 936-0453 
fworden@umich.edu 
Bruce Brockstein, M.D. 
NorthShore University Health System 
2650 Ridge Ave. 
Evanston, IL 60201  
Ph: (847) 570-2515 
 b-brockstein@northwestern.edu 
 
Kevin J. Cullen, M.D. 
Marlene & Stewart Greenbaum Distinguished 
Professor in Oncology, 
Director, University of Maryland Greenbaum 
Cancer Center, 
22 S. Greene Street,Baltimore, MD 21201 
Ph: (410) 328-5506 
kcullen@umm.edu 
 
 
 
 
 
Paul A.S. Fishkin, M.D. 
Illinois CancerCare, P.C.  
8940 N. Wood Sage Road 
Phone: 309-243-3000 
Fax: 309-243-3049 
Peoria, IL 61615 
pfishkin@illinoiscancercare.com 
 
 


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Version Date:    09/25/2019 
 
Additional Sites:  
Naifa L. Busaidy, MD 
MD Anderson Cancer Center 
Endocrine Neoplasia and Hormonal Disorders 
1515 Holcombe Boulevard, Unit 435    
Houston, Texas  77030-4009  
Ph: (713) 792-2841 
nbusaidy@mdanderson.org 
 
  
Amit Oza, MD 
Monika Krzyzanowska, MD 
Princess Margaret Hospital  
Division of Medical Oncology 
5700, 610 University Avenue 
Toronto, ON, Canada  M5G 2M9 
PH: (416) 946-2818 
Fax: (416)946-2082 
amit.oza@uhn.on.ca 
monika.krzyzanowska@uhn.on.ca  
Colleen Veloski, MD 
Fox Chase Cancer Center 
333 Cottman Ave 
Room P3179C 
Philadelphia, PA 19111 
Phone: 215-728-3591 
Fax: 215-214-1525 
Email: Colleen.Veloski@fccc.edu 
 
Dr. Dean Ruether 
Tom Baker Cancer Centre 
1331 29 St NW 
Calgary, AB T2N 4N2 
Ph: 403-521-3093 
Fax: 403-283-1651   
 Dean.Ruether@albertahealthservices.ca 
  
Dr. Cynthia Card 
Tom Baker Cancer Centre 
1331 29 St NW 
Calgary, AB T2N 4N2 
Ph: 403-521-2446 
Fax: 403-283-1651   
Cynthia.Card@albertahealthservices.ca 
 
Eric Winquist M.D., MSc 
University of Western Ontario  
Clinical Cancer Research Program 
London Health Sciences Centre  
790 Commissioners Road  
East London, Ontario  Canada  N6A 4L6 
Ph: (519) 685-8600 
Fax: (519) 685-8624 
eric.winquist@lhsc.on.ca  
  
Dan Sullivan, M.D. 
Tawee Tanvetyanon, MD 
Moffitt Cancer Center and Research Institute 
University of South Florida  
12902 Magnolia Drive 
Tampa, FL 33612  
Ph: (813) 745-3878 or (813) 745-6323 
Fax: (813) 745-7265 or (813) 745-5944 
dan.sullivan@moffitt.org 
Tawee.tanvetyanon@moffitt.org 
Jared Weiss, M.D. 
University of North Carolina Chapel Hill 
Physicians Office Bldg., Third Floor, CB 
#7305 
170 Manning Drive 
Chapel Hill, NC 27599-7305 
Phone: (919) 843-7714 
Fax:  (919) 966-6735 
E-Mail:  jared_weiss@med.unc.edu 
 
 


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Jill Gilbert, MD 
Vanderbilt University Medical Center  
777 Preston Research Building 
Nashville, TN 37232-6307  
Ph : (615) 343-4677 
Fax: (615) 343-7602 
jill.gilbert@vanderbilt.edu  
 Joseph Aisner, MD 
The Rutgers Cancer Institute of New Jersey 
195 Little Albany St. 
New Brunswick, NJ 08901 
Phone: 732-235-7464 
Fax: 732-235-6797 
 aisnerjo@cinj.rutgers.edu 
 
 
 
Dean Lim, MD 
City of Hope 
1500 E. Duarte Rd. 
Duarte, CA 91010 
Phone: 626-256-HOPE (4673)  
Fax: 626-301-8233 
dlim@coh.org 
 
Thomas J. Semrad, MD, MAS 
University of California Davis Cancer Center 
4501 X Street, Sacramento, CA 95817 
Phone: (916) 734-3771 
Fax: (916) 734-7946  
thomas.semrad@ucdmc.ucdavis.edu 
 
Stephen Koehler, MD  
City of Hope Medical Group, Inc., 
209 Fair Oaks Avenue 
South Pasadena, CA 91030 
626/396-2900 
Skoehler@cohmg.com 
 
Barbara Gitlitz, M.D. 
USC/Norris Comprehensive Cancer Center  
1441 Eastlake Avenue 
Los Angeles, CA 90033-0804 
Phone: 323-865-3959 
Fax: (323) 865-0061 
gitlitz@usc.edu 
 
Chandra P. Belani, MD 
Penn State Hershey Cancer Institute 
500 University Drive, CH72 
Hershey, PA 17033 
Phone:  717-531-1078 
Fax:      717-531-0002 
cbelani@psu.edu  
 
Ammar Sukari, MD 
Wayne State University/Karmanos Cancer Institute 
4100 John R Mail code: HW04HO 
Detroit, MI 48201 
Phone: 313 576 8778 
Fax: 313 576 8767 
sukaria@karmanos.org  
 
Anne Traynor, M.D. 
1111 Highland Avenue, 
WIMR Room 3103 
Madison, WI 53705-2275 
Phone: (608) 262-5092 
E-mail: amt@medicine.wisc.edu 
 
 
PJ Flynn, M.D. 
Metro-Minnesota Community Clinical Oncology 
Program 
Minnesota Oncology Hematology, PA 
800 E 28th St, Suite 405 
Minneapolis, MN 55407 
Phone: (612) 863-8585 
Fax: (612) 863-8586 
E-mail: patrick.flynn@usoncology.com 
 
Douglas R. Adkins, M.D. 
Washington University School of Medicine, 
Campus Box 8056, 660 South Euclid Avenue 
St. Louis MO 63110 
Phone: (314) 362-5654 
Fax: (314) 362- 7086 
dadkins@dom.wustl.edu 
 
Bryan R. Haugen, MD 
Professor of Medicine and Pathology 
Head, division of endocrinology, metabolism, 
diabetes  
12801 E. 17
thAve, 8117 RC 1 South, Room 7103 
Aurora, CO 80045  
Phone: 303-724-3921  
 


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Bryan.haugen@ucdenver.edu 
 
 
Study team: 
 
Statistician: 
Theodore Karrison, PhD.                    
University of Chicago 
5841 S. Maryland Ave. MC 2007 
Chicago, IL 60637 
Ph: (773) 702-9326 
tkarrison@health.bsd.uchicago.edu 
Regulatory Affairs Manager: 
 Mary Harris 
 University of Chicago 
 5841 S. Maryland Ave., MC 1140,  
 Chicago, IL 60637 
 Phone:(773) 702-0142 
Email mharris7@bsd.uchicago.edu 
Group Chairman: 
Walter Stadler, M.D. 
Everett Vokes, M.D. 
University of Chicago 
5841 S. Maryland Ave. MC 2115 
Chicago, IL 60637 
Ph: (773) 702-9753 
wstadler@medicine.bsd.uchicago.edu  
Study Registrar: 
BERNIE LIBAO, CCRP 
5841 S. Maryland | Room I-519,  MC 2115 | 
Chicago, IL 60637 
Direct line: 773-702-6634 | Fax: 773-702-
4889 | Pager: 773-702-6800, ID# 6796 
Email: blibao@medicine.bsd.uchicago.edu 
 
 
Research Nurses: 
 
Allison Dekker 
773-702-2068 
adekker@medicine.bsd.uchicago.edu 
 
University of Chicago Medical Center  
5841 S. Maryland Ave. MC2115  
Chicago, IL 60637  
  
Contract #  
 
NCI Approval: 
Approved 
UC Protocol Approval: 
Approved 
 
NCI Supplied Agents: 
  
Cediranib (NSC 732208), Astrazeneca 
Lenalidomide (NSC 703813), Celgene 
 
Protocol Type / Version # / Version Date:  
 
Version Date 
Description of Action 
  2/02/09             
    
Initial submission  
2/8/10 
Consensus Review Response 
2/23/10 
In response to additional recommendation comments. Consent version date 2/3/10 “What 
are the Risks” Updated risk profile for Lenalidomide v. 2.2 1/15/10. 
3/17/10 
Amendment # 1. In response to RRA for Cediranib risk profile update. Face page 
Amendment # 1 Version date 3/17/10. Section 7.1.1 Cediranib CAEPR updated with v. 
2.9 2/19/10.  Consent Phase I & Phase II version date 3/17/10 “What are the Risks” 
Updated risk profile for Cediranib v. 2.9 2/19/10. 


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UC IRB # 10-182-B 
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6/9/10 
Administrative Amendment Changed all reference from patient to subject in appendices 
B, J and K per IRB request.  
7/6/10 
Further IRB requested administrative changes. 
7/9/10 
Amendment # 2 Further IRB requested administrative changes. 
8/4/10 
Follow up response to NCI Follow Up review. Cover Page: Amendment # 3, Version 
Date 8/4/10. Protocol History updated. Dr. Ginny Kamboj removed from the cover page. 
Consent Forms (phase I and II) Cediranib spelling has corrected under “During the 
study”. Cetuximab has been replaced with Cediranib in the last sentence of paragraph 3 
under “Tests for Research Purposes Only.” The “also reported” adverse effects list for 
cediranib, on page 9, has been removed. 
10/25/10 
Amendment #4 – revised eligibility (prior therapies for Ph I, prior RT, change 
documented disease progression from 6 to 12 months), updated study calendar (add 
prophylactic anticoagulation and radiology assessments every 2 cycles) 
12/21/10 
Amendment # 5 Face Sheet: Version Date 12/21/10. Removed Northern Indiana Cancer 
Research Consortium, Medical University of South Carolina and Oncology Care 
Associates as participating affiliates. Updated Francis Worden as PI at U Michigan. 
Section 7.3.1 updated with new AdEERS reporting language. All reference to paper 
AdEERS removed. Section 10.0 Study Calendar LDH removed as a required chemistry 
lab. 
3/2/11 
Amendment #6 In response to RRA for Cediranib risk profile update.  Face page 
Amendment #6 Version Date 3/2/2011.  Section 7.1.1 updated with Cediranib CAEPR 
version 2.10, January 13, 2011. 
4/19/11 
Protocol updated to include Secondary Malignancy reporting in section 7.6. 
5/16/11 
Amendment #8 In response to request for change in reproductive risk language and 
lenalidomide bottle counts.  Face page Amendment #8 Version 5/16/2011.  Section 
3.1.11 eligibility criterion for contraception and pregnancy monitoring updated.  Section 
4.2 updated with requirement for two trained counselors through LCP.  Sections 7.4.1 
and 7.4.2 updated with expedited reporting guidelines for pregnancy occurrence.  
Sections 8.1.2 and 8.1.4 pharmaceutical information for lenalidomide updated.  
Appendices H, I, and J updated.  Appendix K Registration for Lenalidomide Counseling 
Program inserted. 
8/8/2011 
Amendment #9 Face Sheet: Version 8/8/11.  Updated Regulatory Affairs Manager.  
Schema updated with Phase II Cediranib and Lenalidomide dosing.  Section 2.1 updated 
with Phase II Cediranib and Lenalidomide dosing.  Section 3.2.8 updated to state that 
Cediranib can be administered via nasogastric or gastostomy tube.  Section 4 updated to 
remove references to Jeffrey Bozeman as study registrar and update study registrar email 
address,  Section 5.1 updated with information for patients who are unable to swallow 
cediranib.  Section 5.1.1 third row updated to ≤ 1 out of 6.  Section 5.1.2 first bullet point 
updated with Phase II dosing for Cediranib and Lenalidomide.  Section 6 dose 
modification for Phase II Lenalidomide 5 mg days 1-21 added and “<” updated to “≤” 
and “>” updated to “≥.”  Section 7.6 updated to state that all malignant tumors must be 
reported through AdEERs whether or not they are thought to be related to either previous 
or current treatment.  Section 10 footnote m added to TSH and Thyroglobulin to state 
that evaluations will be repeated every 2 cycles. 
9/15/11 
Amendment #10 In response to RRA for Lenalidomide risk profile update.  Face Sheet: 
Version 9/15/11.  Section 7.1.3 updated with Lenalidomide CAEPR v. 2.3, June 27, 
2011. 
12/21/11  
Disapproved 
Amendment #11 Face Sheet: Version 12/21/11, PI contact info removed for Central 
Illinois Hem/Onc, Loyola, Medical College of Wisconsin, PI contact info added for 
Northwestern, Indiana University, St. Joseph Medical Center, Fox Chase Cancer Center, 
Tom Baker Cancer Centre, Nurse contact info updated.  Schema updated with 30 patients 
in Cohort A and 60 patients in Cohort B.  Section 1.2.1 Primary Objectives changed to 
maximal change in target lesion size from baseline.  Section 2.1 updated to state Phase II 
will compare maximal change in target lesion size of cediranib to cediranib plus 
lenalidomide.  Section 3.1.4 updated to state cytotoxic or targeted prior chemotherapy.  
Section 5.1 updated to state lenalidomide may be administered via gastrostomy feeding 
tube.  Section 5.1.1 information regarding phase I toxicity added.  Section 5.1.2 updated 
to state 30 patients in Cohort A and 60 patients in Cohort B, only one cycle of therapy 
will be dispensed each month.  Section 6 updated based on Phase II dose.  Section 7.1.1 


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in response to RA for Cediranib, updated with Cediranib CAEPR v 2.11, November 10, 
2011.  Section 9.1 Removed references to blood and shipping address for archival 
tumour samples was updated.  Section 11.1 updated to state that primary outcome of the 
Phase II study will be maximal change in tumor size.  Section 11.1.4.1 updated to state 
maximal change in target lesion size from baseline.  Maximal change in target lesion size 
compared to baseline.  Section 13.1.2 updated to state that data will be analyzed after 45 
patients have been evaluated and if the combination arm is doing no better the trial will 
be terminated.  Section 13.2 updated to state that Phase II will have sample size of 90 
patients, Section 13.4.1 6 months updated to 12 months in this section.  References 
updated.  Appendix B lenalidomide drug diary updated.  Appendix M Procedure for 
Dosing Lenalidomide Via Gastrostomy Feeding Tube added.I  
1/24/12 
Amendment #12 Face Sheet: Version 1/24/12.  PI contact info removed for Central 
Illinois Hem/Onc, Loyola, Medical College of Wisconsin, PI contact info added for 
Northwestern, Indiana University, St. Joseph Medical Center, Fox Chase Cancer Center, 
Tom Baker Cancer Centre, Nurse and CRA contact info updated.  Section 3.1.4 updated 
to state cytotoxic or targeted prior chemotherapy.  Section 5.1 updated to state 
lenalidomide may be administered via gastrostomy feeding tube.  Section 7.1.1 in 
response to RA for Cediranib, updated with Cediranib CAEPR v 2.11, November 10, 
2011.  Section 9.1 Shipping information for tumor samples updated.  Appendix B 
lenalidomide drug diary updated.  Appendix M Procedure for Dosing Lenalidomide Via 
Gastrostomy Feeding Tube added. 
3/12/12 - 
Disapproved 
Amendment #13 Face Sheet: Version 3/12/12.  PI contact info for Northwestern 
updated.  Schema updated to 36 participants in cohort A and 74 in Cohort B, primary 
objective updated to Progression-free survival.  Section 1.2 Phase II primary objectives 
updated to progression-free survival.  Section 1.3 secondary objectives to determine 
response rates and duration of response and early tumor size changes.  Section 2.1 
grammatical corrections.  Section 2.1 updated to accurately state starting dose of 
cediranib will be 20 mg.  Section 2.1 updated to state that primary endpoint will be 
progression-free survival and that after 18 cycles, radiologic disease re-evaluation will 
occur every 16 weeks.  Section 3.1 updated to state that patients with hyperbilirubinemia 
due to Gilbert’s syndrome may enroll in the trial.  Amended to state that patients who 
have been on trial for greater than 12 months may be counseled every two cycles.  
Section 3.2.8 updated with procedures for patients who are unable to swallow cediranib 
and lenalidomide.  Section 3.2 added prior therapy with a VEGF-pathway inhibitor and 
ECOG performance status added to the required documents to be sent the data manager.  
Section 5.1 added criteria for subjects to receive two cycles of drug after being on study 
12 or more months.  Section 5.1.1added that after 18 cycles, radiologic disease re-
evaluation will occur every 16 weeks.  Section 5.1.2 updated subject number in each 
cohort, added that after 18 cycles, disease re-evaluation will occur every 16 weeks, stated 
that FCBP must still have pregnancy testing at least every 28 days.  Added that subjects 
who have been on protocol for 18 months or more will have radiographic-tumor response 
assessed every 4 cycles.  Section 8.1.2 updated to indicate that after 12 months, patients 
may be able to receive two cycles of drug at a time.  A reference to section 5.1 and 
appendix m was added for patients who cannot swallow lenalidomide.  Section 10 
reference to section 5.1 added to footnote b, footnote l updated to state that subjects on 
protocol 18 months or more will have radiology evaluation every 4 cycles.  Section 11.1 
added that subjects who have been on treatment for 18 months or more will have 
radiological evaluation every 4 cycles.  Section 13.1 updated with new phase II study 
endpoints.  Section 13.2 updated phase II sample size.  Section 13.4 updated analysis of 
Phase II secondary endpoints,   Section 13.5.2 updated made to evaluation of response.  
References updated.  Appendix B updated to state that 2 cycles of lenalidomide may be 
dispensed if subject on study 12 or more months.  Appendix C Grade updated to CTCAE 
v. 4.0 and grady systolic and diastolic values updated.  Appendix D updated references to 
CTCAE v4.0.  Appendix H updated to state that counseling may occur every two cycles 
but pregnancy tests must be done at least every 4 weeks.  Added that after 12 months on 
study two cycles of drug therapy may be dispensed.  Appendix J updated to state that 
after 12 months, you may be eligible to receive a 56 day supply of study drug. 
4/9/12 
Amendment #14 Face Sheet: Version 4/9/12.  PI contact info for Northwestern updated. 
 Schema updated to 36 participants in cohort A and 74 in Cohort B, primary objective 
updated to Progression-free survival.  Section 1.2 Phase II primary objectives updated to 


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progression-free survival.  Section 1.3 secondary objectives to determine response rates 
and duration of response and early tumor size changes.  Section 2.1 grammatical 
corrections.  Section 2.1 updated to accurately state starting dose of cediranib will be 20 
mg.  Section 2.1 updated to state that primary endpoint will be progression-free survival 
and that after 18 cycles, radiologic disease re-evaluation will occur every 16 weeks.  
Section 3.1 updated to state that patients with hyperbilirubinemia due to Gilbert’s 
syndrome may enroll in the trial.  Section 3.2.8 updated with procedures for patients who 
are unable to swallow cediranib and lenalidomide.  Section 3.2 added prior therapy with 
a VEGF-pathway inhibitor and ECOG performance status added to the required 
documents to be sent the data manager.  Section 5.1.1added that after 18 cycles, 
radiologic disease re-evaluation will occur every 16 weeks.  Section 5.1.2 updated 
subject number in each cohort, added that after 18 cycles, disease re-evaluation will 
occur every 16 weeks.  Added that subjects who have been on protocol for 18 months or 
more will have radiographic-tumor response assessed every 4 cycles.   A reference to 
section 5.1 and appendix m was added for patients who cannot swallow lenalidomide.  
Section 10 reference to section 5.1 added to footnote b, footnote l updated to state that 
subjects on protocol 18 months or more will have radiology evaluation every 4 cycles.  
Section 11.1 added that subjects who have been on treatment for 18 months or more will 
have radiological evaluation every 4 cycles.  Section 13.1 updated with new phase II 
study endpoints.  Section 13.2 updated phase II sample size.  Section 13.4 updated 
analysis of Phase II secondary endpoints,   Section 13.5.2 updated made to evaluation of 
response.  References updated.  Appendix B Lenalidomide drug diary updated with 
information about administration via gastrostomy tube.  Appendix C Grade updated to 
CTCAE v. 4.0 and grade systolic and diastolic values updated.  Appendix D updated 
references to CTCAE v4.0.     
11/15/12 
Amendment #15 Face Sheet: Version 11/15/12.  Added new investigators under 
additional sites, Drs, Lim, Belani, Sukari, Semrad, Gitlitz and Koehler. Also updated 
other research personnel (Regulatory Affairs Manager and Research Nurse) on the Face 
page. Section 3.1.8.  Changed the inclusion criteria for creatinine to be “below or equal to 
upper limit of institutional limits.”  The rationale here is be inclusive of subjects whose 
creatinine may be below the normal reference range. Section 6.1.  Management of 
Hypertension.  Updated the language for dose adjustment for hypertension to be more 
consistent with Appendix C and to allow for less ambiguity for treating physicians when 
adjusting study medication for high blood pressure. Section 6.2.  Other Hematologic and 
Non-Hematologic Adverse Events.  Adjusted the recommendations for the management 
for fatigue to give the treating physician more guidance for dose adjustment. Section 10. 
 Study Calendar.  Added footnotes “n” and “o”; n:  After 12 months, subjects can be 
evaluated every 2 cycles; o:  In select patients. See section 3. 1.10 for further details. 
Appendix C.  Management of cediranib-induced hypertension.  Deleted the figure in 
Appendix C.  This figure referred to CTCAEv3.0 guidelines for hypertension 
management and was inconsistent with the management of hypertension as discussed in 
Section 6.1.  
12/12/12 
Amendment #16 Face Sheet: Version 12/12/12. Added a new site, The Cancer Institute 
of New Jersey. Site PI is Joseph Aisner, MD. John Godwin, MD was removed from 
Decatur Memorial Hospital site. St. Joseph Medical Center Cancer Institute also was 
deleted from the face page. Section 3.1.8.  Changed the inclusion criteria for bilirubin as: 
X total serum bilirubin: below or equal to upper limit of institutional normal**. 
Similarly, for creatinine it should read  “OR” instead of “AND” X creatinine clearance  
>50 mL/min/1.73 m2 for patients with  creatinine levels above institutional normal.The 
rationale here is be inclusive of subjects whose bilirubin or creatinine may be below the 
normal reference range.  
03-28-13 
Amendment #17 Face Sheet: Version 3/28/13. UC lead PI, Rebecca Brown is replaced by 
Jonas De Souza, M.D. Indiana University site PI, Noah Hahn is replaced by Romnee 
Clark-Seaberg, M.D. Section 6.2 - Other Hematologic and Non-Hematologic Adverse 
Events: clarifications in the instruction for dose modification for proteinuria. Section 
10.0 -Study calendar: is updated to show Day 113 for clarification.  
04-03-13 
Amendment #18 Face Sheet: Version 4/3/13. Section 7.1.2 : Deleted the lenalidomide CAPER 
and replaced with the new version in its entirety. Section 7.1.2 : Under how supplied, 
removed “Bottles contain either 21 or 28 capsules per container” with “Bottles each 


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contain 100 capsules”. Deleted the italicized paragraph directly below the how supplied 
section. Section 8.1.3 : Removed 2nd paragraph and replaced with updated information. 
07-09-13 
Amendment #19 Face Sheet: Version 7/09/13. Updated the site PI at the University of Maryland.  
07-31-13 
Amendment #20 Face Sheet: Version 7/31/13. Removed Virginia Commonwealth University 
(VCU)/Massey Cancer Center. Added 4 new Mayo consortium sites. Section 7.1.1: 
Deleted the Cediranib CAPER and replaced with the new version in its entirety. Section 
8.1 updated lenalidomide dispensing language and ordering information for PMB 
supplied agents. 
1-14-14 
Amendment #21 Updated language in title page, updated site PI at Indiana University and 
University of Colorado and added new sites. Section 7.0 changed AdEERS to CTEP-AERS. Under 
Section 8.1, corrected Lenalidomide availability section per CTEP recommendations.  Section 10.0 
study calendar edited minor typographical errors. Updated contact/shipping information for the bio 
specimen facility throughout the protocol. 
5-20-14 
Amendment #22 Updated site PI at Illinois Cancer Care, updated Fort Wayne address and added a 
new sub-site/PI. 
10-9-14 
Amendment #23 Section 7.1.2: Deleted the lenalidomide CAPER and replaced with the 
new version in its entirety. 
4-10-15 
Amendment #24 Corrected local PI at University of Coloardo to Byan Haugen and made changes 
to the version date (footer) throughout the protocol. 
5-26-16 
Amendment #25 Updated CAPER for lenalidomide version with version 2.6, December 24, 
2015. 
07-07-16 
Amendment #26 Updated section 8.1- cediranib monograph; IB access; PMB contacts  
12-22-16 
Amendment #27 Updated section 5.1.2 to indicate that as of April 10, 2015, lenalidomide is 
discontinued on Arm B. 
1-11-17 
Amendment #28 Updated section 7.1.1 updated Cediranib CAPER to ver 2.13; section 8.1.3 and 
study schema re discontinuation of lenalidomide  
5-10-17 
Amendment #29 Protocol face page updated to reflect the lead PI change from DeSoza to Seiwert 
8-18-17 
Amendment #30 Protocol face page updated to reflect the change local PI at UNC from Hayes to 
Weiss 
10-13-17 
Amendment #31 Protocol face page updated to reflect the change in IND from 72740 to 132089 
03.05.18 
Amendment #32 Updated site personnel. Per CTEP request updated CTAE v4.0 to v5.0 
throughout the document. 
05.14.18 
Amendment #33 Per CTEP request updated Cediranib CAEPR (Version 2.14, November 14, 
2017).  In addition, as part of the implementation of version 5.0 of the Common Terminology 
Criteria for Adverse Events (CTCAE), the (CAEPR) list for cediranib, which was previously in 
CTCAE 4.0 language, has been migrated to CTCAE 5.0 language. 
01.09.19 
Amendment #34 Per CTEP request updated Cediranib CAEPR (Version 2.15, November 7, 2018) 
03.14.2019 
Amendment #35 Local Principal Investigator contact information updated on face page 
09.25.2019 
Amendment #36 Per CTEP request updated Lenalidomide CAEPR (Version 2.8, June 27, 2019).  
Revision of the ICD to provide further clarification. Updated Study Team information, changing 
the Regulatory Affairs Manager to Mary Harris. 
 
