Clinical trial NCT00790842
Conditions: Multiple Myeloma Plasma Cell Neoplasm
Keywords: Refractory Multiple Myeloma Relapsed Multiple Myeloma Multiple Myeloma with Renal Dysfunction Stage I Multiple Myeloma Stage II Multiple Myeloma Stage III Multiple Myeloma
Sponsor: PrECOG, LLC.
Start date: 2009-01-21; Completion date: 2018-03-08
Enrollment: 63 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients with previously treated multiple myeloma and kidney dysfunction will be treated with lenalidomide and low-dose dexamethasone. Phase I will study the side effects and best dose of lenalidomide when given together with low-dose dexamethasone therapy. After the maximum safe and tolerated dose is found in Phase I, the study will proceed to Phase II. Phase II will study how well the the treatment works in patients with previously treated (relapsed or refractory) multiple myeloma and kidney dysfunction.

Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide together with dexamethasone may kill more cancer cells. Lenalidomide and dexamethasone may have different effects in patients who have changes in their kidney function.

Detailed description:
Multiple Myeloma (MM) affects approximately 20,000 Americans annually and remains an incurable hematologic malignancy characterized by frequent early response followed by universal treatment relapse necessitating multiple sequential therapeutic regimens. Until recently, few effective therapies existed. Several novel agents for MM have now become available including the immunomodulatory drugs thalidomide, lenalidomide, as well as the proteasome inhibitor, bortezomib. Each of these agents is undergoing extensive clinical evaluation in combination with other therapies to produce unprecedented response rates in newly diagnosed and relapsed MM. Lenalidomide has proven to be a highly effective treatment agent, particularly when used in combination with dexamethasone but is renally excreted and little information is available about its use in myeloma patients with impaired kidney function (20% have renal failure at some time after diagnosis). Defining a safe and effective dose of lenalidomide to use is a critical step in MM treatment.

OUTLINE: This is a Phase I, dose-escalation study of lenalidomide followed by a Phase II study. Patients are stratified according to degree of renal dysfunction (moderate \[creatinine clearance 30-60 mL/min\] vs severe \[creatinine clearance \<30 mL/min and does not require dialysis\] vs end-stage renal disease \[creatinine clearance \<30 mL/min and requires dialysis\]).

Patients receive oral lenalidomide on days 1-21 and low-dose oral dexamethasone 40 mg on days 1, 8, 15, and 22. There is a 7 day rest (days 22-28) from lenalidomide. Each cycle is 28 days and repeated in the absence of disease progression or unacceptable toxicity.

Patients enrolled in the phase II portion of the study will undergo blood sample collection periodically for pharmacokinetic analysis of lenalidomide (Mayo Clinic sites only).

After completion of study treatment, patients are followed every 6 months for up to 3 years.

Arms: arm 1: Creatinine clearance 30 - 60 mL/min, lenalidomide dose determined in phase I, dexamethasone 40 mg orally days 1, 8, 15 and 22 of a 28 day cycle, and anticoagulants. arm 2: Creatinine clearance \< 30 mL/min, not on dialysis, lenalidomide dose determined in phase I, dexamethasone 40 mg orally days 1, 8, 15 and 22 of a 28 day cycle, and anticoagulants. arm 3: Creatinine clearance \< 30 mL/min and on dialysis, lenalidomide dose determined in phase I, dexamethasone 40 mg orally days 1, 8, 15 and 22 of a 28 day cycle, and anticoagulants.
Interventions: intervention 1: Lenalidomide intervention 2: Dexamethasone intervention 3: Anticoagulants
Intervention descriptions: intervention 1: Given by mouth days 1-21 of a 28-day cycle. There is a 7 day rest (days 22-28). Continue until disease progression or unacceptable toxicity. intervention 2: 40 mg given by mouth days 1, 8, 15 and 22 of a 28-day cycle. Continue until disease progression or unacceptable toxicity. intervention 3: Anticoagulation consisted of aspirin at either 81 mg/day or 325 mg/day at the physician's discretion. Heparin, low molecular weight heparin, or coumadin could be used if the patient was intolerant to aspirin.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
PrECOG Protocol Number:  PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
1 
 
 
PrECOG Protocol Number: PrE1003 
 
A Phase I/II Study of the Tolerability of Lenalidomide and Low 
Dose Dexamethasone in Previously Treated Multiple Myeloma 
Patients with Impaired Renal Function 
 
STUDY CHAIRS:  
 
 
Joseph R. Mikhael, M.D. 
STUDY CO-CHAIRS: 
 
 
 
 
  
MEDICAL MONITOR: 
  
 
STUDY STATISTICIAN: 
 
 
 
PrECOG STUDY CONTACT:  
Carolyn Andrews, R.N. 
(Internal Use Only) Celgene Ref. ID Number: RV-MM-PrECOG-0394 
IND #:   
 
 
 
 
 
 
 
103014 
NCT #:  
  
 
00790842 
Version Number: 
6.0 
Version Date: 
 
3/28/2011 
 
Release/Revision History 
Version 1.0 December 4, 2008 
MC0885 Released to Mayo Sites only 
MCCC Addendum 1 September 29, 2009 
(Version 2.0) 
MC0885 Released to Mayo Sites only 
MCCC Addendum 2 November 24, 2009 
(Version 3.0) 
MC0885 Released to Mayo Sites only 
MCCC Addendum 3 October 1, 2010 
(Version 4.0) 
MC0885 Released to Mayo Sites only 
Version 5.0: November 03, 2010 
Released to Sites 
Version 6.0: March 28, 2011 
Released to Sites 
 
This protocol contains information that is confidential and proprietary 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
2 
 
 
 
Revision History 
Version 5.0 
11/03/2010 
Released to sites 
THE FOLLOWING AMENDMENT WAS MADE TO VERSION 5.0 OF THE PROTOCOL 
Version 6.0 
3/28/2011 
PrECOG Study Site Contacts 
Added: 
 
Associate Project Manager 
PrECOG, LLC 
1818 Market Suite, Suite 1100 
Philadelphia, PA 19103 
9:00 am-5:00 pm 
Eastern Time Zone 
Phone: 215-789-7001 
 
Version 6.0 
3/28/2011 
Medical Monitor SAE Fax Number 
Was: 
SAE Fax: 888-801-8795 
Is: 
SAE Fax: 888-577-9921 
Version 6.0 
3/28/2011 
Schema 
Was: 
PHASE I only: Prior to discussing protocol entry with the patient, call PrECOG at 
215-789-7001 to ensure that a place on the protocol is open to the patient. 
Is: 
PHASE I only: Prior to discussing protocol entry with the patient, call the 
PrECOG Project Manager to ensure that a place on the protocol is open to the 
patient. The Project Manager contact information is located in the Study 
Reference Manual. 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
3 
 
Version 6.0 
3/28/2011 
1.7 Dosing Recommendation for Lenalidomide in Patients with Renal Impairment, 
Hemodialysis 
Was: 
This study originated December 22, 2008 at Mayo Clinic in Arizona and Rochester. 
As of November 03, 2010, a total of 13 subjects have been enrolled.  
Is: 
This study originated December 22, 2008 at Mayo Clinic in Arizona and Rochester. 
As of November 09, 2010, a total of 15 subjects have been enrolled 
Version 6.0 
3/28/2011 
3.1 Eligibility Criteria 
Was: 
NOTE:  Phase I Only – Prior to discussing protocol entry with the patients AND 
prior to registering in the interactive web registration system (IWRS), call 
PrECOG at 215-789-7001 to ensure that a place on the protocol is open to the 
patient. 
Is: 
NOTE:  Phase I Only – Prior to discussing protocol entry with the patients AND 
prior to registering in the electronic data capture (eDC) system, call the 
PrECOG Project Manager to ensure that a place on the protocol is open to the 
patient. The Project Manager contact information is located in the Study 
Reference Manual. 
Version 6.0 
3/28/2011 
4. Test Schedule 
Footnote 18 for Survival and Malignancy Surveillance 
Was: 
18. Follow-up every 6 months for survival x 3 years. If patient has not progressed at 
off-study, document date of progression. 
Is: 
18. Follow-up every 6 months for survival, second primary malignancy 
diagnosis, and recurrence of any prior malignancy (if applicable) x 3 years. 
If patient has not progressed at off-study, document date of progression. This 
should include subjects who may have discontinued the study at any time 
or for any reason, who may be in a survival follow-up period, or who may 
have died. Following this 3 year time period, reporting of all identified 
cases of subsequently diagnosed second primary malignancies is voluntary 
by the treating physician to the manufacturer. 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
4 
 
Version 6.0 
3/28/2011 
4. Test Schedule 
Footnote 19 
Added: 
19. Bone marrow (with aspirate/FISH/cytogenetics) and skeletal survey may be 
used if performed ≤90 days of study enrollment. In addition to the standard 
evaluation for prolonged cytopenias that do not recover after 
discontinuation of treatment, a bone marrow exam should be considered, in 
patients with the following parameters: no leukopenia at the time of 
multiple myeloma diagnosis, no active multiple myeloma at the time of the 
cytopenia, no vitamin or element deficiency to explain the cause of the 
cytopenia(s). 
Version 6.0 
3/28/2011 
6.31 Phase I Dose Escalation 
Was: 
Prior to discussing protocol entry with patient AND prior to registering a patient 
through the electronic interactive web registration (IWR) system, call PrECOG 
at 215-789-7001 to ensure that a place on the protocol is open to the patient. 
Is: 
Prior to discussing protocol entry with patient AND prior to registering a patient 
through the electronic data capture (eDC) system, call the PrECOG Project 
Manager to ensure that a place on the protocol is open to the patient. The Project 
Manager contact details can be found in the Study Reference Manual. 
Version 6.0 
3/28/2011 
6.3.11 
Patients must not start protocol treatment prior to registration. 
Was: 
Upon determination that a subject meets eligibility criteria, the subject will be 
registered in the study by site personnel via an electronic IWR system. 
Confirmation of registration will be displayed in the IWR system once site 
personnel have verified the subject’s eligibility status. 
Is: 
Upon determination that a subject meets eligibility criteria, the subject will be 
registered in the study by site personnel via an electronic data capture (eDC) 
system. Confirmation of registration will be displayed in the eDC system once site 
personnel have verified the subject’s eligibility status. 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
5 
 
Version 6.0 
3/28/2011 
6.32 Phase II Patient Registration 
Was: 
Upon determination that a subject meets eligibility criteria, the subject will be 
registered in the study by site personnel via an electronic interactive web 
registration (IWR) system. Confirmation of registration will be displayed in the 
IWR system once site personnel have verified the subject’s eligibility status. 
Is: 
Upon determination that a subject meets eligibility criteria, the subject will be 
registered in the study by site personnel via an electronic data capture (eDC) 
system. Confirmation of registration will be displayed in the eDC system once site 
personnel have verified the subject’s eligibility status. 
Version 6.0 
3/28/2011 
8.0 Dose Modification Based on Adverse Events for Phase I and Phase II 
Removed: 
ALERT: ADR reporting may be required for some adverse events (see Section 
10.0). 
 
Version 6.0 
3/28/2011 
8.0 Dose Modification Based on Adverse Events for Phase I and Phase II 
Was: 
Subjects will be evaluated for AEs at each visit with the NCI CTCAE V4.0 used as 
a guide for the grading of severity. Refer to Tables below for specific Lenalidomide 
and Dexamethasone dose reduction steps. Subjects who cannot tolerate lowest dose 
level are to be discontinued from the treatment phase of the study. Subjects 
experiencing ≥grade 3 non-hematologic or grade 4 hematologic adverse events will 
have their study drug held per Table 8.31. 
Is: 
Subjects will be evaluated for AEs at each visit with the NCI CTCAE V4.0 used as 
a guide for the grading of severity. Refer to Tables below for specific Lenalidomide 
and Dexamethasone dose reduction steps. Subjects who cannot tolerate lowest dose 
level are to be discontinued from the treatment phase of the study. Subjects 
experiencing ≥grade 3 non-hematologic or grade 4 hematologic adverse events will 
have their study drug held per Table 8.31. Held doses are not made up. 
Version 6.0 
3/28/2011 
8.0 Dose Modification Based on Adverse Events for Phase I and Phase II 
Removed: 
Omit = The current dose(s) during a cycle is skipped. The patient does not 
make up the omitted dose(s) at a later time. 
Hold = Refers to decision made at the beginning of the cycle to delay the start 
of the cycle until the patient meets the protocol criteria to restart drug. Held 
doses are not made up. 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
6 
 
Version 6.0 
3/28/2011 
8.21 Hematological Requirements for Day 1 of Each Cycle 
Was: 
If either of these two criteria is not met, the start of the cycle should be held and 
CBC should be followed weekly. Once ANC and platelets have recovered to Grade 
2 or less, cycle should be started at next lower dose of lenalidomide. 
Is: 
If either of these two criteria is not met, the start of the cycle should be held and 
CBC should be followed weekly. Once ANC and platelets have recovered to Grade 
2 or less, cycle should be started at next lower dose of lenalidomide. Held doses 
are not made up. 
Version 6.0 
3/28/2011 
Table 8.31: Dose Modification for Lenalidomide 
Add above Table 8.3.1: 
Please note: Held doses are not made up. 
Version 6.0 
3/28/2011 
Table 8.31:  Dose Modification for Lenalidomide 
Was: 
NCI CTC Toxicity Grade 
Day 2-14 of Cycle 
≥Day 15 of Cycle 
Grade 3 neutropenia 
associated with fever 
(temperature ≥38.5oC) or 
Grade 4 neutropenia 
• Hold (interrupt dose). 
• Follow CBC weekly. 
• If neutropenia has 
resolved to ≤grade 2, 
restart at next lower 
dose level and continue 
the cycle until day 2 . 
• Omit lenalidomide 
for remainder of 
cycle. Restart 
lenalidomide next 
cycle (decrease dose 
by one dose level) 
Is: 
NCI CTC Toxicity Grade 
Day 2-14 of Cycle 
≥Day 15 o  Cycle 
Grade 3 neutropenia 
associated with fever 
(temperature ≥38.5oC) or 
Grade 4 neutropenia 
• Hold lenalidomide. 
• Follow CBC weekly. 
• If neutropenia has 
resolved to ≤grade 2, 
restart at next lower 
dose level and continue 
the cycle until day 21. 
• Hold lenalidomide 
for remainder of 
cycle. Restart 
lenalidomide next 
cycle (decrease dose 
by one dose level) 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
7 
 
Version 6.0 
3/28/2011 
Table 8.31: 
Dose Modification for Lenalidomide 
Was: 
NCI CTC Toxicity 
Grade 
Day 2-14 of Cycle 
≥Day 15 of Cycle 
Thrombocytopenia 
≥Grade 3 (platelet 
count <50,000/mm³) 
• Hold (interrupt) 
lenalidomide. 
• Follow CBC weekly. 
• If thrombocytopenia 
resolves to ≤grade 2, 
restart lenalidomide at 
next lower dose level 
and continue the cycle 
through Day 21. 
• Omit lenalidomide for 
remainder of cycle. 
Restart lenalidomide 
next cycle (decrease 
dose by one dose 
level). 
Non-blistering rash 
Grade 3 
• If 
Grade 
3, 
hold 
(interrupt) lenalidomide 
dose. Follow weekly. 
• If the adverse event 
resolves to ≤grade 1, 
restart lenalidomide at 
next lower dose level 
and continue the cycle 
through Day 21. 
• Omit lenalidomide for 
remainder 
of 
cycle. 
Restart 
lenalidomide 
next cycle (decrease 
dose 
by 
one 
dose 
level). 
Is: 
NCI CTC Toxicity 
Grade 
Day 2-14 of Cycle 
≥Day 15 of Cycle 
Thrombocytopenia 
≥Grade 3 (platelet 
count <50,000/mm³) 
• Hold lenalidomide. 
• Follow CBC weekly. 
• If thrombocytopenia 
resolves to ≤grade 2, 
restart lenalidomide at 
next lower dose level 
and continue the cycle 
through Day 21. 
• Hold lenalidomide for 
remainder of cycle. 
Restart lenalidomide 
next cycle (decrease 
dose by one dose 
level). 
Non-blistering rash 
Grade 3 
• If 
Grade 
3, 
hold 
lenalidomide 
dose. 
Follow weekly. 
• If the adverse event 
resolves to ≤grade 1, 
restart lenalidomide at 
next lower dose level 
and continue the cycle 
through Day 21. 
• Hold lenalidomide for 
remainder 
of 
cycle. 
Restart 
lenalidomide 
next cycle (decrease 
dose 
by 
one 
dose 
level). 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
8 
 
Version 6.0 
3/28/2011 
Table 8.31: 
Dose Modification for Lenalidomide 
Was: 
NCI CTC Toxicity 
Grade 
Day 2-14 of Cycle 
≥Day 15 of Cycle 
Sinus 
bradycardia/other 
cardiac arrhythmia 
Grade 2 
• .Hold (interrupt) lenalidomide 
dose. Follow at least weekly. 
• Omit lenalidomide for 
remainder of cycle. 
Restart 
lenalidomide 
next cycle (decrease 
dose by one dose 
level). 
Allergic reaction 
or hypersensitivity  
Grade 2-3 
• Hold (interrupt) lenalidomide 
dose. Follow at least weekly. 
• Omit lenalidomide for 
remainder of cycle. 
Restart 
lenalidomide 
next cycle (decrease 
dose by one dose 
level). 
Venous 
thrombosis/ 
embolism 
≥Grade 3 
• Hold (interrupt) lenalidomide 
and 
start 
therapeutic 
anticoagulation; 
restart 
lenalidomide at investigator’s 
discretion 
(maintain 
dose 
level). 
• Omit lenalidomide for 
remainder of cycle. 
See 
Anticoagulation 
Consideration 
(see 
Section 9.4). Restart 
lenalidomide 
next 
cycle (decrease dose 
by one dose level). 
Hyperthyroidism 
or hypothyroidism 
≥Grade 3 
• Omit 
lenalidomide 
for 
remainder of cycle, evaluate 
etiology, 
and 
initiate 
appropriate therapy. Restart 
lenalidomide 
next 
cycle 
(decrease dose by one dose 
level) 
• Omit lenalidomide for 
remainder of cycle, 
evaluate etiology, and 
initiate 
appropriate 
therapy. 
Restart 
lenalidomide 
next 
cycle (decrease dose 
by one dose level). 
Other non-
hematologic 
adverse events 
assessed as 
lenalidomide 
related ≥Grade 3 
• Hold (interrupt) lenalidomide 
dose. Follow at least weekly. 
• If the adverse event resolves to 
≤grade 2, restart lenalidomide 
and 
continue 
through 
the 
scheduled Day 21 of current 
cycle. Otherwise, omit for 
remainder of cycle. Omitted 
dose are not made up. For 
toxicity 
attributed 
to 
lenalidomide, reduce by one 
dose level when restarting 
lenalidomide 
• Omit lenalidomide for 
remainder of cycle. 
Restart 
lenalidomide 
next cycle (decrease 
dose by one dose 
level). 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
9 
 
Version 6.0 
3/28/2011 
Table 8.31: 
Dose Modification for Lenalidomide 
Is: 
 
NCI CTC 
Toxicity Grade 
Day 2-14 of Cycle 
≥Day 15 of Cycle 
Sinus 
bradycardia/other 
cardiac 
arrhythmia Grade 
2 
• Hold 
lenalidomide 
dose. 
Follow at least weekly. 
• Hold lenalidomide for 
remainder 
of 
cycle. 
Restart lenalidomide next 
cycle (decrease dose by 
one dose level). 
Allergic reaction 
or 
hypersensitivity  
Grade 2-3 
• Hold lenalidomide dose. 
Follow at least weekly. 
• Hold lenalidomide for 
remainder 
of 
cycle. 
Restart lenalidomide next 
cycle (decrease dose by 
one dose level). 
Venous 
thrombosis/ 
embolism 
≥Grade 3 
• Hold lenalidomide and start 
therapeutic anticoagulation; 
restart 
lenalidomide 
at 
investigator’s 
discretion 
(maintain dose level). 
• Hold lenalidomide for 
remainder of cycle. See 
Anticoagulation 
Consideration 
(see 
Section 
9.4). 
Restart 
lenalidomide next cycle 
(decrease dose by one 
dose level). 
Hyperthyroidism 
or 
hypothyroidism 
≥Grade 3 
• Hold 
lenalidomide 
for 
remainder of cycle, evaluate 
etiology, 
and 
initiate 
appropriate therapy. Restart 
lenalidomide 
next 
cycle 
(decrease dose by one dose 
level) 
• Hold lenalidomide for 
remainder 
of 
cycle, 
evaluate etiology, and 
initiate 
appropriate 
therapy. 
Restart 
lenalidomide next cycle 
(decrease dose by one 
dose level). 
Other non-
hematologic 
adverse events 
assessed as 
lenalidomide 
related ≥Grade 3 
• Hold 
lenalidomide 
dose. 
Follow at least weekly. 
• If the adverse event resolves 
to 
≤grade 
2, 
restart 
lenalidomide and continue 
through the scheduled Day 
21 
of 
current 
cycle. 
Otherwise, 
hold 
for 
remainder of cycle. Held 
doses are not made up. For 
toxicity 
attributed 
to 
lenalidomide, reduce by one 
dose level when restarting 
lenalidomide 
• Hold lenalidomide for 
remainder 
of 
cycle. 
Restart lenalidomide next 
cycle (decrease dose by 
one dose level). 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
10 
 
Version 6.0 
3/28/2011 
10.0 Adverse Event (AE) Monitoring and Reporting 
Removed: 
10.11 Adverse event monitoring and reporting is a routine part of every 
clinical trial. First, identify and grade the severity of the event using the 
CTCAE. Next, determine whether the event is expected or unexpected 
(refer to Sections 10.12 and 15.0) and if the adverse event is related to 
the medical treatment or procedure (see Section 10.13). With this 
information, determine whether an adverse event should be reported as 
an expedited report (see Section 10.2) in addition to the routinely 
reported clinical data (see Section 10.31). 
Expedited adverse event reporting requires submission of a written 
report, but may also involve telephone notifications. Telephone and 
written reports are to be completed within the timeframes specified in 
Section 10.2. All expedited adverse event reports should also be 
submitted to the local Institutional Review Board (IRB). 
10.12 Expected vs. Unexpected 
• 
The determination of whether an AE is expected is based on agent-
specific adverse event information provided in Section 15.0 of the 
protocol. 
• 
Unexpected AEs are those not listed in the agent-specific adverse 
event information provided in Section 15.0 of the protocol. 
Version 6.0 
3/28/2011 
Was: 
10.14 When a study includes both investigational and commercial agents, the 
following apply: 
• 
When an investigational agent(s) is used in combination with a commercial 
agent(s), the combination is considered investigational. Expedited reporting 
of adverse events follows the guidelines for investigational agents. 
• 
When a study includes an investigational agent(s) and a commercial 
agent(s) on a separate arm, follow the guidelines for investigational 
agents only if the event is specifically associated with the investigational 
agent(s). If the event is associated with a regimen containing only 
commercial agent(s), expedited reporting follows the guidelines for 
commercial agents. 
Is: 
10.12 When a study includes both investigational and commercial agents, 
the following apply: 
• 
When an investigational agent(s) is used in combination with a commercial 
agent(s), the combination is considered investigational. Reporting of adverse 
events follows the guidelines for investigational agents. 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
11 
 
Version 6.0 
3/28/2011 
Removed: 
10.2 
Expedited Adverse Event Reporting Requirements 
Grade 4 or 51 
Unexpected with 
Attribution of Possible, 
Probable, or Definite 
Other Grade 4 or 5 
or 
Any hospitalization 
during treatment 
Notify PrECOG2 within 
24 hours of becoming 
aware of event 
X 
 
Submit written report 
within 
24 
hours/1 
business day3 
X 
 
Submit Grade 4 or 5 
Non-AE 
Reportable 
Events/Hospitalization 
Form within 5 working 
days. 
 
X4 
1. Includes all deaths within 30 days of the last dose of investigational agent 
regardless of attribution or any death attributed to the agent(s) (possible, 
probable, or definite) regardless of timeframe.  
2. See Section 10.51 for PrECOG contact information.  
3. PrECOG will provide SAE forms. Fax the SAE forms to PrECOG at 888-
577-9921. Within 24 hours of notification, PrECOG will fax the SAE to 
Celgene Drug Safety at 
. 
4. If expedited written report was submitted, this form does not need to be 
completed. 
Version 6.0 
3/28/2011 
Was: 
10.3 Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0 grading unless otherwise stated in the 
table below: 
Is: 
10.2 All Adverse Events are to be graded at each evaluation and all pretreatment 
symptoms/conditions are to be evaluated at baseline per Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.0 grading. The specific Adverse 
Events/Symptoms in the table below are to be collected as indicated below: 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
12 
 
Version 6.0 
3/28/2011 
Was: 
10.4 Serious Adverse Event (SAE) Definition 
A serious adverse event is one that at any dose (including overdose): 
 
Results in death 
 
Is life-threatening
1 
 
Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization 
 
Results in persistent or significant disability or incapacity
2 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event
3 
 
Pregnancy 
Is: 
10.3 Serious Adverse Event (SAE) Definition 
A serious adverse event is one that at any dose (including overdose): 
 
Results in death 
 
Is life-threatening
1 
 
Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization 
 
Results in persistent or significant disability or incapacity
2 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event
3 
 
Diagnosis of a new second primary cancer 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
13 
 
Version 6.0 
3/28/2011 
Was: 
10.42 
Pregnancies 
Pregnancy of a female subject or the female partner of a male subject occurring 
while the subject is on lenalidomide or within 4 weeks after the subject’s last dose 
of lenalidomide are considered expedited reportable events. If the subject is on 
lenalidomide, it is to be discontinued immediately and the subject is to be instructed 
to return any unused portion of lenalidomide to the Investigator. The pregnancy 
must be reported to PrECOG within 24 hours of the Investigator’s knowledge of the 
pregnancy by phone and facsimile using the SAE Form. Within 24 hours of 
notification, PrECOG will fax to Celgene Drug Safety the SAE. 
•  The Investigator will follow the pregnant female until completion of the 
pregnancy, and must notify PrECOG of the outcome as specified below. 
PrECOG will provide Celgene Drug Safety with the outcome The Investigator 
will provide this information as a follow-up to the initial SAE. 
• If the outcome of the pregnancy meets the criteria for immediate classification as 
a SAE (e.g., spontaneous abortion [any congenital anomaly detected in an 
aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for Expedited Reporting 
of SAEs to PrECOG (e.g., report the event to PrECOG by facsimile within 24 
hours of the Investigator’s knowledge of the event). PrECOG will report the 
event to Celgene Drug Safety within 24 hours of the knowledge of the event. 
Is: 
10.32 
Pregnancies 
Pregnancy of a female subject or the female partner of a male subject occurring 
while the subject is on lenalidomide or within 4 weeks after the subject’s last dose 
of lenalidomide are considered expedited reportable events. If the subject is on 
lenalidomide, it is to be discontinued immediately and the subject is to be instructed 
to return any unused portion of lenalidomide to the Investigator. The pregnancy 
must be reported to PrECOG within 24 hours of the Investigator’s knowledge of the 
pregnancy by phone and facsimile using the Pregnancy Form. Within 24 hours of 
notification, PrECOG will fax to Celgene Drug Safety the Pregnancy Form. 
• The Investigator will follow the pregnant female until completion of the 
pregnancy, and must notify PrECOG of the outcome as specified below. 
PrECOG will provide Celgene Drug Safety with the outcome The Investigator 
will provide this information as a follow-up to the initial submission. 
• If the outcome of the pregnancy meets the criteria for immediate classification as 
a SAE (e.g., spontaneous abortion [any congenital anomaly detected in an 
aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for Expedited Reporting 
of SAEs to PrECOG (e.g., report the event to PrECOG by facsimile within 24 
hours of the Investigator’s knowledge of the event). PrECOG will report the 
event to Celgene Drug Safety within 1 business day of the knowledge of the 
event. 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
14 
 
Version 6.0 
3/28/2011 
Was: 
10.42 
Pregnancies 
• Any suspected fetal exposure to lenalidomide must be reported to PrECOG 
within 24 hours of being made aware of the event. PrECOG will report any 
suspected fetal exposure to Celgene Drug Safety within 24 hours of being aware 
of 
the 
event. 
The 
pregnant 
female 
should 
be 
referred 
to 
an 
obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling. 
Is: 
10.32 
Pregnancies 
• Any suspected fetal exposure to lenalidomide must be reported to PrECOG 
within 24 hours of being made aware of the event. PrECOG will report any 
suspected fetal exposure to Celgene Drug Safety within 1 business day of being 
aware of the event. The pregnant female should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling. 
Version 6.0 
3/28/2011 
Was: 
10.5 Expedited Reporting by Investigator to PrECOG 
Is: 
10.4 
Serious Adverse Event Reporting by Investigator to PrECOG 
Version 6.0 
3/28/2011 
Was: 
10.51 
Serious adverse events (SAE) are defined above. The investigator should 
inform PrECOG of any unexpected SAE that is possibly, probably or definitely 
related to drug within 24 hours of being aware of the event. The date of awareness 
should be noted on the report. This must be documented on PrECOG SAE form. 
This form must be completed and supplied to PrECOG within 24 hours/1 business 
day at the latest on the following working day. PrECOG will inform and submit 
SAE Form to Celgene Drug Safety within 24 hours/1 business day of being 
aware of the event. The initial report must be as complete as possible, including 
details of the current illness and (serious) adverse event, and an assessment of the 
causal relationship between the event and the investigational product(s). 
Information not available at the time of the initial report (e.g., an end date for the 
adverse event or laboratory values received after the report) must be documented on 
a follow-up PrECOG SAE report form. A final report to document resolution of the 
SAE is required. The protocol number (RV-MM-PrECOG-0394) (PrE 1003) 
should be included on SAE reports to PrECOG. A copy of the fax transmission 
confirmation of the SAE report to PrECOG should be attached to the SAE and 
retained with the patient records. PrECOG will submit final report to Celgene 
Drug Safety with Celgene Tracking Number RV-MM-PrECOG-0394 
(PrE1003). 


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IND Number: 103014 
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Date: 3/28/2011 
 
 
15 
 
Version 6.0 
3/28/2011 
Is: 
10.41 
Serious adverse events (SAE) are defined above. The investigator should 
inform PrECOG of any SAE within 24 hours of being aware of the event. The date 
of awareness should be noted on the report. This must be documented on PrECOG 
SAE form. This form must be completed and supplied to PrECOG within 24 
hours/1 business day at the latest on the following working day. The initial report 
must be as complete as possible, including details of the current illness and (serious) 
adverse event, and an assessment of the causal relationship between the event and 
the investigational product(s). Information not available at the time of the initial 
report (e.g., an end date for the adverse event or laboratory values received after the 
report) must be documented on a follow-up PrECOG SAE report form. A final 
report to document resolution of the SAE is required. A copy of the fax 
transmission confirmation of the SAE report to PrECOG should be attached to the 
SAE and retained with the patient records. 
Version 6.0 
3/28/2011 
Was: 
10.51 
Serious adverse events (SAE) are defined above. 
PrECOG Drug Safety Contact Information 
PrECOG will forward SAEs that meet expedited reporting requirements and 
related information received from Investigators to Celgene Drug Safety within 
24 hours of receipt of SAE and related documents. 
Is: 
10.41 
Serious adverse events (SAE) are defined above. 
PrECOG Drug Safety Contact Information 
PrECOG will notify Celgene of any SAE within 1 business day of receipt from 
the site. 
Version 6.0 
3/28/2011 
Was: 
10.6 Reporting of Other Second Primary Cancers 
All cases of new primary cancers that occur on PrECOG protocols during or after 
protocol treatment must be recorded as an AE and reported via the eCRF to 
PrECOG. New primary cancers should be reported with 30 days of diagnosis, 
regardless of relationship to protocol treatment. A copy of the pathology report 
should be sent, if available. 
*NOTE:* Once data regarding survival and remission status are no longer 
required by the protocol, no follow-up data should be submitted. 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
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Date: 3/28/2011 
 
 
16 
 
Version 6.0 
3/28/2011 
Is: 
10.5 Reporting of Other Second Primary Malignancies 
All cases of new primary malignancies that occur on PrECOG protocols during or 
after protocol treatment must be reported as a SAE and documented on a 
PrECOG SAE form. New primary malignancies should be reported within 24 
hours of being aware of diagnosis, regardless of relationship to protocol treatment. 
SAE submission process described above in Section 10.4 should be followed. A 
copy of the pathology report should be sent with SAE form, if available. 
*NOTE:* Data regarding survival and remission status, second primary 
malignancies, and recurrence of prior malignancies will be followed 
x 3 years. This should include subjects who may have discontinued 
the study at any time or for any reason, who may be in a survival 
follow-up period, or who may have died. Data for all identified cases 
of subsequently diagnosed second primary malignancies after this 3 
year time will be reported voluntarily by the treating physician to 
the manufacturer. 
Version 6.0 
3/28/2011 
Was: 
11.0 
Treatment Evaluation 
Is: 
11.0 
Treatment Evaluation (Response is to be assessed at the end of each 
treatment cycle within 3 days prior to the start of the next cycle) 
Version 6.0 
3/28/2011 
11.2 
Clarification of Test Indications 
Was: 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study. 
Is: 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study. Response is to be assessed at the end of 
each treatment cycle within 3 days prior to the start of the next cycle. 
Version 6.0 
3/28/2011 
19.7 
Electronic Case Report Form (eCRF) Information 
Was: 
The completed eCRF must be promptly reviewed, electronically signed, and dated 
by a qualified physician who is an Investigator or Sub-investigator. 
Is: 
The completed eCRF must be promptly reviewed, electronically signed and dated 
by the Principal Investigator. 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
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17 
 
Version 6.0 
3/28/2011 
Appendix I Informed Consent Example 
Was: 
Version Date: November 03, 2010 
Is: 
Version Date: March 28, 2011 
Version 6.0 
3/28/2011 
Appendix I Informed Consent Example 
Added: 
Second New Cancers 
According to researchers, patients with cancer have a higher risk of developing 
a second new cancer when compared to people without cancer. In clinical 
studies of newly diagnosed multiple myeloma, a higher number of second 
cancers were reported in patients treated with induction therapy (treatment as 
first step to reducing number of cancer cells) and/or bone marrow transplant 
then lenalidomide for a long period of time compared to patients treated with 
induction therapy and/or bone marrow transplant then placebo (a capsule 
containing no lenalidomide). Patients should make their doctors aware of their 
medical history and any concerns they may have regarding their own 
increased risk of other cancers. 
Version 6.0 
3/28/2011 
Appendix I Informed Consent Example 
What About Confidentiality? 
Added: 
A 
description 
of 
this 
clinical 
trial 
will 
be 
available 
on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not 
include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time. 
Version 6.0 
3/28/2011 
Appendix XI Eligibility Checklist 
Was: 
NOTE:  Phase I Only – Prior to discussing protocol entry with the patient AND 
prior to registering in IWRS, call PrECOG to ensure that a place on the protocol is 
open to the patient. 
Is: 
NOTE:  Phase I Only – Prior to discussing protocol entry with the patient AND 
prior to registering in eDC, call PrECOG to ensure that a place on the protocol is 
open to the patient. 


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IND Number: 103014 
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18 
 
Version 6.0 
3/28/2011 
Appendix XII Investigator’s Statement 
Was: 
1. 
I have carefully read this protocol entitled “A Phase I/II Study of 
the Tolerability of Lenalidomide and Low Dose Dexamethasone 
in Previously Treated Multiple Myeloma Patients with Impaired 
Renal Function, Version 5.0 dated 11/03/2010” (Protocol number 
PrE1003) and agree that it contains all the necessary information 
required to conduct the study. I agree to conduct the study as outlined 
in the protocol. 
Is: 
1. 
I have carefully read this protocol entitled “A Phase I/II Study of 
the Tolerability of Lenalidomide and Low Dose Dexamethasone 
in Previously Treated Multiple Myeloma Patients with Impaired 
Renal Function, Version 6.0 dated 3/28/2011” (Protocol number 
PrE1003) and agree that it contains all the necessary information 
required to conduct the study. I agree to conduct the study as outlined 
in the protocol. 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
19 
 
 
 
 
PrECOG STUDY SITE CONTACTS 
Carolyn Andrews, R.N. 
Project Manager 
PrECOG, LLC 
1818 Market Suite, Suite 1100 
Philadelphia, PA 19103 
9:00 am-5:00 pm 
Eastern Time Zone 
Phone: 215-789-7001 
Email: candrews@ecogchair.org 
 
MEDICAL MONITOR 
 
PrECOG, LLC 
2500 Renaissance Blvd., Suite 170 
King of Prussia, PA 19406 
8:30 am-5:00 pm 
Eastern Time Zone 
Phone: 610-354-0404 
After 5:00 pm Eastern Time Zone 
Phone: 484-574-2367 
 
SAE Fax: 888-577-9921 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
20 
 
Table of Contents 
1.0 
Background ....................................................................................................................................... 22 
2.0 
Objectives .......................................................................................................................................... 27 
3.0 
Patient Eligibility ............................................................................................................................... 28 
4.0 
Test Schedule .................................................................................................................................... 31 
5.0 
Stratification Factors ......................................................................................................................... 34 
6.0 
Registration/Randomization Procedures ........................................................................................... 35 
7.0 
Protocol Treatment ............................................................................................................................ 37 
8.0 
Dosage Modification Based on Adverse Events for Phase I and Phase II ......................................... 42 
9.0 
Ancillary Treatment .......................................................................................................................... 47 
10.0 
Adverse Event (AE) Monitoring and Reporting ................................................................................ 48 
11.0 
Treatment Evaluation ........................................................................................................................ 54 
12.0 
Descriptive Factors ............................................................................................................................ 59 
13.0 
Treatment/Follow-Up Decision at Evaluation of Patient .................................................................. 60 
14.0 
Body Fluid Biospecimens.................................................................................................................. 62 
15.0 
Background Drug Information .......................................................................................................... 66 
16.0 
Statistical Considerations and Methodology ..................................................................................... 71 
17.0 
Pathology Considerations: None ....................................................................................................... 77 
18.0 
Budget Considerations ...................................................................................................................... 78 
19.0 
Administrative ................................................................................................................................... 79 
20.0 
References ......................................................................................................................................... 83 
Appendix I 
 Informed Consent Example .............................................................................................................. 85 
Appendix II 
 Multiple Myeloma Diagnostic Criteria ............................................................................................. 99 
Appendix III 
ECOG Performance Status Scale .................................................................................................... 100 
Appendix IV 
Cockcroft-Gault Estimation of Creatinine Clearance (CrCl) ........................................................... 101 
Appendix V 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods .. 102 
Appendix VI 
Education and Counseling Guidance Document ............................................................................. 106 
Appendix VII Lenalidomide Information Sheet ..................................................................................................... 109 
Appendix VIII Lenalidomide Days 1 to 21 MEDICATION DIARY ...................................................................... 112 
Appendix IX 
Lenalidomide Every Other Day MEDICATION DIARY ............................................................... 113 
Appendix X 
Lenalidomide Two Times Weekly MEDICATION DIARY........................................................... 114 
Appendix XI 
Eligibility Checklist ......................................................................................................................... 115 
Appendix XII Investigator's Statement ................................................................................................................... 118 
 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
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Date: 3/28/2011 
 
 
21 
 
Schema 
PHASE I only: Prior to discussing protocol entry with the patient, call the PrECOG Project 
Manager to ensure that a place on the protocol is open to the patient. The Project Manager contact 
information is located in the Study Reference Manual. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or never received treatment, please refer to Section 13.0 for follow-up 
information. 
1 Cycle = 28 days 
2 If patient is treated beyond 4 cycles, therapy may be interrupted to allow for stem cell harvest and 
mobilization (see Section 7.0). 
3 Patients must also be treated with anticoagulants (see Section 9.4). 
4 Refer to Section 7.21 for Dose Escalation Tables 
5 Dialysis includes hemodialysis or peritoneal dialysis 
6 When lenalidomide treatment day occurs on a dialysis day, lenalidomide must be taken after dialysis 
Generic name: Lenalidomide 
Brand name(s): Revlimid® 
Availability: Provided by Celgene 
Generic name: Dexamethasone 
Brand name: Decadron 
Availability: Commercial 
Registration 
 
Event Monitoring 
PD at any time 
 
 
 
 
 
 
 
 
Follow-Up 
Unacceptable adverse events 
 
 
 
 
 
 
 
 
Surveillance 
Patient refusal 
Treatment Group A: 
 
Patients with  
30-60 CrCl (mL/min) 
 
 
Lenalidomide days 1-21 
Dexamethasone days 1, 8, 
15, 22 
Every Cycle1, 2, 3, 4 
 
Treatment Group C: 
 
Patients with  
<30 CrCl (mL/min) 
requiring dialysis5 
 
Lenalidomide days 1-216 
Dexamethasone days 1, 8, 
15, 22 
Every Cycle1, 2, 3, 4 
 
Treatment Group B: 
 
Patients with  
<30 CrCl (mL/min)  
not requiring dialysis 
 
Lenalidomide every other 
day, days 1-21 
Dexamethasone days 1, 8, 
15, 22 
Every Cycle1, 2, 3, 4 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
22 
 
1.0 
Background 
 
1.1 
Multiple Myeloma (MM) 
 
MM affects approximately 20,000 Americans annually1 and remains an incurable 
hematologic malignancy characterized by frequent early response followed by universal 
treatment relapse necessitating multiple sequential therapeutic regimens.2 Until recently, 
few effective therapies existed. Several novel agents for MM have now become available 
including the immunomodulatory drugs thalidomide,3 lenalidomide,4 as well as the 
proteasome inhibitor, bortezomib.5 Each of these agents is undergoing extensive clinical 
evaluation in combination with other therapies to produce unprecedented response rates 
in newly diagnosed and relapsed MM. Indeed, comparative studies show these agents to 
be more effective than conventional chemotherapies when used as primary induction 
therapy prior to stem cell transplantation6-8 and salvage therapy in patients with MM.9-10 
Lenalidomide has proven to be a highly effective treatment agent, particularly when used 
in combination with dexamethasone11 but is renally excreted and little information is 
available about its use in myeloma patients with impaired kidney function (20% have 
renal failure at some time after diagnosis). Defining a safe and effective dose of 
lenalidomide to use is then a critical step in MM treatment. 
 