 
 


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SCHEMA 
PHASE I 
 
Cediranib 20 mg (28/28 days) + Lenalidomide 15 mg (21/28days) 
or 
 
Cediranib 30 (28/28 days) + Lenalidomide 15 (21/28 days) or 
 
Cediranib 30 (28/28 days) + Lenalidomide 15 mg (28/28 days) or 
 
Cediranib 30 (28/28 days) + Lenalidomide 20 mg (21/28 days) or 
 
Cediranib 30 (28/28 days) + Lenalidomide 20 mg (28/28 days) 
 
 
 
 
 
Determine maximum tolerated dose (MTD)* of combined therapy 
 
 
 
 
PHASE II 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Cediranib 30 mg + Lenalidomide 20 mg will be maximal dose escalation. Please note as of April 10, 2015, patients 
on Arm B are no longer receiving lenalidomide. For further details refer to section 5.1.2. 
 
Cohort A: 
 
Cediranib 30 mg day 1-28 
N = 36 
Cohort B:  
Cediranib 30 mg day 1-28 + 
Lenalidomide at 15 mg day 1-21 
(from PHASE I)  
N = 74 
Progression-free Survival 


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TABLE OF CONTENTS 
SCHEMA ....................................................................................................................................... X 
1. 
OBJECTIVES ....................................................................................................................... 14 
1.1. 
Phase I ............................................................................................................................ 14 
1.2. 
Phase II ........................................................................................................................... 14 
1.3. 
Secondary Objectives ..................................................................................................... 14 
2. 
BACKGROUND .................................................................................................................. 15 
2.1. 
Differentiated Thyroid Cancer ....................................................................................... 15 
2.2. 
CTEP-Supplied Investigational Agent(s) ....................................................................... 17 
2.3. 
Rationale........................................................................................................................  18 
2.4. 
Correlative Studies Background..................................................................................... 18 
3. 
PATIENT SELECTION ....................................................................................................... 32 
3.1. 
Eligibility Criteria .......................................................................................................... 32 
3.2. 
Exclusion Criteria ........................................................................................................... 34 
3.3. 
Inclusion of Women and Minorities............................................................................... 36 
3.4. 
Accrual Targets .............................................................................................................. 36 
4. 
REGISTRATION PROCEDURES ...................................................................................... 36 
4.1. 
General Guidelines ......................................................................................................... 36 
4.2. 
Registration Process ....................................................................................................... 37 
5. 
TREATMENT PLAN ........................................................................................................... 38 
5.1. 
Agent Administration ..................................................................................................... 38 
5.2. 
General Concomitant Medication and Supportive Care Guidelines .............................. 44 
5.3. 
Duration of Therapy ....................................................................................................... 45 
5.4. 
Duration of Follow Up ................................................................................................... 46 
5.5. 
Criteria for Removal from Study ................................................................................... 46 
6. 
DOSING DELAYS/DOSE MODIFICATIONS .................................................................. 46 
6.1. 
Management of Treatment-Emergent Hypertension ...................................................... 47 
6.2. 
Other Hematologic and Non-Hematologic Adverse Events .......................................... 48 
6.3. 
Management of Other Clinically Significant AEs (not specifically addressed above) .. 53 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................... 53 
7.1. 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .......................... 53 
7.2. 
Adverse Event Characteristics ....................................................................................... 64 
7.3. 
Expedited Adverse Event Reporting .............................................................................. 64 
7.4. 
Expedited Reporting Guidelines .................................................................................... 65 
7.5. 
Routine Adverse Event Reporting.................................................................................. 69 
7.6. 
Secondary Malignancies (including AML and MDS) ................................................... 69 
8. 
PHARMACEUTICAL INFORMATION ............................................................................. 69 


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8.1. 
CTEP-Supplied Investigational Agents ......................................................................... 70 
9. 
CORRELATIVE/SPECIAL STUDIES ................................................................................ 76 
9.1. 
Rationale......................................................................................................................... 76 
9.2. 
Laboratory Correlative Studies ...................................................................................... 79 
10. 
STUDY CALENDAR ....................................................................................................... 79  
11. 
MEASUREMENT OF EFFECT........................................................................................ 81 
11.1. 
Antitumor Effect – Solid Tumors ............................................................................... 81 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ........................................... 88 
12.1. 
Data Reporting ............................................................................................................ 88 
12.2. 
CTEP Multicenter Guidelines .................................................................................... 89 
12.3. 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA)
 
……………………………………………………………………………………….89 
13. 
STATISTICAL CONSIDERATIONS............................................................................... 91 
13.1. 
Study Design/Endpoints ............................................................................................. 91 
13.2. 
Sample Size/Accrual Rate .......................................................................................... 92 
13.3. 
Stratification Factors................................................................................................... 92 
13.4. 
Analysis of Secondary Endpoints ............................................................................. 932 
13.5. 
Reporting and Exclusions ........................................................................................... 93 
REFERENCES ............................................................................................................................. 95 
APPENDIX A 
Performance Status Criteria .......................................................................................................... 98 
APPENDIX B 
Subject’s Study Drug Diary .......................................................................................................... 99 
APPENDIX C 
Hypertension Monitoring and Management ............................................................................... 101 
APPENDIX D 
Collection/Recording of Blood Pressure Information ................................................................ 103 
APPENDIX E 
CTEP Multicenter Guidelines ..................................................................................................... 105 
APPENDIX F 
Tissue Collection Form ............................................................................................................... 107 
APPENDIX G 
New York Heart Association Classifications ............................................................................. 108 


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APPENDIX H 
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods....................................................................................................................................... 109 
APPENDIX I  
Lenalidomide Education and Counseling Guidance Document ................................................. 113 
APPENDIX J 
Lenalidomide Information Sheet ................................................................................................ 117 
 
APPENDIX K 
Registration for Lenalidomide Counseling Program……………….......................................120 
APPENDIX L 
Subject’s Blood Pressure Diary .................................................................................................. 122 
 
APPENDIX M 
    Procedure for Dosing Lenalidomide Via Gastrostomy Feeding Tube……………………….123 
 
  


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OBJECTIVES 
 
1.1. 
Phase I 
 
1.1.1. 
Primary Objective  
 
• 
Determine the MTD of cediranib plus lenalidomide. 
 
1.1.2. 
Secondary Objectives 
 
• 
Determine the response rate of cediranib in combination with lenalidomide in 
patients with iodine refractory, unresectable DTC who have evidence of disease 
progression within 12 months of study enrollment. 
 
• 
Determine the toxicity, duration of response, progression free survival, and 
overall survival in patients with DTC treated with cediranib plus lenalidomide. 
 
1.2. 
Phase II 
 
1.2.1  Primary Objectives 
 
• 
Determine the progression-free survival rates of single agent cediranib in patients 
with iodine refractory, unresectable differentiated thyroid cancer (DTC) who have 
evidence of disease progression within 12 months of study enrollment. 
 
• 
Determine the progression-free survival rates of cediranib in combination with 
lenalidomide in patients with iodine refractory, unresectable DTC who have 
evidence of disease progression within 12 months of study enrollment. 
 
• 
Compare the progression-free survival curves of single agent cediranib to 
combination therapy with cediranib with lenalidomide. 
 
1.3. 
Secondary Objectives 
 
• 
Determine response rates and duration of response, early tumor size changes, the 
toxicity, and overall survival in patients with DTC treated with cediranib or 
cediranib plus lenalidomide. 
 
• 
Determine whether the presence of B-RAF or K-RAS mutations in patients with 
DTC predict response to cediranib or cediranib plus lenalidomide. 
 


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2. BACKGROUND 
 
2.1. 
Differentiated Thyroid Cancer 
 
The annual incidence of thyroid cancer is between 14.2 cases per 100,000 in women 
and 4.9 per 100,000 in men.1  There will be an estimated 37,200 new cases of thyroid 
cancer (27,200 in women, and 10,000 in men) in the United States alone in 2009.2    
In 2008, thyroid cancer became the 6th most diagnosed cancer in women.2  Although 
several types of cancer are derived from the thyroid gland, differentiated thyroid 
cancer (DTC) accounts for up to 90% of cases.  DTC arises from thyroid follicular 
cells and comprises both papillary and follicular histologies.    Papillary thyroid 
cancer is by far the most common subtype, accounted for 70-80% of thyroid cancer 
overall.  The prognosis for DTC is extremely good, with overall 10-year survival 
rates of greater than 90%. 
 
Total thyroidectomy is the recommended initial treatment for thyroid carcinoma.  Several 
retrospective studies have suggested that near-total or total thyroidectomy improves 
disease-free survival and reduces recurrence rates.3-5 Following surgery, radioactive 
iodine (131I) treatment has been shown to decrease recurrence and mortality in high risk 
patients.6-8  Radioactive iodine is effective because well-differentiated DTCs are able to 
concentrate iodine. 131I emits short path-length (1-2 mm) -radiation that is cytotoxic to 
thyroid cells. The success of 131I ablation is dependent on the amount of residual thyroid 
tissue that is present after surgery (131I is more effective with less tissue) and its ability to 
concentrate iodine in the setting of TSH stimulation.  
 
Patients who develop recurrent disease are offered surgery if possible. For locoregional 
recurrences that are not surgically resectable, repeat radioactive iodine and/or external 
beam radiation can be considered. For metastatic disease, palliative surgery can be 
performed especially if the tumor involves weight-bearing bones. Other options include 
131I if the radioiodine scan is positive and/or external beam radiation.6 
 
Post surgical radioactive iodine is not effective in patients whose tumors do not 
concentrate iodine.  These tumors have become less differentiated and have lost the 
ability to express thyroid-specific markers, specifically, the sodium iodine symporter, 
which allows iodine into the thyroid follicle.  Tumors that are not amenable to surgical 
resection that have lost the ability to concentrate iodine currently have no effective 
therapeutic options. 
 
VEGF and thyroid cancer: 
Thyroid carcinomas are characteristically vascular.  Therefore, anti-angiogenic strategies 
have been postulated to be effective in DTCs. Preclinical and anecdotal clinical evidence 
has accumulated suggesting that anti-angiogenic strategies indeed have efficacy.7, 8  
Vascular endothelial growth factor (VEGF) is a key component in angiogenesis and is 
important in the pathogenesis of thyroid carcinomas. Viglietto et al. have shown that 
elevated VEGF expression was associated with a high tumorigenic potential in human 


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thyroid tumor cell lines.12 Viglietto et al. also showed that the VEGF receptors, FLT-1 
and flk/KDR, were expressed in endothelial cells that lined tumor-embedded 
microvascular vessels, suggesting that VEGF, contributes to thyroid tumor development. 
There is now mounting clinical evidence from Phase II trials that the inhibition of VEGF 
signaling has activity in thyroid cancers. Phase II studies of axitinib and motesanib 
diphosphate, two tyrosine kinase inhibitors with specific activity against VEGFR, 
showed 30% and 14% partial tumor response, respectively.13, 14  A large number of 
patients also had stable disease (42% and 67%, respectively).  Cediranib is a potent and 
selective tyrosine kinase inhibitor with activity against VEGFR1, VEGFR2, and VEGFR3. 
Although it has not been studied in thyroid cancer, the efficacy of axitinib and motesanib 
diphosphate in thyroid cancer suggests that cediranib may have anti-thyroid cancer activity. 
 
Thalidomides and thyroid cancer: 
Thalidomide was originally developed as a sedative in the 1950s, but its teratogenic 
effects led to its discontinued usage in that setting.  Thalidomide, however, was noted to 
have anti-angiogenic effects.  It has been shown to be an effective therapy for multiple 
myeloma; in addition, it is currently under evaluation for treatment of a variety of other 
cancers although its exact mechanism remains uncertain. Because thalidomide is not 
activated in rodent models, preclinical efficacy studies have not been useful.  Ain and 
colleagues assessed thalidomide’s effectiveness in patients with progressive thyroid 
cancer in a Phase II trial.9  A total of 36 patients (11 PTC, 2 tall cell PTC, 4 FTC, 8 HCC, 
4 insular, 7 MTC) with radioiodine-unresponsive progressive disease were recruited.  
Daily oral thalidomide was administered at a starting dose of 200 mg and increased over 
6 weeks to 800 mg or to the maximum tolerated dose.  Of 28 patients available for 
evaluation, 5 had partial responses with a median duration of 4 months and 9 had stable 
disease for a median duration of 6 months.  Fatigue was the most commonly reported 
side effect.  Serious adverse events included infection, pericardial effusion, and 
pulmonary embolus.  A Phase II study with lenalidomide, a derivative of thalidomide 
with less toxicity, also showed anti-cancer activity.  Data from a Phase II study of 
lenalidomide in patients with progressive iodine-refractory thyroid cancer has been 
presented.10  A total of 25 patients were initiated on 25 mg of oral lenalidomide daily.  
Of 18 evaluable patients, 67% were responders (22% with partial response and 44% with 
stable disease.)  Grade 3 toxicities, neutropenia and thrombocytopenia responded to dose 
reduction.  The mean daily dose was 20 mg. 
 
Patient Population: 
Patients with iodine refractory DTC have few therapeutic options. Cytotoxic 
chemotherapy is often ineffective and the most studied agent, doxorubicin, is associated 
with significant toxicity. 
 
Study Design: 
This is a phase I study followed by a phase II, 2 arm, open-label, randomized trial of 
cediranib alone or in combination with lenalidomide.   
 
Patients should have measurable disease (papillary, follicular, Hürthle cell type, or other 


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papillary/follicular variants) and evidence of disease progression (objective growth of 
existing tumors within the last 12 months). 
 
Prior to the randomized phase II portion of this study, we will evaluate cediranib plus 
lenalidomide in a phase I trial at three dose levels of lenalidomide (10, 15, and 20 mg).  
Cediranib will be administered at a starting dose of 20 mg daily. Dose escalation will not 
exceed 30 mg cediranib with 20 mg of lenalidomide.  The MTD from the Phase I was 
determined at cediranib 30 mg day 1-28 and lenalidomide 15 mg on day 1-21 of the 28 
day cycle. 
After determining the MTD, we will initiate recruitment for a Phase II trial comparing 
cedirinib alone to cedirinib plus lenalidomide. Subjects will be randomized in a 1:2 ratio 
to one of two arms. Randomized stratification will employ prior therapy with a VEGF-
pathway inhibitor (yes vs. no) and performance status (0 and 1 vs. 2).  Subjects in Arm A 
will receive cediranib alone at 30 mg daily.  Subjects on Arm B will receive cediranib 30 
mg daily and lenalidomide 15 mg on day 1-21 of  the 28 day cycle (as determined above 
in the Phase I trial).  
 
Each cycle will be 4 weeks in length.  Disease re-evaluation will occur every 8 weeks 
using RECIST guidelines.*  The primary endpoint will be progression-free survival.  
Patients without evidence of anti-thyroglobulin antibodies will continue to have 
thyroglobulin levels measured at each response assessment (usually every 8 weeks).  All 
patients are expected to be on thyroxine suppression therapy and thyroid stimulating 
hormone (TSH) levels will be monitored pre-therapy and every 8 weeks. 
 
*After 18 cycles, radiologic disease re-evaluation will occur every 16 weeks. 
 
2.2. 
CTEP-Supplied Investigational Agent(s) 
 
2.2.1. 
Cediranib 
 
Cediranib is a potent inhibitor of all three vascular endothelial growth factor (VEGF) 
receptors (VEGFR-1, -2 and -3) at nanomolar concentrations. Inhibition of VEGF 
signaling leads to the inhibition of angiogenesis, lymphangiogenesis, neovascular 
survival and vascular permeability. Cediranib also inhibits c-Kit tyrosine kinase, 
which could be relevant in c-Kit-dependent tumors.  Cediranib inhibited the growth 
of tumors in preclinical models in a dose-dependent manner.  A reduction in micro-
vessel density and metastasis was also observed in these preclinical models. 
Collectively, these changes indicate that cediranib inhibits tumor growth, metastases 
and vascular permeability.11  Cediranib is in Phase III clinical development in 
colorectal cancer (CRC) and recurrent glioblastoma (GBM) and is being evaluated in 
a Phase II program against a broad range of tumors. 
 
Mechanism of Action 
Angiogenesis, the process of new blood vessel formation, is an essential step in tumor 
growth and metastasis.  The inhibition of angiogenesis has therefore emerged as a key 


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strategy for the treatment of cancer. Although it is possible to disrupt blood vessel 
formation at several stages in the angiogenic process, VEGF and its receptor 
(VEGFR) provide a promising target since VEGF is known to be the most important 
proangiogenic factor.12, 13  Two high-affinity receptors for VEGF with associated 
tyrosine kinase activity have been identified on human vascular endothelium: 
VEGFR-1 and VEGFR-2. VEGFR-3, a third member of the VEGFR gene family, is 
thought to be important for lymphangiogenesis and activated by the ligands, VEGF-C 
and VEGF-D. Although their relative contributions in mediating tumor progression 
have not been resolved, a number of studies suggest VEGFR-2 performs a 
predominant role.13 
 
Cediranib is a potent inhibitor of all three vascular endothelial growth factor (VEGF) 
receptors (VEGFR-1, -2 and -3) at nanomolar concentrations. Inhibition of VEGF 
signaling leads to the inhibition of angiogenesis, lymphangiogenesis, neovascular 
survival and vascular permeability. Cediranib also inhibits c-Kit tyrosine kinase, 
which could be relevant in c-Kit dependent tumors. 
 
Cediranib inhibited the growth of tumors in preclinical models in a dose-dependent 
manner.  A reduction in micro-vessel density and metastasis was also observed in 
these preclinical models. Collectively, these changes indicate that cediranib inhibits 
tumor growth, metastases and vascular permeability.11 
 
Nonclinical Specificity and Efficacy Studies 
Using enzyme-linked immunoabsorbent assays or scintillation proximity based 
assays,11 cediranib potently inhibited the tyrosine kinase activity associated with the 
VEGF receptors, VEGFR-2 (IC50 <0.001 μM), VEGFR-1 (IC50=0.005 μM) and 
VEGFR-3 (IC50 ≤0.003). Cediranib was also found to have activity versus additional 
structurally-related Class III RTKs (c-Kit, PDGFR)
 at nanomolar concentrations, 
but demonstrated selectivity versus other tyrosine and serine/threonine kinases 
examined.  The ability of cediranib to directly inhibit tumor cell growth in vitro was 
examined using a variety of histologically distinct tumor cell types. The IC50 values 
(mean ±SE ) for the inhibition of tumor cell growth were 3.0 ±0.4 μM(SKOV-3), 3.8 
±0.5 μM (MDA-MB-231),5.8 ±0.2 μM (PC-3), 6.4±0.6 μM (Calu-6) and 7.4 ±0.7 μM 
(SW620).11  These concentrations are between 7500- and 18500-fold greater than 
those required to inhibit VEGF-stimulated human umbilical vein endothelial cell 
proliferation .  The data are consistent with cediranib anti-tumor activity in vivo being 
attributable to inhibition of VEGF signaling in endothelial cells, rather than a direct 
anti-proliferative effect on tumor cells. 
 
Nonclinical Toxicology Studies 
Single- and multiple-dose toxicology studies were conducted in rats, dogs, and 
monkeys (Investigator’s Brochure, Cediranib (AZD2171), 2009).  Cediranib has not 
shown mutagenic or clastogenic potential. 
 


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Hypertension after dosing with cediranib has been observed in rats, dogs, and primates. 
These changes were thought to be mechanistically related to VEGF.  Histopathologic 
changes seen in rats treated with cediranib included choroid plexus vasculitis, ventricular 
myocarditis and coronary arteritis; these findings were consistent with systemic 
hypertension.  Other changes were seen in the adrenal glands, pancreas, thyroid, liver and 
biliary system. 
 
In primates, doses of 0.5, 1.5 and 2.5 mg/kg/day were not tolerated.  Pathologic changes were 
observed in the choroid plexus and kidney; these changes were consistent with hypertension 
although a direct effect on these tissues could not be excluded.  In addition, mucosal 
hypertrophy of the gall bladder and bile duct hyperplasia in the liver were seen.  A dose of 
0.2 mg/kg/day given to primates for 6 months produced minimal changes in the choroid 
plexus and kidney; the majority of changes showed reversibility after a 3-month off-
treatment. A dose of 0.025 mg/kg/day was considered to be the no adverse effect level. 
 
As anticipated, cediranib showed reversible effects on female fertility and significant 
findings on embryo-fetal development, consistent with its pharmacological activity. 
 
Nonclinical Pharmacokinetics and Pharmacology 
Bioavailability of cediranib after oral administration was high: 70% to 75% in rat and 24% to 
74% in dog.  Absorption was relatively slow with peak concentrations occurring 4 to 6 h 
after dosing. Cediranib pharmacokinetics indicate high clearance and very high volume of 
distribution.   
 
Over the dose ranges examined in rat, plasma concentrations and exposure generally 
increased in proportion to dose; however, in monkey, plasma cediranib concentration-time 
profiles obtained following a single oral dose indicated that systemic exposure increased in a 
greater than dose-proportional manner over the dose range 0.05 to 2.5 mg/kg.   On multiple 
dosing, there was limited accumulation (<2-fold) and no evidence of auto-induction in rat, 
but a slightly greater degree of accumulation (2- to 3-fold) was observed in monkey at higher 
dose levels. 
 
Protein binding of cediranib (90% to 95%) was relatively high across all species examined.  
In the rat and monkey, cediranib was extensively metabolized and considerable amounts of 
metabolites plus unchanged cediranib were present in the feces (the major route of 
elimination) and urine.   
 
Cediranib did not induce rat hepatic microsomal P450 activities, but caused a 40% to 60% 
reduction in CYP1A activity at the 5 mg/kg dose level.  Cediranib showed minimal 
inhibitory effects on the activity of human P450 CYP2D6 and CYP3A4 in vitro; the IC50 
values were far in excess of clinically relevant concentrations. 
 
Clinical Experience 
Cediranib has been in evaluated in a number of clinic trials.    Phase I studies with cediranib 
were designed primarily to identify the safety, tolerability, and PK profiles of the drug rather 


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than to determine efficacy; however, encouraging evidence of biological and anti-tumour 
activity has also been seen in these studies.  In Phase I studies, cediranib has shown single 
agent activity in a wide variety of tumors including prostate, renal, colorectal, lung, liver, 
breast, skin/soft tissue, stomach, head and neck, ovarian, biliary duct, thyroid, thymus, 
pancreatic tumors, acute myeloid leukemia.16-20  A number of Phase II/III studies have been 
completed or are underway. 
 
Phase I experience.  Several dose escalation and pharmacokinetic studies have assessed the 
MTD for cedirinib.  The MTD is reported between 20 mg and 45 mg daily, depending on the 
study.   
 
In one study, 83 patients with advanced solid tumors received cedirinib.18  After a 
single dose, maximum plasma (peak) drug concentration after a single-dose 
administration (Cmax) was achieved 1 to 8 hours postdosing with a mean half-life of 
22 hours.  Cedirinib doses of less than 45 mg/d were generally well-tolerated.  The 
most frequently dose related adverse events were fatigue, diarrhea, dysphonia and 
hypertension.  Preliminary results showed two confirmed partial responses and 22 
patients with stable disease.   
 
In a second study in Japanese patients with advanced solid tumors, cediranib 30 
mg/day was considered the MTD since 50% of evaluable patients received 45 mg/day 
experienced dose limiting toxicities (proteinuria, diarrhea, thrombocytopenia).14  Of  
32 evaluable patients, two had partial responses and 24 had stable disease greater than 
8 weeks.   
 
Cediranib has been evaluated in Phase I studies of particular tumors.  In a study of 
patients with hormone refractory prostate cancer, the MTD was found to be 20 
mg/day.15  One objective response and several PSA declines were noted after the 
discontinuation of therapy.  A Phase I study of cediranib in patients with acute 
myeloid leukemia reported that cediranib was generally well-tolerated at doses less 
than 30 mg/day.16  Six of 35 patients had an objective response. Cediranib at two 
doses (30 mg and 45 mg) was evaluated in combination with cisplatin and 
gemcitabine in a Phase I study of patients with advanced non-small cell lung cancer.23 
 At 45 mg/day, toxicity was increased compared to the 30 mg/day dose.  Confirmed 
responses were observed in four of 12 evaluable patients.   
 
Cediranib is being evaluated in a number of other Phase I studies.  Cedinanib in 
combination with gefitinib is under evaluation in patients with advanced solid tumors 
to determine the MTD of combination therapy.  It is also being evaluated in patients 
with advanced solid tumors in combination with different standard chemotherapy 
regimens.  Another study is looking at cediranib in combination with AZD0530.  
 
Phase II and III Experience 
To determine the optimal timing of cediranib administration, 34 patients with 
advanced solid tumors were randomized to receive cediranib 45 mg in a fed or fasted 


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state.17  Both the AUC and Cmax of cediranib were lower in the presence of food by a 
mean of 24% and 33% respectively.  Therefore, it is recommended that cediranib be 
administered at least 1 hour before or 2 hours after food.   
 
Because hypertension is a main adverse effect of cediranib, a Phase II study 
investigated hypertension management strategies in 125 patients.  Cediranib 30 mg or 
45 mg daily was administered with or without anti-hypertension prophylaxis.   The 
overall response rate was similar across the treatment groups with evidence of anti-
tumor activity apparent at both 30 mg and 45 mg dose levels, and irrespective of 
whether the patient was receiving prophylaxis.  
 
A Phase II randomized, double-blind, parallel-group study comparing the efficacy of 
cediranib to placebo in patients with renal cell cancer showed promising anticancer 
activity.18  At 12 weeks, 20.8% of the 53 patients randomized to cediranib had a 
partial response compared with none on placebo. The disease control rate (responders 
+ SD) at this stage was 81% in the cediranib arm versus 22% in the placebo arm. 
Overall, for patients originally randomized to cediranib: 34% had partial response, 
47.2% had stable disease, 17% had disease progression, and 1 was not evaluable.  
Some 78% of the 18 patients with partial response had responses lasting ≥10 months, 
and 61% had responses lasting for ≥1 year. 
 
A total of 36 patients were enrolled in a Phase II, open-labeled study of cediranib 45 
mg in patients with metastatic gastrointestinal stromal tumors (GIST) or soft tissue 
sarcomas (STS).   Some 62.5% of GIST patients had stable disease.  In the 6 alveolar 
soft part sarcoma patients, 3 had partial response and 3 had stable disease. 
 
Efficacy of cediranib has also been evaluated in 8 Phase II NCI-sponsored 
monotherapy studies.  Anti-cancer activity has been observed in some patients with a 
wide range of cancer types including recurrent glioblastoma, recurrent epithelial 
ovarian cancer, recurrent or persistent ovarian, peritoneal or fallopian tube cancer, 
docetaxel-resistant, castrate-resistant prostate cancer, malignant pleural 
mesothelioma, and progressive stage IV breast cancer.  In some trials, the initial dose 
of cediranib 45 mg daily was decreased to 30 mg daily due to toxicity.   
 
Cediranib is under evaluation in both Phase II/III studies and Phase III studies.  The 
efficacy of cediranib in combination with FOLFOX versus bevacizumab in 
combination with FOLFOX in patients with metastatic colorectal cancer is under 
evaluation (HORIZON III).  Following the Phase II portion, patients in the Phase III 
portion received the selected dose of cediranib 20 mg.   In another Phase III study 
(HORIZON II), patients with previously untreated metastatic colorectal cancer are 
being randomized to receive cediranib + FOLFOX or XELOX with placebo + 
FOLFOX or XELOX.  Cediranib 20 mg was the dose selected for the Phase III 
portion in this study as well.   
 


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Another Phase III study is looking at the efficacy of cediranib monotherapy, cediranib 
in combination with lomustine, or lomustine with placebo in patients with recurrent 
glioblastoma.    A Phase II/III study of cediranib in combination with standard 
paclitaxel/carboplatin chemotherapy in patients with Stage IIIB or IV NSCLC was 
halted following a recommendation by the Data Safety Monitoring Committee prior 
to the Phase III portion as discussed below. 
 
Safety Profile 
Commonly reported adverse events (AEs) include fatigue, hypertension, diarrhea, 
nausea, vomiting, and anorexia. (Investigator’s Brochure, Cediranib (AZD2171), 
2009) Although cediranib 45 mg daily was determined as the MTD in early studies, 
later studies have found that 30 mg or 20 mg daily are better tolerated.17, 19, 20 
 
Hypertension has emerged as an important AE and serious adverse event (SAE) with 
cediranib therapy.  It is the major cardiovascular adverse event associated with 
cediranib therapy.  Hypertension is an expected AE with agents that inhibit VEGF 
signaling. In cediranib studies, increases in blood pressure have been observed, 
including CTC Grade 4 hypertension and end-organ damage related to hypertension, 
such as cerebrovascular events.  A Phase II study with looked at cediranib 30 mg or 
45 mg +/- hypertension prophylaxis found that no single treatment strategy emerged 
as clearly better managing high blood pressure.  Overall, treatment of hypertension in 
a stepwise fashion with rigorous monitoring of blood pressure appears to be effective 
in managing cediranib-induced hypertension.   
 
Left ventricular dysfunction, in some cases leading to cardiac failure, has been 
observed in patients receiving cediranib with risk factors for left ventricular 
dysfunction (including previous or concomitant anthracycline treatment).  To 
investigate left ventricular dysfunction, two Phase II studies of cediranib included 
serial echocardiogram/MUGA studies. (Investigator’s Brochure, Cediranib 
(AZD2171), 2009)  The changes in LVEF observed in these two studies appeared to 
be mild and occurred more frequently in patients who had received prior 
anthracyclines. Based on these findings, it was not considered necessary to implement 
additional monitoring of LVEF dysfunction in studies with cediranib. 
 
A number of events of bleeding and hemorrhage have occurred. Some events of 
hemorrhage were fatal but causality could not be unequivocally assigned to cediranib. 
Gastrointestinal perforation, sometimes associated with fistula formation, has been 
observed in patients receiving cediranib. Some events of gastrointestinal perforation 
have been fatal but causality could not be unequivocally assigned to cediranib. 
 
Fatigue, hand and foot syndrome, diarrhea, headache, nausea, vomiting, anorexia and 
weight loss are commonly occurring AEs in cediranib studies. Dehydration has been 
observed in clinical studies as a consequence of cediranib-related or chemotherapy-
related diarrhea, vomiting, anorexia, or reduced oral intake.   
 


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Hoarseness (dysphonia) has been reported as common and dose-related. 
 
Muscle weakness, proteinuria, dry mouth and oral mucosal inflammation have been 
observed in cediranib studies. 
 
Reversible posterior leukoencephalopathy syndrome (RPLS) has been observed in 
patients receiving cediranib in clinical studies.  RPLS is a rare syndrome affecting 
vascular endothelial cells in the brain that may lead to capillary leak and edema. It has 
been associated with a number of conditions, including renal failure, hypertension, 
fluid retention, and the use of cytotoxic or immunosuppressive drugs. RPLS also been 
reported in association with the use of VEGF inhibitors including bevacizumab, 
sunitinib, and sorafenib. 
 
Increases in transaminases, which are sometimes associated with increases in total 
bilirubin, have been seen. Thrombocytopenia, of CTC Grade 1 or 2 in the majority of 
cases, has been seen with monotherapy and combination cediranib treatment. In 
addition, cediranib has been associated with increases in TSH which may be 
associated with clinical hypothyroidism.  
 
A Phase II/II study of cediranib in combination with standard paclitaxel/carboplatin 
chemotherapy in patients with Stage IIIB or IV NSCLC was halted following a 
recommendation by the Data Safety Monitoring Committee prior to the Phase III 
portion.  There was a significantly higher response rate seen in cediranib patients.19 
However, although the overall number of deaths in each arm was similar, there 
appeared to be an imbalance in the number of fatal SAEs that were reported, with 
more patients on cediranib having been reported as experiencing fatal SAEs than on 
placebo (11 patients vs 1 patient). While some of these reported fatal SAEs appeared 
to be drug-related, others appeared to be a consequence of disease progression.  
 
Clinical Pharmacokinetics, Pharmacology, and Pharmacodynamics 
Cediranib has a PK profile that supports once-daily oral dosing.  Although absolute 
bioavailability has not been determined, cediranib appears well absorbed with 
apparently linear PK for single and multiple doses ranging from 0.5 to 60 mg. After 
multiple once-daily oral doses, steady-state plasma concentrations are attained after 
approximately 7 days. There is limited accumulation, consistent with the t½λz observed 
following single doses, and steady-state plasma concentrations are predicted by the 
single dose PK, indicating no time-dependent changes in PK.  
 
In vitro protein binding studies showed that cediranib binds to human plasma proteins 
(95.4%), including serum albumin and α1-acid glycoprotein, and was independent of 
concentration over the range 0.06 to 22 μM (30 to 1000 ng/mL) 
 
Cediranib showed minimal inhibitory effects on the activity of human P450 CYP2D6 
and CYP3A4 (testosterone and midazolam) in vitro; the IC50 values were far in excess 
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of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1.  Co-
administration of known inhibitors or inducers of hepatic CYP enzymes would not be 
expected to have significant effects on the clearance of cediranib. However, since 
potent inhibitors or inducers of CYP enzymes can also affect drug disposition by 
interaction with transporter proteins and phase II metabolism, two clinical studies are 
currently ongoing to investigate the PK of cediranib when co-administered with a 
potent inhibitor ketoconazole and the potent inducer rifampin.   
 
Clearance of cediranib is moderate, approximating 64% of nominal hepatic plasma flow. 
Following a single dose of 14C-labelled cediranib, the ratios of whole blood to plasma 
radioactivity suggest that the radioactive components in whole blood are confined to plasma. 
Concentrations of total radioactive material in plasma were also higher than those measured 
for cediranib itself, particularly at later times, demonstrating the presence of circulating 
metabolites. In patients able to provide samples during the entire collection period, the 
majority of the radioactivity was eliminated in feces.  The large number of metabolites 
detected in the feces and urine show that cediranib is cleared extensively by metabolism. 
Less than 1% of the administered dose of cediranib was excreted unchanged in the urine. 
 
Cediranib has been administered in combination with a number of chemotherapy 
regimens.  There was little or no apparent effect (<1.5-fold change) on exposure to 
paclitaxel, carboplatin, oxaliplatin, 5-FU (given as mFOLFOX6), docetaxel, 
pemetrexed, irinotecan +SN38, gefitinib, gemcitabine or fulvestrant, when given in 
the presence of cediranib steady state plasma concentrations. Steady-state PK 
parameters of cediranib in combination with the chemotherapy agents are comparable 
with those seen previously with cediranib monotherapy. 
 
Data obtained following a single 45-mg cediranib dose in the presence and absence of 
a standard high-fat meal, showed that food decreases the Cmax by 33% and AUC by 
24%. Cediranib should be administered at least 1 h before or 2 h after food. 
 
Initial pharmacodynamic assessments indicated potential biological activity of 
cediranib in clinical studies. Reductions in blood flow in hepatic metastases have 
been detected by DCE-MRI in patients with solid tumors and metastatic liver disease, 
and initial biomarker assessments have shown increases in serum VEGF, bFGF, and 
PLGF and reductions in sVEGFR-2 levels. Decreases in sVEGFR-2 levels may be a 
surrogate for decreased angiogenesis and changes in VEGF could potentially indicate 
acute vascular effects. The general trends for soluble biomarkers of angiogenesis 
(increases in serum VEGF and decreases in sVEGFR-2) were also observed in a 
Phase II study in patients with renal cell carcinoma. 
 
Proposed Dose and Schedule for Phase 2 Clinical Trials 
Based on the totality of the safety, tolerability, efficacy, PK, and pharmacodynamic 
data that are currently available from both AZ-sponsored and collaborative group 
studies with cediranib, at daily dose of cediranib 30 mg is the recommended dose for 


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monotherapy. Cediranib 20 mg is the recommended dose in combination with 
chemotherapy agents.    
 
2.2.2. 
Lenalidomide 
 
Lenalidomide is the lead compound in a new class of immunomodulatory drugs known as the 
IMiDs®. The IMiDs are characterized by a wide range of effects, including the enhancement 
of T cells and natural killer (NK) cell activity, the inhibition of angiogenesis, the inhibition of 
tumor cell proliferation, the modulation of stem cell differentiation, and inhibition of 
inflammation and hyperalgesia. On the basis of this varied pharmacological profile, 
lenalidomide is under investigation as a treatment for a range of oncologic and non-oncologic 
indications. 
 
On 27 December 2005, the United States (US) Food and Drug Administration (FDA) 
approved lenalidomide for the treatment of patients with transfusion-dependent anemia due 
to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 
5q cytogenetic abnormality with or without additional cytogenetic abnormalities. 
Lenalidomide also received approval for MDS from Argentina (on 15 February 2008) and 
conditional approval from Canada (on 17 January 2008). Subsequently, the FDA (on 29 June 
2006) and the European Commission (on 14 June 2007) approved lenalidomide in 
combination with dexamethasone for the treatment of patients with multiple myeloma (MM) 
who received at least 1 prior therapy. 
 
Mechanism of Action 
Although lenalidomide shows immunomodulatory activity both in vitro and in vivo, its exact 
mechanism is uncertain.   
 
Nonclinical Specificity and Efficacy Studies 
The pharmacologic activity of lenalidomide has been characterized in an extensive series of 
nonclinical studies. In several in vitro assays, lenalidomide was shown to inhibit monocyte 
production of various proinflammatory cytokines; inhibit expression of cyclooxygenase-2 
(COX-2) and release of prostaglandin E2 (PGE2); and elevate interleukin (IL)-10 production. 
Both in vitro and in vivo, lenalidomide increased the proliferation and production of IL-2 and 
interferon gamma (IFN-γ) by T cells and enhanced T cell and natural killer (NK) cell-
mediated killing of tumors. The proliferation of various hematopoietic tumor cell lines was 
also inhibited by lenalidomide in vitro. In vivo tumor growth models have demonstrated that 
lenalidomide inhibits growth of MM cells. In a model of hematopoietic progenitor 
differentiation, lenalidomide increased expression of fetal hemoglobin in CD34+ stem cells. 
Lenalidomide also suppressed edema and mechanical and thermal hyperalgesia in a model of 
inflammatory pain. 
 
The antiangiogenic activity of lenalidomide, demonstrated using human endothelial cells and 
arterial explant models in vitro, has also been shown to result in reduced growth of solid 
tumors. As a single agent, lenalidomide has demonstrated some activity toward a prostate 
tumor xenograft and had an additive effect in combination with docetaxel (Investigator’s 


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Brochure, Lenalidomide, 2008).  Lenalidomide, in combination with sorafenib, inhibited 
angiogenesis in vitro and reduced tumor growth in an ocular melanoma xenograft model.20 
Lenalidomide, in combination with sunitinib and cyclophosphamide, also inhibited 
angiogenesis in vitro and effectively blocked tumor growth in ocular melanoma, colon 
cancer, pancreatic cancer, and cutaneous melanoma models.21  
 
Nonclinical Toxicology Studies 
Lenalidomide has been evaluated in rats, rabbits and monkeys (Investigator’s Brochure, 
Lenalidomide, 2008). Lenalidomide has a low potential for acute toxicity; minimum lethal 
doses after oral administration were > 2000 mg/kg in rodents. Chronic administration of 
lenalidomide to rats resulted in kidney pelvis mineralization, most notably in females. The no 
observed adverse effect level (NOAEL) in rats is considered to be < 75 mg/kg.  
 
In monkeys, repeated oral administration resulted in a dose-dependent decrease in neutrophil 
count, an effect that is related to the pharmacodynamic effects of the drug. Repeated oral 
administration of 4 and 6 mg/kg to monkeys for up to 52 weeks produced mortality and 
significant toxicity (marked weight loss, reduced red and white blood cell and platelet counts, 
multiple organ hemorrhage, gastrointestinal tract inflammation, lymphoid, and bone marrow 
atrophy). Monkeys dosed with 1 and 2 mg/kg/day exhibited changes in bone marrow 
cellularity, a slight decrease in the myeloid: erythroid cell ratio, and thymic atrophy. Mild 
suppression of white blood cell count was observed at 1 mg/kg/day. The NOAEL in monkeys 
was identified as 1 mg/kg/day. 
 
Studies in rats administered up to 500 mg/kg/day of lenalidomide indicate it has no effects on 
male or female reproductive performance or fertility or prenatal and postnatal reproductive 
toxicity. Lenalidomide is not genotoxic.  
 
An embryofetal development study was conducted in monkeys administered lenalidomide at 
doses up to 4 mg/kg/day. Findings from this ongoing study indicate that lenalidomide 
produced malformations in the offspring of female monkeys who received the drug during 
pregnancy.  
 
In rats, lenalidomide was not teratogenic at doses up to 500 mg/kg/day. In rabbits 
administered 3, 10, and 20 mg/kg/day orally, developmental toxicity at the 10 and 20 
mg/kg/day dose levels was characterized by slightly reduced fetal body weights, increased 
incidences of postimplantation loss (early and late resorptions and intrauterine deaths), and 
gross external findings in the fetuses associated with morbidity and pharmacotoxic effects of 
lenalidomide (purple discoloration of the skin on the entire body). In rabbits, the maternal 
and developmental NOAELs for lenalidomide were 3 mg/kg/day. 
 
Nonclinical Pharmacokinetics and Pharmacology 
Pharmacokinetics of lenalidomide was evaluated in male beagle dogs, male cynomolgus 
monkeys, and male Sprague-Dawley rats (Investigator’s Brochure, Lenalidomide, 2008).  
Following oral administration, lenalidomide was absorbed rapidly, with tmax achieved at 0.5, 
1.3, and 1.5 hours postdose in rats, dogs, and monkeys, respectively.  High plasma 


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concentrations were achieved, with good oral bioavailability in all the species examined (≥ 
50%). 
 
Protein binding was low in all species, including humans (19% to 29%). Lenalidomide is not 
a substrate of human cytochrome P450 enzymes.  Lenalidomide was excreted largely as 
unchanged drug (approximately 55% of the dose) in both rats and monkeys. Hydrolysis of 
the glutarimide ring of lenalidomide was another important clearance mechanism in animal 
models. In both rats and monkeys, the major route of elimination of radioactivity following 
intravenous (IV) administration was renal. Excretion of radioactivity following oral 
administration to rats and monkeys was also similar; radioactivity was eliminated in almost 
equal proportions in the urine and feces for both species. 
 
Clinical Experience 
Phase I Experience.   
Several Phase I studies in healthy volunteers have investigated the single-dose safety, 
tolerability, and pharmacokinetics of lenalidomide.  Lenalidomide had an acceptable safety 
profile in healthy male subjects at doses of 5 to 400 mg.  The most frequently reported 
adverse events were rhinitis, headache, pruritus, rash, and cough.  Analysis of CD4 blood 
counts showed a significant decrease from baseline CD4 levels at 24 hours postdose for the 
5-, 200-, and 400-mg lenalidomide dose levels, each administered in the fasted state, with the 
greatest decrease being observed at the 200-mg dose level. 
 
Two phase I/II, single-center, open-label, and dose-escalation studies were performed to 
determine the MTD and to evaluate the safety and efficacy of lenalidomide in subjects with 
relapsed or refractory multiple myeloma (MM).  In the Phase I portion, subjects received 
lenalidomide at a dose of 5, 10, 25, or 50 mg/day for the first 28 days under fasting 
conditions. Subjects who tolerated the therapy were allowed to continue on treatment after 
Day 28 until disease progression occurred.   The MTD of lenalidomide was determined to be 
25 mg/day. 
 
The safety of lenalidomide in patients with solid tumors refractory to conventional treatment 
has been evaluated in several Phase I studies. Tumor types have included metastatic 
melanoma, pancreatic cancer, NSCLC, lymphoma, and high grade gliomas.   The majority 
(85.6%) of subjects in the pooled Phase I studies received doses between 25 -150 mg. The 
most frequently reported adverse events in patients who received these doses were fatigue, 
nausea, and constipation. Other clinically relevant events occurring in fewer than 20% of 
subjects who received lenalidomide at any dose included anemia, thrombocytopenia, DVT, 
thrombosis and thrombophlebitis.   
 
Lenalidomide has also been evaluated in a Phase I study in combination with docetaxel in 
patients with advanced solid tumors.  Diarrhea, fatigue, and nausea were the most frequently 
reported adverse events.  Other clinically relevant events occurring in fewer than 20% of 
subjects included DVT, febrile neutropenia, and jugular vein thrombosis.  The recommended 
Phase II dosing was doxetaxel 75 mg/m2 on Day 1, lenalidomide 25 mg on days 1-14, and 
pegfilgrastim 6 mg on day 2, given every three weeks.22   


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Phase II and III Experience 
The safety and efficacy of lenalidomide has been explored in a number of oncologic 
indications. 
 
Thirteen studies of lenalidomide in the treatment of MM have been undertaken to evaluate 
lenalidomide as monotherapy, in combination with high-dose dexamethasone therapy, and as 
part of a lenalidomide, doxorubicin, vincristine, and dexamethasone (DVd) regimen. As a 
result, lenalidomide has been shown to be an effective treatment for MM with a favorable 
safety profile, and has been approved by a number of regulatory agencies for use in 
combination with dexamethasone for the treatment of MM in patients who have had at least 1 
prior therapy. Cytopenias are the primary adverse events associated with the administration 
of lenalidomide, particularly in subjects with compromised bone marrow. These, however, 
are manageable with dose interruptions and reductions. 
 
Three multicenter, single-arm, open-label studies of lenalidomide in subjects with red blood 
cell transfusion-dependent anemia and Low- or Intermediate-1-risk MDS are ongoing: one 
phase I/II study in subjects with or without a del 5 (q31-33) cytogenic abnormality, one phase 
2 study in subjects without a del 5 (q31-33), and one phase 2 study in subjects with a del 5 
(q31-33). In the del 5 (q31-33) population, hematological improvement, manifested clinically 
as transfusion independence, is supported objectively by sustained elevations and 
improvements in hemoglobin values, cytogenetic responses, and bone marrow. More 
recently, a phase III, multicenter, randomized, double-blind, placebo-controlled study of the 
efficacy and safety of 2 doses of lenalidomide versus placebo has been initiated in red blood 
cell (RBC) transfusion—dependent subjects with Low- or Intermediate-1-risk MDS 
associated with a del 5 (q31-33). 
 
Several studies of lenalidomide in the treatment of solid tumors have been completed, and 
data for others are currently being analyzed. 
 
Lenalidomide has been evaluated in a Phase II study of patients with progressive, iodine-
resistant thyroid cancer.10  Some 25 patients received lenalidomide 25 mg daily.  Of 18 
evaluable patients, 22% had a partial response and 44% had stable disease.  Main toxicities 
were hematological and responded to dose reduction.  The mean daily dosage was 20 mg.   
 
A phase II open-label study to evaluated the safety and efficacy of lenalidomide in subjects 
with androgen independent prostate cancer. These subjects had increasing serum prostate-
specific antigen (PSA) levels but did not have detectable metastatic disease. The study was 
terminated for lack of efficacy. Two Phase I/II studies of lenalidomide in patients with 
advanced ovarian and primary peritoneal carcinoma were terminated prematurely.  The first 
was to evaluate lenalidomide in combination with liposomal doxorubicin.  A Grade 1 adverse 
event of left ventricular systolic dysfunction was reported in Subject 1. The event was 
suspected as study drug related and resulted in study discontinuation prior to establishing the 
MTD.  A second study intended to determine the MTD of oral lenalidomide given on Days 1 
to 14 and topotecan given on Days 1 to 5 every 21 days as combination therapy for subjects 


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with advanced ovarian or primary peritoneal carcinoma. The study was prematurely 
terminated due to toxicity. Neutropenia, thrombocytopenia and anemia were the most 
commonly experienced treatment –related adverse events. One subject experienced a 
pulmonary embolism considered to be related to study drug.  
 