1.2 
Lenalidomide 
 
The immunomodulatory drugs thalidomide (Thal) and lenalidomide especially in 
combination with dexamethasone have proven to be the standard for relapsed/refractory 
disease as well as front line MM therapy. In phase II clinical studies, single-agent 
thalidomide or lenalidomide therapy administered to heavily pre-treated patients with 
relapsed or refractory MM has resulted in response rates of 20-30%.4, 12
 
Lenalidomide is a 
proprietary IMiD® compound of Celgene Corporation. IMiDs®, of which thalidomide is 
the parent compound, has both immunomodulatory and anti-angiogenic properties which 
could confer anti-tumor and anti-metastatic effects.13-14 
 
1.3 
Clinical Experience in Multiple Myeloma with Lenalidomide 
 
In two phase I studies in multiple myeloma, a total of 40 patients have been treated with 
lenalidomide. In one study at the University of Arkansas, 15 patients who relapsed or 
were refractory to high dose melphalan therapy with stem cell transplant were treated for 
4 weeks in an open-label safety study and were permitted to continue therapy in an 
extension phase of the trial.15 Patient cohorts were treated at the following daily doses: 5 
mg, 10 mg, 25 mg, and 50 mg. In a similar study at the Dana Farber Cancer Institute, 25 
patients with rapidly advancing refractory multiple myeloma were treated.16 
 
Anti-myeloma activity was observed in each of these two phase I studies. Decreases in 
neutrophil and platelet counts were the dose-limiting toxicities associated with 
lenalidomide. The maximum tolerated dose (MTD) was not reached within 28 days. Due 
to dose modifications associated with myelosuppression observed beyond Day 28 at the 
25 mg and 50 mg daily dose levels, the dose schedule most widely used in future studies 
has been lenalidomide 25 mg on Days 1-21, repeated every 28 days. 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
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Date: 3/28/2011 
 
 
23 
 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the 
phase I studies.16 Absorption was found to be rapid on both Day 1 and Day 28 with time 
to maximum blood levels ranging from 0.7 to 2.0 hours at all dose levels (5 mg, 10 mg, 
25 mg and 50 mg). Plasma lenalidomide declined in a monophasic manner with 
elimination half-life ranging from 2.8 to 6.1 hours on both Day 1 and 28 at all 4 doses. 
No plasma accumulation was observed with multiple daily dosing. Peak and overall 
plasma concentrations were dose proportional over the dosing range of 5 mg to 50 mg. 
 
A multicenter, randomized, phase II trial compared 2 syncopated dose schedules of 
lenalidomide used alone or in combination with dexamethasone in the treatment of 
relapsed or refractory multiple myeloma.17 All patients were treated on Days 1-21 of a 
28-day cycle. Patients treated with 15 mg BID experienced more myelosuppression and 
dose reductions compared with patients treated with 30 mg daily. Anti-myeloma activity 
was observed with each dose and schedule of single agent lenalidomide. The addition of 
dexamethasone to lenalidomide yielded responses in some patients who had not 
responded to lenalidomide alone. 
 
A recent phase II trial utilizing lenalidomide plus dexamethasone for newly diagnosed 
multiple myeloma patients was recently reported by the Mayo Clinic.7 Lenalidomide was 
given orally 25 mg daily on days 1-21 of a 28-day cycle. Dexamethasone was given 
orally 40 mg daily on days 1-4, 9-12, 17-20 of each cycle. Objective response was 
defined as a decrease in serum monoclonal protein by 50% or greater and a decrease in 
urine M protein by at least 90% or to a level less than 200 mg/24 hours, confirmed by 
two consecutive determinations at least 4 weeks apart. Thirty-one of 34 patients achieved 
an objective response, including 2 (6%) achieving complete response (CR), and 11 (32%) 
meeting criteria for both very good partial response and near complete response, resulting 
in an overall objective response rate of 91%. Of the 3 remaining patients not achieving an 
objective response, two had minor response (MR) and one had stable disease. Forty-
seven percent of patients experienced grade 3 or higher non-hematologic toxicity, most 
commonly fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%), and 
rash (6%). Lenalidomide and dexamethasone is a highly active regimen with manageable 
side-effects in the treatment of newly diagnosed myeloma.
 
 
 
Celgene Corporation sponsored 2 multicenter, randomized, double-blinded, placebo-
controlled phase III trials, one U.S. (MM-009)11 and one international (MM-010),18 in 
patients with relapsed or refractory multiple myeloma. More than 350 patients were 
enrolled into each of these studies. All patients had to be considered sensitive to 
dexamethasone and were treated with dexamethasone 40 mg qd, Days 1-4, 9-12 and 17-
20. In addition to receiving dexamethasone, patients were randomized to lenalidomide 25 
mg qd or placebo, Days 1-21. Cycles were repeated every 28 days. After 4 cycles, there 
was a predetermined reduction of the dexamethasone dose to 40 mg qd, Days 1-4 
repeated every 28 days. In both studies, a pre-specified interim analysis conducted by an 
Independent Data Monitoring Committee demonstrated that subjects receiving the 
combination of lenalidomide plus dexamethasone had significantly longer times to 
progression and higher response rates than those treated with single-agent 
dexamethasone. These studies led to the FDA approval of lenalidomide in combination 
with dexamethasone for the treatment of multiple myeloma in patients that have received 
at least one prior therapy. 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
24 
 
An additional subgroup analysis was performed on patients with impaired creatinine 
clearance (CrCl).19 No significant difference in response rate, time to progression, or 
overall survival was noted for patients with CrCl above or below 50 ml/min who were 
treated with Lenalidomide and dexamethasone, but for 16 patients with CrCl <30 ml/min, 
median time to progression (TTP) and overall survival (OS) was shorter than for those 
with CrCl >30 ml/min, but still significantly higher than for patients treated with 
dexamethasone. Grade 3-4 thrombocytopenia was significantly higher in patients with 
impaired renal function (<50 ml/min, 13.8%; >50 ml/min 4.6%, p<.01; <30 ml/min, 
18.8%, >30 ml/min, 5.5%, p<.05), but there was no difference for grade 3-4 neutropenia 
at either cutoff.
 
 
 
1.4 
Lenalidomide Pharmacokinetics 
 
Absorption: 
 
 
 
 
 
Multiple dosing at the recommended dose-
regimen does not result in drug accumulation.20 
 
 
 
 In multiple myeloma 
patients, those with mild renal impairment had an AUC 56% greater than those with 
normal renal function.21 
 
Distribution: In vitro (14C)-lenalidomide binding to plasma proteins is approximately 
30%.20 
 
Metabolism and Excretion: 
 
 
 
 
 
Steady-state levels are 
achieved by Day 4.20 
 
This drug is known to be substantially excreted by the kidneys, and the risk of toxic 
reactions to this drug may be greater in patients with impaired renal function.22 Dysuria, 
renal failure, hematuria, acute renal failure, azotemia, calculus ureteric, and renal mass 
are listed as reported adverse events in the package insert. 
 
1.5 
Experience in Newly Diagnosed Myeloma with Renal Failure 
 
Niesvizky et al. evaluated 58 newly diagnosed multiple myeloma patients on 
lenalidomide 25 mg daily on days 1-21 of a 28 day cycle, dexamethasone 40 mg weekly, 
and Biaxin 500 mg twice daily (BiRD).22 Eleven of 36 patients who achieved a partial 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
25 
 
response to therapy required a dose reduction of lenalidomide for neutropenia and/or 
thrombocytopenia. Ten of these 11 patients had a serum creatinine level >1.4 mg/dL 
(p<0.0001). When using the Cox proportional hazards regression model, it indicated 6.4-
fold increased dose-reduction likelihood for each 1-unit increase in baseline serum 
creatinine level. A creatinine clearance ≤40 ml/min was similarly associated with 
lenalidomide dose reductions. The authors state that myelosuppression and renal 
dysfunction potentiate the need for lenalidomide dose reductions. 
 
1.6 
Experience in Relapsed/Refractory Multiple Myeloma 
 
The combination of lenalidomide ± corticosteroid was evaluated in 69 patients with 
relapsed/refractory multiple myeloma.23 Of the 69 patients, 23 had an elevated baseline 
creatinine (cr) level (group 1: median cr=138 umol/L, range 110-412 umol/L) and 46 had 
normal cr level (group 2: 80 umol/L, range 51-109 umol/L). After 3 cycles of therapy, 
median cr was 104 umol/L (range 61-372) in group 1 and 79 umol/L (range 53-180) in 
group 2. Creatinine was decreased in 39% of patients in both groups, and increased in 
26% and 32% of patients in group 1 and 2, respectively (p=0.56). In addition, it was seen 
that patients with an elevated creatinine had a lower baseline platelet count, and during 
therapy experienced more grade 3-4 thrombocytopenia and were more likely to require 
platelet transfusion. 
 
A subgroup analysis from the registration trials for patients with previously treated 
myeloma concluded that no significant difference was noted in response rate, time to 
progression or overall survival between patients whose creatinine clearance was above or 
below 50 ml/min. In the 16 patients with creatinine clearance below 30 ml/minute, time 
to progression and overall survival was shorter than for those with creatinine clearance 
above 30 ml/min. Grade 3-4 thrombocytopenia (but not grade 3-4 neutropenia) was also 
noted to be significantly higher in patients with impaired renal function.19 
 
1.7 
Dosing Recommendation for Lenalidomide in Patients with Renal Impairment, 
Hemodialysis  
 
Chen et al.21 conducted a multi-center study with lenalidomide 25 mg a day as a single 
oral dose in five groups of subjects defined by renal function [1] normal (CrCl >80 
mL/min); [2] mild (CrCl: >50- <80 mL/min); [3] moderate (CrCl:>30- <50 mL/min); [4] 
severe (CrCl <30 mL/min but not on dialysis); [5] End Stage Renal Disease (requiring 
dialysis). Thirty subjects over the age of 35 were included in the study. Subjects with 
normal, mild, moderate or severe renal insufficiency received a single 25 mg oral dose of 
lenalidomide. Subjects with end stage renal disease (ESRD) received 2 single 25 mg 
doses, separated by 7-10 days: one dose on a non-dialysis day and the other dose 3 hours 
before a 4-hour hemodialysis.  21 Blood and urine samples were collected over 72 hours 
and creatinine clearance was estimated with a 24-hour urine collection (Celgene 
Corporation 2006). Assessments included PK and safety parameters. All subjects 
completed the study. Total and renal clearance of lenalidomide were strongly correlated 
with CrCl (R >0.9, p <0.01). As a result, AUC∞ increased with decreasing CrCl. The 
mean difference in AUC∞ between normal renal function (NRF) and mild renal 
insufficiency (RI) was <20%. Compared with the pooled data from NRF and mild RI 
groups, mean AUC∞ increased approximately 140% in moderate RI, 240% in severe RI, 
and 360% in ESRD (off dialysis). There was no correlation between Cmax or Tmax and 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
26 
 
CrCl. Approximately 10% of the dose was recovered in the dialysate of subjects with 
ESRD. Protein binding of lenalidomide was not markedly affected by RI (~35 - 44%). 
The drug was well tolerated. On the basis of these data, recommendations for initial 
starting doses were made. 
 
The following dose recommendations were suggested by Chen et al. for patients with 
MM and MDS and renal dysfunction and were based on Area Under the Curve for entire 
exposure to the drug (AUC 0-∞). The lower doses of lenalidomide recommended for 
patients with renal dysfunction are derived from modeling to produce AUCs comparable 
to those produced by the administration of a 25 mg or 10 mg dose of lenalidomide, 
respectively, in patients with normal renal function. (Note: For previously treated 
multiple myeloma dosing is for 21 days of a 28-day cycle. Dosing is continued or 
modified based on clinical and laboratory findings.) 
 
Renal Function (CrCL) Multiple Myeloma 
 
• 
Mild (CrCl ≥50 mL/min) 25 mg qd (Full Dose) 
• 
Moderate (30 ≤ CrCl <50 mL/min) 10 mg qd * 
• 
Severe (CrCl <30 mL/min, not requiring dialysis) 15 mg q 48 hr 
• 
ESRD (CrCl <30 mL/min, requiring dialysis) 15 mg 3x a week following each 
dialysis 
 
*The dose may be escalated to 15 mg qd after 2 cycles if patient is tolerating drug well 
but not responding to treatment. 
 
In summary since data on the maximum tolerated dose of lenalidomide in impaired renal 
function is lacking and this remains a clinically significant issue we plan to do this phase 
I/II trial in previously treated MM patients with varying degrees of renal impairment to 
clinically assess the MTD per risk group. This trial is designed after the Chen et al.21 
experience. 
 
This study originated December 22, 2008 at Mayo Clinic in Arizona and Rochester. As of 
November 09, 2010, a total of 15 subjects have been enrolled. It is now being opened at 
multiple institutions through PrECOG with 10 sites for Phase I (including above Mayo 
sites) and 30 sites for Phase II. 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
27 
 
 
2.0 
Objectives 
 
2.1 
Primary Objectives 
 
2.11 
Phase I Trial: To establish the maximum tolerated dose of lenalidomide in each of three 
groups of myeloma patients with impaired renal function. 
 
2.12 
Phase II Trial: To assess the efficacy (response rate [CR, sCR, VGPR, PR]) of this 
combination across the three groups of myeloma patients with impaired renal function. 
 
2.2 
Secondary Objectives 
 
2.21 
To describe the overall survival, progression-free survival, duration of response, and time 
to treatment failure of myeloma patients with impaired renal function treated with 
lenalidomide and dexamethasone. 
 
2.22 
To evaluate the safety profile of lenalidomide given in combination with weekly 
dexamethasone in myeloma patients with impaired renal function. 
 
2.23 
To describe renal function over time and to evaluate the safety profile of a onetime 
increase in lenalidomide dose at least 2 cycles after start of treatment due to improved 
renal function. 
 
2.24 
To determine the pharmacokinetics of lenalidomide administration in myeloma patients 
with impaired renal function (pharmacokinetic analysis will be performed in up to 12 
consented Mayo Clinic subjects treated during the Phase II component of the trial only). 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
28 
 
 
3.0 
Patient Eligibility 
 
3.1 
Eligibility Criteria  
 
NOTE:  Phase I Only – Prior to discussing protocol entry with the patients AND prior to 
registering in the electronic data capture (eDC) system, call the PrECOG Project 
Manager to ensure that a place on the protocol is open to the patient. The Project 
Manager contact information is located in the Study Reference Manual. 
 
3.11 
≥18 years of age. 
 
3.12 
Diagnosed with previously treated multiple myeloma (please see Appendix II for 
definition of myeloma). 
 
3.13 
Patients must have measurable disease assessed by one of the following ≤21 days prior to 
registration: 
• 
Serum monoclonal protein ≥1 g by protein electrophoresis* 
• 
>200 mg of monoclonal protein in the urine on 24 hour electrophoresis*  
• 
Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum 
immunoglobulin kappa to lambda free light chain ratio 
• 
Monoclonal bone marrow plasmacytosis ≥30% (evaluable disease) 
*NOTE:  If both serum and urine m-components are present, both must be 
followed in order to evaluate response. 
 
3.14 
All previous cancer therapy including chemotherapy, radiation, hormonal therapy and 
surgery, must have been discontinued ≥2 weeks prior to registration. 
 
3.15 
ECOG Performance Status (PS) 0, 1, or 2 (see Appendix III). 
 
3.16 
Acceptable organ and marrow function ≤21 days prior to registration as defined below: 
• 
Absolute neutrophil count ≥1000 cells/mm3 
 
 
• 
Platelet count ≥75,000 cells/mm3  
• 
Total bilirubin ≤2 mg/dL. 
• 
AST (SGOT) and ALT (SGPT) ≤3 x ULN 
 
3.17 
Renal impairment at baseline as measured by serum creatinine clearance (CrCl) ≤60  
mL/min ≤21 days prior to registration (see Appendix IV). 
 
 
 
 
 
 
 
 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
29 
 
3.18 Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy 
test with a sensitivity of at least 25 mIU/mL within 10 – 14 days and again within 24 hours 
prior to starting Cycle 1 of lenalidomide 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 V: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods, AND also Appendix VI: Education and Counseling Guidance 
Document. 
 
3.19a 
Able to take required prophylactic anticoagulation (see Section 9.4). 
 
3.19b Ability to understand and the willingness to sign a written informed consent document. 
 
3.19c 
Patient willing to provide blood samples for research purposes (see Sections 4.0 and 
14.0). Only applies to selected subjects registered at Mayo Clinic only to the Phase II 
component (12 subjects total). 
 
3.19d If previously received lenalidomide, demonstration of clinical response of any duration or 
stable disease with progression-free interval of ≥6 months from the start of that therapy. 
 
3.2 
Exclusion Criteria 
 
3.21 
Concurrent use of other anti-cancer agents or treatments. NOTE: Growth factors and 
bisphosphonates are allowed as medically indicated. Steroids may be used with an 
equivalency of up to 20 mg Prednisone per day as long as the dose has not been adjusted 
upwards in past 2 weeks prior to study registration. 
 
3.22 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina 
pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
3.23 
Any of the following as this regimen may be harmful to a developing fetus or nursing 
child: 
• 
Pregnant women 
• 
Breast-feeding women 
• 
Men or women of childbearing potential or their sexual partners who are unwilling 
to employ adequate contraception (condoms with spermicidal agent, diaphragm, 
birth control pills, injections, intrauterine device [IUD], surgical sterilization, 
subcutaneous implants, or abstinence, e.g.). 
                                                     
 
† A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not 
rule out childbearing potential) for at least 24 consecutive months (e.g., has had menses at any time in the preceding 
24 consecutive months). 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
30 
 
 
3.24 
HIV-positive patients on combination antiretroviral therapy (because of the potential for 
pharmacokinetic interactions with lenalidomide. NOTE: 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). 
 
3.25 
Known hypersensitivity to thalidomide or other immunomodulary drugs (IMiDs®). 
 
3.26 
History of Stevens-Johnson syndrome characterized by a desquamating rash while taking 
thalidomide or similar drugs. 
 