Lenalidomide has been evaluated in a Phase II/III and Phase III trial in patients with 
refractory metastatic melanoma.  A phase II/III, controlled, randomized, parallel-group study 
compared the efficacy and safety of 2 dose regimens (5 mg daily for 28 days or 25 mg daily 
for 21 days, followed by a 7-day rest).  No significant differences in response rates were 
observed between the two doses.  A phase III, multicenter, controlled, randomized, placebo-
controlled, parallel group study evaluated the efficacy and safety of lenalidomide in subjects 
with previously treated metastatic malignant melanoma. Subjects were randomized to receive 
either 25 mg/day of lenalidomide or placebo for 21 days of a 28-day cycle. There were no 
significant differences between lenalidomide and placebo in overall survival, time to 
progression, or RECIST criteria.    In contrast with those seen in the MDS studies, the 
incidences of neutropenia and thrombocytopenia were low (≤ 8% and ≤ 3%, respectively) 
among subjects treated with lenalidomide in these melanoma studies.  
 
Safety Profile 
Data on the safety of lenalidomide had developed from over 6000 subjects from clinical trials 
(Investigator’s Brochure, Lenalidomide, 2008).  
 
Lenalidomide is associated with anemia, neutropenia, febrile neutropenia, thrombocytopenia, 
and pancytopenia. Grade 3/4 neutropenia and thrombocytopenia are the most common, dose 
limiting adverse events associated with the administration of lenalidomide.  The adverse 
event profile of lenalidomide, particularly with regard to cytopenias, is milder in patients 
with MM, malignant melanoma, solid tumors or gliomas, CRPS, or Crohn’s disease than that 
in patients with MDS, likely reflecting the underlying bone marrow disease of the MDS 
patients. 
 
Lenalidomide, in combination with dexamethasone, has been associated with an increased 
incidence in thrombotic or thromboembolic events, including deep vein thrombosis (DVT), 
pulmonary embolism, thrombosis, and thromboembolism, particularly among MM patients 
receiving concomitant therapy with an erythropoietic agent. DVT has been reported with 
both indications but is more frequent in MM than in MDS.  
 
Constipation, diarrhea, nausea, and vomiting were the most commonly reported 
gastrointestinal adverse events during treatment with lenalidomide. Occasional treatment-
emergent adverse events like atrial fibrillation, myocardial infarction, and congestive heart 
failure have been reported with the use of lenalidomide from clinical studies. Treatment-
emergent adverse events of infections specifically pneumonia are commonly seen with 
lenalidomide.  The rare treatment-emergent adverse event of rhabdomyolysis has been 
observed with lenalidomide. 
 


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Rare treatment-emergent adverse events of angioedema and serious dermatologic reactions 
including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with 
lenalidomide during commercial use. These events have the potential to be fatal. Permanent 
discontinuation of lenalidomide should be considered if skin rash ≥Grade 2 is exfoliative or 
bullous or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected. 
 
Considering an unclear, temporal relationship of angioedema to lenalidomide, clinicians 
should exercise caution when prescribing lenalidomide for patients who have had a history of 
hypersensitivity adverse reactions, specifically to thalidomide. Clearly, once angioedema has 
been identified, the risks and benefits of lenalidomide therapy should be considered. Review 
of current postmarketing data, which consists of thousands of patient exposure, did not 
identify any additional significant safety signal. 
 
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human 
teratogenic active substance that causes severe life-threatening birth defects. If lenalidomide 
is taken during pregnancy, a teratogenic effect of lenalidomide in humans cannot be ruled 
out. 
 
Clinical Pharmacokinetics, Pharmacology, and Pharmacodynamics 
The clinical pharmacology experience with lenalidomide includes 9 completed studies (8 in 
healthy subjects and 1 in subjects with renal impairment); 2 ongoing studies in healthy 
subjects; and 3 completed pharmacokinetic reports (2 in subjects with MM and 1 in subject 
with MDS). 
 
Single doses of lenalidomide over the dose range of 5 to 400 mg and multiple doses of 200 
mg/day (administered as 100 mg twice daily) had a favorable safety profile in healthy 
subjects. No clinically significant changes in ECGs, blood pressure, or pulse rate were 
observed. 
 
In healthy subjects, lenalidomide was rapidly absorbed following single- and multiple-dose 
oral administration, with the maximum concentration (Cmax) occurring between 0.5 and 1.5 
hours postdose. The Cmax and area under the concentration-time curve (AUC) values 
increased proportionally from 5 to 400 mg/day in single-dose studies. Steady-state levels 
were observed within 4 days of multiple dosing. There was no accumulation of drug with 
multiple dosing. Coadministration with food delayed absorption somewhat, but did not alter 
the extent of absorption. 
 
Approximately, 65% to 85% of lenalidomide was eliminated unchanged through urinary 
excretion. The mean renal clearance of lenalidomide was approximately 180 to 220 mL/min 
across all doses, which exceeded the glomerular filtration rate, and therefore is at least 
partially active. The mean total clearance of lenalidomide was approximately 300 mL/min, 
and it was independent of time and dose. The mean half-life of elimination (t1/2) was 
approximately 3 to 4 hours on all study days at the clinically relevant doses (5 to 50 mg/day). 
 


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Following a single 25-mg dose of of [14C]-lenalidomide as an oral suspension, total recovery 
of urinary radioactivity indicated that approximately 90% of the administered dose was 
absorbed systemically. The mean AUC∞ ratio of unchanged lenalidomide to the radioactivity 
in plasma was about 92%, suggesting that the parent compound was the primary radioactive 
component circulating in plasma. The total recovery of the radioactivity over 10 days 
averaged approximately 94% of the administered dose, with approximately 90% in urine, 4% 
in feces, and 0.006% in semen. Two identified metabolites are hydroxy-lenalidomide 
(pharmacological activity unknown) and N-acetyl-lenalidomide (CC-15656; 
pharmacologically inactive), with either being less than 5% of the parent in plasma and urine. 
 
No pharmacokinetic or pharmacodynamic interactions were observed between lenalidomide 
and warfarin; therefore, lenalidomide and warfarin may be co-administered. The effects of 
lenalidomide on digoxin pharmacokinetics (if any) are small, but a drug interaction cannot be 
excluded based on the available data. 
 
Proposed Dose and Schedule for Phase 2 Clinical Trials 
 
Lenalidomide doses between 5 mg and 25 mg per day have commonly been used in 
clinical trials.  Because the optimal dose of lenalidomide when given in combination 
with cediranib is unknown, we will perform a Phase I escalation study.  Because 
lenalidomide 20 mg daily was the mean tolerated dose in the Phase II study of single 
agent lenalidomide in thyroid cancer,10 we will start our dose escalation of 
lenalidomide at 15 mg on 21 days of a 28 day cycle and designate 20 mg daily as the 
maximal possible dose.   
 
2.3. 
Rationale 
 
Patients with DTC have few therapeutic options once surgery and RAI have proven 
ineffective. There are currently no widely accepted standards of care for patients in 
this setting.  Doxorubicin is approved for patients with iodine-refractory thyroid 
cancer, but response rates are poor and short-lived.  There is now mounting clinical 
data that inhibition of VEGF stimulated angiogenesis has anti-cancer activity.  
Although cediranib has not been evaluated in thyroid cancer, clinical trials with other 
VEGFR inhibitors have shown promising results.  Likewise, clinical trials with 
thalidomide and its derivative lenalidomide also show anti-cancer activity.  The 
rationale for combination therapy is to simultaneously target different aberrant 
pathways implicated in thyroid cancer.  We hypothesize that this will limit resistance 
as seen in single agent therapy and improve response rates. 
 
2.4. 
Correlative Studies Background  
 
2.4.1. 
MAPK pathway   
 
RET/PTC rearrangements and B-RAF mutations are the most commonly reported 
molecular aberrations reported in papillary thyroid cancer.  B-RAF mutations have 


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been associated with more aggressive iodine-resistant cancers.  Additionally, RAS 
mutations have commonly been document in follicular thyroid cancers.  When 
available, patients enrolled in the phase II study will have archival tumor tissue 
analyzed for B-RAF and K-RAS mutations.  Testing for these mutations will be done 
at the University of Chicago. 
 
2.4.2. 
Plasma 
 
TSH and thyroglobulin measurements will be performed at the respective institution 
of the enrollee. TSH can stimulate thyroid cancer growth.  Participants will have TSH 
measured pretherapy and every 8 weeks to assess for adequate TSH suppression.  
Thyroglobulin serves as a tumor marker in thyroid cancer.  It is not always reliable 
because some patients have anti-thyroglobulin antibodies that falsely alter the 
thyroglobulin measurement and because some advance cancers lose the ability to 
make thyroglobulin effectively.  However, in patients with cancers that make 
thyroglobulin, this protein can serve as a useful surrogate of targeted agent activity.  
Patients who do not have anti-thyroglobulin antibodies will have thyroglobulin 
measurements pretherapy and at 8 week intervals.   
 
   
 
3. PATIENT SELECTION 
 
3.1. 
Eligibility Criteria 
 
3.1.1. 
Patients must have histologically or cytologically confirmed papillary, 
follicular, papillary/follicular variant or Hürthle cell carcinoma.  Patients must be felt 
to be poor candidates for or refractory to further surgery or radioactive I-131 therapy. 
 I-131 therapy must have been completed at least 4 weeks prior to enrollment. All 
patients are expected to be on thyroxine suppression therapy.  
 
3.1.2. 
Patients must have radiographically measurable disease. 
Radiographically measurable disease is defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>20 mm with conventional techniques or as >10 mm with spiral CT scan.  Lesions in 
previously irradiated anatomic areas (external beam radiation) cannot be considered 
target lesions unless there has been documented growth of those lesions after 
radiotherapy.   
 
3.1.3. 
Patients must have evidence of disease progression (20% objective 
growth of existing tumors by RECIST criteria) within the last 12 months.   
 
3.1.4. 
In the Phase I portion, there is no limit on prior systemic therapies 
(cytotoxic or targeted therapies).  However, patients who have discontinued previous 
VEGF inhibitors secondary to adverse events are not eligible.  In the Phase 2 portion, 


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patients cannot have received more than 1 prior chemotherapy (cytotoxic or targeted) 
regimen.  Prior VEGF-pathway inhibitors or B-RAF inhibitors are permissible.   
 
3.1.5. 
Although there are data for lenalidomide in pediatric populations,23 no 
dosing or adverse event data is currently available on the use of cediranib or 
cediranib with lenalidomide in patients <18 years of age.  Therefore, children are 
excluded from this study but will be eligible for future pediatric phase II combination 
trials.   
 
3.1.6. 
Life expectancy of greater than 12 weeks. 
 
3.1.7. 
ECOG performance status 0-2 (Karnofsky >60%; see Appendix A). 
 
3.1.8. 
Patients must have normal organ and marrow function as defined 
below: 
 leukocytes 
>3,000/mcL 
 absolute neutrophil count 
>1,500/mcL 
 platelets 
>100,000/mcL 
 hemoglobin 
>9 g/dL 
 serum calcium 
<12.0 mg/dL 
 total serum bilirubin 
below or equal to upper limit of         
                                                         institutional normal** 
 AST(SGOT)/ALT(SGPT) 
2.5 X institutional upper limit of 
 
 
 
 
 
 
 
 
 
normal 
 creatinine 
below or equal to upper limits of       
                                                         institutional limits  
                                                             
 
OR 
 creatinine clearance 
>50 mL/min/1.73 m2 for patients with       
                                                    creatinine levels above institutional            
                                                      normal 
** Patients with hyperbilirubinemia due to Gilbert’s syndrome may enroll in the 
trial. 
 
3.1.9. 
Patients must have QTc < 480 msec. 
 
3.1.10. 
The following groups of patients are eligible provided they have New 
York Heart Association Class II (NYHA; see Appendix G) cardiac function on 
baseline ECHO/MUGA: 
* 
those with a history of Class II heart failure who are asymptomatic on 
treatment 
* 
those with prior anthracycline exposure 
* 
those who have received central thoracic radiation that included the 
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3.1.11. 
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 prior to and again within 24 hours of starting lenalidomide and must either 
commit to continued abstinence from heterosexual intercourse or begin TWO 
acceptable methods of birth control, one highly effective method and one additional 
effective method AT THE SAME TIME, at least 28 days before she starts taking 
lenalidomide.  FCBP must also agree to ongoing pregnancy testing.  Men must agree 
to use a latex condom during sexual contact with a FCBP even if they have had a 
successful vasectomy.  All patients must be counseled at a minimum of every 28 days 
about pregnancy precautions and risks of fetal exposure.   See Appendix H: Risks of 
Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods, AND also Appendix I: Education and Counseling Guidance Document.   
 
† A female of childbearing potential is a sexually mature woman who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in 
the preceding 24 consecutive months). 
 
3.1.12. 
Females of childbearing potential (FCBP)† who receive cediranib 
alone must also have a negative initial and ongoing pregnancy tests as described 
above in 3.1.11.  FCBP who receive cediranib alone must also commit to continued 
abstinence from heterosexual intercourse or begin TWO acceptable methods of birth 
control, one highly effective method and one additional effective method AT THE 
SAME TIME, at least 28 days before she starts taking cediranib.    Men on cediranib 
alone must agree to use a latex condom during sexual contact with a FCBP even if 
they have had a successful vasectomy.  All patients receiving cediranib alone must be 
counseled at a minimum of every 28 days about pregnancy precautions and risks of 
fetal exposure.       
 
3.1.13. 
Ability to understand and the willingness to sign a written informed 
consent document. 
 
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.  At least 4 weeks must have elapsed since any major surgery. Patients 
with prior use of thalidomide or lenalidomide are excluded. 
 
3.2.2. 
Patients may not be receiving any other investigational agents. 
 
3.2.3. 
Patients with known brain metastases should be excluded because of 
their poor prognosis and because they often develop progressive neurologic 


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dysfunction that would confound the evaluation of neurologic and other adverse 
events. N.B.: Patients with brain metastases with stable neurologic status following 
local therapy (surgery or radiation) for at least 8 weeks from definitive therapy and 
without neurologic dysfunction that would confound the evaluation of neurologic and 
other adverse events are eligible for participation.  
 
3.2.4. 
History of allergic reactions attributed to compounds of similar 
chemical or biologic composition to cediranib or lenalidomide or other agents used in 
the study. 
 
3.2.5. 
Patients with poorly controlled hypertension (systolic blood pressure 
of 140 mmHg or higher or diastolic blood pressure of 90 mmHg or higher) are 
ineligible.   
 
3.2.6. 
Patients with 1+ proteinuria or greater on urinalysis should collect a 24 
hour urine collection.  Patients with greater then 1.5 gram protein/ 24 hours are 
excluded. 
 
3.2.7. 
Because lenalidomide may increase the risk of DVT or PE, patients 
must stop Epogen at least 4 weeks prior to enrollment.  
 
3.2.8. 
 Patients with any condition (e.g., gastrointestinal tract disease 
resulting in malabsorption, prior surgical procedures affecting absorption, or active 
peptic ulcer disease) that impairs their ability to absorb cediranib tablets or 
lenalidomide capsules are excluded.  However, for patients who are unable to 
swallow cediranib tablets, cediranib tablets may be administered as a dispersion in 
water (ie, either drinking water, sterile water [for injection] or purified water).  
Cediranib can be administered via nasogastric tube or gastostomy tube.  See section 
5.1 for recommended procedure.  For patients unable to swallow lenalidomide whole, 
lenalidomide can be administered via gastrostomy feeding tube following the 
instructions in Appendix M.    
 
3.2.9. 
Patients with any of the following conditions are excluded: 
 
• 
Serious or non-healing wound, ulcer, or bone fracture. 
• 
History of abdominal fistula, gastrointestinal perforation, or intra-
abdominal abscess within 28 days of treatment. 
• 
Any history of cerebrovascular accident (CVA) or transient ischemic 
attack within 12 months prior to study entry. 
• 
History of myocardial infarction, cardiac arrhythmia, stable/unstable 
angina, symptomatic congestive heart failure, or coronary/peripheral 
artery bypass graft or stenting within 12 months prior to study entry. 
• 
History of pulmonary embolism within the past 12 months. 
• 
Class III or IV heart failure as defined by the NYHA functional 
classification system (see Appendix G).  


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3.2.10. 
Patients with uncontrolled intercurrent illness including, but not 
limited to, ongoing or active infections or psychiatric illness/social situations that 
would limit compliance with study requirements are ineligible.  
 
3.2.11. 
Pregnant women are excluded from this study because cediranib and 
lenalidomide are agents with the potential for teratogenic or abortifacient effects.  
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with cediranib or lenalidomide, breastfeeding 
should be discontinued if the mother is treated with cediranib with or without 
lenalidomide. 
 
3.2.12. 
HIV-positive patients on combination antiretroviral therapy are 
ineligible because of the potential for pharmacokinetic interactions with cediranib or 
cediranib with lenalidomide.  In addition, these patients are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.  Appropriate studies will 
be undertaken in patients receiving combination antiretroviral therapy when 
indicated. 
 
3.3. 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.  Below is an estimate of expected accrual targets for this trial. 
 
3.4. 
Accrual Targets 
 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
8 
+ 
8 
= 
16 
Not Hispanic or Latino 
47 
+ 
47 
= 
94 
Ethnic Category: Total of all subjects 
55 
+ 
55 
= 
110 
Racial Category 
 
American Indian or Alaskan Native 
2 
+ 
2 
= 
4 
Asian 
2 
+ 
2 
= 
4 
Black or African American 
7 
+ 
7 
= 
14 
Native Hawaiian or other Pacific Islander 
2 
+ 
2 
= 
4 
White 
42 
+ 
42 
= 
84 
Racial Category: Total of all subjects 
55 
+ 
55 
= 
110 
 
4. REGISTRATION PROCEDURES 
 
4.1. 
General Guidelines 
 
Eligible patients will be entered on study centrally at the University of Chicago by the 
Study Registrar.  All sites should call the Study Registrar at 773-834-3095 or 
PhaseIICRA@medicine.bsd.uchicago.edu, to verify agent availability.  The UC 


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Phase II Consortium Affiliate Forms are available on the University of Chicago 
Cancer Research Center website.   
 
• 
http://uccrc.uchicago.edu/current/home.html 
• 
Click on the Staff Resources link and scroll down to “UC Phase II Consortium 
Forms” section. 
 
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. Eligible patients will be entered on study centrally at the University of 
Chicago by the Registrar.  All sites should call the Registrar at (773) 834-3095 to 
verify agent availability.   
 
Following registration, patients should begin protocol treatment within 14 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 Registrar should be notified 
of cancellations as soon as possible. 
 
4.2. 
Registration Process 
 
All patients must be registered with the University of Chicago Registrar at least 48 
hours prior to the commencement of treatment. The following documents should be 
completed by the research nurse or data manager and faxed (773) 702-4889 or 
emailed PhaseIICRA@medicine.bsd.uchicago.edu to the Registrar: 
 
• 
Provider of information 
• 
Treating Physician 
• 
Patient name and hospital ID number 
• 
Patient's zip code of residence 
• 
Date & copy of signed informed consent 
• 
Race, gender, date of birth of patient 
• 
Diagnosis and date of initial diagnosis 
• 
Prior therapy with a VEGF-pathway inhibitor (yes/no)  
• 
ECOG performance status  
• 
Complete Phase II Consortium Affiliate Clinical Trial Patient Registration 
Form 
• 
Source documentation for eligibility and pre-study procedures 
 
The research nurse or data manager at the participating site will then call (773-834-
3095) or e-mail PhaseIICRA@medicine.bsd.uchicago.edu to confirm all selection 
criteria listed in Section 4.0.  To complete the registration process, the Coordinator 
will: 


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• Assign a patient study number 
• Register the patient on the study 
• 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. 
 
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 K 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 PMB for documentation. Sites may not order 
lenalidomide until documentation for two trained counselors is provided to the 
appropriate office. 
 
5. TREATMENT PLAN 
 
5.1. 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Cediranib tablets should be taken 
either 1 hour before or 2 hours after meals.   Cediranib will be taken daily on a continuous 
basis for each 28 day cycle.  If a dose of cediranib 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. 
Lenalidomide will either be taken for 21 days of the 28 day cycle or daily, depending on the 
level of dose escalation.  Lenalidomide can be taken with or without food.  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 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.   
 
Lenalidomide capsules should be swallowed whole.  For patients who are unable to swallow 
lenalidomide whole, lenalidomide can be administered via gastrostomy feeding tube 
following the instructions in Appendix M.   
 
For  patients who are unable to swallow cediranib tablets, cediranib tablets may be 
administered as a dispersion in water (ie, either drinking water, sterile water [for injection] or 
purified water).  The following procedure is recommended: 
 
Cediranib tablets may be dispersed in half a glass (2 fluid ounces or 50 ml) of non-
carbonated drinking water. No other liquids should be used. The tablet is dropped in water, 
without crushing, stirred until dispersed (approximately 10 minutes) and the resultant 
dispersion swallowed immediately. Any residues in the glass are mixed with half a glass of 


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water and swallowed. The liquid can also be administered through nasogastric or 
gastrostomy tubes. Where patients require the dose to be administered by nasogastric or 
gastrostomy tubes, cediranib tablet(s) dispersed in water can be dosed with: Polyurethane 
(PUR) or Poly vinylchloride (PVC) naso-gastric, naso-intestinal or percutaneous endoscopic 
gastrostomy (PEG) feeding systems in conjunction with PUR syringes. PVC syringes are not 
recommended for use. Two system washes are conducted through the giving set to ensure the 
correct dose is obtained. 
 
Only one cycle of therapy may be dispensed to the patient each month. 
 
 
Reported adverse events and potential risks for cediranib and lenalidomide are 
described in Section 7.  Appropriate dose modifications for cediranib and 
lenalidomide are described in Section 6.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to 
treat the patient's malignancy.   
 
All patients on lenalidomide should receive prophylactic anti-coagulation.  See 5.1.3 
Anticoagulation Consideration. 
 


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5.1.1. 
Phase I 
 
To determine the MTD, a 3+3 design will be used (see below).  Dose modifications 
are listed below.  Three patients will be enrolled with a starting dose of cediranib 20 
mg daily (28 days of 28 day cycle) with lenalidomide 15 mg on day 1-21 of the 28 
day cycle.  If cediranib 20 mg daily is not tolerated with lenalidomide 15 mg on day 
1-21 of a 28 day cycle, a new cohort will be added with cediranib 20 mg daily (28 
days of 28 day cycle) and lenalidomide 10 mg on day 1-21 of 28 day cycle.  After 4 
weeks of therapy, if no DLTs are observed, 3 patients will be enrolled at the next 
dose, cediranib 30 mg daily (28 days of 28 day cycle) with lenalidomide 15 mg on 
day 1-21 of 28 day cycle. If no DLTs are observed after 4 weeks, 3 addition patients 
will be enrolled with cediranib 30 mg daily (28 days of 28 day cycle)   and 
lenalidomide 15 mg daily (28 days of 28 day cycle). After 4 weeks of therapy, if no 
DLTs are observed, 3 patients will be enrolled at the next dose, cediranib 30 mg daily 
(28 days of 28 day cycle) with lenalidomide 20 mg on day 1-21 of the 28 days cycle. 
After 4 weeks, if no DLTs are observed, 3 patients will be enrolled at the next dose, 
cediranib 30 mg daily (28 days of 28 day cycle) with lenalidomide 20 mg daily (28 
days of 28 day cycle).  Dose escalation beyond cediranib 30 mg daily and 
lenalidomide 20 mg daily will not be performed.  At any level, if more than 2 patients 
experience a DLT, this dose will declared the maximally administered dose.  Three 
additional patients will be entered at the next lowest dose level if only 3 patients were 
treated previously at that dose.  If 1 out of 3 patients develop a DLT at a certain dose, 
3 additional subjects will be entered at this dose.  If 0 of 3 patients develop a DLT, an 
additional 3 patients will proceed to the next dose.  If 1 of 3 patients develops a DLT, 
dose escalation will stop.  Three additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously at that dose.   
 