3.27 
Other active malignancy with the exception of non melanoma skin cancer or in situ 
cervical or breast cancer. 
 
3.28 
Concurrent radiation therapy, except for palliation of a single painful bone lesion or 
fracture. 


 
 
 
 
 
 
PrECOG Protocol Number:  PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
31 
 
4.0 
Test Schedule 
 
*Treatment should begin ≤7 working days from registration 
 
*Variations of +/- 3 days of the scheduled visits are permitted 
 
 
≤21 days 
prior to 
registration 
 
Cycle 
1 only 
For Each of the First Four Cycles 
End of 
Cycle 4 
Day 1 Each 
additional 
cycle17 
Day 1 of cycle 
9 or at end of 
treatment 
Follow-Up16,18 
 
Day 6 
Day 1 
Day 8 
Day 15 
Day 22 
 
 
 
 
History & Exam, Wt., PS Assessment 
X 
 
X12 
  
  
  
X 
X 
X 
 
Height 
X 
 
  
  
  
  
  
  
  
 
CBC w/differential 
X 
 
X13 
X 
X 
X 
 
X13 
 
 
Chemistry Panel 
(Na,K,Ca,AST,ALT,Alk Phos,Total 
Bili, Glucose, Creatinine, Albumin) 
X 
 
X 
 X14 
 X14 
 X14 
X 
X 
X 
 
Serum Creatinine Clearance1 
X 
 
X 
 
 
 
X 
X 
X 
 
LDH, Beta-2 Microglobulin,  
C-Reactive Protein 
X 
 
  
  
  
  
X 
  
X 
 
Serum TSH2 
X 
 
X 
 
 
 
 
X 
 
 
SPEP3 
X 
 
X12 
 
 
 
X 
X 
X 
 
UPEP (24hr collection)3 
X 
 
X12 
 
 
 
X 
X 
X 
 
Quantitative Immunoglobulins3 
X 
 
X12 
 
 
 
X 
X 
X 
 
Serum Free Light Chains3 
X 
 
X12 
 
 
 
X 
X 
X 
 
Immunofixation-Serum & Urine4 
X 
 
  
  
  
  
X 
 
X 
 
Bone Marrow Biopsy w/aspirate 
X5 
 
  
  
  
  
X15 
 
X15 
X19 
Bone Marrow-FISH, cytogenetics 
X5 
 
  
  
  
  
  
 
  
 
Metastatic Bone Survey w/ long bones 
X5 
 
  
  
  
  
X 
 
X 
 
Chest X-Ray 
X 
 
  
  
  
  
  
 
  
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
32 
 
 
≤21 days 
prior to 
registration 
 
Cycle 
1 only 
For Each of the First Four Cycles 
End of 
Cycle 4 
Day 1 Each 
additional 
cycle17 
Day 1 of cycle 
9 or at end of 
treatment 
Follow-Up16,18 
 
Day 6 
Day 1 
Day 8 
Day 15 
Day 22 
 
 
 
 
ECG 
X 
 
  
  
  
  
  
 
  
 
Pharmacokinetics6, R 
 
X6 
 
 
 
 
 
 
 
 
INR7 
 
 
X7 
X7 
X7 
X7 
X7 
X7 
X7 
 
Pregnancy Testing8 
X8 
 
X8 
  
 
  
  
X8 
X8  
 
Education and Counseling Guidance 
Document9 
 
 
X9 
 
 
 
 
X9 
X9 
 
Dispense Study Drug10 
 
 
X10 
 
 
 
 
X10 
 
 
Study Drug Compliance (Medication 
Diary) 
 
 
X 
 
 
 
 
X 
X 
 
Adverse Event Assessment11 
 
 
 
X 
X 
X 
X16 
X 
X16 
 
X16 
Survival and Malignancy Surveillance 
 
 
 
 
 
 
 
 
 
 
X18 
 
1. 
Creatinine clearance will be estimated using the Cockroft-Gault formula. If the patient is >65 y/o and creatinine is <1, use 1 as serum 
creatinine value to calculate the creatinine clearance, see Appendix IV. 
2. 
To be completed at baseline and then every 3 months. 
3. 
Required at baseline, and then only required if used to assess disease response (see Section 11.2, Table 11.2). 
4. 
Is required at study entry only if not previously performed or test results not available. If complete response is seen a 2nd immunofixation 
should be performed 4 weeks later to confirm. Urine immunofixation is only required if positive at study entry. 
5. 
Bone marrow (with aspirate/FISH/cytogenetics) and skeletal survey may be used if performed ≤90 days of study enrollment. 
6. 
Only applies to selected Mayo Clinic subjects registered to the Phase II component. Pharmacokinetics of lenalidomide: 5cc of blood is 
to be drawn and put into an EDTA tube at the following time points on Day 6 of Cycle 1: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hr at 
all dose groups and at 48 and 72 hr for patients in Group B with severe renal impairment or in Group C on dialysis (hemodialysis or 
peritoneal dialysis). Please see Section 14.2 for processing procedures. Pharmacokinetic samples will be collected from up to 12 Mayo 
Clinic participants with a minimum of two patients in each group (Groups A, B and C) of the Phase II component. 
7. 
Treatment with Coumadin should be used with caution. If a patient is being treated with Coumadin, close monitoring of INR is required. 
8. 
Pregnancy tests for females of childbearing potential. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has 
not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
33 
 
therapy does not rule out childbearing potential) for at least 24 consecutive months (e.g., has had menses at any time in the preceding 24 
consecutive months). Pregnancy tests must occur within 10–14 days prior to initiation of Cycle 1 of lenalidomide and again within 24 
hours prior to initiation of Cycle 1 of lenalidomide. FCBP with regular or no menstruation must have a pregnancy test weekly for the 
first 28 days and then every 28 days while on lenalidomide therapy (including breaks in therapy); at discontinuation of lenalidomide and 
at Day 28 post the last dose of lenalidomide. Females with irregular menstruation must have a pregnancy test weekly for the first 28 days 
and then every 14 days while on lenalidomide therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 
and Day 28 post the last dose of lenalidomide (see Appendix V: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods). 
9. 
All patients must be counseled about pregnancy precautions, risks of fetal exposure and other risks. The counseling must be done on 
Day 1 of each cycle (or at a minimum of every 28 days) throughout the entire duration of lenalidomide treatment, including dose 
interruptions, and at lenalidomide discontinuation. The Appendix VI: Education and Counseling Guidance Document must be 
completed by a trained Counselor (Counselors will be trained by Celgene). 
10. Only enough lenalidomide for 1 cycle of therapy may be provided to the patient each cycle. 
11. Refer to Section 10.2 for minimum events to be collected at baseline and each evaluation. 
12. Except Day 1 of Cycle 1. 
13. On Day 1of each cycle, the ANC must be ≥1,000/µL and the platelet count must be ≥50,000/µL. 
14. Serum creatinine only. 
15. Bone marrow aspirate and biopsy are only required to document or confirm CR or sCR, except for patients with evaluable disease only, 
where a bone marrow is required to document all response categories including progression (see Section 11.3). However, a second 
confirmatory bone marrow is not required to confirm response.  
16. An additional safety assessment will be done 30 days (+/- 2 days) following the last dose of study drug. 
17. Therapy may be interrupted to allow for stem cell harvest and mobilization for patients treated beyond 4 cycles. 
18. Follow-up every 6 months for survival, second primary malignancy diagnosis, and recurrence of any prior malignancy (if applicable) x 3 
years. If patient has not progressed at off-study, document date of progression. This should include subjects who may have discontinued 
the study at any time or for any reason, who may be in a survival follow-up period, or who may have died. Following this 3 year time 
period, reporting of all identified cases of subsequently diagnosed second primary malignancies is voluntary by the treating physician to 
the manufacturer. 
19. Note: In addition to the standard evaluation for prolonged cytopenias that do not recover after discontinuation of treatment, a bone 
marrow exam should be considered, in patients with the following parameters: no leukopenia at the time of multiple myeloma diagnosis, 
no active multiple myeloma at the time of the cytopenia, no vitamin or element deficiency to explain the cause of the cytopenia(s). 
 
 
 
 R 
Research test. Will be charged to study and not to patient’s account. 


 
 
 
 
 
 
PrECOG Protocol Number:  PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
34 
 
5.0 
Stratification Factors 
 
5.1 
Renal Impairment: Group A: Moderate renal dysfunction 30-60 CrCl mL/min) vs. Group 
B: Severe renal dysfunction (CrCl <30 mL/min, not requiring dialysis) vs. Group C: 
ESRD renal dysfunction (CrCl <30 mL/min, requiring hemodialysis or peritoneal 
dialysis) 
 
5.2 
Component: Phase I vs. Phase II  
 
5.3 
Dose Level: 1 vs. 2 vs. 3 vs. 4  


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
35 
 
 
6.0 
Registration/Randomization Procedures 
 
6.1 
Ethics 
 
This study will be conducted in accordance with the ethical principles that have their 
origin in the current Declaration of Helsinki and will be consistent with applicable US 
regulatory requirements and International Conference on Harmonization Good Clinical 
Practice (ICH GCP). 
 
The study will be conducted in compliance with the protocol. The protocol and any 
Amendments and the patient informed consent will receive Institutional Review Board 
(IRB) approval prior to initiation of the study. 
 
Freely given written informed consent must be obtained from every patient or their 
legally acceptable representative prior to clinical trial participation, including informed 
consent for any screening procedures conducted to establish patient eligibility for the 
trial. 
 
Study personnel involved in conducting this trial will be qualified by education, training, 
and experience to perform their respective task(s). This trial will not use the services of 
investigators or study personnel where sanctions have been invoked or where there has 
been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
Investigators are responsible for the conduct of the study at their study site. 
 
6.2 
Regulatory Requirements 
 
Before a site may enter patients, protocol-specific regulatory and other documents must 
be submitted to PrECOG representatives as noted in study materials. Detailed 
information regarding document submission and control is provided to each site in 
separate study materials. 
 
Once all required documents are received, reviewed, and approved by PrECOG or their 
representative, a registration information packet will be forwarded to the site. Any 
changes to site regulatory documents must be submitted by the investigator to the 
responsible party in a timely manner. Initial study drug shipment will not occur until the 
regulatory packet is complete. No patients should begin protocol therapy without formal 
registration as per the process below. 
 
6.3 
Registration Procedures 
 
6.31 
Phase I Dose Escalation – Prior to discussing protocol entry with patient AND prior to 
registering a patient through the electronic data capture (eDC) system, call the PrECOG 
Project Manager to ensure that a place on the protocol is open to the patient. The Project 
Manager contact details can be found in the Study Reference Manual. 
 
6.311 Patients must not start protocol treatment prior to registration. 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
36 
 
Patients must meet all of the eligibility requirements listed in Section 3.0 prior to 
registration. Treatment should begin ≤7 working days from registration. 
 
An eligibility checklist is included in Appendix XI and a usable version is available in 
separate study materials provided to the site. A confirmation of eligibility assessment by 
the investigator and/or site will be performed during the registration process. 
 
Upon determination that a subject meets eligibility criteria, the subject will be registered 
in the study by site personnel via an electronic data capture eDC system. Confirmation of 
registration will be displayed in the eDC system once site personnel have verified the 
subject’s eligibility status.  
 
Full information regarding registration procedures and guidelines can be found in the 
Study Reference Manual provided to your site. All correspondence regarding patient 
registration must be kept in the study records.  
 
6.32 
Phase II Patient Registration 
 
Patients must not start protocol treatment prior to registration. 
 
Patients must meet all of the eligibility requirements listed in Section 3.0 prior to 
registration. Treatment should begin ≤7 working days from registration. 
 
An eligibility checklist is included in Appendix XI and a usable version is available in 
separate study materials provided to the site. A confirmation of eligibility assessment by 
the investigator/site will be performed during the registration process. 
 
Upon determination that a subject meets eligibility criteria, the subject will be registered 
in the study by site personnel via an electronic data capture (eDC) system. Confirmation 
of registration will be displayed in the eDC system once site personnel have verified the 
subject’s eligibility status. 
 
Full information regarding registration procedures and guidelines can be found in the 
Study Reference Manual provided to your site. All correspondence regarding patient 
registration must be kept in the study records. 
 
6.321 Body Fluid Biospecimens  
 
A mandatory translational research component for blood specimens is part of this study; 
the patient will be automatically registered onto this component (Sections 3.18c, 4.0 and 
14.0). Only applies to select Mayo Clinic subjects registered to the Phase II component. 
 
6.4 
Pretreatment tests must be completed within the guidelines specified on the test schedule. 
 
6.5 
All required baseline symptoms must be documented and graded. 
 
6.6 
Study drug availability checked. 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
37 
 
 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule 
 
7.11 
Phase I Component: 
 
• 
Lenalidomide at assigned dose (Section 7.21, Tables 7.211, 7.212 or 7.213)  
• 
Dexamethasone 40 mg orally on days 1, 8, 15 and 22  
• 
Anticoagulation (see Section 9.4) 
 
Dosing for lenalidomide for each group is per the assigned cohort; see tables in Section 
7.21. Each cycle is 28 days. All groups get a 7 day rest (days 22-28) from lenalidomide. 
Dosing will be in the morning at approximately the same time each day. Only one cycle 
of study drug will be supplied to the patient each cycle. 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 (this applies to all dosing schedules). For patients in 
Group C, when a lenalidomide treatment day occurs on a dialysis day, lenalidomide must 
be taken after dialysis. 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. 
 
Compliance with therapy will be assessed at the beginning of each cycle and at the end of 
treatment.  Patients will be given a medication diary for recording of doses of study drugs 
as provided by each study site.  
 
Dexamethasone will be given at a fixed dose of 40 mg by mouth once weekly on a 28 day 
treatment cycle. If a dose of dexamethasone is missed, it is up to the treating physician 
whether the dose should be made up. In addition, continuing dexamethasone if 
lenalidomide is stopped is also at the discretion of the treating physician. 
 
Treatment is to be continued as tolerated until disease progression, intolerable toxicity or 
patient refusal. 
 
Subjects experiencing adverse events may need study treatment modifications. 
 
If patient is treated beyond 4 cycles, therapy may be interrupted to allow for stem cell 
harvest and mobilization.  
 
7.111 Phase I Dose Assignment 
 
We want to determine the MTD for patients with MM in three different risk groups: 
• 
Moderate Renal Dysfunction (30-60 CrCl mL/min) 
• 
Severe Renal Dysfunction (CrCl <30 mL/min, not requiring dialysis) 
• 
ESRD Renal Dysfunction (CrCl <30 mL/min, requiring hemodialysis or peritoneal 
dialysis) 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
38 
 
 
 
7.112 Creatinine Clearance will be estimated by using the Cockcroft and Gault equation  
(see Appendix IV): 
Males: 
CrCl (mL/min) =               (140 –age) x (weight, kg)__      
                                    72 x (serum creatinine, mg/dL) 
Females: 
CrCl (mL/min) =               (140 –age) x (weight, kg)_   _ x 0.85 
                                     72 x (serum creatinine, mg/dL) 
 
If the patient is >65 y/o and creatinine is <1, use 1 as serum creatinine value to calculate 
the creatinine clearance.  
 
7.12 
Phase II Component:  
 
• 
Lenalidomide at assigned dose (as determined by studies in Phase 1 component)  
• 
Dexamethasone 40 mg orally on days 1, 8, 15 and 22 
• 
Anticoagulation (see Section 9.4) 
 
The dose for lenalidomide will be determined for each group in the Phase 1 portion of the 
study. Each cycle is 28 days. All groups get a 7 day rest (days 22-28) from lenalidomide. 
Dosing will be in the morning at approximately the same time each day. Only one cycle 
of study drug will be supplied to the patient each cycle. 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 (this applies to all dosing schedules). For patients in 
Group C, when a lenalidomide treatment day occurs on a dialysis day, lenalidomide must 
be taken after dialysis. 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. 
 
Dexamethasone will be given at a fixed dose of 40 mg by mouth once weekly on a 28 day 
treatment cycle. If a dose of dexamethasone is missed, it is up to the treating physician 
whether the dose should be made up. In addition, continuing dexamethasone if 
lenalidomide is stopped is also at the discretion of the treating physician. 
 
Treatment is to be continued as tolerated until disease progression, intolerable toxicity or 
patient refusal. 
 
 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
39 
 
 
 
7.2 
Phase I Dose Escalation and Determination of MTD. 
 
7.21 
Dose Escalation of Lenalidomide: 
 
Table 7.211: 
Group A = Patients with a 30-60 CrCl (mL/min)¤ 
Dose Level  
Dose  
Treatment Day 
Rest Day 
Route 
1* 
Lenalidomide 
10 mg 
1-21 
22-28 
Orally 
2 
Lenalidomide 
15 mg 
1-21 
22-28 
Orally 
3 
Lenalidomide 
25 mg 
1-21 
22-28 
Orally 
 
 
Table 7.212: 
Group B = Patients with CrCl <30 mL/min who are NOT on 
dialysis⌂ 
Dose Level  
Dose  
Treatment Day 
Rest Day 
Route 
1* 
Lenalidomide 
15 mg 
Every other day, 
days 1-21 
22-28 
Orally 
2 
Lenalidomide 
25 mg 
Every other day, 
days 1-21 
22-28 
Orally 
3 
Lenalidomide 
15 mg 
1-21 
22-28 
Orally 
4 
Lenalidomide 
25 mg 
1-21 
22-28 
Orally 
 
 
Table 7.213: 
Group C = Patients with CrCl <30 mL/min who are on dialysis#◊ 
Dose Level  
Dose  
Treatment Day 
Rest Day 
Route 
1*† 
Lenalidomide 
5 mg 
1-21₤  
 
22-28 
Orally 
2 
Lenalidomide 
10 mg 
1-21₤ 
22-28 
Orally 
3 
Lenalidomide 
15 mg 
1-21₤ 
22-28 
Orally 
4 
Lenalidomide 
25 mg 
1-21₤   
22-28 
Orally 
 
* 
Starting dose level 
# 
Dialysis includes hemodialysis or peritoneal dialysis. 
† 
The starting dose for patients in Group C accrued to dose level 1 cohort (completed 
September 2010) was lenalidomide 15 mg post dialysis three times weekly on Days 
1-21. Starting with protocol version 5.0, if a return to dose level 1 is indicated, 
lenalidomide 5 mg on Days 1-21 should be used according to the package insert. 
₤ 
When a lenalidomide treatment day occurs on a dialysis day, lenalidomide must be 
taken after dialysis. 
¤ 
Group A: As of November 03, 2010, dose level 1 is completed. Dose level 2 is open. 
⌂ 
Group B: As of November 03, 2010, dose level 1 is completed. Dose level 2 is open. 
◊ 
Group C: As of November 03, 2010, dose level 1 is completed. Dose level 2 is open. 
 
 
 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
40 
 
 
 
7.22 
Definition of Dose-Limiting Adverse Events 
 
Dose Limiting Adverse Events: 
 
Dose Limiting Toxicity (DLT) will be defined as any of the following events that is 
determined to be possibly, probably, or definitely related to lenalidomide (as determined 
by the investigator) within the first cycle of therapy irrespective of whether the adverse 
events resolved: 
 
• 
Grade 3 or higher neutropenia with fever ≥38.5oC 
• 
Grade 4 neutropenia ≥7 days  
• 
Grade 4 or higher thrombocytopenia 
• 
Other non-hematologic Grade 4 or higher adverse event not present prior to starting 
therapy or not due to underlying cause 
 
Management and dose modifications associated with the above AEs are outlined in 
Section 8.0. 
 
7.23 
Dose Escalation Phase: 
 
A standard cohort of 3 phase I design will be used where subjects will be initially 
enrolled in groups of three and individually assessed for safety and DLT. For a subject to 
be considered evaluable for dose limiting toxicity the subject must have received at least 
one dose of both drugs in Cycle 1 and have not been withdrawn from the study prior to 
Cycle 2 secondary to a drug related AE. If a subject withdraws from the study without 
meeting these criteria for reasons other than adverse events, the subject will be replaced 
in that cohort. 
Doses will be escalated until the first observation of a DLT as defined in Section 7.22 in 
the first treatment cycle in a group of at least 3 subjects treated at that dose level. All 
DLTs occurring in the first 3 cycles of the Phase I and II components will be collected 
and considered in the overall analysis, however, only DLTs occurring in Cycle 1 will 
define MTD during the Phase I component. Severity grading will be defined using 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE V4.0). A one-time dose escalation of lenalidomide after 2 cycles of treatment 
due to improvement of renal function is allowed within an individual patient as described 
in Section 8.3. 
A standard 3+3 phase I design will be used to determine the recommended dose in each 
renal dysfunction group. Dose level 1 will be the initial dose level (see Tables in Section 
7.21). 
 
• 
For current dose level accrue 3 patients (accrual for the group [Group A, B, or C] will 
be temporarily closed while the 3 patients are evaluated for DLT). 
• 
If exactly 0/3 experience a DLT, then proceed to the next higher dose level. 
 


PrECOG Protocol Number: PrE1003 
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41 
 
• 
If exactly 1/3 experience a DLT, then accrue 3 more patients at the current dose level 
(accrual for the group [Group A, B, or C] will be temporarily closed while the 3 
additional patients are evaluated for DLT). If (out of 6 patients) there are at least 2 
that experienced a DLT, the recommended dose level has been exceeded. Drop down 
one dose level. 
• 
If 2 or more (out of 3) patients experience a DLT, the recommended dose level has 
been exceeded. Drop down one dose level. 
 
The recommended dose level for the phase II portion of the trial is the maximum dose 
level that resulted in less than 2/6 patients with DLTs. Patients who experience DLTs will 
be dose reduced to the next lower dose level.  
 
Dose escalation will proceed within each group [Group A, B, or C] according to the 
following scheme. A DLT is defined above. 
 
Number of Patients with DLT at 
a Given Dose Level 
Phase I 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. 
 
Once the MTD is reached in the Phase I component for Group A, B or C, the group 
with the defined MTD dose will immediately be eligible to go to the Phase II 
component, and will not have to wait for the MTD in the other two groups 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
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42 
 
 
8.0 
Dosage Modification Based on Adverse Events for Phase I and Phase II 
 
Treatment modifications are based on adverse events. All adverse events should be 
graded according to the NCI Common Terminology Criteria for Adverse Events Version 
4.0 (CTCAE V4.0).  
 
Subjects will be evaluated for AEs at each visit with the NCI CTCAE V4.0 used as a 
guide for the grading of severity. Refer to Tables below for specific Lenalidomide and 
Dexamethasone dose reduction steps. Subjects who cannot tolerate lowest dose level are 
to be discontinued from the treatment phase of the study. Subjects experiencing ≥grade 3 
non-hematologic or grade 4 hematologic adverse events will have their study drug held 
per Table 8.31. Held doses are not made up. Grade 3 or 4 AEs must resolve to ≤grade 2 
in severity prior to resumption of study medications. Administration of the next drug dose 
is to be continued with a one-level dose reduction of the relevant drug as indicated in 
dose reductions. Once a subject’s dose has been reduced, no dose re-escalation is 
permitted except for a possible one-time dose escalation of lenalidomide in the event of 
improved renal function as described in Section 8.3. 
 
8.1 
Lenalidomide Dose Levels (Based on Adverse Events in Table 8.31) 
 
Table 8.11: 
Group A Dose Modifications# 
Dose Level 
 
Dose  
Treatment Day 
Rest Day 
Route 
3 
Lenalidomide 
25 mg 
1-21 
22-28 
Orally 
2 
Lenalidomide 
15 mg 
1-21 
22-28 
Orally 
1* 
Lenalidomide 
10 mg 
1-21 
22-28 
Orally 
-1 
Lenalidomide 
5 mg 
1-21 
22-28 
Orally 
-2 
Lenalidomide 
10 mg 
Every other day, 
days 1-21 
22-28 
Orally 
-3 
Lenalidomide 
5 mg 
Every other day, 
days 1-21 
22-28 
Orally 
 
 
Table 8.12: 
Group B Dose Modifications# 
Dose Level 
 
Dose  
Treatment Day 
Rest Day 
Route 
4 
Lenalidomide 
25 mg 
1-21 
22-28 
Orally 
3 
Lenalidomide 
15 mg 
1-21 
22-28 
Orally 
2 
Lenalidomide 
25 mg 
Every other day, 
days 1-21 
22-28 
Orally 
1* 
Lenalidomide 
15 mg 
Every other day, 
days 1-21 
22-28 
Orally 
-1 
Lenalidomide 
10 mg 
Every other day, 
days 1-21 
22-28 
Orally 
-2 
Lenalidomide 
5 mg 
 Every other day, 
days 1-21 
22-28 
Orally 
 
 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
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43 
 
Table 8.13: 
Group C Dose Modifications# 
Dose Level 
 
Dose  
Treatment Day 
Rest Day 
Route 
4 
Lenalidomide 
25 mg 
1-21₤ 
22-28 
Orally 
3 
Lenalidomide 
15 mg 
1-21₤ 
22-28 
Orally 
2 
Lenalidomide 
10 mg 
1-21₤ 
22-28 
Orally 
1*† 
Lenalidomide 
5 mg† 
1-21₤† 
22-28 
Orally 
-1 
Lenalidomide 
5 mg 
Every other day, 
days 1-21₤  
22-28 
Orally 
-2 
Lenalidomide 
5 mg 
Twice weekly₤ 
22-28 
Orally 
* 
Starting dose level 
#  
GCSF may be used beginning in cycle 2 for neutropenia. Consistent with ASCO 
guidelines, the recommended starting dose for G-CSF is 5 mcg/kg/d administered 
subcutaneously until the occurrence of an ANC of 10,000/uL or adequate neutrophil 
recovery is achieved. 
† 
The starting dose for patients in Group C accrued to dose level 1 cohort (completed 
September 2010) was lenalidomide 15 mg post dialysis three times weekly on Days 
1-21. Starting with protocol version 5.0, if a return to dose level 1 is indicated, 
lenalidomide 5 mg on Days 1-21 should be used according to the package insert. 
₤ 
When a lenalidomide treatment day occurs on a dialysis day, lenalidomide must be 
taken after dialysis. 
 
8.2 
Lenalidomide Dose Modification Based on Hematological Toxicity (see Table 8.31 
below) 
 
8.21 
Hematologic Requirements for Day 1 of Each Cycle 
• 
ANC is ≥1,000/μL 
• 
Platelet count is ≥50,000/μL 
If either of these two criteria is not met, the start of the cycle should be held and CBC 
should be followed weekly. Once ANC and platelets have recovered to Grade 2 or less, 
cycle should be started at next lower dose of lenalidomide. Held doses are not made up. 
 
8.3 
Lenalidomide Dose Modification Based On Non-Hematological Toxicity  
(see Table 8.31) 
 
A one-time dose escalation in lenalidomide of one dose level is allowed at any one time 
point after completion of 2 cycles of treatment if one of the following conditions is met: 
1. The patient was originally registered in Group C but has renal function improvement 
to a point that dialysis is no longer needed; or 
2. The patient was originally registered in Group B but has renal function improvement 
to ≥30 CrCl (mL/min). 
All previously established or new toxicities observed any time, are to be managed as per 
Table 8.31 and Table 8.4. 
 
If drug must be discontinued, the patient comes off treatment and goes to follow-up per 
Section 4.0 and event monitoring per eCRF completion guidelines. If the toxicity resolves 
and drug is to be restarted, the dose must be reduced by dose levels as indicated in the 
dose reduction table. 


PrECOG Protocol Number: PrE1003 
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44 
 
 
Please note: Held doses are not made up. 
Table 8.31: Dose Modification for Lenalidomide 
NCI CTC Toxicity Grade 
Day 2-14 of Cycle 
≥Day 15 of Cycle 
 
Grade 3 neutropenia associated 
with fever (temperature 
≥38.5oC) or Grade 4 
neutropenia 
• 
Hold lenalidomide. 
• 
Follow CBC weekly. 
• 
If neutropenia has resolved to 
≤grade 2, restart at next lower dose 
level and continue the cycle until 
day 21. 
• Hold lenalidomide for remainder 
of cycle. Restart lenalidomide 
next cycle (decrease dose by one 
dose level). 
 
 
Thrombocytopenia ≥Grade 3 
(platelet count <50,000/mm³) 
• Hold lenalidomide. 
• Follow CBC weekly. 
• If thrombocytopenia resolves to 
≤grade 2, restart lenalidomide at 
next lower dose level and continue 
the cycle through Day 21. 
• Hold lenalidomide for remainder 
of cycle. Restart lenalidomide 
next cycle (decrease dose by one 
dose level). 
 
Non-blistering rash 
Grade 3 
 
 
 
 
 
 
 
Grade 4 
• If Grade 3, hold lenalidomide dose. 
Follow weekly. 
• If the adverse event resolves to 
≤grade 1, restart lenalidomide at 
next lower dose level and continue 
the cycle through Day 21. 
 
 
• Discontinue 
lenalidomide 
study 
drug and go to follow-up and event 
monitoring. 
• Hold lenalidomide for remainder 
of cycle. Restart lenalidomide 
next cycle (decrease dose by one 
dose level). 
 
 
 
 
• Discontinue lenalidomide study 
drug and go to follow-up and 
event monitoring. 
Desquamating (blistering) 
rash- any Grade 
• Discontinue 
lenalidomide 
study 
drug and go to follow-up and event 
monitoring. 
• Discontinue lenalidomide study 
drug and go to follow-up and 
event monitoring. 
Erythema multiforme  
≥Grade 3 
• Discontinue 
lenalidomide 
study 
drug and go to follow-up and event 
monitoring. 
• Discontinue lenalidomide study 
drug and go to follow-up and 
event monitoring. 
 
 
Sinus bradycardia/other 
cardiac arrhythmia Grade 2 
 
 
 
 
 
≥Grade 3 
• Hold lenalidomide dose. Follow at 
least weekly. 
• If the adverse event resolves to 
≤grade 1, restart lenalidomide at 
next lower dose level and continue 
the cycle through Day 21. 
 
• Discontinue 
lenalidomide 
study 
drug and go to follow-up and event 
monitoring. 
• Hold lenalidomide for remainder 
of cycle. Restart lenalidomide 
next cycle (decrease dose by one 
dose level). 
 
 
 
 
• Discontinue lenalidomide study 
drug and go to follow-up and 
event monitoring. 


PrECOG Protocol Number: PrE1003 
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45 
 
Allergic reaction or 
hypersensitivity  
Grade 2-3 
 
 
 
 
 
Grade 4 
• Hold lenalidomide dose. Follow at 
least weekly. 
• If the adverse event resolves to 
≤grade 1, restart lenalidomide at 
next lower dose level and continue 
the cycle through Day 21. 
 
• Discontinue 
lenalidomide 
study 
drug and go to follow-up and event 
monitoring. 
• Hold lenalidomide for remainder 
of cycle. Restart lenalidomide 
next cycle (decrease dose by one 
dose level). 
 
 
 
• Discontinue lenalidomide study 
drug and go to follow-up and 
event monitoring. 
Venous thrombosis/embolism 
≥Grade 3 
• Hold 
lenalidomide 
and 
start 
therapeutic anticoagulation; restart 
lenalidomide 
at 
investigator’s 
discretion (maintain dose level). 
• Hold lenalidomide for remainder 
of cycle. See Anticoagulation 
Consideration (see Section 9.4). 
Restart lenalidomide next cycle 
(decrease dose by one dose 
level).  
Hyperthyroidism or 
hypothyroidism 
≥Grade 3 
• Hold lenalidomide for remainder of 
cycle, evaluate etiology, and initiate 
appropriate 
therapy. 
Restart 
lenalidomide next cycle (decrease 
dose by one dose level) 
• Hold lenalidomide for remainder 
of cycle, evaluate etiology, and 
initiate 
appropriate 
therapy. 
Restart lenalidomide next cycle 
(decrease dose by one dose 
level). 
Other non-hematologic 
adverse events assessed as 
lenalidomide related ≥Grade 3 
• Hold lenalidomide dose. Follow at 
least weekly. 
• If the adverse event resolves to 
≤grade 2, restart lenalidomide and 
continue through the scheduled 
Day 21 of current cycle. Otherwise, 
hold for remainder of cycle. Held 
doses are not made up. For toxicity 
attributed to lenalidomide, reduce 
by one dose level when restarting 
lenalidomide. 
• Hold lenalidomide for remainder 
of cycle. Restart lenalidomide 
next cycle (decrease dose by one 
dose level). 
 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
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Date: 3/28/2011 
 
 
46 
 
8.4 
Dexamethasone Dose Modifications 
 
Table 8.41: Dose Modifications for Dexamethasone 
NCI CTC Category 
Adverse Event 
Dosage Change 
Gastrointestinal 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1-2 (requiring 
medical management) 
Treat with H2 blockers, sucralfate, or omeprazole. 
 
If symptoms persist despite above measures, decrease 
dexamethasone dose by 1 dose level. 
 
≥Grade 3 (requiring 
hospitalization or surgery) 
Hold dexamethasone until symptoms adequately controlled. 
Restart by decreasing dose by 1 dose level along with 
concurrent therapy with H2 blockers, sucralfate, or 
omeprazole. 
 
Acute pancreatitis 
Discontinue dexamethasone and do not resume. 
Cardiovascular 
Edema 
≥Grade 3 (limiting 
function and unresponsive 
to therapy or anasarca) 
Diuretics as needed, and decrease dexamethasone dose by 1 
dose level.  
Neurology 
Confusion or Mood alteration  
≥Grade 2 (interfering with 
function +/- interfering 
with activities of daily 
living) 
Hold dexamethasone until symptoms adequately controlled. 
Restart by decreasing dose by 1 dose level. 
Musculoskeletal 
Muscle weakness  
≥Grade 2 (symptomatic 
and interfering with 
function +/- interfering 
with activities of daily 
living) 
Decrease dexamethasone dose by 1 dose level. If weakness 
persists decrease dose by 1 dose level as needed.  
Metabolic 
 
Hyperglycemia 
≥Grade 3 or higher 
Treatment with insulin or oral hypoglycemics as needed. If 
uncontrolled despite above measures, decrease dose by 1 
dose level. 
Any Other 
≥Grade 3 or higher  
Hold dexamethasone until symptoms adequately controlled. 
Restart by decreasing dose by 1 dose level. 
 
Table 8.42: Dexamethasone Dose Levels 
  
Dosage  
Days 
Starting Dose 
40 mg 
Days 1, 8, 15, 22 
Dose Level -1 
20 mg  
Days 1, 8, 15, 22  
Dose Level -2 
20 mg  
Days 1,15 only 
Dose Level -3 
10 mg  
Days 1, 15 only 
Dose Level -4 
Discontinue Dexamethasone 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
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47 
 
 
9.0 
Ancillary Treatment 
 
9.1 
Growth Factors: 
 
9.11 
Erythropoietin (Procrit or Aranesp) may be used to treat anemia beginning in treatment 
cycle 2 at the discretion of the treating physician in accordance with the published 
ASCO/ASH guidelines (JCO 2002, 20: 4083-4107). 
 
9.12 
G-CSF/GM-CSF: G-CSF/GM-CSF may be used beginning in treatment cycle 2 in 
accordance with published NCNN guidelines (see Section 8.0 Treatment Modification 
Based on Toxicity). 
 
9.2 
Infection Prophylaxis: Ciprofloxacin or Levofloxacin daily (or other quinolone/broad 
spectrum antibiotic) is allowed. 
 
The dose of ciprofloxacin should be modified in impaired renal function as follows: 
• 
250 to 500 mg every 12 hours for creatinine clearance between 30 to 60 mL/min 
• 
250 to 500 mg every 18 hours for creatinine clearance between 5-29 mL/min 
 
The dose of levofloxacin should be modified in impaired renal function as follows: 
• 
250 mg every 24 hours for creatinine clearance between 20-49 mL/min 
• 
250 mg every 48 hours for creatinine clearance between 10-19 mL/min 
 
9.3 
GI Toxicity: Routine prophylaxis with H2 blockers or proton pump inhibitors should be 
considered for all patients during days of dexamethasone administration.  
 
9.4 
Anti-Coagulation: Lenalidomide increases the risk of thrombotic events in patients who 
are at high risk or with a history of 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. Prophylactic anti-coagulation with 
aspirin (ASA) is required for all patients at either 81 mg daily or 325 mg daily (dose per 
MD discretion). Heparin, low molecular weight heparin or coumadin may be utilized in 
patients that are intolerant to ASA. Coumadin should be used with caution and close 
monitoring of INR. 
 
9.5 
Any other supportive measures consistent with optimal patient care should be given 
throughout the study. 


PrECOG Protocol Number: PrE1003 
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48 
 
 
10.0 
Adverse Event (AE) Monitoring and Reporting 
 
Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a pre-existing medical condition in a patient administered a medicinal product in a 
clinical investigation and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (e.g., including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a product (investigational or marketed), whether or not considered related to the 
product (investigational or marketed). 
 
Following written consent to participate in the study, the collection of AEs/SAEs should 
begin at the initiation of therapy, unless related to a protocol related procedure. 
 
10.1 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event 
reporting. A copy of the CTCAE Version 4.0 can be downloaded from the CTEP 
homepage (http://ctep.info.nih.gov). All appropriate treatment areas should have access 
to a copy of the CTCAE Version 4.0. All adverse clinical experiences, whether observed 
by the investigator or reported by the patient, must be recorded, with details about the 
duration and intensity of each episode, the action taken with respect to the test drug, and 
the patient’s outcome. The investigator must evaluate each adverse experience for its 
relationship to the test drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical 
significance. If any abnormal laboratory result is considered clinically significant, the 
investigator must provide details about the action taken with respect to the test drug and 
about the patient’s outcome. 
 
10.11 Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, 
the following attribution categories are utilized: 
Definite:   
The adverse event is clearly related to the investigational agent(s). 
Probable:   The adverse event is likely related to the investigational agent(s). 
Possible:   
The adverse event may be related to the investigational agent(s). 
Unlikely:   The adverse event is doubtfully related to the investigational agent(s). 
Unrelated:   The adverse event is clearly NOT related to the investigational agent(s). 
 
10.12 When a study includes both investigational and commercial agents, the following apply: 
 
• 
When an investigational agent(s) is used in combination with a commercial agent(s), 
the combination is considered investigational. Reporting of adverse events follows 
the guidelines for investigational agents. 
 
 


PrECOG Protocol Number: PrE1003 
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49 
 
10.2 
All Adverse Events are to be graded at each evaluation and all pretreatment 
symptoms/conditions are to be evaluated at baseline per Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0 grading. The specific Adverse 
Events/Symptoms in the table below are to be collected as indicated  below: 
 
Category 
Adverse Event/Symptoms 
Baseline 
Each 
Evaluation 
 
Blood/Bone Marrow 
Hemoglobin 
X 
X 
Neutrophils/Granulocytes 
(ANC/AGC) 
X 
X 
Platelets 
X 
X 
 
Constitutional Symptoms 
Fatigue (lethargy, malaise, 
asthenia) 
X 
X 
 
Neurology 
 
Neuropathy-Sensory 
X 
X 
 
Dermatology/Skin 
 
Rash/Desquamation 
X 
X 
 
Renal/Genitourinary 
 
Cystitis 
X 
X 
 
Lymphatics 
 
Edema: Limb 
X 
X 
 
Gastrointestinal 
 
Nausea 
X 
X 
 
Vomiting 
X 
X 
 
# of stools per day 
X 
 
 
Diarrhea 
 
X 
Musculoskeletal/Soft 
Tissue 
Muscle 
Weakness/Lower 
Extremity 
X 
X 
 
10.21 Submit via appropriate electronic Case Report Forms (eCRFs) the following AEs 
experienced by a patient and not specified in Section 10.2. If known, the diagnosis of the 
underlying illness or disorder should be recorded, rather than individual symptoms. The 
following information should be documented for all AEs: date of onset and resolution, 
severity of the event; the investigator’s opinion of the relationship to investigational 
product; treatment required for the AE; cause of the event (if known); and information 
regarding resolution/outcome. 
 
• 
Grade 1 and 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
• 
Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure 
• 
Grade 5 AEs (Deaths) 
o Any death within 30 days of the patient’s last study treatment or procedure 
regardless of attribution to the study treatment or procedure. 


PrECOG Protocol Number: PrE1003 
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50 
 
o Any death more than 30 days after the patient’s last study treatment or procedure 
that is felt to be at least possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution assigned. 
 
10.22 Refer to the instructions in the eCRF Study Manual regarding the submission of late 
occurring AEs following completion of the Active Monitoring Phase (e.g., compliance 
with Test Schedule in Section 4.0). 
 
10.3 
Serious Adverse Event (SAE) Definition 
 
A serious adverse event is one that at any dose (including overdose): 
 
Results in death 
 
Is life-threatening
1 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability or incapacity
2 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event
3 
 
Diagnosis of new second primary cancer 
1 “Life-threatening” means that the subject was at immediate risk of death at the time of 
the serious adverse event; it does not refer to a serious adverse event that hypothetically 
might have caused death if it were more severe. 
2 “Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
3 Medical and scientific judgment should be exercised in deciding whether serious 
adverse event reporting is appropriate in situations where none of the outcomes listed 
above occurred. Important medical events that may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above should 
also usually be considered serious. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. A new diagnosis of cancer during the 
course of a treatment should be considered as medically important. 
 
10.31 The investigator must appraise all abnormal laboratory results for their clinical 
significance. If any abnormal laboratory result is considered clinically significant, the 
investigator must provide details about the action taken with respect to the test drug and 
about the patient’s outcome. 
 
 
 
 


PrECOG Protocol Number: PrE1003 
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51 
 
 
 
10.32 Pregnancies 
 
Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of 
the importance of avoiding pregnancy during trial participation and the potential risk 
factors for an unintentional pregnancy, documented in the informed consent. In addition, 
all WOCBP should be instructed to contact the Investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
 
Pregnancy of a female subject or the female partner of a male subject occurring while the 
subject is on lenalidomide or within 4 weeks after the subject’s last dose of lenalidomide 
are considered expedited reportable events. If the subject is on lenalidomide, it is to be 
discontinued immediately and the subject is to be instructed to return any unused portion 
of lenalidomide to the Investigator. The pregnancy must be reported to PrECOG within 
24 hours of the Investigator’s knowledge of the pregnancy by phone and facsimile using 
the Pregnancy Form. Within 24 hours of notification, PrECOG will fax to Celgene Drug 
Safety the Pregnancy Form. 
 
•  The Investigator will follow the pregnant female until completion of the pregnancy, 
and must notify PrECOG of the outcome as specified below. PrECOG will provide 
Celgene Drug Safety with the outcome The Investigator will provide this information 
as a follow-up to the initial submission. 
 
•  If the outcome of the pregnancy meets the criteria for immediate classification as a 
SAE (e.g., spontaneous abortion [any congenital anomaly detected in an aborted fetus 
is to be documented], stillbirth, neonatal death, or congenital anomaly), the 
Investigator should follow the procedures for Expedited Reporting of SAEs to 
PrECOG (e.g., report the event to PrECOG by facsimile within 24 hours of the 
Investigator’s knowledge of the event). PrECOG will report the event to Celgene Drug 
Safety within 1 business day of the knowledge of the event. 
 
•  Any suspected fetal exposure to lenalidomide must be reported to PrECOG within 24 
hours of being made aware of the event. PrECOG will report any suspected fetal 
exposure to Celgene Drug Safety within 1 business day of being aware of the event. 
The pregnant female should be referred to an obstetrician/gynecologist experienced in 
reproductive toxicity for further evaluation and counseling. 
 
•  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 suspect is related to the in utero exposure to lenalidomide should also be 
reported. 
 