Dose modification for 
Phase I study 
Cediranib + Lenalidomide 
-1 
Cediranib 20 mg (28/28 days) + Lenalidomide 10 mg (21/28 days) 
0 
Cediranib 20 mg (28/28 days)  + Lenalidomide 15 mg (21/28 days) 
+1 
Cediranib 30 mg (28/28 days)   + Lenalidomide 15 mg (21/28 days) 
+2 
Cediranib 30 mg (28/28 days)   + Lenalidomide 15 mg (28/28 days) 
+3 
Cediranib 30 mg (28/28 days)   + Lenalidomide 20 mg (21/28 days) 
+4 
Cediranib 30 mg (28/28 days)   + Lenalidomide 20 mg (28/28 days) 
 


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Number of Patients with 
DLT at a Given Dose Level 
Escalation Decision Rule 
 
0 out of 3 
 
Enter 3 patients at the next dose level 
 
> 2 
 
Dose escalation will be stopped.  This dose level will be declared the 
maximally administered dose (highest dose administered).  Three (3) additional 
patients will be entered at the next lowest dose level if only 3 patients were 
treated previously at that dose. 
 
1 out of 3 
 
Enter at least 3 more patients at this dose level. 
If 0 of these 3 patients experience DLT, proceed to the next dose level. 
If 1 or more of this group suffer DLT, then dose escalation is stopped, and this 
dose is declared the maximally administered dose.  Three (3) additional patients 
will be entered at the next lowest dose level if only 3 patients were treated 
previously at that dose. 
 
≤1 out of 6 at highest dose 
level below the maximally 
administered dose 
 
This is generally the recommended phase 2 dose.  At least 6 patients must be 
entered at the recommended phase 2 dose. 
 
Dose Limiting Toxicity (DLT) will be determined during the first cycle for dose 
escalation.  Toxicity occurring in subsequent cycles will not be considered dose 
limiting but will require dose modification.  (See Section 6.0 for Dose Modification) 
 
DLT will be defined as follows: 
 
• 
Hematological toxicities: 
o Any grade 4 neutropenia (ANC < 500) lasting more than 5 days 
o Any grade 4 neutropenia with concomitant fever (temperature > 38.5) 
o Any grade 4 neutropenia and sepsis or other severe infection 
o Any grade 4 thrombocytopenia 
 
• 
Any other grade 3-4 non-hematological adverse drug reactions, except untreated 
nausea/vomiting, or hypersensitivity reactions. 
 
• 
Grade 4 hypertension 
 
• 
Grade 4 proteinuria 
 
• 
Delay in the administration of a subsequent dose of cediranib and lenalidomide 
exceeding 2 weeks, due to an adverse drug reaction. 
 
For patients in the Phase I trial, disease re-evaluation will occur every 8 weeks using 


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RECIST guidelines.* Patients without evidence of anti-thyroglobulin antibodies will 
continue to have thyroglobulin levels measured at each response assessment (usually 
every 8 weeks). All patients are expected to be on thyroxine suppression therapy and 
thyroid stimulation hormone (TSH) levels will be monitored pre-therapy and every 8 
weeks during therapy. 
 
*After 18 cycles, radiologic disease re-evaluation will occur every 16 weeks. 
 
Phase I toxicity:  In the Phase I study,  of 15 evaluable patients,  4 were enrolled at 
the starting dose (cediranib 20 mg daily with lenalidomide 15 mg on days1- 21 of 28 
days), 6 were enrolled in the +1 dose modification, 5 in the + 2 dose modification.  
DLTs in the +2 dose modification were Grade 3 fatigue and Grade 3 mucocitis.   The 
DLT in the +1 modification was Grade 3 fatigue.  Since 1 of 6 patients in the +1 
group (cediranib 30 mg daily and lenalidomide 15 mg on day 1-21,) this was 
determined to be the starting dose for the Phase II trial.   
 
5.1.2. 
Cediranib and lenalidomide administration 
 
Please note, as of April 10, 2015, patients assigned to Arm B (Combination of 
cediranib and lenalidomide) are to discontinue lenalidomide and may continue on 
cediranib alone.  
 
After determining the MTD or reaching the maximum dose specified above of 
cediranib with lenalidomide in the Phase I portion of this study, the Phase II study 
will be initiated.   
 
Subjects will be randomized in a 1:2 ratio to one of two arms. Randomized stratification 
will employ prior therapy with a VEGF-pathway inhibitor (yes vs. no) and performance 
status (0 and 1 vs. 2).  In Cohort A, subjects (n = 36) will receive cediranib alone at 30 
mg daily.  In Cohort B, subjects (n = 74) will receive cediranib and lenalidomide at the 
dose determined in the Phase I study.  Each cycle will be 4 weeks in length.  Disease re-
evaluation will occur every 8 weeks using RECIST guidelines.  After 18 cycles, disease 
re-evaluation will occur every 16 weeks.  Patients without evidence of anti-thyroglobulin 
antibodies will continue to have thyroglobulin levels measured at each response 
assessment (usually every 8 weeks). All patients are expected to be on thyroxine 
suppression therapy and thyroid stimulation hormone (TSH) levels will be monitored 
pre-therapy and every 8 weeks during therapy. 
 
• Patients will take cediranib or cediranib and lenalidomide.  Cediranib will be 
taken daily at 30 mg.  Lenalidomide will be taken on day 1-21 of the 28 day cycle 
at 15 mg.   Proper administration of cediranib and lenalidomide is described in 
Section 5.1.  A 4-week period constitutes one cycle of treatment. 
 
• Patients will be provided with a Medication Diary for cediranib and lenalidomide 
(Appendix B), instructed in its use, and asked to bring the diary with them to each 


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appointment.  A new copy of the Medication Diary will be given to patients each 
cycle and for those whose dose is reduced due to adverse events. 
 
• Because hypertension is a known and potentially serious but rare adverse event 
associated with cediranib treatment, patients will have their blood pressure 
monitored and recorded at least weekly during the first cycle of therapy and then 
at least every two weeks for the duration of the study, either at the doctor’s office 
or using any calibrated electronic device (such as those found at a local drug store 
or pharmacy).  The health care team may request for more frequent blood pressure 
checks as clinically indicated.  Patients will be provided a Blood Pressure Diary 
(Appendix L) to record blood pressure.  Patients should be asked to bring the 
diary with them to each appointment.  (See Section 6.1 for hypertension 
management and dose reduction guidelines.)  
 
• Routine monitoring for cardiac function (ECHO/MUGA) should be performed at 
baseline and every other cycle of treatment in the following groups of patients:  
(1) those entering the trial with NYHA Class II cardiac dysfunction (see 
Appendix G), (2) those with a history of Class II heart failure who are 
asymptomatic on treatment, and (3) in those previously exposed to anthracyclines 
or thoracic irradiation if the heart was included in the radiotherapy port.  Routine 
cardiac monitoring is not required in patients with no known cardiac dysfunction 
at entry or in the absence of clinically observed adverse cardiac events. 
 
• Patients with bulky solid tumors should be monitored closely for pneumothorax, 
intestinal fistulae, or intestinal perforation in the event of rapid tumor destruction. 
 
• Subjects who have been on protocol for 12 months or more can be evaluated 
every 2 cycles (8 weeks).  (However, only one cycle of therapy may be 
dispensed to the patient each month) 
 
  
• Subjects who have been on protocol for 18 months or more will have radiographic 
tumor response assessed every 4 cycles (16 weeks).   
 
5.1.3. 
Anticoagulation Consideration 
 
Lenalidomide increases the risk of thrombotic events in patients who are at high risk or with 
a history a thrombosis, in particular when combined with other drugs known to cause 
thrombosis. When lenalidomide is combined with other agents such as steroids (e.g. 
dexamethasone, prednisone), anthracyclines (Doxil, Adriamycin) and erythropoietin the risk 
of thrombosis is increased.  
 
• 
All patients receiving lenalidomide should receive prophylactic anti-coagulation.  
Aspirin (81 or 325 mg) is the recommended agent for anti-coagulation prophylaxis.  


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Low molecular weight heparin may be utilized in patients that are intolerant to ASA. 
Coumadin should be used with caution and close monitoring of INR. 
 
• 
Prophylactic anti-coagulation should be held for platelet counts < 50,000/mm³and then 
restarted when platelet counts are above this level.  
 
• 
Full therapeutic anti-coagulation should be considered for patients who have a history of 
venous thromboembolism.  Whether therapeutic anti-coagulation is used or not, patients 
with a history of venous thromboembolism should be closely monitored throughout the 
study, especially during periods of fluctuating platelet counts. 
   
5.2. 
General Concomitant Medication and Supportive Care Guidelines 
 
The case report form (CRF) must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies including herbal supplements, 
specifically, St. John’s wort.   
 


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5.2.1. 
Concomitant Medications 
 
The use of coumarin-derivative anticoagulants such as warfarin (Coumadin®) is not 
recommended.  It may be used for both thrombosis prophylaxis and treatment.  However, 
coumadin should be used with caution and close monitoring of INR.  When possible, low 
molecular weight heparin should be used instead of coumadin. 
 
5.2.2. 
Supportive Care 
 
• 
Nausea/vomiting  Patients with treatment-related nausea should be treated 
initially with a phenothiazine (prochlorperazine – 10 mg every 8 hours orally as 
needed or promethazine – 12.5-25 mg IV every 6 hours as needed).  If this is 
inadequate, a benzodiazepine should be added until acute nausea is controlled or 
toxicity is limiting.  Should this prove inadequate acutely, a steroid may be 
added (e.g., dexamethasone 4 mg every 6 hours as needed). (Steriod use must be 
limited to 5 consecutive days within a 4 week cycle.) 
 
After acute nausea has resolved, consideration should be given to initiation of 
prophylactic antiemetic therapy.  If nausea recurs despite reasonable medical 
intervention (as outlined above), dose reduction will be needed as described in 
Section 6. 
 
• 
Diarrhea should be managed with loperamide:  4 mg at first onset, then 2 mg 
every 2-4 hours until diarrhea is controlled (maximum = 16 mg loperamide per 
day).  
 
• 
Hand-foot syndrome may be treated with topical emollients (such as 
Aquaphor), topical/systemic steroids, and/or antihistamine agents.  Vitamin B6 
(pyridoxine; 50-150 mg orally each day) may also be used. 
 
• 
Patients with neutropenic fever or infection should be evaluated promptly and 
treated with IV antibiotic therapy plus/minus therapeutic colony-stimulating 
factors as appropriate following the ASCO guidelines.24 Packed red blood cell 
and platelet transfusion should be administered as clinically indicated. GCSF 
may be used at the discretion of the treating physician. 
 
5.3. 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
• 
Disease progression, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 


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• 
Unacceptable adverse events(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. 
 
5.4. 
Duration of Follow Up 
 
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  Unless the patient withdraws from the 
study, the subject will be followed until disease progression or death, whichever 
comes first. 
 
5.5. 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 
applies.  The reason for study removal and the date the patient was removed will be 
documented in the Case Report Form. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The dose levels and the general approach to dose modification of cediranib and lenalidomide 
on this trial are shown below.  Managing patients on combination therapy will be discussed 
below.  Adverse events (AEs) should be treated with the appropriate maximum supportive 
care, and dose reductions should be clearly documented in the case report form (CRF).   
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting.   
 
 CTCAE v5.0 documents, including a mapping document, are available on the CTEP 
website: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
Dose Level for Phase II study 
Cediranib  
-2 
15 mg cediranib daily 
-1 
20 mg cediranib daily 
0 
30 mg cediranib daily 
 
Dose Level for Phase II study 
Lenalidomide 
 
-2 
Lenalidomide 5 mg on day 1-21 of 28 day cycle 
-1 
Lenalidomide 10 mg on day 1-21 of 28 day cycle 
0 
Lenalidomide 15 mg on day 1-21 of 28 day cycle 


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6.1. 
Management of Treatment-Emergent Hypertension 
 
Hypertension is more frequently associated with cediranib than lenalidomide.  Increases in 
blood pressure (BP) and cases of hypertension have been associated with many drugs acting 
on the VEGF pathway.  The proposed mechanism for this increase is through inhibition of 
VEGF-induced peripheral vasodilation.  Specific guidelines for management of this adverse 
event and a table of various antihypertensive medications are provided in Appendix C.  In 
addition, guidance on the collection and recording of BP information is provided in 
Appendix D.  
 
6.1.1 Management of Hypertension 
 
Adverse event 
NCI CTCAE v.5 grade 
Management 
Cediranib administration 
Hypertension Grade 1 
Systolic 120-139 mmHg or 
diastolic 80-89 mmHg  
 
Consider increased BP monitoring 
No change 
Grade 2-Mild 
 
Stage 1 hypertension:  
(140-159 mmHg Systolic or 
90-99 mmHg Diasolic) 
 
 
Start/ add long acting DHP CCB 
(See Appendix C). Gradually 
increase dose to control BP up to 
maximum dose.  
If partial or no control and still 
moderate hypertension, see 
Persistent Moderate Hypertension. 
 
First occurrence: 
Continue cediranib at full 
dose or decrease dose by 
one level 
 
Second occurrence: 
Decrease cediranib dose by 
one level  
Grade 2-Persistent Moderate 
Hypertension 
 
Stage 1 hypertension:  
(140-159 mmHg Systolic or 
90-99 mmHg Diasolic) 
Recurrent or persistent > 24-
48 hrs);  
Start/ add long acting DHP CCB 
(See Appendix C). Gradually 
increase dose to control BP up to 
maximum dose.  
If partial or no control and still 
moderate hypertension, add an 
additional drug and increase dose 
until BP control up to maximum 
dose.  
 
Hold cediranib and add 
additional drugs.  Restart 
cediranib at one lower dose 
level (when controlled). 
Grade 3 
 
Stage 2 hypertension 
(systolic > 160 mmHg or 
diastolic > 100 mmHg);  
 
If asymptomatic: Hold cediranib and 
start immediate antihypertensive 
therapy with 2 drug combination 
including at least a DHP CCB.  
 
Increase dose until BP control up to 
maximum dose of both agents.  
 
If partial or no BP control, add 
another drug up to 4; increase to 
optimal or maximal doses on all 
drugs.   
First occurrence: 
Hold cediranib until blood 
pressure within Stage 1 
hypertension range 
(systolic 140-159 mmHg or 
diastolic 90-99 mmHg);  
and decrease cediranib 
dose by one level 
 
Second occurrence: 
Hold cediranib until blood 
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If symptomatic: stop cediranib, 
hospitalize with aggressive IV 
therapy as per hypertensive crisis 
management 
hypertension range 
(systolic 140-159 mmHg or 
diastolic 90-99 mmHg);   
and either decrease 
cediranib by one dose level 
or stop cediranib 
permanently 
Grade 4 
 
Life-threatening 
consequences (e.g. 
malignant hypertension, 
transient or permanent 
neurological deficit, 
hypertensive crisis); urgent 
intervention indicated 
 
Stop cediranib, hospitalize with 
aggressive IV therapy as per 
hypertensive crisis management. 
Stop cediranib permanently 
 
• 
While patients are receiving treatment with cediranib, the early initiation of 
antihypertensive treatment for grade 1 or 2 hypertension to minimize more 
severe or persistent hypertension is not considered a grade 3 adverse event. 
 
• 
Decisions to hold or decrease the cediranib dose during treatment must be 
based on BP readings taken in the clinic by a medical professional. 
 
6.2. 
Other Hematologic and Non-Hematologic Adverse Events 
 
In the setting of combination therapy, it may be difficult to identify the agent causing 
the adverse event. When the adverse event could be due to either agent, the dose of 
lenalidomide should be decreased.  When an adverse event is more commonly 
associated with a particular agent, that drug will be decreased. 
 
Event 
AE Grade  
or Observation 
Dose modification 
(single agent cediranib) 
Dose modification (cediranib 
+ lenalidomide) 
Neutropenia 
Grades 1 and 2 
Maintain dose 
Maintain dose 
 
Grade 3 
• Hold cediranib dose 
• 
Follow CBC weekly 
• 
Hold cediranib until 
≤ grade 2, then resume 
treatment at same dose 
cediranib or reduce 1 dose 
level G-CSF may be used 
for treatment. 
• 
Dose reduction 
should be considered for 
recurrent episodes. 
• 
Hold cediranib and 
lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If neutropenia has 
resolved to ≤ grade 2 
prior to the scheduled 
end of the cycle, restart 
lenalidomide at next 
lower dose level and 
cediranib at the same 
dose and continue 
through the scheduled 
end of the cycle.  
Otherwise, omit for 
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reduce the dose of 
lenalidomide by 1 dose 
level at the start of the 
next cycle.  Maintain 
cediranib dose.  Omitted 
doses are not made up.  
If neutropenia is the only 
toxicity for which a dose 
reduction is required, G-
CSF (or other white 
blood cell growth factor) 
may be used  for 
treatment and the 
lenalidomide dose 
maintained 
• 
Dose reduction should be 
considered for recurrent 
episodes. 
 
Grade 4 
• Hold cediranib dose 
• Follow CBC weekly 
• Hold cediranib until ≤ 
grade 2, then resume 
treatment at same dose 
cediranib or reduce 1 dose 
level 
• G-CSF may be used for 
treatment. 
• Dose reduction should be 
considered for recurrent 
episodes. 
• 
Hold cediranib and 
lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If neutropenia has 
resolved to ≤ grade 2 
prior to the scheduled 
end of the cycle, restart 
lenalidomide at next 
lower dose level and 
cediranib at the same 
dose and continue 
through the scheduled 
end of the cycle.  
Otherwise, omit for 
remainder of cycle and 
reduce the dose of 
lenalidomide by 1 dose 
level at the start of the 
next cycle. Cediranib 
dose will be maintained. 
 Omitted doses are not 
made up.  If neutropenia 
is the only toxicity for 
which a dose reduction is 
required, G-CSF (or 
other white blood cell 
growth factor) may be 
used for treatment and 
the lenalidomide dose 
maintained.  Dose 
reduction should be 
considered for recurrent 
episodes. 
Thrombocytopenia 
Grades 1 and 2 
Maintain Dose 
Maintain Dose 
 
Grade 3 
• Hold cediranib dose 
• 
Hold cediranib and 


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• Follow CBC weekly 
• Hold cediranib until ≤ 
grade 2, then resume 
treatment at same dose 
cediranib or reduce 1 dose 
level  
• Repeated episodes require 
dose reduction 
lenalidomide dose. 
• 
Follow CBC weekly. 
• 
Hold prophylactic anti-
coagulation for platelet 
counts ≤ 50,000/mm3. 
Prophylactic anti-
coagulation should be 
resumed when 
lenalidomide is restarted. 
• 
If thrombocytopenia 
resolves to ≤ grade 2 
prior to the scheduled 
end of the cycle, restart 
lenalidomide at next 
lower dose level and 
cediranib at same dose 
and continue through the 
scheduled end of the 
cycle.  Otherwise, omit 
for remainder of cycle 
and reduce the dose of 
lenalidomide by 1 dose 
level at the start of the 
next cycle.  Cediranib 
dose will remain the 
same.  Omitted doses are 
not made up. 
 
Grade 4 
• Hold cediranib dose. 
• Follow weekly CBC 
• Hold cediranib until ≤ 
grade 2, then resume 
treatment at same dose 
cediranib or reduce 1 dose 
level  
• Repeated episodes require 
dose reduction 
• Hold cediranib and 
lenalidomide dose. 
• Follow CBC weekly. 
• Hold prophylactic anti-
coagulation for platelet 
counts ≤ 50,000/mm3. 
Prophylactic anti-
coagulation should be 
resumed when 
lenalidomide is restarted. 
• If thrombocytopenia 
resolves to ≤ grade 2 prior 
to the scheduled end of 
the cycle, restart 
lenalidomide at next lower 
dose level and cediranib at 
same dose and continue 
through the scheduled end 
of the cycle.  Otherwise, 
omit for remainder of 
cycle and reduce the dose 
of lenalidomide by 1 dose 
level at the start of the 
next cycle.  Cediranib 
dose will remain the same. 
 Omitted doses are not 
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Fever, chills, flu-
like symptoms 
Grades 1-4 
Maintain dose 
Maintain dose 
Fatigue (lethargy, 
malaise, asthenia) 
Grades 1 and 2 
Maintain dose.  For sustained 
Grade 2 fatigue, cediranib may 
be held until ≤ grade 1.  Then 
resume same dose. 
Maintain dose. For sustained 
Grade 2 fatigue, cediranib 
and lenalidomide may be held 
until ≤ grade 1.  Then resume 
same dose or reduce 1 dose 
level of lenalidomide.  If 
fatigue recurs, cediranib may 
be reduced 1 dose level.  If no 
further dose reductions are 
available, the lowest doses of 
cediranib and lenalidomide 
may be continued at the 
discretion of the treating 
physician. 
Grade 3  
Hold cediranib until < grade 2, 
then resume treatment at same 
dose cediranib or reduce 1 
dose level  
Hold cediranib and 
lenalidomide  until < grade 2, 
then resume treatment at 
same dose or reduce 1 dose 
level of lenalidomide.  If 
fatigue recurs, cediranib may 
be reduced 1 dose level . 
Grade 4 
Hold cediranib until < grade 2, 
then resume treatment at same 
dose or reduce 1 dose level of 
cediranib 
Hold cediranib and 
lenalidomide  until < grade 2, 
then resume treatment at 
same dose or reduce 1 dose 
level of lenalidomide.  If 
fatigue recurs, reduce 1 dose 
level of cediranib.   
Hand-foot 
syndrome 
 
 
Grades 1 and 2 
Maintain dose 
Maintain dose 
Grade 3  
Hold cediranib until ≤ grade 1, 
then resume treatment at same 
dose or reduce 1 dose level of 
cediranib 
Hold cediranib and 
lenalidomide until ≤  grade 1, 
then resume treatment at 
same dose or reduce 1 dose 
level of cediranib 
Grade 4 
Hold cediranib until ≤ grade 1, 
then reduce 1 dose level or 
discontinue treatment 
Hold cediranib and 
lenalidomide until ≤ grade 1, 
then reduce 1 dose level of 
cediranib or discontinue 
treatment 
AST and/or ALT 
elevation 
(SGOT, SGPT) 
Grades 1 and 2 
Maintain dose  
Maintain dose  
Grade 3 
Maintain dose.  If recurrent, 
reduce cediranib 1 dose level 
Maintain dose.  If recurrent, 
reduce lenalidomide 1 dose 
level 


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Grade 4 
Reduce cediranib 1 dose level 
Reduce lenalidomide 1 dose 
level 
Proteinuria** 
Grade 1  
Maintain dose 
Maintain dose 
Grade 2 
Hold cediranib.  Collect 24 
hour urine.  If 24 hour urine 
results with ≤ Grade 2, 
continue at same dose.  
Hold cediranib and 
lenalidomide.  Collect 24 
hour urine.  If 24 hour urine 
results with ≤  Grade 2, 
continue at same dose.  
Grade 3 
Hold cediranib.  Collect 24 
hour urine.  If 24 hour urine = 
Grade 3, hold cediranib until 
urinalysis ≤ grade 2, then 
reduce 1 dose level of 
cediranib 
Hold cediranib and 
lenalidomide.  Collect 24 
hour urine.  If 24 hour urine 
= Grade 3, hold cediranib and 
lenalidomide until urinalysis 
≤ grade 2, then reduce 1 dose 
level of cediranib 
Grade 4 
(Nephrotic 
syndrome) 
Discontinue treatment 
Discontinue treatment 
DVT/ Pulmonary 
Embolism 
 
Hold cediranib until 
therapeutic on anti-
coagulation.  Then resume 
cediranib at same dose* 
Discontinue treatment if 
recurrent DVT/PE when fully 
anticoagulated. 
Hold cediranib and 
lenalidomide until 
therapeutic on anti-
coagulation.  Then resume 
cediranib and lenalidomide at 
same dose*  
Discontinue treatment if 
recurrent DVT/PE when fully 
anticoagulated. 
Anaphylaxis, 
Stevens Johnson 
syndrome, TEN 
 
Discontinue treatment 
Discontinue treatment 
Bowel perforation 
 
Discontinue treatment 
Discontinue treatment 
Suspected 
pregnancy, positive 
HCG, missed 
menses 
 
Hold cediranib.  If pregnancy 
ruled out, continue treatment 
at same dose cediranib. 
Hold cediranib and 
lenalidomide.  If pregnancy 
ruled out, continue treatment 
at same dose cediranib and 
lenalidomide 
Confirmed 
pregnancy 
(endocrine, other 
fetal exposure to 
drug) 
Grade 4  
Discontinue treatment.  
Appropriate follow-up, see 
Section 7.3.3. 
Discontinue treatment. 
Appropriate follow-up, see 
Section 7.3.3. 
 
 
*Low Molecular Weight Heparin (LMWH) should be first choice for 
anticoagulation.  Coumadin can be used but requires close monitoring of INR.  
Aspirin can be discontinued in patients who are on therapeutic anticoagulation. 
 
** For proteinuria +2 or greater on urinalysis, study drugs should be held and 
24 hour urine should be collected to confirm degree of proteinuria.  Dose 
modification based on 24 hour urine protein assessment as above.   
 