•  In the case of a live “normal” birth, PrECOG should be advised as soon as the 
information is available. PrECOG will advise Celgene Drug Safety as soon as the 
information is available. 


PrECOG Protocol Number: PrE1003 
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52 
 
 
 
10.4 
Serious Adverse Event  Reporting by Investigator to PrECOG 
 
10.41 Serious adverse events (SAE) are defined above. The investigator should inform 
PrECOG of any SAE within 24 hours of being aware of the event. The date of awareness 
should be noted on the report. This must be documented on PrECOG SAE form. This 
form must be completed and supplied to PrECOG within 24 hours/1 business day at the 
latest on the following working day. The initial report must be as complete as possible, 
including details of the current illness and (serious) adverse event, and an assessment of 
the causal relationship between the event and the investigational product(s). Information 
not available at the time of the initial report (e.g., an end date for the adverse event or 
laboratory values received after the report) must be documented on a follow-up PrECOG 
SAE report form. A final report to document resolution of the SAE is required. A copy of 
the fax transmission confirmation of the SAE report to PrECOG should be attached to the 
SAE and retained with the patient records. 
 
PrECOG Drug Safety Contact Information 
 
All SAEs should be faxed to: 
 
888-577-9921 
 
as per the instructions found in study materials provided to the investigator site. 
 
  
 
 
 
 
 
Manager, Clinical Safety 
Medical Monitor  
 
 
 
 
 
 
During Normal Business Hours 
During Normal Business Hours  
 
 
 
8:30 am-5:00 pm EST 
8:30 am-5:00 pm EST  
 
 
 
 
 
Tel: 610-354-0404 ext 143 
Tel: 610-354-0404 
 
 
 
 
 
 
After Normal Business Hours 
After Normal Business Hours 
 
 
 
 
Cell: 484-574-2367 
Tel: 484-574-2367 
 
 
PrECOG will notify Celgene of any SAE within 1 business day of receipt from the site. 
 
Collection of complete information concerning SAEs is extremely important. Full 
descriptions of each event will be followed. Thus, follow-up information which becomes 
available as the SAE evolves, as well as supporting documentation (e.g., hospital 
discharge summaries and autopsy reports), should be collected subsequently, if not 
available at the time of the initial report, and immediately sent using the same procedure 
as the initial SAE report. 
 
 
 
 
 


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53 
 
All SAEs must be collected which occur within 30 days of discontinuation of dosing for 
lenalidomide and/or dexamethasone, whichever is the last to be received. In addition, the 
Investigator should notify PrECOG or designee of any SAE that may occur after this time 
period which they believe to be definitely, probably or possibly related to investigational 
product. 
 
10.5 
Reporting of Other Second Primary Malignancies 
 
All cases of new primary malignancies that occur on PrECOG protocols during or after 
protocol treatment must be reported as a SAE and documented on a PrECOG SAE form. 
New primary malignancies should be reported within 24 hours of being aware of 
diagnosis, regardless of relationship to protocol treatment. SAE submission process 
described above in Section 10.4 should be followed. A copy of the pathology report 
should be sent with SAE form, if available.  
 
*NOTE:* Data regarding survival and remission status, second primary malignancies, and 
recurrence of prior malignancies will be followed x 3 years. This should include subjects 
who may have discontinued the study at any time or for any reason, who may be in a 
survival follow-up period, or who may have died. Data for all identified cases of 
subsequently diagnosed second primary malignancies after this 3 year time will be 
reported voluntarily by the treating physician to the manufacturer. 
 


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54 
 
 
11.0 
Treatment Evaluation  
(Response is to be assessed at the end of each treatment cycle within 3 days prior to 
the start of the next cycle) 
 
11.1 
Terms and Definitions 
 
• M-Protein: synonyms include M-spike, monoclonal protein and myeloma protein, 
paraprotein, M-component. 
 
Serum M-protein level is quantitated using densitometry on SPEP except in cases 
where the SPEP is felt to be unreliable. 
 
• 
M-proteins migrating in the β-region (usually IgA M-proteins) 
• 
Cases in which the M-spike is so large and narrow on agarose (some specimens 
>4 g/dL) that they underestimate the actual immunoglobulin (Ig) level (by greater 
than 1500 mg/dL) due to technical staining properties of the agarose gel 
• 
Cases in which there are multiple peaks of same monoclonal protein (aggregates 
or dimers) 
 
If SPEP is not available or felt to be unreliable (above examples) for routine M-
protein quantitation, then quantitative immunoglobulin levels derived from 
nephelometry or turbidometry can be accepted. However, this must be explicitly 
reported at baseline, and only nephelometry can be used for that patient to assess 
response. 
SPEP 
derived 
M-spike 
values 
and 
quantitative 
nephelometric 
immunoglobulin values cannot be used interchangeably. In determining response, if 
the quantitative immunoglobulin result contradicts the M-spike result (or vice-versa), 
the treating physician may request permission from the PI to alter which parameter 
will be followed for response determination. This adjustment may be made once 
during a patient’s course. 
 
Urine M-protein measurement is estimated using 24-h UPEP only. Random or 24-h 
urine tests measuring kappa and lambda light chain levels are not reliable and are not 
accepted for this study. 
 
Free light chain (FLC) estimation is currently carried out using the serum FLC assay 
(Freelite, The Binding Site Limited, UK). Patients with kappa/lambda FLC ratio 
<0.26 are defined as having monoclonal lambda FLC and those with ratios >1.65 as 
having a monoclonal kappa FLC. The monoclonal light chain isotype is considered 
the involved FLC isotype, and the opposite light chain type as the uninvolved FLC 
type. 
 
•  Response Terms: The following response terms will be used: stringent Complete 
Response (sCR), complete response (CR), very good partial response (VGPR), partial 
response (PR), stable disease (SD), progressive disease (PD) and relapse from CR 
(RFCR). 
 


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55 
 
 
 
 
In addition, for each response category, there will be an “unconfirmed” response 
category, which will be for internal use, for the purpose of guiding decision making 
and test ordering. These designations will be applied at the time of the first 
measurement at which the quantitative aspect of the response category has been 
satisfied without the confirmation step having been satisfied. The designation “u” 
will precede the standard abbreviations, and will include usCR, uCR, uVGPR, uPR, 
uPD. 
 
• 
Measurable Disease: Patients who have a measurable serum or urine M-protein. 
o Serum M-protein ≥1 g/dl  
o Urine M-protein ≥200 mg/24 h 
o Serum FLC assay: Involved FLC level ≥10 mg/dl provided serum FLC ratio is 
abnormal 
o Bone marrow plasma cells ≥30% 
 
The serum free light chain (FLC) assay is of particular use in monitoring response to 
therapy in patients who have oligo-secretory or non-secretory disease and should be used 
in assessing response only if the baseline serum and/or urine M proteins are not 
“measurable” as above, and the baseline level of the involved FLC is “measurable.” 
When using this assay, it is important to note that the FLC levels vary considerably with 
changes in renal function and in patients with renal insufficiency, the levels of both the 
kappa and lambda may remain elevated, but the ratio normalizes with achievement of 
CR. Thus both the level of the involved and the uninvolved FLC isotype (e.g., the 
involved/uninvolved ratio or involved-uninvolved difference) should be considered in 
assessing response. Patients included on the study on the basis of FLC alone (e.g., no 
measurable serum/urine) should be the only ones who are evaluated using FLC 
response criteria. The others should follow usual criteria and ignore FLC results. 
 
• Evaluable Disease: Patients who do not have a “measurable” serum M-spike, serum 
free light chain, or urine M-spike. 
 
• Oligosecretory Myeloma: Patient with multiple myeloma who has NEVER had 
“measurable” serum M-spike or urine M-spike, but has had a detectable monoclonal 
protein in his/her serum and/or urine and/or measurable serum free light chain. 
 
• Non-Secretory Myeloma: Patient with multiple myeloma who has NEVER had a 
detectable monoclonal protein in his/her serum and/or urine. 
 
 
 
 
 
 
 


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56 
 
11.2 
Clarification of Test Indications 
 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study. Response is to be assessed at the end of each 
treatment cycle within 3 days prior to the start of the next cycle. 
Table 11.2 
Tests Required To Assess Response (Must Be Done At Each Disease Measurement Visit) 
On Study Baseline Value 
SPEP  24 hr 
UPEP  
Ig 
FLC 
BM Bx 
Serum M-spike ≥1 g/dl, and urine M-spike ≥200 
mg/24 hrs 
X 
X 
 
 
Serum M-spike ≥1 g/dl, but urine M-spike <200 
mg/24 hrs 
X 
 
 
 
Serum M-spike <1 g/dl, and urine M-spike ≥200 
mg/24 hrs 
 
X 
 
 
Serum M-spike <1 g/dl, urine M-spike <200 
mg/24 hrs, but involved Ig FLC is ≥10 mg/dL 
 
 
X 
 
Serum M-spike <1 g/dl, urine M-spike <200 
mg/24 hrs, involved Ig FLC is <10 mg/dL, bone 
marrow ≥30% plasma cells 
 
 
 
Xa 
Immunofixation studies of both serum and urine are required to document CR regardless of 
registration values, and in addition FLC measurement and bone marrow immunophenotyping 
is required to document sCR. 
 aException: bone marrow biopsy does not have to be confirmed. 
 
11.3 
Confirmed Response  
 
In order to be classified as a hematologic response, confirmation of serum monoclonal 
protein, serum immunoglobulin free light chain (when primary determinant of response) 
and urine monoclonal protein (when primary determinant of response) results must be 
made by verification on two consecutive determinations. 
 
• 
Bone marrow aspirate and biopsy are only required to document or confirm CR or 
sCR, except for patients with evaluable disease only, where a bone marrow is 
required to document all response categories including progression. However, a 
second confirmatory bone marrow is not required to confirm response. 
• 
Radiographic studies are not required to satisfy these response requirements, 
however, if radiographic studies were performed there should be no evidence of 
progressive or new bone lesions. 
 
Appropriate tests required to document and confirm response are listed in Table 11.2 and 
11.5. 
 
11.4 
Bone Progression  
 
Caution must be exercised to avoid rating progression or relapse on the basis of variation 
of radiologic technique alone. Compression fracture does not exclude continued response 


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57 
 
and may not indicate progression. When progression is based on skeletal disease alone, it 
should be discussed with the medical monitor before removing the patient from the study. 
Palliative radiation alone for bone pain during treatment does not qualify as progressive 
disease. 
 
11.5 
Response and Progression 
 
Criteria for response and progression are listed in Table 11.5.  
Table 11.5 
CATEGORY 
RESPONSE CRITERIA a 
stringent Complete 
Response (sCR) 
 
• 
CR as defined below plus all of the following 
o Normal serum FLC ratio  
o Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescence b 
 
Complete Response 
(CR) 
• 
Negative immunofixation of the serum and urine  
• 
If at on study, the only measurable non-bone marrow parameter was FLC, 
normalization of FLC ratio 
• 
<5% plasma cells in bone marrow 
• 
Disappearance of any soft tissue plasmacytomas  
 
Very Good Partial 
Response (VGPR)e 
 
• 
PR as defined below plus all of the following: 
o Serum and urine M-component detectable by immunofixation but not 
on electrophoresis or 
o If at on study, serum measurable, ≥90% or greater reduction in serum 
M-component 
o Urine M-component <100 mg per 24h  
 
Partial Response 
(PR) 
• 
One of the following: 
 If at on study, serum and urine measurable, a ≥50% reduction of serum M-
protein and reduction in 24h urinary M-protein by ≥90% or to <200 mg per 
24h 
 If at on study, only serum measurable (but urine not), a ≥50% reduction of 
serum M-protein  
 If at on study, urine measurable (but serum not), a reduction in 24 h urinary 
M-protein by ≥90% or to <200 mg per 24h 
 If at on study, the only measurable non-bone marrow parameter was FLC, a 
≥50% decrease in the difference between involved and uninvolved FLC 
levels or a 50% decrease in level of involved FLC with 50% decrease in 
ratio 
 If at on study, the bone marrow was only measurable parameter, ≥50% 
reduction in bone marrow plasma cells is required in place of M-protein, 
provided baseline percentage was ≥30% 
• 
In addition to the above criteria, if a plasmacytoma present at baseline, ≥50% 
reduction in the size of soft tissue plasmacytomas is also required 
 


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58 
 
Stable Disease (SD) 
Not meeting criteria for CR, VGPR, PR or progressive disease 
 
Progressive Disease 
(PD) 
Any one or more of the following: 
• 
Increase of 25% from lowest confirmed response in: 
 Serum M-component (absolute increase must be ≥0.5 g/dl)c  
 Urine M-component (absolute increase must be ≥200 mg/24h)  
 If at on study, only the only measurable non-bone marrow parameter was 
FLC, the difference between involved and uninvolved FLC levels (absolute 
increase must be >10 mg/dl)  
 Bone marrow plasma cell percentage (absolute % must be 10%)d 
• 
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas 
• 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dl) that 
can be attributed solely to the plasma cell proliferative disorder 
 
Relapse from CR 
or sCR  
 
Patient who has achieved confirmed CR who has any one or more of the following: 
• 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis 
• 
Development of ≥5% plasma cells in the bone marrow d 
• 
Appearance of any other sign of progression (e.g., new plasmacytoma, lytic 
bone lesion, or hypercalcemia) 
 
a All response categories require two consecutive assessments made at any time before the institution of 
any new therapy; complete and PR and SD categories also require no known evidence of progressive or 
new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy 
these response requirements. Bone marrow assessments need not be confirmed. Each category, except 
for stable disease, will have a working subcategory of “unconfirmed” [prefix ‘u”] to designate first time 
point at which response category MAY have been achieved if confirmed. 
b Presence/absence of clonal cells is based upon the k/  ratio. An abnormal k/  ratio by 
immunohistochemistry and/or immunofluorescence require a minimum of 100 plasma cells for analysis. 
An abnormal ratio reflecting presence of an abnormal clone is k/  of >4:1 or <1:2. 
c For progressive disease, serum M-component increases of ≥1 gm/dl are sufficient to define relapse if 
starting M-component is ≥5 g/dl. Positive immunofixation alone in a patient previously classified as CR 
will not be considered progression. 
d Relapse from CR has the 5% cutoff versus 10% for other categories of relapse. 
e This response category is not available for those patients being followed by either free light chain only 
or by bone marrow only. 


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59 
 
 
12.0 
Descriptive Factors 
Below is additional data that will be collected as part of this protocol and recorded in the 
eCRFs. 
 
12.1 
Serum M-Spike ≥1 g/dL: Yes vs. No. 
 
12.2 
Serum Immunoglobulin Free Light Chain ≥10 mg/dL: Yes vs. No. 
 
12.3 
Urine M-Spike ≥200 mg/24 hours: Yes vs. No. 
 
12.4 
Bone Marrow Plasma Cells ≥30%: Yes vs. No. 
 
12.5 
Number of Previous Myeloma Therapies: 1 vs. 2 vs. 3 vs. 4 vs. ≥5. 
 
12.6 
Type of Dialysis: Hemodialysis vs. Peritoneal vs. None. 
 
12.7 
Beta-2 Microglobulin: <3.5 mg/L vs. ≥3.5, <5.5 mg/L vs. ≥5.5 mg/L. 
 
12.8 
Albumin: ≥3.5 g/dL vs. <3.5 g/dL. 


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13.0 
Treatment/Follow-Up Decision at Evaluation of Patient 
 
13.1 
If it is determined that after registration a patient did not satisfy each and every eligibility 
criteria, the patient will be noted as being ineligible. The patient may continue treatment 
off-protocol at the discretion of the physician as long as there are no safety concerns, and 
the patient was properly registered. The patient will go directly to the follow-up/event 
monitoring phase of the study. 
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Follow-up per Section 4.0 and event monitoring per 
eCRF completion guidelines will be required. 
• 
If the patient never received treatment, on-study material must be submitted. Follow-
up per Section 4.0 and event monitoring per eCRF completion guidelines will be 
required. 
 
13.2 
If a required treatment/procedure in cycle 1 is not done and the violation is deemed 
severe, the patient will be noted as having a major violation. All data up until the point of 
confirmation of a major violation must be submitted. The patient will go directly to 
follow-up/event-monitoring phase of the study. The patient may continue treatment off-
protocol at the discretion of the physician as long as there are no safety concerns, and the 
patient was properly registered. Follow-up per Section 4.0 and event monitoring per 
eCRF completion guidelines will be required. 
 
13.3 
If a patient is removed from the study for any reason before any study treatment is given, 
the patient will be noted as having been cancelled. On-study material and the End of 
Active Treatment/Cancel Notification Form must be submitted. No further data 
submission is necessary. 
 
13.4 
Criteria for Patient Withdrawal 
 
Patients may be withdrawn from the study for the following reasons: 
• 
Progressive multiple myeloma 
• 
Patient withdraws consent to continue in the trial 
• 
Patient develops an intercurrent illness that precludes further participation, or 
requires a prohibited concomitant treatment 
• 
The Investigator withdraws the patient in the patient’s best interests 
• 
Patient is lost to follow-up (defined as the inability to contact the patient on 3 
separate occasions over a period of 2 weeks) 
• 
Administrative reasons (e.g., the patient is transferred to hospice care) 
• 
An adverse event, which in the opinion of the Investigator, precludes further trial 
participation 
• 
Pregnancy 
• 
Closure of study by PrECOG 
 
 
 


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61 
 
13.5 
All attempts should be made to complete the End of Study procedures if a patient 
withdraws from the trial early. 
 
13.6 
Phase I: If a patient fails to complete one cycle of treatment for reasons other than 
toxicity, the patient will be regarded as inevaluable and will be replaced. 
 
13.7 
Patients who develop progressive disease while receiving therapy will go to the event-
monitoring phase. 
 
13.8 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase. 
 
13.9 
Patients who are in sCR, CR, VGPR, PR, or SD (or usCR, uCR, uVGPR, uPR) may have 
stem cells harvested at any time after 4 cycles at the discretion of the Investigator. If the 
patient is continued on therapy, lenalidomide and dexamethasone may be discontinued 
during the harvest period and the dates of cessation and resumption recorded.  


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14.0 
Body Fluid Biospecimens  
(Mandatory only for Mayo Clinic subjects registered onto the Phase II component). 
Biospecimens will be collected from at least two patients in each patient group on 
the Phase II component (Groups A, B and C) for a total of 12 patients. 
 
14.1 
Rationale: To determine the pharmacokinetics of lenalidomide in impaired renal function. 
 
14.2 
Blood Sample Collection, Processing and Storage 
 
14.21 Fill ice bucket with enough ice before drawing blood. 
 
14.22 Collect 5 mL of whole blood into 5 mL EDTA tube. Gently invert the tube 3-5 times and 
immerse it into the ice immediately to prevent possible compound degradation at room 
temperature. (Record drawing time immediately). 
 
14.23 Within 15 min of blood collection, sample will be processed by centrifuging at 1500g for 
10 min at 4oC to obtain plasma. A refrigerated desktop centrifuge should be used. 
 
14.24 The plasma (approx. 2 mL) will then be separated and put into 2 clean pre-labeled 
polypropylene tube. (Note – each tube should contain at least 0.8 mL of plasma). 
 
14.25 Store all plasma samples (within 1 hr of collection) in -70oC freezer until shipping to the 
bioanalytical laboratory. 
 
14.26 The samples can be batched (weekly or monthly) and sent to the bioanalytical Lab 
(pending arrangement). Additional information will be provided in separate study 
materials.  
 
14.27 Sampling Labeling: The label should contain at minimum the following information: 
1. Subject number 
2. Subject initials 
3. Treatment Dose group 
4. Lenalidomide in plasma 
5. Sampling date and time (hr/mm) 
6. Study ID Number (PrECOG1003, Celgene study number RV-MM-PrECOG-0394) 
7. Date of drug administration 
8. Primary sample or secondary sample 
14.3 
Packaging and Shipping of Biological Samples 
14.31 Shipping to QPS Laboratories, Inc. 
• Biological samples should be shipped on dry ice. 
• Samples should be shipped only on a Monday, Tuesday, or Wednesday, to minimize 
the possibility of them being in transit over a weekend. 


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63 
 
• If duplicate samples are being shipped, please send one set of samples and await 
confirmation of arrival at QPS Laboratories before shipping the second set. 
14.32 Sample Packing 
• Arrange the sample collection, with your courier. 
• Use a styrofoam box, for example 19” x 19” x 12”. Use a larger one if you are 
shipping many samples. 
• Obtain 20 lbs. of dry ice pellets. Use as much dry ice as possible, to help safeguard 
against any possible delays. 
• Place a 4” layer of dry ice in the bottom of the styrofoam box. 
• Samples should be identified using self-adhesive labels that should be applied prior to 
freezing the samples. 
• Wrap the frozen samples in bundles using an elastic band and place the sample 
bundles in a plastic freezer bag. 
• Use newspaper or other similar material to insulate the bagged sample bundles from 
direct contact with the dry ice. 
• Place the sample bundles in the styrofoam box and fill the excess space with the 
remaining dry ice pellets. 
• 
Record the estimated weight of the dry ice used per box. 
• 
Place the lid on the styrofoam box and seal completely with tape. 
• Tape a list of the samples contained inside the box, to the lid (e.g., plasma, subjects 1 
– 6 pre-dose, 30 min., and 1hr). In order to protect this paperwork insert it into a 
plastic bag. 
• 
Place the Styrofoam box in a cardboard shipping carton, seal securely with tape. 
14.33 Labeling on Shipping Containers 
• 
Label the cardboard box as follows: 
1. Mark the outside of the cartons with tally number e.g., 1 of 3, 2 of 3, and 3 of 3. 
 


PrECOG Protocol Number: PrE1003 
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64 
 
2. Affix an address label, with the information below, to the outside of each box: 
Please ship the samples via Fed Ex to: 
 
 
 
 
 
 
• 
Affix the following labels on each box: 
• 
1 x carbon dioxide label with the weight included. Example: 
 
Carbon Dioxide Solid UN-1845 
Class 9 PKG GR III 
KG _______________________ 
 
• 
2 x internationally recognized dry ice symbols (Class 9) - one on either side 
of the box. Example: 
 
 
 
• 
1 x KEEP FROZEN label 
 


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65 
 
 
14.34 Paperwork to Accompany Shipment 
These human biological samples are not known to be infectious or hazardous. For 
laboratory use only. 
Beginning with the first shipment: 
The following information must accompany all shipments: 
• 
Subject Identification 
• 
Time Point Identification 
• 
Protocol Number 
• 
Sponsor Name 
Any missing information may cause a delay in analysis. 
Notify QPS Lab, by email or fax immediately after the courier has collected the samples. 
Please provide the following information: 
• 
Name of courier or transport company. 
• 
Date and time the shipment left your premises. 
• 
The airway bill number. 
14.35 QPS Lab Shipping Contacts 
The contact person at QPS Lab for all shipments is: 
 
 
 
 
 
If the shipment labeling and documentation are not completed correctly, the shipment 
may be delayed. Upon arrival at QPS Lab, the shipment will be unpacked and you will be 
advised of its safe arrival. 


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66 
 
 
15.0 
Background Drug Information 
15.1 
Lenalidomide (REVLIMID®), a thalidomide analogue, is an immunomodulatory agent 
with anti-angiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -
2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure: 
Chemical Structure of Lenalidomide 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3. 
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in 
organic solvents and low pH solutions. Solubility was significantly lower in less acidic 
buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon 
atom and can exist as the optically active forms S(-) and R(+), and is produced as a 
racemic mixture with a net optical rotation of zero. 
15.11 Clinical Pharmacology 
Mechanism of Action:  
 
 
 
 
 
 
 
 
 
 
 


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67 
 
15.12 Pharmacokinetics and Drug Metabolism: 
Absorption: 
 
 
 
 
 
Multiple dosing at the recommended dose-
regimen does not result in drug accumulation. 
Pharmacokinetic
 
 
 
 
15.13 Pharmacokinetic Parameters: 
Distribution: In vitro (14C)-lenalidomide binding to plasma proteins is approximately 
30%. 
15.14 Metabolism and Excretion: 
 
 
 
 
15.15 Supplier(s) 
Supplied: Celgene Corporation will supply Revlimid® (lenalidomide). 
Dosage Form: Lenalidomide will be supplied as 5 mg and 25 mg capsules for oral 
administration. 
 
Packaging: Lenalidomide will be shipped to the pharmacy at the study site in individual 
bottles. Bottles will contain a sufficient number of capsules to last for one cycle of 
dosing. Study drug must be dispensed in the original packaging with the label clearly 
visible. Only enough lenalidomide for 1 cycle of therapy may be provided to the patient 
each cycle. 
 
Labeling: Lenalidomide investigational supplies are dispensed to the patients in 
individual bottles of capsules. Each bottle will identify the contents as study medication. 
In addition, the label will bear Celgene’s name, quantity contained and the standard 
caution statement as follows: Caution: New drug - Limited by Federal law to 
investigational use. The study drug label must be clearly visible. For appropriate drug 


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68 
 
accountability, it is recommended that each bottle be marked with the institutional or 
Celgene protocol number (RV-MM-PrECOG-0394) upon receipt. Additional labels must 
not cover the Celgene label. 
 
Receipt of Study Drug: The Investigator or designee is responsible for taking an 
inventory of each shipment of study drug received, and comparing it with the 
accompanying study drug accountability form. The Investigator will verify the accuracy 
of the information on the form, sign and date it, retain a copy in the study file, and return 
a copy to PrECOG or its representative. 
 
Storage: At the study site, all investigational study drugs will be stored in a locked, safe 
area to prevent unauthorized access. The study drug should be stored at room temperature 
away from direct sunlight and protected from excessive heat and cold. 
 
Unused Study Drug Supplies: PrECOG will instruct the Investigator on the return or 
destruction of unused study drug. If any study drug is lost or damaged, its disposition 
should be documented in the source documents. Study drug supplies will be retained at 
the clinical site pending instructions for disposition by PrECOG. Patients will be 
instructed to return empty bottles or unused capsules. 
 
Drug Dispensing Requirements: In investigational studies, lenalidomide will be 
dispensed through a qualified healthcare professional (including but not limited to, 
nurses, pharmacists and physicians). These healthcare professionals will be trained by 
Celgene in requirements specific to counseling of subjects. 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 Education and Counseling Guidance Document 
(Appendix VI), and no drug will be dispensed until this step occurs. Counseling includes 
verification with the patient that required pregnancy testing was performed and results 
were negative. A Lenalidomide Information Sheet (Appendix VII) will be supplied with 
each medication dispense. 
 
15.16 Human Toxicology: 
 
Complete and updated adverse events are available in the Investigational Drug Brochure 
and the IND Safety Letters. 
 
Likely Risks: Neutropenia; thrombocytopenia; fatigue; constipation; diarrhea. 
 
Less Likely Risks: anemia; fever; itching and dry skin; back or joint pain; headache; 
dizziness, cough; shortness of breath or difficulty catching your breath; upper respiratory 
infection; decreased appetite; difficulty sleeping, nausea; muscle cramps; peripheral 
edema; rash; lack or loss of strength. 
 
 


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Rare Cases of the following have been reported: Tumor Lysis syndrome (TLS) which is a 
metabolic disorder that results from the rapid killing of tumor cells most often connected 
with cancers of the blood and can lead to increased levels of phosphorous, potassium, 
uric acid and low levels of calcium which can lead to kidney failure; angioedema; 
Stevens-Johnson syndrome and toxic epidermal necrolysis – serious allergic skin 
reactions that begin as a rash in one area and later cover more of the body; 
rhabdomyolysis, a serious condition involving the destruction of skeletal muscle that can 
lead to kidney failure; anaphylaxis; tumor flare reaction; increase in blood levels of lipase 
due to inflammation of pancreas gland. 
 
Serious Risks: Neutropenia associated with fever; pulmonary embolism in or around the 
lungs; deep vein thrombosis in a larger blood vessel, atrial fibrillation; progression of the 
disease; pneumonia; sepsis; dehydration; kidney failure; myocardial infarction; 
congestive heart failure. 
 
Other Risks: Patients should be instructed to inform the study staff if any physician other 
than the study doctor prescribes medication for them for another condition or if they are 
taking any over-the-counter medications or vitamins. 
 
Lenalidomide has been shown to increase the level of digoxin in the blood in some 
patients; please instruct patients to inform the study staff if they are taking digoxin. 
 
15.17 Nursing Implications:   
 
1. The most common side effects are neutropenia and thrombocytopenia. 
 
2. Due to the highly teratogenic potential of the closely related thalidomide, it is highly 
recommended that all women of childbearing age group and all men use effective 
contraception during therapy (see Appendix V for required birth control and other 
information related to the risks of fetal exposure). All staff who are pregnant or who 
can become pregnant should not handle this drug outside of its original packaging. 
 
3. Instruct patient to report any rash immediately to the study team. 
 
4. Lenalidomide capsules should be swallowed whole, and should not be broken, 
chewed or opened. 
 
5. 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. 
 
6. 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. 
15.2 
Dexamethasone 
 
15.21 Other Names: Decadron, Dexameth, Dexon, DXM, Hexadrol 
 


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15.22 Classification: Adrenal Corticosteroid 
 
15.23 Mode of Action: 
Dexamethasone is a potent synthetic glucocorticoid that affects almost every body 
system. It has anti-inflammatory, immunosuppressant, antineoplastic, and antiemetic 
properties and very little mineralocorticoid activity. As an antineoplastic agent, 
Dexamethasone may bind to specific proteins (receptors) within the cell forming a 
steroid-receptor complex. Binding of the receptor-steroid complex with nuclear 
chromatin alters mRNA and protein synthesis within the cell. 
 
15.24 Storage and Stability: The drug is stored at room temperature in a dry place. 
 
15.25 Dose Specifics: 40 mg/day orally on days 1, 8, 15 and 22 each 28 day cycle 
Route of Administration: Oral. 
 
15.26 Availability: Commercially available in 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 6 mg tablets. 
 
15.27 Main Side Effects: 
1. Gastrointestinal: Nausea, vomiting, anorexia, increased appetite, weight gain; 
aggravation of peptic ulcers. 
2. Dermatologic: Rash, skin atrophy, facial hair growth, acne, facial erythema, 
ecchymoses. 
3. Genitourinary: Menstrual changes (amenorrhea, menstrual irregularities). 
4. Neurologic: Insomnia, euphoria, headache, vertigo, psychosis, depression, seizures, 
and muscle weakness. 
5. Cardiovascular: Fluid retention and edema, hypertension; rarely, thrombophlebitis. 
6. Ocular: Cataracts, increased intraocular pressure, exophthalmos. 
7. Metabolic: Hyperglycemia, decreased glucose tolerance, aggravation or precipitation 
of diabetes mellitus, adrenal suppression (with Cushinoid features), hypokalemia. 
8. Hematologic: Leukocytosis. 
9. Other: Osteoporosis (and resulting back pain), appearance of serious infections 
including herpes zoster, varicella zoster, fungal infections, Pneumocystis carinii, 
tuberculosis; muscle wasting; delayed wound healing; suppression of reactions to 
skin tests. 
 
15.28 Nursing / Patient Implications: 
1. When administered orally, give with food or milk. 
2. Observe for signs of hyperglycemia. 
3. Observe for subtle signs of infection (fever, pain). 


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16.0 
Statistical Considerations and Methodology 
 
16.1 
Study Design: This phase I/II study involves three single arm phase I trials designed to 
determine the MTD and toxicity of lenalidomide in the treatment of multiple myeloma in 
three groups of patients defined by renal dysfunction. Once an MTD is determined within 
a group, an additional 15 patients will be accrued within the group and treated with the 
MTD as part of the phase II study to assess efficacy of lenalidomide and dexamethasone 
in the treatment of multiple myeloma. The 6 phase I patients treated at the MTD plus 15 
additional patients accrued in each group will be combined (total = 63 patients) to assess 
efficacy using a one-stage design. 
 
The first phase I study enrolls patients with moderate renal dysfunction (Group A); the 
second one enrolls patients with severe renal dysfunction (Group B); and the third one 
enrolls patients with ESRD renal dysfunction (Group C). Groups A, B, and C have a 
maximum of 3, 4, and 4 dose levels respectively. The MTD for each group will be 
determined concurrently. 
 
16.11 Sample Size: Phase I: For Group A, the study may involve a maximum of 18 patients (6 
for each of the 3 dose levels) but would likely require 15 patients (3 at the first dose level, 
6 for the dose level prior to the MTD, and 6 at the MTD). For Group B, the study may 
involve a maximum of 24 patients (6 for each of the 4 dose levels) but would likely 
require 18 patients (3 at the first 2 dose levels, 6 for the dose level prior to the MTD, and 
6 at the MTD). For Group C, the study may involve a maximum of 24 patients (6 for each 
of the 4 dose levels) but would likely require 18 patients (3 at the first 2 dose levels, 6 for 
the dose level prior to the MTD, and 6 at the MTD). Phase II: Each group will accrue an 
additional 15 patients at the MTD. Overall: Therefore, overall, the study needs a 
maximum of 111 patients, and an expected number of 96 patients. 
 
In addition, the protocol allows replacement of patients in phase I who withdraw before 
completing cycle 1 for reasons other than toxicity. 
 
16.12 MTD Determination: MTD is defined as the dose level below the lowest dose that 
induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 
6 new patients). MTD will be determined independently for each group as outlined in 
Section 7.2. 
 
16.13 Accrual and Study Duration: We expect a 3-month period at the beginning of the study 
during which IRB approvals will be obtained. Then, given accrual history from PrECOG 
sites and assuming equal accrual to all three cohorts, it is estimated that 1.15 patients per 
week in each group will be accrued to this trial. Maximum total time per dose/group 
cohort of 6 patients will be: 
 
2.5 weeks to enroll the first 3 patients  
4 weeks to treat the first 3 patients through one cycle 
1 week to assemble data and evaluate the outcome 
 
 


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2.5 weeks to enroll the second 3 patients 
4 weeks to evaluate their outcome 
1 week to assemble data and evaluate the outcome 
 
This corresponds to a maximum requirement of approximately 15 weeks to enroll, treat, 
and evaluate 6 patients. Therefore, the accrual time for Groups A, B, and C will be 45 
weeks, 60 weeks, and 60 weeks, respectively (note- these occur concurrently so the total 
duration of the phase I component is maximally 60 weeks with expected duration of 45 
weeks) and the overall study duration will be 60 weeks (phase I component) + 15 weeks 
(accrual for 15 additional patients per group at 1 patient per group per week) + 24 weeks 
(6 cycles to treat and evaluate patients in the phase II component) = 99 weeks (about 23 
months). 
 
16.14 Operating Characteristics: The following table gives the probability of dose escalation at 
a single dose level as a function of the true probability of DLT at that level using the 
cohorts of 3 design described in Section 7.2. 
 
True Rate 
of DLT (%) 
Probability of Dose Escalation 
10 
0.91 
20 
0.71 
30 
0.49 
40 
0.31 
50 
0.17 
 
16.2 
Phase I Analysis Plans: Data will be analyzed separately within the three patient groups 
with the exception of the additional 15 patients per group accrued at the MTD (e.g., 
patients included in the phase II component). However, the analysis procedures, 
described below, are the same for the three groups. All the relevant phase I results 
pertaining to toxicity, MTD, response, timed endpoints and laboratory correlates will be 
examined in an exploratory and hypothesis-generating fashion. 
 
16.21 Adverse Events Profile 
 
The number and severity of all adverse events (overall and by dose-level) will be 
tabulated and summarized within the three patient groups. The grade 3+ adverse events 
will also be described and summarized in a similar fashion. This will provide an 
indication of the level of tolerance for this treatment combination in the three patient 
groups. 
 
16.22 Toxicity Profile 
 
As per NCI CTCAE V4.0, the term “toxicity” is defined as adverse events that are 
classified as either possibly, probably, or definitely related to study treatment. Non-
hematologic toxicities will be evaluated via the ordinal CTCAE standard toxicity grading. 
Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be 


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assessed using continuous variables as the outcome measures (primarily nadir) as well as 
categorization via CTCAE standard toxicity grading. 
 
Overall toxicity incidence as well as toxicity profiles by dose level will be explored and 
summarized. Frequency distributions, graphical techniques and other descriptive 
measures will form the basis of these analyses. 
 
Further, the overall toxicity profiles and the MTD will be compared in an exploratory 
fashion among the three groups for any possible differences. 
 
Lastly, the duration of treatment, dose level and total dose per agent each cycle will be 
summarized using descriptive statistics overall per group and by dose level per group. 
 
16.23 Timed Endpoints 
The data on time-related variables will be summarized descriptively. These include time 
until any treatment related toxicity, time until treatment related grade 3+ toxicity, time 
until hematologic nadirs (WBC, ANC, platelets), time to progression and time to 
treatment failure, where time to treatment failure is defined as the time from registration 
to documentation of progression, unacceptable toxicity, or refusal to continue 
participation by the patient. 
 
16.3 
Phase II Design and Analysis 
 
16.31 Primary Endpoint and Estimation: The primary endpoint is the proportion of patients who 
have at least a partial response to treatment. Throughout Section 16.3, partial response or 
better will be considered synonymous with “success”, unless specified otherwise. The 6 
patients treated at the recommended dose level (MTD) within each group will be 
included in the analysis for this portion of the study. The efficacy population will include 
the 63 patients across groups and include all patients meeting eligibility criteria who 
signed a consent form and began treatment. 
 
The proportion of successes will be estimated by the number of successes divided by the 
total number of patients in the efficacy population. Eligible, treated patients who are 
unevaluable for response will be included in the denominator when estimating the 
proportion of successes. Confidence intervals for the true success proportion will be 
calculated according to the properties of the binomial distribution. Secondary analyses 
include estimation of the proportion of successes with confidence intervals for each 
group. 
 
16.32 Statistical Design: The largest success proportion where the proposed treatment regimen 
would be considered ineffective in this population is 40%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in this 
patient population is 55%. The following one-stage design based on the binomial 
distribution uses 63 patients to test the null hypothesis that the true success proportion in 
a given patient population is at most 40%. 
 


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The success rate of 40% is based on the results of two phase III studies of lenalidomide 
plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple 
myeloma (MM-009, North America, 353 patients; MM-010, Europe, Australia, and 
Israel, 351 patients). The overall response (≥PR) rates associated with lenalidomide and 
dexamethasone were 61% and 59.1% in MM-009 and MM-010, respectively, and the 
overall response rates associated with dexamethasone (plus placebo) were 20.5% and 
24% in MM-009 and MM-010, respectively, with a median follow-up of 17.1 months 
(MM-009) and 16.5 months (MM-010) as reported by Weber et al19. An additional 
pooled subgroup analysis was reported by Weber et al19 investigating renal dysfunction 
groups. Overall response rate to lenalidomide and dexamethasone was not significantly 
different between patients with creatinine clearance above 60 ml/min and patients with 
creatinine clearance below 60 ml/min. However, for 16 patients with creatinine clearance 
below 30 ml/min, median time to progression and overall survival were significantly 
shorter than for those with creatinine clearance above 30 ml/min. Further, the median 
time to progression and overall survival of patients with creatinine clearance below 30 
ml/min was significantly greater than patients with creatinine clearance below 30 ml/min 
on the dexamethasone (and placebo) arm. Results for overall response rate in the <30 
ml/min group were not reported. Based on this, it is reasonable to anticipate that the 
overall response rate in (at least) Group B and Group C of the current study will be less 
than 60%. However, the study chairs felt that an overall response rate of 40% would be 
the minimum acceptable in this context. 
 
16.33 Decision Rule: Enter 63 patients into the study. If 30 or fewer successes are observed in 
63 eligible, treated patients, we will consider this regimen ineffective in this patient 
population and terminate this study. If 31 or more successes are observed among 63 
eligible, treated patients, we may recommend further testing of this regimen in 
subsequent studies in this population. 
 
16.34 Over Accrual: If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any decision making 
process but will be included in all final point estimates. 
 
16.35 Power and Significance Level: Assuming that the number of successes is binomially 
distributed, the significance level is ≥10% and the probability of declaring that this 
regimen warrants further studies (e.g., statistical power) under various success 
proportions can be tabulated as a function of the true success proportion as shown in the 
following table. 
 
If the true success proportion is . . . . . . 
0.4 
0.45 
0.5 
0.55 
0.6 
then the probability of declaring that the 
regimen warrants further studies is . . . . . . 
0.09 
0.29 
0.60 
0.85 
0.97 
 
16.36 Analysis Plan: The analysis for this trial will commence at planned time points and at the 
time the patients have become evaluable for the primary endpoint. Such a decision will 
be made by the Statistician and Study Chair, in accord with PrECOG Standard Operating 
Procedures, availability of data for secondary endpoints (e.g., laboratory correlates), and 


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the level of data maturity. It is anticipated that the earliest date in which the results will 
be made available via manuscript, abstract, or presentation format is 24 months. 
 
16.37 
Definitions and Analyses of Secondary Endpoints: 
 
Survival time is defined as the time from registration to death due to any cause. The 
distribution of survival time will be estimated using the method of Kaplan-Meier. 
 
Progression-free survival time is defined as the time from registration to the earliest date 
of documentation of disease progression. If a patient dies without a documentation of 
disease progression the patient will be considered to have had disease progression at the 
time of their death. If the patient is declared to be a major treatment violation, the patient 
will be censored on the date the treatment violation was declared to have occurred. In the 
case of a patient starting treatment and then never returning for any evaluations, the 
patient will be censored for progression on day 1 post-registration. The distribution of 
progression-free survival time will be estimated using the method of Kaplan-Meier. 
 
Duration of response is defined for all eligible, treated patients who have achieved a 
partial response or better as the date at which the patient’s earliest objective status is first 
noted to be either a partial response or better to the earliest date progression is 
documented.  
 