 


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6.3. 
Management of Other Clinically Significant AEs (not specifically addressed above) 
 
General Management Guidelines 
Observation 
Action: Cediranib alone 
Action:  Cediranib and 
lenalidomide 
AE resolves promptly with supportive care 
Maintain dose level 
Maintain dose level 
1. Grade 3 or higher (non-hematologic or 
grade 4 (hematologic) AE related to 
cediranib or lenalidomide and lasting >5 
days that does not resolve to grade 2 or 
below despite maximum supportive care 
for < 48 hours. 
 
2. Lower grade but related AEs (e.g., 
creatinine) 
 
 
Hold cediranib until ≤ grade 2.  
Resume same dose cediranib.  If 
recurs, reduce one dose level of 
cediranib  
Hold cediranib and 
lenalidomide until ≤ grade 
2.  Resume same dose of 
cediranib and lenalidomide. 
 If recurs, reduce 1 dose 
level of lenalidomide.  If 
recurs again, reduce 
cediranib 1 dose level.   
AE does not resolve to grade 2 or below 
after treating patient at the lowest reduced 
dose level. 
In general, remove patient from 
study * 
In general, remove patient 
from study * 
* 
After consultation with study sponsor (DCTD, NCI), a lower dose of single or combination therapy may be 
considered for patients on study > 3 months who are benefiting from the agent.  
 
7. 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 (via CTEP-AERS) 
reporting in addition to routine (via CDUS) reporting.   
 
7.1. 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
 
 
7.1.1. 
CAEPR for Cediranib (AZD2171, NSC 732208) 
 
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 1608 patients. Below is the CAEPR for Cediranib (AZD2171). 
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 


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required. 
 
Version 2.15, November 7, 20181 
 
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Hemolytic uremic syndrome   
 
 
Thrombotic 
thrombocytopenic purpura 
  
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
ENDOCRINE DISORDERS 
  
 
Hyperthyroidism 
 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
  
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dysphagia 
 
 Dysphagia (Gr 2) 
 
 
 Gastrointestinal fistula2 
  
 
 
 Gastrointestinal perforation3   
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
 
Pancreatitis 
  
 
Rectal mucositis 
 
 Rectal mucositis (Gr 2) 
 
Small intestinal mucositis 
 
 Small intestinal mucositis (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
 Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased  
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Lymphocyte count decreased 
 
  


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 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
Thyroid stimulating hormone 
increased 
 
 Thyroid stimulating hormone 
increased (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Generalized muscle weakness  
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
Lethargy 
 
  
 
 
Leukoencephalopathy 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
 
Nephrotic syndrome 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Laryngeal mucositis 
 
 Laryngeal mucositis (Gr 2) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
Tracheal mucositis 
 
 Tracheal mucositis (Gr 2) 
Voice alteration 
 
 
 Voice alteration (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Palmar-plantar 
erythrodysesthesia syndrome 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 2) 
VASCULAR DISORDERS 
  
 
 
Arterial thromboembolism 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 4) 
 
Vascular disorders - Other 
(hemorrhage)5 
 
  
 
 
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. 
 


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2Gastrointestinal 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. 
 
3Gastrointestinal 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. 
 
4Infections includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5Hemorrhage is a known consequence of VEGF/VEGFR signaling inhibition. The majority of hemorrhage 
events reported were mild; however, serious events, defined as symptomatic bleeding in a critical area or 
organ system (e.g., eye, gastrointestinal tract, genitourinary [GU] tract, respiratory tract, and nervous system) 
have been reported. 
 
 
 
Adverse events reported on cediranib (AZD2171) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that cediranib (AZD2171) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system disorders - Other 
(polycythemia); Bone marrow hypocellular; Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Cardiac disorders - Other (premature 
ventricular complexes); Cardiac disorders - Other (valvular heart disease); Chest pain - cardiac; Mobitz (type) 
II atrioventricular block; Myocardial infarction; Palpitations; Pericardial effusion; Pericarditis; Restrictive 
cardiomyopathy; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (ears feel full/plugged); Ear and 
labyrinth disorders - Other (viral labyrinthitis); Tinnitus; Vertigo 
EYE DISORDERS - Blurred vision; Eye disorders - Other (blindness); Eye disorders - Other (visual 
disturbance); Papilledema; Photophobia; Retinal vascular disorder 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal pain; Ascites; Bloating; Colitis; Colonic 
obstruction; Duodenal ulcer; Dyspepsia; Enterocolitis; Esophageal necrosis; Esophageal ulcer; Esophagitis; 
Flatulence; Gastric necrosis; Gastric ulcer; Gastroesophageal reflux disease; Gastrointestinal disorders - 
Other (diverticulitis); Gastrointestinal disorders - Other (hydrops); Gastrointestinal disorders - Other (tongue 
sensitivity); Ileus; Oral pain; Periodontal disease; Peritoneal necrosis; Rectal pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Edema limbs; 
Fever; Gait disturbance; Hypothermia; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder obstruction; Hepatic pain; Hepatobiliary 
disorders - Other (bile duct obstruction); Hepatobiliary disorders - Other (jaundice cholestatic) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Immune system disorders - Other (systemic 
inflammatory response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; Fracture; 
Injury, poisoning and procedural complications - Other (tracheostomy malfunction); Intestinal stoma leak; 
Venous injury; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; Blood lactate 
dehydrogenase increased; CPK increased; Cardiac troponin I increased; Cardiac troponin T increased; 
Cholesterol high; Creatinine increased; Ejection fraction decreased; Electrocardiogram QT corrected interval 
prolonged; GGT increased; Hemoglobin increased; INR increased; Investigations - Other (elevated ammonia 
level); Investigations - Other (increased blood erythropoietin); Lipase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; Hyperkalemia; 
Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Avascular necrosis; Back 


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pain; Bone pain; Chest wall pain; Muscle cramp; Muscle weakness lower limb; Muscle weakness upper limb; 
Myalgia; Myositis; Neck pain; Pain in extremity; Rotator cuff injury 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Central nervous system necrosis; Cognitive disturbance; 
Depressed level of consciousness; Dysarthria; Dysgeusia; Dysphasia; Encephalopathy; Hydrocephalus; 
Ischemia cerebrovascular; Memory impairment; Muscle weakness left-sided; Nervous system disorders - 
Other (coma); Nervous system disorders - Other (right hemiparesis); Olfactory nerve disorder; Peripheral 
motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; Spinal cord compression; Stroke; 
Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Depression; Hallucinations; Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Cystitis noninfective; 
Hematuria; Urinary retention; Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Menorrhagia; Vaginal 
fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Aspiration; Hypoxia; Pharyngolaryngeal 
pain; Pleural effusion; Pneumonitis; Pneumothorax; Pulmonary edema; Pulmonary fistula; Pulmonary 
hypertension; Sinus pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail loss; Pruritus; 
Purpura; Rash acneiform; Rash maculo-papular; Skin and subcutaneous tissue disorders - Other (petechiae); 
Skin and subcutaneous tissue disorders - Other (plantar warts); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Capillary leak syndrome; Flushing; Hypotension; Vasculitis 
 
 
 
Note: Cediranib (AZD2171) 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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7.1.2. 
CAEPR for Lenalidomide (CC-5013, NSC 703813) 
 
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 2.8, June 27, 20191 
 
 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 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) 
 
Blood and lymphatic system 
disorders - Other (pancytopenia) 
 
  
 
Febrile neutropenia 
 
  
 
Hemolysis 
 
  
CARDIAC DISORDERS 
  
 
 
Atrial fibrillation 
  
 
 
Heart failure 
  
 
 
Myocardial infarction2 
  
EAR AND LABYRINTH DISORDERS 
  
 
Vertigo 
 
  
ENDOCRINE DISORDERS 
  
 
 
Hyperthyroidism 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 3) 
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Cataract 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
Constipation 
 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
  
 
Dyspepsia 
 
  
 
Nausea 
 
 Nausea (Gr 3) 


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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 3) 
 
Generalized edema 
 
  
 
Non-cardiac chest pain 
 
  
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
 
 
Hepatobiliary disorders - Other 
(cholestasis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
 
 
Anaphylaxis 
  
 
 
Immune system disorders - Other 
(angioedema) 
  
 
 
Immune system disorders - Other 
(graft vs. host disease)3 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
 Infection4 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
  
 
Fall 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
 
Blood bilirubin increased 
 
  
 
GGT increased 
 
  
 
Investigations - Other (C-
Reactive protein increased) 
 
  
 
 
Lipase increased 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 4) 
Neutrophil count decreased  
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hyperglycemia 
 
  
 
Hyperuricemia 
 
  


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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hyponatremia 
 
  
 
Hypophosphatemia 
 
  
 
Iron overload 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
 
Bone pain 
 
  
 
Generalized muscle weakness 
 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
 
 
Rhabdomyolysis5 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
 
Leukemia secondary to oncology 
chemotherapy6 
  
 
 
Myelodysplastic syndrome6 
  
 
 
Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) - 
Other (tumor flare)7 
  
 
 
Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) - 
Other (second primary malignancies) 
  
 
 
Treatment related secondary 
malignancy6 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Depressed level of consciousness  
  
 
Dysesthesia 
 
  
 
Dysgeusia 
 
  
 
Headache 
 
  
 
Paresthesia 
 
  
 
Peripheral motor neuropathy 
 
  
 
Peripheral sensory neuropathy 
 
  
 
 
Stroke2 
  
 
Syncope 
 
  
 
Tremor 
 
  
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
 
Psychiatric disorders - Other 
(mood altered) 
 
  
RENAL AND URINARY DISORDERS 
  


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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 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 3) 
 
Epistaxis 
 
  
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
  
 
 
Erythema multiforme 
  
 
Hyperhidrosis 
 
 Hyperhidrosis (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
 
 
Skin and subcutaneous tissue 
disorders - Other (drug reaction with 
eosinophilia and systemic symptoms 
[DRESS]) 
  
 
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)8 
  
VASCULAR DISORDERS 
  
 
Hematoma 
 
  
 
Hypertension 
 
  
 
Hypotension 
 
  
 
Peripheral ischemia 
 
  
 
Thromboembolic event9 
 
 Thromboembolic event9 (Gr 3) 
 
Vasculitis 
 
  
 
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. 
 
5The rare adverse event of rhabdomyolysis has been observed with lenalidomide. The reports of rhabdomyolysis were 
confounded by concurrent use of statins and dexamethasone, concurrent viral and bacterial infections, trauma, and 


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serotonin syndrome. Statins, infections, trauma, and serotonin syndrome are known risk factors for rhabdomyolysis. 
 
6There has been an increased frequency of secondary malignancies (SPM) including ALL, AML, and MDS, and certain 
other types of cancers of the skin and other organs in multiple myeloma (MM) patients being treated with melphalan, 
prednisone,  and lenalidomide post bone marrow transplant.  The use of lenalidomide in cancers other than MM, shows 
that invasive SPMs occurred in a small number of patients.  Patients treated with lenalidomide should be closely 
followed for the occurance of SPMs. 
 
7Serious tumor flare reactions have been observed in patients with chronic lymphocytic leukemia (CLL) and lymphoma. 
 
8A decrease in the number of stem cells (CD34+ cells) collected from patients treated with >4 cycles of lenalidomide has 
been reported. 
 
9Significantly 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. 
 
10Gastrointestinal 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. 
 
11Gastrointestinal 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. 
 
12Osteonecrosis 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. 
 
NOTE: In a trial of first line treatment of patients with chronic lymphocytic leukemia (CLL), single agent lenalidomide 
(CC-5013) increased the risk of death as compared to control arm (chlorambucil). 
 
NOTE: In two randomized trials of patients with multiple myeloma (MM), the addition of MK-3475 (pembrolizumab) 
to a thalidomide analog plus dexamethasone, resulted in increased mortality.  Treatment of patients with MM with a PD-
1 or PD-L1 blocking antibody, such as MK-3475 (pembrolizumab), in combination with a thalidomide analog, such as 
lenalidomide, is not recommended outside of controlled clinical trials. 
 
NOTE:  In a clinical trial in patients with Mantle cell lymphoma (MCL), there was an increase in early deaths (within 20 
weeks); 12.9% in the lenalidomide (CC-5013) arm vs. 7.1% in the control arm. 
 
 
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 (monocytosis); 
Disseminated intravascular coagulation; Eosinophilia 
CARDIAC DISORDERS - Atrial flutter; Atrioventricular block first degree; Cardiac arrest; Cardiac disorders - Other 
(cardiovascular edema); Cardiac disorders - Other (ECG abnormalities); Chest pain - cardiac; Left ventricular systolic 
dysfunction; Palpitations; Pericarditis; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia; Ventricular 


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tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Cushingoid 
EYE DISORDERS - Dry eye; Flashing lights; Retinopathy 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal mucositis; Ascites; Colonic perforation; 
Dysphagia; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (Crohn's disease aggravated); 
Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other (pale feces); Gastrointestinal 
hemorrhage10; Gastrointestinal obstruction11; Ileus; Mucositis oral; Pancreatitis; Rectal mucositis; Small intestinal 
mucositis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Multi-organ failure 
HEPATOBILIARY DISORDERS - Cholecystitis 
INFECTIONS AND INFESTATIONS - Conjunctivitis; Infections and infestations - Other (opportunistic infection 
associated with >=Grade 2 Lymphopenia); Myelitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Hip fracture; Vascular access 
complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Cholesterol high; Creatinine increased; 
Electrocardiogram QT corrected interval prolonged; INR increased; Investigations - Other (hemochromatosis) 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; Hypoglycemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall pain; Joint effusion; 
Muscle weakness lower limb; Neck pain; Osteonecrosis of jaw12 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dysphasia; Edema cerebral; Encephalopathy; 
Intracranial hemorrhage; Ischemia cerebrovascular; Leukoencephalopathy; Memory impairment; Nervous system 
disorders - Other (hyporeflexia); Spinal cord compression; Seizure; Somnolence; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; 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; Hypoxia; Laryngeal mucositis; Pharyngeal mucositis; Pleural 
effusion; Pulmonary hypertension; Respiratory failure; Tracheal mucositis; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Nail loss; Photosensitivity; Rash acneiform; Skin 
and subcutaneous tissue disorders - Other (Sweet’s Syndrome); Urticaria 
VASCULAR DISORDERS - Hot flashes; 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 5.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 5.0.  
• 
 CTCAE v5.0 documents, including a mapping document, are available on the CTEP website: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 
above) for expedited reporting purposes only.  ‘Expected’ AEs (the ASAEL) 
are bold and italicized in the CAEPR (Section 7.1.1). 
 
• 
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 (Adverse Event Expedited 
Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements” which can be downloaded from the CTEP home 
page (http://ctep.cancer.gov).  These requirements are briefly outlined in the table below 
(Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is disrupted a 24-hour 
notification is to be made to NCI by telephone at 301-897-7497. An electronic 
report MUST be submitted immediately upon reestablishment of internet 
connection. Please note that all paper CTEP-AERS forms have been removed 
from the CTEP website.  
 
7.3.2. 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 
other e-mail recipients.  
 


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7.4. 
Expedited Reporting Guidelines 
  
7.4.1. CTEP-AERS Reporting Requirements for Adverse Events That Occur Within 30 Days1 
of the Last Dose of the Investigational Agent on Phase 1 Trials 
 
Phase 1 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52,3 
Unexpected  
and Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  
and 
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose 
of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 4  unexpected events  
• 
Grade 5 expected events and unexpected events 
 
1. Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report 
is required as outlined in the table. 
3 Pregnancy is Grade 4/5 unexpected event. 
 
December 15, 2004 
 
Note:  All deaths on study require both routine and expedited reporting 
regardless of causality.  Attribution to treatment or other cause must be provided. 
 
• 
Expedited AE reporting timelines defined: 
➢ 
“24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
➢ 
“10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the exception 
of any events identified as protocol-specific expedited adverse event reporting 
exclusions.   
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 


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• 
Pregnancy (Grade 4/5 unexpected event) must be reported within 24 hour of learning 
of the event.   This applies to patients on cediranib alone or cediranib and 
lenalidomide. 
 
For patients who become pregnant while on cediranib alone.  Discontinue cediranib 
immediately.  The Investigator will follow the subject until completion of the 
pregnancy, and must notify CTEP-AERS reporting system of the outcome as specified 
below.  The Investigator will provide this information as a follow-up to the initial 
SAE.  All neonatal deaths that occur within 30 days of birth should be reported, 
without regard to causality, as SAEs.  In addition, any infant death after 30 days that 
the Investigator suspects is related to the in utero exposure to cediranib should also be 
reported. 
 
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 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 


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immediately. 
 
 
 
 
 
7.4.2. CTEP-AERS Reporting Requirements for Adverse Events That Occur Within 30 Days1 
of the Last Dose of the Investigational Agent on Phase 2 and 3 Trials 
 
Phase 2 and 3 Trials 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52,3 
Unexpected  
and Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of 
treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report is required 
as outlined in the table. 
3 Pregnancy is Grade 4/5 unexpected event. 
 
December 15, 2004 
 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
• 
Expedited AE reporting timelines defined: 
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
➢ “10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions.   


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• 
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS if the 
event occurs following treatment with an agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports. 
 
• 
Pregnancy (Grade 4/5 unexpected event) must be reported within 24 hour of 
learning of the event.   This includes pregnancies while on cediranib or 
lenalidomide or within 4 weeks after a subjects last dose of cediranib or 
lenalidomide.   
 
For patients who become pregnant while on cediranib alone.  Discontinue 
cediranib immediately.  The Investigator will follow the subject until completion 
of the pregnancy, and must notify CTEP-AERS reporting system of the outcome 
as specified below.  The Investigator will provide this information as a follow-up 
to the initial SAE.  All neonatal deaths that occur within 30 days of birth should 
be reported, without regard to causality, as SAEs.  In addition, any infant death 
after 30 days that the Investigator suspects is related to the in utero exposure to 
cediranib should also be reported. 
 
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 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 


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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. 
 
 
 
7.5. 
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. 
 
7.6. 
Secondary Malignancies (including AML and MDS) 
 
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 5.0.  Refer to the CTEP web site 
(http://ctep.cancer.gov) for additional information about secondary AML/MDS 
reporting.  
o 
In addition to all routine AE reporting mechanisms and any 
Cooperative Group-specific second/secondary malignancy reporting 
requirements, 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.  
o 
Using CTCAE v5.0, 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).   
o 
These events should be reported for the duration of the study treatment 
and during any protocol-specified follow-up periods.  Refer to the “CTEP 
website http://ctep.cancer.gov) for additional information about secondary 
AML/MDS reporting.   
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or 


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commercial agents administered in this study can be found in Section 7.1. 
 
8.1. 
      CTEP-Supplied Investigational Agents 
 
8.1.1. 
Cediranib (AZD2171, NSC 732208) 
 
Chemical Name:  4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidin-1- yl)propoxy] quinazoline 
maleate 
 
Other Names: cediranib, AZD2171 maleate  
 
CAS Registry Number: 288383-20-0 (for the free base) 
 
Molecular Formula: C25H27FN4O3 · C4H4O4        M W: 566.59 (maleate salt), 450.52 (free base) 
 
Approximate Solubility: The aqueous solubility of AZD2171 (cediranib) is 0.0006 mg/mL for the free base (distilled water, 
pH 8.1 at 25°C) and 1.76 mg/mL for the maleate salt (distilled water, at 25°C).  
 
Mode of Action: AZD2171 (cediranib) is a highly potent tyrosine kinase inhibitor of all three vascular endothelial growth 
factor receptors (VEGFR-1, -2 and -3). Inhibition of VEGF signaling leads to inhibition of angiogenesis, 
neovascular survival and vascular permeability. Pre-clinical tumor models show that AZD2171 (cediranib) reduces 
micro-vessel density and metastasis, indicating that it limits tumor growth. 
 
How Supplied:  Astra-Zeneca supplies and CTEP, NCI, DCTD distributes AZD2171 (cediranib). The agent is available as 
beige, round, biconvex, film-coated tablets containing 15 mg, and 20 mg of AZD2171 (cediranib) free base.  The 15 
mg and 20 mg tablets are 7 mm and 8 mm in diameter, respectively.  Each high-density polyethylene bottle contains 
35 tablets. 
 
Tablet excipients include mannitol, dibasic calcium phosphate anhydrous, sodium starch glycolate, microcrystalline 
cellulose, and magnesium stearate with a film coat containing hypromellose 2910, polyethylene glycol 400, red iron 
oxide, yellow iron oxide, black iron oxide, and titanium dioxide.  
 
Storage: Store intact bottles at controlled room temperature 20°C to 25°C (68 to 77°F) and protect from light and 
moisture.  
 
Stability: Stability studies are ongoing. Dispense AZD2171 (cediranib) tablets in their original containers. Alternatively, 
if exact quantity is dispensed in a pharmacy bottle, the supply should be assigned a 30-day expiration. 
 
If a storage temperature excursion is identified, promptly return AZD2171 (cediranib) to room temperature and 
quarantine the supplies.  Provide a detailed report of the excursion (including documentation of temperature 
monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for determination of suitability.   
 
Route and Method of Administration:  Oral.   AZD2171 (cediranib) tablets should be taken either one hour before or two 
hours after meals.  
 
 
If the study sponsor determines appropriate, cediranib tablets may be administered as a dispersion in plain water. 
Liquids other than non-carbonated water should not be used and the tablets should not be crushed or ground. The 
following procedure is recommended by the manufacturer for patients who can swallow liquids: 
 
Drop the appropriate dose of cediranib tablet/s into a glass containing 50-60 mL non-carbonated water. Stir 
the tablet/s until dispersed in the water, about 10 minutes (no crushing). Swallow the liquid immediately 
after dispersion is completed. Any residue in the glass is mixed with a half glass of water and swallowed. 


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The manufacturer recommends the following for naso-gastric or gastrostomy tube administration: 
 
Follow the dispersion instructions above. Administer the dispersion using polyurethane or PVC naso-
gastric, naso-intestinal or percutaneous endoscopic gastrostomy feeding systems in conjunction with 
polyurethane syringes. PVC syringes are not recommended. Conduct two system washes to ensure the 
patient receives the full dose. 
 
Potential Drug Interactions: AZD2171 (cediranib) is primarily metabolized by flavin-containing monooxygenase enzymes 
(FMO1 and FMO3) and UGT1A4. It is not a substrate of CYP450 enzymes. In vitro studies suggest that AZD2171 
(cediranib) is a substrate for P-glycoprotein (Pgp), but not breast cancer resistance protein (BCRP). Since 
clinically relevant induction or inhibition of FMO enzymes is uncommon, use caution in patients taking 
concomitant medications that are strong inhibitors (e.g. ketoconazole) or strong inducers (e.g. rifampicin, 
carbamazepine, phenobarbital, phenytoin and St. John’s Wort) of UGT1A4 or Pgp in particular. If chronic 
concomitant administration of strong inducers or inhibitors is unavoidable, consult the protocol document 
and/or the principal investigator before making any dose adjustments. 
 
In vitro studies show that AZD2171 (cediranib) did not inhibit CYP 1A2, 2A6, 2C8, 2C9, 2C19 and 2E1 and 
showed no induction of CYP 1A2, 2B6 and 3A4/5. It did weakly inhibit CYP 2D6 and 3A4/5, but this 
inhibition not expected to cause any clinically relevant drug interactions. 
 
In vitro studies show that AZD2171 (cediranib) is a weak inhibitor of BCRP, but not Pgp. Use caution in 
patients who are taking concomitant medications that are sensitive substrates of  BCRP transporters since there 
is a potential for drug-drug interactions.  
 
AZD2171 (cediranib) is approximately 95% bound to human plasma proteins, with human serum albumin and 
α1-acid glycoprotein accounting for most of this binding. Use caution in patients taking concomitant 
medications with narrow therapeutic ranges that are also highly protein-bound. 
 
Oral anticoagulants are not absolutely contraindicated during treatment with AZD2171 (cediranib); however, 
use AZD2171 (cediranib) with caution and increase monitoring in patients while on study. Patients who receive 
VEGF inhibitors are at increased risk of bleeding and hemorrhage. 
 
Patient Care Implications: Agents that inhibit VEGF signaling have the potential to affect wound healing. For patients 
already enrolled onto the protocol, the manufacturer recommends holding AZD2171 (cediranib) for 2 weeks 
prior to elective surgery and restarting when the surgical wound is healed. Protocol exclusion criteria should 
include patients who have had major thoracic or abdominal surgery within 2 weeks prior to start of study or 
patients with any surgical incision that is not fully healed.  
 
 
 
 
8.1.2. 
Lenalidomide (CC-5013, NSC 703813) 
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. 
 


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Chemical Name:   
 
3-(4’aminoisoindoline-1’-one)-1-piperidine-2,6-dione;   
   
α-(3-aminothalamido) glucaride. 
 
Other Names:        
 
Lenalidomide,  Revlimid™ (formerly known as 
Revimid™), CDC-501 
 
Classification:      
 
Immunomodulatory Agent  
 
CAS Registry Number:       191732-72-6 
 
Molecular Formula:    
C13H13N303 
 
 
M.W.:   259.26 
 
Mode of Action:   
 
CC-5013, a thalidomide analog, is an immunomodulatory 
agent with a spectrum of activity that is not fully 
characterized.  In vitro, it inhibits  secretion of the pro-
inflammatory cytokines TNF-α, IL-1β, and IL-6 and 
increases secretion of the anti-inflammatory cytokine IL-10. 
 It also induces T-cell proliferation, IL-2 and IFN-γ 
production in vitro.  
 
How Supplied:     
 
Celgene supplies and CTEP, NCI, DCTD distributes lenalidomide 
5 mg (size 2) hard gelatin capsules in tamper-evident, child-
resistant, opaque, high density polyethylene (HDPE) bottles with 
HDPE caps. Bottles contain 100 capsules per container. The 21-
count and 28-count bottles are no longer available. 
The capsules also contain anhydrous lactose, microcrystalline 
cellulose, croscarmellose sodium, and magnesium stearate. 
. 
Storage:   
 
 
The capsules should be stored at room temperature (15-
30°C) away from moisture and direct sunlight.   
 
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.  See Section 5.1 and 
Appendix M for patients who cannot swallow lenalidomide.  
 
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 


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Lenalidomide is structurally related to thalidomide. Thalidomide is a known human 
teratogenic active substance that causes severe life-threatening birth defects.  An embryo 
fetal 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 mI U/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 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. 
 


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• 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 I) 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 J) 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.    
 
Potential Drug Interactions:   
Periodic monitoring of digoxin levels is recommended during coadministration with  CC-
5013.  Digoxin levels were slightly higher when digoxin was administered with CC-5013 in 
a clinical study.  There was no effect on CC-5013 pharmacokinetics.  
 
Warfarin and CC-5013 may be co-administered without additional monitoring.  No 
pharmacokinetic or pharmacodynamic interactions were observed between CC-5013 and 
warfarin.  
 
Nonclinical in vitro metabolism studies suggest that CC-5013 is not likely to result in 
metabolic drug interactions in humans.  In vitro, CC-5013 did not significantly inhibit 
marker enzyme activities for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or 
CYP3A4.  In rats, no induction of any CYP450 enzymes was observed. Administration of 
CC-5013 in monkeys showed no effects on the activities of CYP1A, CYP2B, CYP2C, 
CYP2E, CYP3A, or CYP4A.  
 
Availability 
Lenalidomide is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Lenalidomide is provided to the NCI under a Collaborative Agreement between    
Celgene and the DCTD, NCI (see Section 12.3). 
 
8.1.3. 
Agent Ordering 
 
Please note, as of April 10, 2015, patients on Arm B are no longer receiving 


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lenalidomide. For further details refer to section 5.1.2 
 
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. 
 
8.1.4. 
Agent Accountability 
 
Agent Inventory Records – The investigator, or a responsible party designated by the 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.).   
 
8.1.5. 
IB access 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB Online Agent Order Processing (OAOP) application.  Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password.  Questions about IB access may 
be directed to the PMB IB coordinator via email. 
 


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8.1.6. 
PMB contacts 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• 
PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• 
CTEP Identity and Access Management (IAM) account: https://eapps-ctep.nci.nih.gov/iam/ 
• 
CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
IB Coordinator: IBCoordinator@mail.nih.gov 
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) 
 
9. CORRELATIVE/SPECIAL STUDIES 
 
All subjects will be asked to provide archival tumor tissue. 
 
9.1. 
Rationale 
 
Archival tumor tissue:  
B-RAF gene 
K-RAS gene 
 
Pharmacogenomics: 
Advanced thyroid carcinoma is a heterogenous group of diseases likely caused by a 
variety of molecular defects.  Variable responses in previous clinical trials are likely 
due in part to differences in the underlying disease processes.  Data from studies with 
other targeted agents suggest that different molecular aberrations may affect clinical 
response.  For example, in the Phase II clinical trial with motesanib diphosphate with 
advanced DTC, DNA from 33 tumors of trial patients was screened for mutations 
often observed in DTC.  Six of the 10 patients (60%) whose tumor contained the B-
RAFV600E mutation had either a partial response or durable stable disease.  In contrast 
5 of 15 patients without the mutation (33%) had a partial response or durable stable 
disease.25  While the number of tumor samples was too small to show significance, 
the findings do suggest that B-RAF mutations may affect response.  In addition, in a 
Phase II study of the multi-target tyrosine kinase inhibitor sorafenib, of sixteen DTC 
patients who had genotype testing, those with B-RAFV600E mutations had significantly 
longer PFS compared to those who did not (84+ weeks versus weeks).26  B-RAF 
mutations have been reported in 29-83% of PTCs and K-RAS mutations have been 
found in 21-50% of FTCs.27 We plan to evaluate B-RAF mutations and K-RAS 
mutations in available tumor samples to assess whether these mutations predict 
response.  This study will provide an excellent opportunity to further clarify the role 
of the previously described polymorphisms in thyroid carcinoma. 


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Shipping Instructions: 
The shipment of all human samples (tissue) must comply with appropriate 
regulations as specified by the carrier. Paraffin archival tissue can be shipped at 
room temperature.   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 shipments must contain a completed Sample Identification form (Appendix F).  
 
Archival Tumour Samples can be shipped to the address below Monday through 
Thursday. 
Shipping address: 
University of Chicago 
HTRC, Room P-616 
5835 S. Cottage Grove 
Chicago, IL 60637 
Phone: 773-834-8391 
E-mail: tissuebank@bsd.uchicago.edu 
 
On arrival, each sample will be assigned a Study Number.  All subsequent handling of 
the tissue samples will be blinded to the investigators performing various tests, except for 
the clinical pathologists. Only biopsy samples determined by the pathologist to contain 
tumor will be subjected to immunohistochemical analysis. For all immunohistochemical 
studies, samples will only be marked with an assigned study number.  Patient name, 
diagnosis and other information will be unknown to the laboratory/clinical investigators 
involved and will be revealed only after studies are completed for further data analysis 
and statistics. 
 
 
9.2 Laboratory Correlative Studies 
 
B-RAF and K-RAS mutations 
Formalin-fixed paraffin-embedded (FFPE) tissue blocks and H&E stained slides will be 
collected at the site of the enrollee when available and packed and shipped by FedEX to the 
University of Chicago as described above.  H&E stained slides will be reviewed and the 
optimal block will be picked for molecular analysis.   It should have a contiguous convex 
area at least 3 mm in minimum dimension with at least 50% involvement by tumor.  DNA 
will be prepared from the FFPE tissue blocks. Ten unstained 5 micron  sections are then cut, 
the 5th slide in the set is stained (H&E) to confirm pathology and guide macrodissection (if 
necessary) of the other slides.   Following deparaffinization DNA is extracted and quantified 
using either the Nanodrop(TM-superscript) or a Picogreen dye binding assay. 
 
DNA is analysed for any K-RAS mutation in codons 12 or 13 following the procedure 
described by Nikiforova et a.l28 This is a real-time hybridization probe polymerase chain 
reaction assay run on a LightCyclerTM 2.0. To increase sensitivity (when tumor involves less 
than 20% of section) a modified form of this assay LightMix® Kit k-ras Mutations Codons 


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12/1 3 TM from TIB-MolBiol may be used. This uses a ‘blocking’ probe modified with locked 
nucleic acids to block amplification of the normal sequence at codons 12 and 13. At present 
this modification is for research use only. 
 
Detection of B-RAFV600E mutation will be performed using real-time PCR and fluorescence 
melting curve analysis (FMCA) from DNA as previously reported by our group. Briefly, a 
pair of oligonucleotide primers flanking the mutation site have been designed, together with 
two fluorescent probes, with the sensor probe spanning the nucleotide position 1799. 
Amplification will be performed in a glass capillary using 50 ng of DNA in a 20 microliter 
volume. The reaction mixture is then to 45 cycles of rapid PCR consisting of denaturation at 
94 degrees C for 1 sec, annealing at 55 degrees C for 20 sec, and extension at 72 degrees C 
for 10 sec. Post-amplification FMCA is performed by gradual heating of samples at a rate of 
0.2degreesC/sec from 45 degrees C to 95 degrees C. All PCR products that showed deviation 
from the wild-type (placental DNA) melting peak are sequenced to verify the presence of 
mutation. 
 
 
10. STUDY CALENDAR 
Baseline evaluations are to be conducted within 2 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 k 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50 
Day 
57 
Day 
64 
Day 
71 
Day 
78 
Day 
85 
Day 113 
Off 
Study k 
Cediraniba 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lenalidomideb  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anticoagulationc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAo 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examn 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
Vital signsn 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weightn 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
Performance statusn 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
CBC w/diff, pltsn 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Serum chemistryd, n 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Blood pressure 
measuremente 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 


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EKG  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisi, n 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
B-HCG 
Xf,g 
Xf,g 
Xf,g 
Xf,g 
Xf,g 
Xf,g 
 
Xf,g 
 
Xf,g 
 
Xf,g 
 
Xf,g 
Xf,g 
Xf,g 
Patient Education 
and counselingh 
Xh 
Xh 
 
 
 
Xh 
 
 
 
Xh 
 
 
 
Xh 
Xh 
Xh 
TSH 
X 
 
 
 
 
 
 
 
 
Xm 
 
 
 
 
 
X 
Throglobulin 
X 
 
 
 
 
 
 
 
 
Xm 
 
 
 
 
 
X 
Radiology studies l 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Archival tissue for 
correlative studies j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: Cediranib:  Dose as assigned; administration schedule 
b: Lenalidomide:  Dose as assigned, only enough lenalidomide for 28 days or one cycle of study treatment (whichever is shorter) may be provided to the patient 
each cycle; administration schedule 
c: Anticoagulation:  All patients receiving lenalidomide should receive prophylactic anti-coagulation.  Aspirin (81 or 325 mg) is the recommended agent for anti-
coagulation prophylaxis.  Low molecular weight heparin may be utilized in patients that are intolerant to ASA.  Coumadin should be used with caution and close 
monitoring of INR.   
d: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, potassium, total protein, SGOT [AST], 
SGPT [ALT], sodium. 
e: Blood pressure measurement may be performed more frequently as dictated by clinical observations.  See Appendix D for blood pressure measurement 
guidelines.   
f: 
Pregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months).   
g: Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to initiation 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 therapy (including breaks in therapy); at discontinuation of lenalidomide and at Day 28 
post the last dose of lenalidomide.  Females with irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while on 
therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix H: Lenalidomide 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).    
h: The Lenalidomide Education and Counseling Guidance Document (Appendix I) 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 J) 
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. 
i: 
Pre-study, all patients with 1+ protein reading or greater on urinalysis should collect a 24 hour urine collection to measure protein.  During the study, patients 
with 2 + or greater proteinuria should collect a 24 hour urine collection to measure protein.  Study medication should be held until 24 hour urine collected and 
evaluated.  See Section 6.2 for dose modification. 
j: 
Archival tissue should be requested pre-study but should not delay the start of therapy. 
k: Study calendar can vary +/- 3 days without a study violation. 
l: 
Radiology evaluation repeated every 2 cycles.   Subjects on protocol 18 months or more will have radiology evaluation every 4 cycles.    
k: Off-study evaluation. 
m: TSH and thyroglobulin evaluation repeated every 2 cycles. 
n:  After 12 months on study, subjects can be evaluated every 2 cycles. 
m: O:  In  select patients see section 3.1.10 for further detail 
 
11. MEASUREMENT OF EFFECT 
 
11.1. Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every   8   weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained  8 weeks following 
initial documentation of objective response.  Subjects who have been on treatment for 18 
months or more will have radiological evaluation every 4 cycles. 
 
Response and progression will be evaluated in this study using the new international criteria 


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proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
11.1.1. 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with cediranib or cediranib in combination with lenalidomide. 
 
Evaluable for objective response.  Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their response 
classified according to the definitions stated below.  (Note:  Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
non-target disease.  The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
 
11.1.2. 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded for non-nodal lesions and short 
axis for nodal lesions) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area are not considered 
measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 


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not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters.  If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline.  Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up.  
 
11.1.3. 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
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.  
 


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Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans.  Body 
scans should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation 
is not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In 


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addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
  
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4. 
Response Criteria 
 
11.1.4.1. Evaluation of Target Lesions 
 
Complete Response (CR):     Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10 mm. 
 


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Partial Response (PR):    
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
 
Progressive Disease (PD):      At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD):               Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study 
 
11.1.4.2. Evaluation of Non-Target Lesions 
 
Complete Response (CR):      Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis) 
 
Note:  If tumor markers are initially above the upper normal 
limit, they must normalize for a patient to be considered in 
complete clinical response. 
 
Non-CR/Non-PD:                   Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
 
Progressive Disease (PD):      Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It 
must be representative of overall disease status change, not a 
single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3. Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 


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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:       Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD 
is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
 
11.1.5. 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented.    
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
 
11.1.6. 
Progression-Free Survival 
 
Progression free survival (PFS) is defined as the duration of time from start of treatment to 
time of progression or death of any cause. 
 
11.1.7. 
Response Review 
 
All responses will be reviewed by an expert(s) independent of the study at the study’s 
completion. 
 
12. 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 
 


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This study will be monitored by the Clinical Data Update System (CDUS) version 
3.0.  Cumulative CDUS data will be submitted quarterly to CTEP by electronic 
means.  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).  Note:  All adverse events that have occurred on the study, 
including those reported throughCTEP-AERS, must be reported via CDUS. 
 
12.1.2. 
Responsibility for Data Submission 
 
Study participants are responsible for submitting CDUS data and/or data forms to the 
Coordinating Center quarterly by January 31, April 30, July 31, and October 31 to allow 
time for Coordinating Center compilation, Principal Investigator review, and timely 
submission to CTEP (see Section 12.1.1.).  For trials monitored by CTMS, the monthly 
data submission to CTEP from Theradex should be copied to the Coordinating Center 
 
The Coordinating Center is responsible for compiling and submitting CDUS data to 
CTEP for all participants and for providing the data to the Principal Investigator for 
review.   
 
12.2. CTEP Multicenter Guidelines 
 
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 E. 
 
• 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. Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to 
the NCI 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 


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Option to Collaborator (http:// ctep.cancer.gov/industry) 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 investigational 
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 investigational 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 
NIH, 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 investigational 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 investigational Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a 
Collaborative Agreement will be made available exclusively to 
Collaborator(s), the NCI, and the FDA, as appropriate and unless additional 
disclosure is required by law or court order.  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. 
 


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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 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: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@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 Collaborators confidential/ proprietary information. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1. Study Design/Endpoints 
 
13.1.1. 
Phase I. 
 
The phase I trial will use a 3+3 design with the MTD defined as the highest dose level such 
that <2 of 6 patients experience dose-limiting toxicity.   
 


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13.1.2. 
Phase II. 
 
There is no standard therapy for differentiated thyroid cancer that is refractory to radioactive 
iodine.  The best studied agent in this disease, doxorubicin, has an estimated response rate of 
10%.  Although cediranib has not been studied in thyroid cancer, a phase II study of the 
VEGF inhibitor motesanib diphospate showed a median progression-free survival (PFS) of 
40 weeks.  Because we hypothesis that combination therapy will be more effective than 
single agent treatment, we will randomize in a 1:2 ratio, which should enhance recruitment.  
The randomization will be stratified by prior therapy with a VEGF-pathway inhibitor (yes vs. 
no) and performance status (0-1 vs. 2) 
 
The primary endpoint will be PFS, which will be compared between the two treatment arms 
using a stratified logrank test. To determine the sample size, we noted that the median PFS in 
93 patients with radioiodine-resistant thyroid cancer treated with motesanib diphosphate25 
was 40 weeks. We therefore assume a median of 40 weeks for the cediranib alone arm. In 
order to have 85% power to detect a 75% improvement in the median to 70 weeks with 
combination therapy (hazard ratio [HR]=1.75), 110 patients will be required (36 randomized 
to cediranib and 74 to cediranib plus lenalidomide), based on a one-sided test at the 
alpha=0.10 significance level.  This calculation assumes 1 year of accrual (9 patients per 
month) and 1.5 years of additional follow-up for a total study duration of 2.5 years.  Kaplan-
Meier30 curves will be generated for each treatment arm and the median PFS times estimated 
using the Brookmeyer and Crowley method31.  In addition to the logrank test, PFS in the two 
groups will be analyzed by fitting a Cox32 proportional hazards regression model, adjusting 
for prior VEGF inhibitor use, performance status, and other baseline risk factors.  The 
goodness of fit of the Cox model and the appropriate functional form for continuous 
covariates will be assessed using graphical techniques, including inspection of martingale 
residual plots.   
 
An interim futility analysis will be performed after half of the total number of projected 
events (40 of 80 projected events). The trial will stopped for futility if the conditional power 
at this time point is 15% or less, reducing the power by 2-3%.  
 
 
13.2. Sample Size/Accrual Rate 
 
 
Phase I1: 9-18 patients.  Accrual 3 patient/mo 
Phase II: Sample size 110 patients.  Accrual 9-10 patients/mo. 
 
13.3. Stratification Factors 
 
Phase II.  Patients will be stratified on prior use of VEGF-pathway inhibitors (yes vs 
no) and performance status (0 and 1 vs 2).   
 
13.4. Analysis of Secondary Endpoints 
 


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13.4.1. 
Phase I.   
 
The objective response rate of cediranib in combination with lenalidomide in patients with 
iodine refractory, unresectable DTC who have evidence of disease progression within 6 
months of study enrollment will be estimated.  In addition, the toxicity, duration of response, 
progression free survival, and overall survival in patients with DTC treated with cediranib 
plus lenalidomide will be evaluated. 
 
13.4.2. 
Phase II.   
 
Overall survival (OS) rates will be estimated and compared between groups using 
methods similar to that described above for PFS   Response rates will be compared 
using a chisquare test followed by logistic regression analysis to adjust for covariates. 
  
 
The percent change in tumor size from baseline to the end of cycle 2 (two months) 
will be compared between the two groups using a two-sample t test33.  The post-
treatment total sum of lengths for a patient with a new lesion will be scored as 
1.2*max(pre-sum, post-sum) to ensure that the appearance of new lesions 
corresponds to a disease progression per RECIST criteria.  In the event of any early 
deaths prior to two months, a nonparametric rank sum test will be used in place of the 
t test, with deaths ranked at the extreme end of the distribution.   
 
Adverse events will be summarized by type and grade.  Adverse event rates will be 
compared between the two treatment groups using a chisquare test for common 
toxicities and Fisher’s exact test for less frequent events.   
 
Repeated measures analysis of variance (RM ANOVA) will be performed to 
determine the effect of the treatments on serial measurements of TSH and 
thyroglobulin.  It is hypothesized that these levels will decrease over time.  Baseline 
tissue biomarker expression, scored as present or absent, of B-RAF and RAS 
mutations will be correlated with response rates using Fisher’s exact test, and with 
PFS and OS by fitting a Cox proportional hazards regression model.    
 
 
 
13.5. Reporting and Exclusions 
 
13.5.1. 
Evaluation of toxicity.  All patients (Phase I and II) will be evaluable for toxicity 
from the time of their first treatment with cediranib or cediranib plus lenalidomide. 
 
13.5.2. 
Evaluation of response.  All patients included in the study (Phase I and II) will 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 


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death from malignant disease, 6) early death from toxicity, 7) early death because of 
other cause, or 9) unknown (not assessable, insufficient data).   
 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) will be included in the main analysis of 
the response rate.  Patients in response categories 4-9 will be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or 
drug administration will not result in exclusion from the analysis of the response 
rate.   
 
All conclusions will 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 will not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis will 
be clearly reported. Data will be reported to CTEP using CDUS -Complete. 
 
 
 


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1. National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) 
Program. http://seer.cancer.gov/ Accessed 2009. 
2. American Cancer Society. www.cancer.org/docroot/home//.  Accessed 2009. 
3. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in 
papillary thyroid carcinoma: development of a reliable prognostic scoring system in a 
cohort of 1779 patients surgically treated at one institution during 1940 through 1989. 
Surgery 1993;114(6):1050-7; discussion 7-8. 
4. DeGroot LJ, Kaplan EL, Straus FH, Shukla MS. Does the method of management of 
papillary thyroid carcinoma make a difference in outcome? World J Surg 
1994;18(1):123-30. 
5. Mazzaferri EL, Young RL. Papillary thyroid carcinoma: a 10 year follow-up report of 
the impact of therapy in 576 patients. Am J Med 1981;70(3):511-8. 
6. Bernier MO, Leenhardt L, Hoang C, et al. Survival and therapeutic modalities in 
patients with bone metastases of differentiated thyroid carcinomas. J Clin Endocrinol 
Metab 2001;86(4):1568-73. 
7. Schoenberger J, Grimm D, Kossmehl P, et al. Effects of PTK787/ZK222584, a 
tyrosine kinase inhibitor, on the growth of a poorly differentiated thyroid carcinoma: 
an animal study. Endocrinology 2004;145(3):1031-8. 
8. Bauer AJ, Patel A, Terrell R, et al. Systemic administration of vascular endothelial 
growth factor monoclonal antibody reduces the growth of papillary thyroid carcinoma 
in a nude mouse model. Annals of clinical and laboratory science 2003;33(2):192-9. 
9. Ain KB, Lee C, Williams KD. Phase II trial of thalidomide for therapy of radioiodine-
unresponsive and rapidly progressive thyroid carcinomas. Thyroid 2007;17(7):663-70. 
10. Ain K LC, Holbrook KM, Dziba JM, Williams KD. Phase II study of lenalidomide in 
distantly metastatic, rapidly progressive, and radioiodine-unresponsive thyroid 
carcinomas: preliminary results. J Clin Oncol 26: 2008 (May 20 suppl; abstr 6027) 
2008. 
11. Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally 
bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for 
the treatment of cancer. Cancer research 2005;65(10):4389-400. 
12. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 
2002;2(10):795-803. 
13. Ferrara N. Role of vascular endothelial growth factor in the regulation of angiogenesis. 
Kidney international 1999;56(3):794-814. 
14. Yamamoto N, Tamura T, Yamamoto N, et al. Phase I, dose escalation and 
pharmacokinetic study of cediranib (RECENTIN), a highly potent and selective 
VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors. Cancer 
chemotherapy and pharmacology 2009;64(6):1165-72. 
15. Ryan CJ, Stadler WM, Roth B, et al. Phase I dose escalation and pharmacokinetic 
study of AZD2171, an inhibitor of the vascular endothelial growth factor receptor 
tyrosine kinase, in patients with hormone refractory prostate cancer (HRPC). 
Investigational new drugs 2007;25(5):445-51. 


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16. Fiedler W, Mesters R, Heuser M, et al. An open-label, Phase I study of cediranib 
(RECENTIN) in patients with acute myeloid leukemia. Leukemia research 2009. 
17. Jayson GC ET, Harris A, Mitchell CL,  Kelly C,  Middleton M,  Fielding A, Laud P, 
Robertson J, Puchalski TA. J Clin Oncol 26: 2008 (May 20 suppl; abstr 14533)  
18. Mulders P HR, Nathan P, de Jong I, Mookerjee B, Osanto S, et al. Cediranib 
(RECENTINTM) in patients with advanced renal cell carcinoma: results of a 
randomized Phase II study. 7th International Kidney Cancer Symposium 2008: 
abstract 21. 
19. Laurie SA AA, Shepherd FA, Dediu M, Ciuleanu T, Fenton D, et al. Randomized, 
double-blind phase II trial of carboplatin + paclitaxel [C+P] with either daily oral 
cediranib,an inhibitor of vascular endothelial growth factor receptor [VEGFR] tyrosine 
kinases, or placebo, in advanced non-small cell lung cancer [NSCLC]: a study of the 
National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 2008:19(Suppl 
8):viii90, abstract231PD. 
20. Mangiameli DP, Blansfield JA, Kachala S, et al. Combination therapy targeting the 
tumor microenvironment is effective in a model of human ocular melanoma. Journal 
of translational medicine 2007;5:38. 
21. Blansfield JA, Caragacianu D, Alexander HR, 3rd, et al. Combining agents that target 
the tumor microenvironment improves the efficacy of anticancer therapy. Clin Cancer 
Res 2008;14(1):270-80. 
22. Sanborn SL, Gibbons J, Krishnamurthi S, et al. Phase I trial of docetaxel given every 3 
weeks and daily lenalidomide in patients with advanced solid tumors. Investigational 
new drugs 2009;27(5):453-60. 
23. Berg S. Phase I and pharmacokinetic (PK) study of lenalidomide (LEN) in pediatric 
patients with relapsed/refractory solid tumors or myelodysplastic syndrome (MDS): A 
Children's Oncology Group Phase I Consortium study. J Clin Oncol 27:15s, 2009 
(suppl; abstr 10023)  
24. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the 
use of white blood cell growth factors: an evidence-based clinical practice guideline. J 
Clin Oncol 2006;24(19):3187-205. 
25. Sherman SI, Wirth LJ, Droz JP, et al. Motesanib diphosphate in progressive 
differentiated thyroid cancer. N Engl J Med 2008;359(1):31-42. 
26. Brose MS TA, Redlinger M, Harlacker K, Redlinger C, Chalian AA,  Flaherty KT, 
Loevner LA, Mandel SJ,  O'Dwyer PJ Effect of BRAFV600E on response to sorafenib 
in advanced thyroid cancer patients. J Clin Oncol 2009;27:15s, 2009 (suppl; abst 
6002). 
27. Trovisco V, Soares P, Sobrinho-Simoes M. B-RAF mutations in the etiopathogenesis, 
diagnosis, and prognosis of thyroid carcinomas. Hum Pathol 2006;37(7):781-6. 
28. Nikiforova MN, Lynch RA, Biddinger PW, et al. RAS point mutations and PAX8-
PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular 
pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab 2003;88(5):2318-
26. 
29. Sherman SI SM, Droz J, M. Hoffmann, L. Wirth, L. Bastholt, R. G. Martins, L. 
Licitra, Y. Shi, D. E. Stepan. Initial results from a phase II trial of motesanib 
diphosphate (AMG 706) in patients with differentiated thyroid cancer (DTC). Journal 


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of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I Vol 25, No 18S 
(June 20 Supplement), 2007: 6017;25(18S):6017. 
30.  Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations.  
Journal of the American Statistical Assoc, 1958; 53:457-81. 
31.  Brookmeyer R, Crowley J.  A confidence interval for the median survival time.  
Biometrics, 1982; 38:29-41. 
32. Cox DR.  Regression models and life tables (with discussion).  Journal of the Royal 
Statistical Soc B, 1972; 34:187-220. 
33 Karrison TG, Maitland ML, Stadler WM, Ratan MJ.  Design of phase II cancer trials 
using a continuous endpoint of change in tumor size:  Application to a study of 
sorafenib and erlotinib in non-small-cell lung cancer.  Journal Natl Cancer Inst, 2007; 
99:1455-61. 
 


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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 
Subject’s Study Drug Diary 
 
 
SUBJECT’S STUDY DRUG DIARY – CEDIRANIB 
Today’s date ________ Subject Name_____________________ (initials acceptable) Subject Study ID ___________ 
INSTRUCTIONS TO THE SUBJECT: 
1. 
Complete one form for each 4 week-period while you take cediranib. 
2. 
You will take your dose of cediranib each day in the morning.  You will take ____15 mg tablets, and 
 
____ 20 mg tablets every morning.  You can take cediranib at least 1 hour before you eat or 2 hours after you eat.   If a dose of cediranib 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. 
3.       Record the date, the number of tablets 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 tablets taken 
Comments 
15 mg 
20 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 subject started protocol _____________________________2.Date subject was removed from study______________________ 
3. 
Subject planned total daily dose_________________________________ 4.Total number of capsules taken this month (each 
size)________________________________ 5.Physician/Nurse/Data Manager’s Signature _____________________________________ 
 
Subject’s signature _____________________________________________________________________________ 
 
 
CTEP-assigned Protocol #___________ 
 
Local Protocol # ___________________ 


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                                               SUBJECT’S STUDY DRUG DIARY – LENALIDOMIDE 
Today’s date __________ Subject’s Name_____________________ Subject’s Study ID ___________________ 
INSTRUCTIONS TO THE  SUBJECT: 
1. 
Complete one form for each 4 week-period while you take lenalidomide.  Only one cycle of study drug may be dispensed each month. 
2. 
You will take your dose of lenalidomide each day in the morning.  You will take ____5 mg capsules. You may take the capsules with or without 
food as you wish.   
3.     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 it is missed for the entire day, it should not be made up.  If you cannot swallow lenalidomide, you may be able to 
take it via gastrostomy tube.  Your doctor will explain the procedure. 
4.      If you take more than the prescribed dose of lenalidomide, you should seek emergency medical care if needed and contact study staff immediately.   
5. 
Record the date, the number of capsules you took, and when you took them.   
6. 
If you have any comments or notice any side effects, please record them in the Comments column.   
7. 
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 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
Physician’s Office will complete this section: 
1. 
Date subject started protocol _______________2.Date subject was removed from study_________________ 
3. 
Subject’s planned total daily dose___________________4.Total number of capsules taken this month (each 
size)__________________ 5.Physician/Nurse/Data Manager’s Signature ____________________________________ 
Subject’s signature ______________________________________________________________________________ 
 
CTEP-assigned Protocol #___________ 
 
Local Protocol # ___________________ 


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APPENDIX C 
Hypertension Monitoring and Management* 
 
Grade 
(CTCAEv5.0) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Cediranib 
Dose Modification 
Grade 1 
120-139 mmHg Systolic 
80-89   mmHg Diastolic 
None 
Baseline 
Standard monitoring 
Consider diuretics  
No Change 
Grade 2- Mild 
140-159 mmHg Systolic 
90-99   mmHg Diastolic 
Initiate BB or 
 
Initiate DHP 
CCB &/or 
 
Increase doses of existing 
medications until BP 
controlled or at maximum 
dose 
Increased frequency of 
monitoring until stabilized 
No Change 
Persistent Moderate 
Hypertension 
140-159 mmHg Systolic 
90-99 mmHg Diastolic 
Initiate BB or 
 
Initiate DHP 
CCB or  
 
ACEI or 
 
Vasodilator &/or 
 
Increase doses or number of 
medications until BP 
controlled or at maximum 
dose 
Increased frequency of 
monitoring until stabilized 
(e.g., every 48 hours) 
 
Supervised by healthcare 
professional 
If partial or no control and BP still 
in a moderate range for 24-48 
hours, hold cediranib and add 
additional drugs, increasing to a 
maximum dose until hypertension 
controlled; monitor for 
hypotension.  
 
Decrease cediranib by 1 dose 
level 
Grade 3- Severe 
> 160 mmHg Systolic 
> 100 mmHg Diastolic 
Start immediate therapy 
with 2 drug combination 
including at least a DHP 
CCB 
 
Escalate doses to achieve 
optimal control of BP, up to 
the maximum dose 
 
If partial or no BP control, 
add additional drugs up to 4; 
increase to optimal or 
maximum doses of all drugs 
 
Increased frequency of 
monitoring until stabilized 
(e.g., every 48 hours) 
 
Supervised by healthcare 
professional 
Hold cediranib; if control of BP 
in the Mild range, restart 
cediranib at the next lower dose 
level 
 
If partial or no control, decrease 
cediranib by another dose level or 
discontinue therapy per 
investigator  
 
Stop cediranib if hypertension is 
symptomatic, and hospitalize 
patient for management of BP 
Grade 4 
Hypertensive Crisis 
Optimal management with 
intensive IV support in ICU 
Hospitalize patient for 
management 
Off protocol therapy, discontinue 
cediranib, and monitor closely for 
hypotension 
Abbreviations: Dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), Angiotensin Converting 
Enzyme Inhibitors (ACEI), Angiotensin II Receptor Blockers (ARB) 
 
*See table below for suggested antihypertensive medications by class 
If patients require a delay of >2 weeks for management of hypertension, discontinue protocol therapy 
If patients require >2 dose reductions, discontinue protocol therapy 
Patients may have up to 2 drugs for management of hypertension prior to any dose reduction in cediranib 
24-48 hours should elapse between modifications of antihypertensive therapy 
Hypertension should be graded using the NCI CTCAEv5.0 
 
 


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Oral Antihypertensive Medications: *Agents in bold characters are suggested as optimal choices to avoid or minimize potential drug-interactions with cediranib through 
CYP450. 
Agent  
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
and inhibitor 
Selective 
 Blockers 
(BB) 
metoprolol 
25 mg  
twice daily 
50 mg 
twice daily 
100 mg  
twice daily 
CYP 2D6 substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
acebutolol 
100 mg  
twice daily 
200-300 mg 
twice daily 
400 mg  
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg daily 
20 mg daily 
Yes (CYP450 
unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x 
daily 
25 mg 3x daily 
50 mg 3x daily 
CYP 2D6 substrate 
enalapril 
5 mg daily 
10-20 mg daily 
40 mg daily 
CYP 3A4 substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used:       
perindopril 
 
4 mg daily 
 
none 
 
8 mg daily 
 
Yes, but not 
CYP450 
Rarely used:       
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin II 
Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not 
CYP450 
 and   
Blocker 
labetolol 
100 mg twice 
daily 
200 mg twice 
daily 
400 mg twice 
daily 
CYP 2D6 substrate 
and inhibitor 


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APPENDIX D 
Collection/Recording of Blood Pressure Information 
 
1.0 
General Guidelines 
1.1 
Frequency of monitoring.  Blood pressure (BP) should be monitored weekly during 
the first cycle of cediranib therapy, then at least every 2 weeks for the duration of 
treatment.  More frequent monitoring may be considered on a study by study basis, 
particularly during the first two cycles of cediranib therapy. 
 
1.2 
Data recording.  All required data should be recorded in the appropriate CRF or on 
the patient’s blood pressure monitoring diary, as appropriate.  The following data 
are required at baseline and at each subsequent assessment: 
• Assessment date and time 
• Pulse 
• Systolic and diastolic BP (2 readings/assessment taken 5 minutes apart while 
patient sitting) 
 
1.3 
Risk factors for hypertension (assess and record data in baseline history/physical 
CRF) 
• Diabetes (type 1 or type 2) 
• Renal disease (specify on CRF) 
• Endocrine condition associated with HTN (specify on CRF) 
• Use of steroids or NSAIDs (specify all concomitant meds) 
• Underlying cardiovascular condition – specify (i.e., ischemic heart disease) 
 
2.0 
Baseline data collection  (at study entry) 
2.1 
All patients 
• Current BP 
• Proteinuria, if present 
 
2.2 
Patients with preexisting hypertension (i.e., those for whom “hypertension” is entered 
as a concomitant condition at study entry, or those who are currently receiving 
therapy with antihypertensive medication) – also record: 
• Date of HTN diagnosis (original) 
• Type HTN (essential or secondary) 
• CTCAE v5.0 grade of HTN (at time of study entry) 
• Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the 
following: 
- 
Antihypertensive agents taken at study entry 
- 
Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack 
of efficacy) 
 
3.0 
Follow up BP data collection (during study) 
3.1 
All patients (at each clinic visit) 


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• Current BP 
• Proteinuria, if present 
 
3.2 
Patients with treatment-emergent hypertension [defined as BP increase of >20 mmHg 
(diastolic) OR BP >150/100 (if previously within normal limits)] – record at time of 
hypertension diagnosis and at all subsequent clinic visits: 
• BP changes from baseline (or from previous assessment) (specify CTCAE 
v5.0 grade changes) 
• Hypertension-related symptoms as reported by patient (e.g., headache) 
• Other relevant changes associated with development of hypertension (e.g., 
ECG abnormalities) 
• Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of 
currently prescribed antihypertensive agents 
3.3 
Patients with preexisting hypertension at study entry – record at each clinic visit 
• BP changes from previous clinic visit (specify CTCAE v5.0 grade changes) 
• Hypertension-related symptoms reported by patient (e.g., headache) 
• Other relevant changes associated with development of hypertension (e.g., 
ECG abnormalities) 
• Changes in antihypertensive medications since last assessment (e.g., dose 
change, add/discontinue drug) 
 
Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha blockers, 
beta blockers, diuretics, angiotension II receptor antagonists. 


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APPENDIX E 
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. 
 


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• 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. 
 
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 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.  


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APPENDIX F 
 
 
 
 
The University of Chicago 
 
 
Tissue Collection Form 
Clinician: Please Fill Out 
Tissue Samples 
Patient Name: ___________________ 
            
Patient Protocol ID #:______________ 
            Date Tissue Obtained: _________________ 
Date of Birth: ______________________________ Attending Physician: __________________ 
Site of Biopsy: ___________________________ 
Institution: _________________ 
Date consent was signed: ___________________      Diagnosis:__________________ 
Pre/Post Therapy  (Please circle) 
 
 
Day started on clinical protocol:__________ 
Did Surgical Pathology receive tissue for diagnosis?  Yes   No 
Contact Person’s Phone Number and email Address at Affiliate: 
Researcher: Please Fill Out 
Date Samples received: _________________ 
 
 
 
 
Questions regarding tissue/blood specimens: Contact HTRC 
Phone: 773-834-8391 
                                                    
 
Protocol 8317 


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APPENDIX G 
New York Heart Association Classifications 
 
Clinical Evaluation of Functional Capacity of Patients 
with Heart Disease in Relation to Ordinary Physical Activity 
 
 
 
Class 
 
 
Cardiac Symptoms 
 
 
Limitations 
 
Need for 
Additional Rest* 
 
Physical Ability  
      to work**__ 
 
 
 
 
 
I 
None 
None 
None 
Full time 
 
 
 
 
 
II 
Only moderate 
Slight 
Usually only slight 
or occasional 
Usually full  
time 
 
 
 
 
 
III 
Defined, with  
less than  
ordinary activity 
Marked 
Usually moderate 
Usually part  
time 
 
 
 
 
 
IV 
May be present  
even at rest,  
and any activity 
increases discomfort 
Extreme 
Marked 
Unable to work 
 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
** 
At accustomed occupation or usual tasks. 
 
Reference: 
 
 Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956.  (Modified from New York Heart 
Association, 1953. 
 
 
 
 


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APPENDIX H 
 
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 
• She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 


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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 


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− Partner’s vasectomy 
• Additional effective methods: 
− Male condom 
− Diaphragm 
− Cervical Cap 
 
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 


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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. 
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.  
 
 


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Appendix I: 
Lenalidomide Education and Counseling Guidance Document 
 
To be completed prior to each dispensing of study drug. 
Protocol Number: ____________________________________________ 
Patient Name (Print): __________________ DOB: _____/_____/_____ (mm/dd/yyyy) 
(Check the appropriate box to indicate risk category) 
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: 
□ 
 
Do Not Dispense study drug 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 contact) [at least 28 days prior to 
treatment, during treatment and during dose interruption]. 
FCBP: 
1. I verified that the required pregnancy tests performed are negative. 


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2. I counseled FCBP regarding the following: 
• Potential risk 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 contact [at least 28 days prior to treatment, during treatment, 
during dose interruption and 28 days after discontinuation of lenalidomide]. 
• 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:   
− Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants) 
o Tubal ligation 
o Partner’s vasectomy 
− Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
• Pregnancy tests before, during, and after treatment, even if the patient agrees not to 
have reproductive heterosexual contact.  Two pregnancy tests will be performed prior 
to receiving study drug, one within 10 to 14 days and the second within 24 hours of 
the start of study drug. 
• Frequency of pregnancy tests to be done: 
− 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.   


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− If the patient missed a period or has unusual menstrual bleeding.   
− 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. 
− 
Stop taking study drug immediately in the event of becoming pregnant and to call 
their study doctor as soon as possible.  
− 
NEVER share study drug with anyone else. 
− 
Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
− 
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 study drug capsules. 
− 
Return unused study drug to the study doctor. 
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): 
4. I counseled the female NOT of child bearing potential regarding the following: 
− Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP) 
− NEVER share study drug with anyone else. 
− Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
− Do not break, chew, or open study drug capsules 
− Return unused study drug capsules to the study doctor. 
5. Provide Lenalidomide Information Sheet to the patient. 
MALE: 
6. I counseled the Male patient regarding the following: 


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− Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP). 
− To engage in complete abstinence or use a condom when engaging in sexual 
contact (including those who have had a vasectomy) with a pregnant female or a 
female of childbearing potential,  while taking study drug, during dose 
interruptions and for 28 days after stopping study drug. 
− Males should notify their study doctor when their female partner becomes 
pregnant and female partners of males taking study drug should be advised to call 
their healthcare provider immediately if they get pregnant. 
− NEVER share study drug with anyone else. 
− Do not donate blood, semen or sperm while taking study drug and for 28 days 
after stopping study drug. 
− Do not break, chew, or open study drug capsules. 
− Return unused study drug capsules to the study doctor. 
7. Provide Lenalidomide Information Sheet to the patient. 
 
Counselor Name (Print): ____________________  
 
Counselor Signature: _______________________  Date: _____/_____/_____ 
 
**Maintain a copy of the Lenalidomide Education and Counseling Guidance Document in the patient 
records.** 


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APPENDIX J 
Lenalidomide Information Sheet 
FOR SUBJECTS ENROLLED IN CLINICAL RESEARCH STUDIES  
Please read this Lenalidomide Information Sheet before you start taking study drug and each 
time you get a new supply. 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? 
8. 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) 


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• 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: 
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. 
9. 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. 


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• 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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APPENDIX K 
REGISTRATION FOR LENALIDOMIDE COUNSELING PROGRAM 
Counselor Information  
 
 
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 Yes, which Protocol: ________________  
 
 
 
 
 
 
 
 
 
Document A _Version 2.0 July 20, 2010 
 
 
 
 
 
 
CTEP-assigned Protocol #___________ 
 
Local Protocol # ___________________ 


119 
UC IRB # 10-182-B 
NCI # 8317 
Version Date:    09/25/2019 
 
 
 
• 
Please provide at least two (2) counselors and fax back to 908.673.2779  
• 
Use one form per counselor.  
• 
Identified counselors must be a licensed healthcare professional (e.g. RN, PA, RPh, PhD, LPN, CNP 
or MD).  
• 
If you have any questions, please contact tfranco@celgene.com  
 
General Information  
 
 
Principal Investigator: ___________________Institution Name: _______________________ 
CTEP site ID: _________________   
 
Today’s Date: ________/________/_________  Subject Name: 
_________________________________  Subject ID ___________________    (initials acceptable)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX L: SUBJECT’S BLOOD PRESSURE DIARY 


120 
UC IRB # 10-182-B 
NCI # 8317 
Version Date:    09/25/2019 
 
INSTRUCTIONS TO THE SUBJECT: 1. Your blood pressure readings have two numbers.  The first number is the 
pressure in your blood vessels during a heart beat (systolic), and the second number is the pressure in the vessels when 
the heart rests in between beats (diastolic).  These numbers are usually written with a slash in between them (for 
example, normal blood pressure is 120/80). 2. Record the date, then record your blood pressure using a home blood 
pressure monitor.  You should check you blood pressure at least once a week for your first cycle but more often 
depending on your doctor’s instructions 3. If you take your blood pressure at other times of the day, please record the 
numbers and time under “Other readings.” 4. If your systolic pressure is greater than 150 or your diastolic blood 
pressure is greater than 90, repeat after several hours.  If it remains elevated, please contact your doctor’s office at 
_______________________________ for instructions. 5. Please bring this form to every clinic visit or appointment.  
Date  
AM 
readings  
PM 
readings  
Other readings 
(include time of day)  
Date  
AM 
readings  
PM 
readings  
Other readings (include 
time of day)  
 
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Subject’s Signature: ________________________________________________________ Date: ____________________  
Physician’s Office will complete this section: ________/________/_________ Date of this clinic visit 
Physician/Nurse/Data Manager’s Signature  
 


 
121 
 
APPENDIX M 
Procedure for Dosing Lenalidomide Via Gastrostomy Feeding Tube 
 
1) 
Obtain One (1) cup of HOT water. 
 
2) 
Arrange the required articles for dose administration 
• One (1) clean 20cc disposable syringe with plunger rod. 
• One (1) clean 10cc disposable syringe with plunger rod. 
• One (1) 3-way Stop Cock valve 
o 3-Way Stop Cock valve – Qosina Part # 99729  
o All Plastic Disposable Syringe 20mL capacity Luer Lock Syringe – 
National Scientific Target Part # 03-377-24  
• One (1) adapter (for use from valve to tube) 
o Adapter – Qosina Part # 11519  
 
3) 
Using the 20CC syringe, place the luer-lock end in the cup of hot water and fill the 
syringe completely by pulling back on the plunger rod until it stops.  This syringe will 
be designated as the “RINSE SYRINGE.”  Set “RINSE SYRINGE” down and allow 
water to cool.   
 
4) 
Connect the 3-way valve to the 10CC syringe via the luer-lock at the “C’ position 
(luer-lock opposite the Fixed Male Luer leaving the second luer lock to the right @ 
the “B” position) (see Figure 1).   
 
5) 
Position the valve handle @ the “B” position (see Figure 1).   
 
6) 
Pull back on the plunger rod and remove the plunger rod from the syringe barrel.  
This will be the “DOSING SYRINGE.” 
 
7) 
Insert the required dose (capsules) into the barrel of the “DOSING SYRINGE.” 
 
8) 
Replace the plunger rod into the syringe barrel and slowly depress the plunger rod 
until it touches the capsules. 
 
9) 
Place the Fixed Luer (“A”) end of the valve into the cup of HOT water and draw the 
plunger rod back filling the syringe with hot water until it stops (see Figure 1).   
 
10) 
Immediately position the valve handle to the “C” position (see Figure 1).  This 
will prevent any leakage from the syringe as the capsules begin to dissolve.  Note: a 
few drops may leak from the Fixed Luer end of the valve.  This will only be water 
downstream of the closed valve. 
  
11) 
Gently swirl the syringe to assist in the hot water dissolving the gelatin capsules.  
Verify that the capsules have dissolved and allow the solution to come to a suitable 
temperature for dosing.  The temperature in the “RINSE SYRINGE” should be 
checked as well (warm to the touch on the exterior of the syringe body). 


 
122 
 
 
12) 
Once a suitable temperature (warm to the touch on the exterior of the syringe body) is 
reached and the capsules appear dissolved, connect the “RINSE SYRINGE” to the 2nd 
luer-lock fitting on the 3-way valve (Position “B”) (see Figure 1).   
 
13) 
Attach the adapter to the Fixed Male Luer end (position “A”) of the valve (see Figure 
1).   
   
14) 
The daily dose is now ready to be administered (see Figure 2).   
 
15) 
Insert the adapter into the port on the Feeding Tube, making sure it is a tight fit that 
will not allow leaking. 
 
16) 
Turn the valve handle on the 3-way valve to the “B” position (see Figure 1).  Depress 
the plunger rod on the “DOSING  SYRINGE” until it stops. 
   
17) 
Turn the valve handle to the “A” position (see Figure 1).  Gently pull back on the 
plunger rod of the “DOSING SYRINGE” allowing approximately 1/3 (7cc) of rinse 
water to enter the “DOSING SYRINGE” from the “RINSE SYRINGE.” 
   
18) 
Turn the 3-way valve back to the “B” position and depress the plunger rod on the 
“DOSING SYRINGE” until it stops (see Figure 1).  
 
19) 
Turn the valve handle to the “A” position (see Figure 1).  Gently pull back on the 
plunger rod of the “DOSING SYRINGE” allowing approximately 1/3 (7cc) of rinse 
water to enter the “DOSING SYRINGE” from the “RINSE SYRINGE.” 
 
20) 
Turn the 3-way valve back to the “B” position and depress the plunger rod on the 
“DOSING SYRINGE” until it stops (see Figure 1).  
 
21) 
Turn the valve handle to the “A” position (see Figure 1).  Gently pull back on the 
plunger rod of the “DOSING SYRINGE” allowing the remaining rinse water to enter 
the “DOSING SYRINGE” from the “RINSE SYRINGE.” 
 
22) 
Turn the 3-way valve back to the “B” position and depress the plunger rod on the 
“DOSING SYRINGE” until it stops (see Figure 1).  
 
23) 
Visually verify that the three (3) rinse steps have removed the entire dose from the 
“DOSING SYRINGE” and the Feeding Tube is clear.  If additional rinse water is 
needed remove the “RINSE SYRINGE” from the 3-way valve.  Draw additional 
WARM water into the syringe.  Reconnect the “RINSE SYRINGE” to the 3-way 
valve and repeat Steps #17 through #22 or until the “DOSING SYRINGE” and 
Feeding Tube are clear. 
        
24) 
Disconnect the adapter from the Feeding Tube, secure the port on the Feeding Tube. 
 


 
123 
 
25) 
Dissemble the adapter, 3-way Stop Cock Valve and both the “DOSING” and “RINSE 
SYRINGES”.  Thoroughly rinse all items in clean water and allow them to air dry 
before returning them to the storage container. 
 


 
124 
 
Figure 1: 3-Way Stopcock Valve and Adapter 
 
 
 
 
 
 
 
 
Syringe Part # 03-377-24 National Scientific Target All Plastic Disposable Syringe 
20mL capacity Luer Lock 
 
Adapter Part # 11519 Supplier Qosina  
 
3-Way Stop Cock valve Part # 99729 Supplier Qosina 


 
125 
 
Figure 2: Assembled Dosing Device