Time to treatment failure is defined to be the time from registration to the date at which 
the patient is removed from treatment due to progression, adverse events, or refusal. If 
the patient is considered to be a major treatment violation or is taken off study as a non-
protocol failure, the patient will be censored on the date they are removed from treatment. 
 
Adverse Events: All eligible patients who began treatment will be considered evaluable 
for assessing adverse event rate(s). The maximum grade for each type of adverse event 
will be recorded for each patient, and frequency tables will be reviewed to determine 
patterns. Additionally, the relationship of the adverse event(s) to the study treatment will 
be taken into consideration. The duration of treatment, dose level and total dose per agent 
each cycle will also be summarized using descriptive statistics. Lastly, renal function 
over time will be described using descriptive statistics. 
 
16.38 Pharmacokinetic Analysis: 
 
Pharmacokinetic (PK) analysis will be performed in consented subjects administered a 
dose during the “Phase II” portion of the trial. 
 
The following pharmacokinetic parameters will be determined using the non-
compartmental methods: 
 
• Maximum observed plasma concentration (Cmax) 
• Time to maximum plasma concentration (tmax) 
• Area under the plasma concentration-time curve from Time 0 to the last measurable 
time point (AUC) 


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• Area under the plasma concentration-time curve from Time 0 to infinity (AUC∞) 
• Apparent total body clearance when dosed orally (CL/F) 
• Apparent volume of distribution when dosed orally (Vz/F) 
• Terminal elimination half-life in plasma (t½,z) 
 
The relationship between renal function (CrCl) and PK parameters will be explored. 
 
The results will be summarized by descriptive statistics. 
 
16.4 
Data & Safety Monitoring: 
 
Study Monitoring: PrECOG, LLC will be responsible for study monitoring. Refer to 
Section 19.5 for details.  
 
Adverse Event Stopping Rule: The stopping rule specified below is based on the 
knowledge available at study development. We note that the Adverse Event Stopping 
Rule may be adjusted in the event of either (1) the study re-opening to accrual or (2) at 
any time during the conduct of the trial and in consideration of newly acquired 
information regarding the adverse event profile of the treatment(s) under investigation. 
The study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to a group if at any time we observe events 
considered at least possibly related to study treatment (e.g., an adverse event with 
attribute specified as “possible”, “probable”, or “definite”) that satisfy the following: 
 
• If 7 or more patients in the first 20 treated patients (or 33% of patients after 20 have 
been accrued) experience a grade 4 or higher non-hematologic adverse event. 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence of a 
previously unrecognized treatment-related adverse event. The adverse event rule will be 
evaluated for each group using all patients in the group who initiate treatment (e.g., will 
include patients in the phase I and phase II components). 
 
 
16.5 
Inclusion of Women and Minorities 
 
This study will be available to all eligible patients regardless of race, gender, or ethnic 
group.  
 
There is no information currently available regarding differential agent effects of this 
regimen in subsets defined by gender, race, or ethnicity, and there is no reason to expect 
such differences exist. Therefore, although the planned analyses will, as always, look for 
differences in treatment effect based on gender and racial groupings, the samples sizes 
are not increased in order to provide additional power for such subset analyses. 
 


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77 
 
To predict the characteristics of patients likely to enroll in this trial we have reviewed the 
Mayo registration classified by race and gender. This revealed that roughly 3% of 
patients registered into cancer trials during the past five years could be classified as 
minorities and about 50% of patients were women. Expected sizes of racial by gender 
subsets are shown in the following table: 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
2 
2 
 
4 
Not Hispanic or Latino 
53 
54 
 
107 
Ethnic Category: Total of all subjects* 
55 
56 
 
111 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
 
0 
Asian 
0 
0 
 
0 
Black or African American 
1 
1 
 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
 
0 
White 
54 
55 
 
109 
Racial Category: Total of all subjects* 
55 
56 
 
111 
*These totals must agree.  Enter actual estimates (not percentages) 
 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central American, or other 
Spanish culture or origin, regardless of race. The term “Spanish origin” can also be used in addition to 
“Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original peoples of North, 
Central, or South America, and who maintains tribal affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast Asia, or the 
Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, 
the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have been 
recorded as Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial groups of Africa. Terms 
such as “Haitian” or “Negro” can be used in addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original peoples of 
Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle East, or North 
Africa. 
 
 
17.0 
Pathology Considerations: None
 


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18.0 
Budget Considerations 
 
18.1 
Costs Charged to Patient: 
 
18.11 Tests and clinical visits considered part of standard care will be charged to the patient. Patient 
will also be charged for the cost of dexamethasone and associated preparation charges. 
 
18.12 Lenalidomide will be provided complimentary by Celgene. 
 
18.13 Patients randomized to the pharmacokinetic portion of the study will not be charged for the 
pharmacokinetic samples.   


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19.0 
Administrative 
 
19.1 
Protocol Compliance 
 
The study shall be conducted as described in this protocol. All revisions to the protocol must be 
discussed with, and be prepared by PrECOG and/or representatives. The Investigator should 
not implement any deviation or change to the protocol or consent without prior review and 
documented approval/ from PrECOG and/or representatives and the IRB of an amendment, 
except where necessary to eliminate an immediate hazard(s) to study patients. 
 
If a deviation or change to the approved protocol is implemented to eliminate an immediate 
hazard(s) prior to obtaining IRB approval, notification will be submitted to the IRB for review 
and approval as soon as possible afterward. Documentation of approval signed by the 
chairperson or designee of the IRB(s) should be in the study records. If PrECOG and/or 
representatives provides an amendment that substantially alters the study design or increases 
the potential risk to the patient; the consent form must be revised and submitted to the IRB(s) 
for review and approval; the revised form must be used to obtain consent from patients 
currently enrolled in the study if they are affected by the amendment; and the new form must 
be used to obtain consent from new patients prior to study entry. Information as to who 
investigators should send correspondence will be provided in additional study documents. 
 
19.2 
Institutional Review Board 
 
Before study initiation, the Investigator must have written and dated approval from their 
respective IRB for the protocol, consent form, patient recruitment materials/process and any 
other written information to be provided to patients. The Investigator should also provide the 
IRB with a copy of the Investigator Brochure or product labeling, and any updates. 
 
The Investigator should provide the IRB with reports, updates, and other information (e.g., 
Safety Updates, Amendments, and Administrative Letters) according to regulatory 
requirements, IRB or study site procedures. 
 
19.3 
Informed Consent Procedures 
 
Investigators must ensure that patients who volunteer for clinical trials or their legally 
acceptable representative are clearly and fully informed about the purpose, potential risks and 
other information. 
 
A protocol specific informed consent form (ICF) template will be provided to sites. Preparation 
of the site-specific consent form is the responsibility of the site Investigator and must include 
all applicable regulatory and IRB requirements, and must adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki. All changes to the ICF template 
will be approved by PrECOG and/or their representatives prior to implementation. 
 
 
 


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80 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
consent process will also include written authorization by patients to release medical 
information to allow PrECOG and/or its agents, regulatory authorities, and the IRB of record at 
the study site for access to patient records and medical information relevant to the study, 
including the medical history. This will be documented in the informed consent form or other 
approved form obtained at the time of informed consent per institutional policies. This form 
should also be submitted to PrECOG and/or its agents for review prior to its implementation. 
 
The Investigator must provide the patient or legally acceptable representative with a copy of 
the consent form and written information about the study in the language in which the patient is 
most proficient. The language must be non-technical and easily understood. The Investigator 
should allow time necessary for patient or patient's legally acceptable representative to inquire 
about the details of the study, then informed consent must be signed and personally dated by 
the patient or the patient's legally acceptable representative and by the person who conducted 
the informed consent discussion. The patient or legally acceptable representative should 
receive a copy of the signed informed consent and any other written information provided to 
study patients prior to patient's participation in the trial. The investigator is responsible for 
assuring adequate documentation of this process and for storage and maintenance of the 
original signed consent form for each patient/subject. 
 
The informed consent and any other information provided to patients or the patient's legally 
acceptable representative, should be revised whenever important new information becomes 
available that is relevant to the patient's consent, and should receive IRB approval prior to use. 
The Investigator, or a person designated by the Investigator should inform the patient or the 
patient's legally acceptable representative of all pertinent aspects of the study and of any new 
information relevant to the patient's willingness to continue participation in the study. This 
communication should be documented in the patient record. During a patient's participation in 
the trial, any updates to the consent form and any updates to the written information will be 
provided to the patient. 
 
19.4 
Safety Communication 
 
Investigators will be notified of all AEs that are serious, unexpected, and certainly, probably, or 
possibly related to the investigational product. Upon receiving such notices, the Investigator 
must review and retain the notice with the Investigator Brochure and submit a copy of this 
information to the Institutional Review Board (IRB) according to local regulations. The 
Investigator and IRB will determine if the informed consent requires revision. The Investigator 
should also comply with the IRB procedures for reporting any other safety information. All 
revisions should be submitted to PrECOG and/or agents for review. 
 
19.5 
Monitoring 
 
Representatives and agents of PrECOG and, as applicable to the study, the manufacturer of 
Investigational Product must be allowed to visit all study site locations periodically to assess 
the data, quality and study integrity. The purpose of this visit is to review study records and 
directly compare them with source documents and discuss the conduct of the study with the 
Investigator, and verify that the facilities remain acceptable. 
 


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81 
 
The study may be evaluated by other auditors and government inspectors who must be allowed 
access to eCRFs, source documents and other study files. The investigator must notify 
PrECOG of any scheduled visits by regulatory authorities, and submit copies of all reports. 
Information as to who investigators should notify of an audit or where to address questions will 
be provided in additional study materials. 
 
19.6 
Study Records 
 
An Investigator is required to maintain adequate regulatory files with corresponding 
communication and approvals, accurate histories, observations and other data on each 
individual treated. Full details of required regulatory documents will be provided in additional 
study materials. Data reported on the CRF must be consistent with the source documents as 
part of the patient record. 
 
The confidentiality of records that could identify patients must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
 
A study specific signature record will be maintained to document signatures and initials of all 
persons at a study site who are authorized to make entries and/or corrections on eCRFs as well 
as document other study-specific roles. 
 
19.7 
Electronic Case Report Form (eCRF) Information 
 
Additional information regarding eCRF instructions, timelines for data entry/ submission and 
query completion can be found in supplemental materials provided to the site. Sites will be 
expected to complete eCRFs as per the schedule provided and submit all relevant data as per 
the specified timelines. All items recorded on eCRFs must be found in source documents. 
 
The completed eCRF must be promptly reviewed, electronically signed, and dated by the 
Principal Investigator. 
 
Instructions for management of patients who do not receive any protocol therapy: 
If a patient is registered and does not receive any assigned protocol treatment, baseline, Serious 
Adverse Event and End of Active Treatment/Cancel Notification Form will still be entered and 
must be submitted according to the eCRF instructions. Document the reason for not starting 
protocol treatment on the appropriate eCRF.  
 
19.8 
Records Retention 
 
FDA Regulations (21 CFR 312.62) require clinical investigators to retain all trial-related 
documentation, including source documents for the periods described below for studies 
performed under a US IND: 
 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of trials and that 
an application will not be submitted. 
 


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The Investigator must retain investigational product disposition records, copies of eCRFs (or 
electronic files), and source documents for the maximum period required by applicable 
regulations and guidelines, or Institution procedures, whichever is longer. The Investigator 
must contact PrECOG and/or representatives prior to destroying any records associated with 
the study. 
 
Information as to who investigators should contact for questions will be provided in additional 
study documents. PrECOG and/or representatives will notify the Investigator when the trial 
records for this study are no longer needed. 


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20.0 
References 
 
1. 
Jemal, A, et al. Cancer statistics, 2007. CA Cancer J Clin 2007; 57:43. 
2. 
Kyle, RA, Rajkumar, SV. Multiple myeloma. N Engl J Med 2004; 351:1860-1873. 
3. 
Prince HM, Schenkel B, Mileshkin L. An analysis of clinical trials assessing the efficacy and 
safety of single-agent thalidomide in patients with relapsed or refractory multiple myeloma. 
Leuk Lymphoma 2007; 48(1):46-55. 
4. 
Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, 
Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney 
ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, 
Zeldis J, Knight R, Weller E, Anderson KC. Immunomodulatory drug CC-5013 overcomes drug 
resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2006; 
108(10):3458-64. 
5. 
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, 
Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, 
Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC. 
Bortezomib or high-dose dexamethasone for relapsed multiple myeloma.  N Engl J Med 2005; 
16; 352(24):2487-98. 
6. 
Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, Geyer S, Iturria N, 
Fonseca R, Lust JA, Kyle RA, Witzig TE. Combination therapy with thalidomide plus 
dexamethasone for newly diagnosed myeloma J Clin Oncol 2002; 20(21):4319-23. 
7. 
Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, 
Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA. 
Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed 
myeloma. Blood. 2005; 106(13):4050-3. 
8. 
Jagannath S, Durie BG, Wolf J, Camacho E, Irwin D, Lutzky J, McKinley M, Gabayan E, 
Mazumder A, Schenkein D, Crowley J. Bortezomib therapy alone and in combination with 
dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 2005; 
129(6):776-83. 
9. 
Kyriakou C, Thomson K, D'Sa S, Flory A, Hanslip J, Goldstone AH, Yong KL. Low-dose 
thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a 
well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma. 
Br J Haematol 2005; 129(6):763-70. 
10. Orlowski, RZ, Zhuang, SH, Parekh, T, et al. The combination of pegylated liposomal 
doxorubicin and bortezomib significantly improves time to progression of patients with 
relapsed/refractory multiple myeloma compared with bortezomib alone: Results from a planned 
interim analysis of a randomized phase III study. Blood 2006; 108:124a. Final results: Orlowski 
RZ, Nagler A, Sonneveld P, Blade J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska 
A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, 
Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin 
plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: 
combination therapy improves time to progression. J Clin Oncol 2007; 25(25) 3892-901. 
11. Weber D, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple 
myeloma in North America. NEJM 2007; 21: 357:2133-2142. 
12. Glasmacher A, Hahn C, Hoffmann F, Naumann R, Goldschmidt H, von Lilienfeld-Toal M, 
Orlopp K, Schmidt-Wolf I, Gorschluter M. A systematic review of phase-II trials of thalidomide 
monotherapy in patients with relapsed or refractory multiple myeloma. Br J Haematol. 2006; 
132(5):584-93. 


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13. Davies FE, Raje N, Hideshima T, et al.  Thalidomide and immunomodulatory derivatives 
augment natural killer cell cytotoxicity in multiple myeloma.  Blood 2001;98(1):210-6.   
14. Dredge K, Horsfall R, Robinson SP, et al.  Orally administered lenalidomide (CC-5013) is anti 
angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. 
Microvasc Res. 2005; 69(1-2):56-63. 
15. Barlogie B. Thalidomide and CC-5013 in multiple myeloma: the University of Arkansas 
experience. Semin Hematol. 2003;40(4 Suppl 6):25-7. 
16. Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, LeBlanc R, 
Catley LP, Doss D, Kelly K, McKenney M, Mechlowicz J, Freeman A, Deocampo R, Rich R, 
Ryoo JJ, Chauhan D, Balinski K, Zeldis J, Anderson KC. Immunomodulatory drug CC-5013 
overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma.  
Blood 2002; 100(9):3063-7. 
17. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, 
Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney 
ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, 
Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide 
therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006; 
108(10): 3458-64. 
18. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, 
Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, 
Knight RD. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N 
Engl J Med 2007; 357(21): 2123-32. 
19. Weber D, Wang M, Chen C, et al. Lenalidomide plus high-dose dexamethasone provides 
improved overall survival compared to high-dose dexamethasone alone for relapsed or 
refractory multiple myeloma (MM): results of 2 phase III studies (MM-009, MM-010) and 
subgroup analysis of patients with impaired renal function. Blood 2006; 108; 3547a. 
20. Revlimid® package insert. Summit, NJ Celgene Corporation 2007. 
21. Chen N, Lau H, Kong L, et al. Pharmacokinetics of lenalidomide in subjects with various 
degrees of renal impairment and in subjects on hemodialysis. J of Clinical Pharmacology 2007; 
47(12):1466-75. 
22. Niesvizky R, Naib T, Christos PJ, Jayabalan D, Furst JR, Jalbrzikowski J, Zafar F, Mark T, Lent 
R, Pearse RN, Ely S, Leonard JP, Mazumdar M, Chen-Kiang S, Coleman M.  Lenalidomide-
induced myelosuppression is associated with renal dysfunction: adverse events evaluation of 
treatment-naive patients undergoing front-line lenalidomide and dexamethasone therapy. Br J 
Haematol. 2007; 138(5):640-3.  
23. Reece DE, Masih-Khan E, Chen C, Wang L, Dean S, Kukreti V, Mikhael JR, Trudel S, Knight 
R, Zeldis J. Use of lenalidomide +/- corticosteroids in relapsed/refractory multiple myeloma 
patients with elevated baseline serum creatinine levels. Blood 2006; 108(11): 3550. 


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Appendix I 
Informed Consent Example 
 
PrECOG 1003: A Phase I/II Study of the Tolerability of Lenalidomide and Low Dose 
Dexamethasone in Previously Treated Multiple Myeloma Patients with Impaired Renal 
Function 
Version Date: March 28, 2011 
This is a clinical trial, a type of research study. Your doctor will explain the clinical trial to you. Clinical trials 
include only people who choose to take part. Please take your time to make your decision after getting the 
information you need. You may discuss your decision with your friends and family. You can also discuss it with 
your health care team. If you have any questions, you can ask your doctor for more explanation. The information 
in this form is part of a process called informed consent, which will allow you to make a decision about whether 
you want to volunteer for this clinical trial. Please take your time to make your decision and discuss it with your 
friends and family. 
Once all of your questions have been answered, if you still wish to take part, you will be asked to sign this form. 
Your study doctor and/or a member of the study team will also sign the form. You will receive a copy of the form 
to keep. If you have any questions at any time during the research study, you should feel free to ask them. You 
will receive answers to your questions in a way that you will be able to understand. You are not giving up any of 
your legal rights by volunteering for this research study or signing this consent form. 
WHY HAVE YOU BEEN ASKED TO TAKE PART IN THIS STUDY? 
You are being asked to take part in this research study to find out what is the best way to give the drug 
lenalidomide (Revlimid®) in patients with previously treated multiple myeloma and kidney problems. It is 
designed to find out the correct dose of the drug and its effect on multiple myeloma when patients have kidney 
damage. 
WHO IS DOING THIS STUDY? 
This study is being conducted by PrECOG LLC, in conjunction with Celgene Corporation. Your study doctor has 
agreed to participate in this study as a study investigator and will receive payments to cover some research costs 
such as the cost of performing research tests and collecting and reporting study information. 
WHY IS THIS STUDY BEING DONE? 
This study is divided into 2 phases. Phase I will establish the maximum tolerated dose of the combination of 
lenalidomide with dexamethasone therapy in patients with previously treated multiple myeloma with kidney 
damage. Phase II will study how effective the treatment is against previously treated multiple myeloma in 
patients who have kidney damage. 
Lenalidomide is approved by the Food and Drug Administration (FDA) for the treatment of specific types of 
myelodysplastic syndrome (MDS) and in combination with dexamethasone for patients with multiple myeloma 
(MM) who have received at least one prior therapy. MDS and MM are cancers of the blood. Lenalidomide is 
currently being tested in a variety of cancer conditions. 
 


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HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
Approximately 111 patients from 30 different study centers will be entered into the study. 
WHAT IS INVOLVED IN THIS STUDY? 
Before you are enrolled in the study, you will undergo certain tests to ensure that it is safe for you to go on the 
study and that your enrollment in the study will provide important information towards answering the question 
that the study is addressing. You will have a full medical history and physical examination along with blood, 
urine, bone marrow tests and x-rays as shown below. Some of these tests would be done even if you do not take 
part in this study. 
If you meet all of the criteria for being in the study, you will receive the study treatment. The study is broken 
down into three periods: screening, treatment and post-treatment. The screening period includes a number of 
procedures to evaluate your cancer and overall health. The treatment period consists of the time that you will take 
the medication. Post-treatment is when you have follow-up testing.  
Below is a description of the procedures and study visits: 
Screening Procedures 
• 
Medical History 
•  
Physical Exam, including height and weight 
•  
Routine blood and urine tests  
•  
Bone marrow biopsy and aspirate (removal of bone marrow with a needle and syringe)  
•  
EKG (Electrocardiogram-a measurement of your heart’s electrical activity)  
•  
Chest x-ray and Bone survey (x-ray) 
•  
Pregnancy test (only for females of childbearing potential) 10-14 days prior to and again within 
24 hours of starting lenalidomide therapy.  
Treatment Procedures 
If you are found to be eligible, you will start treatment. During the treatment period, you will be asked to come to 
the hospital/outpatient clinic/MD office to receive a supply of the study medicine. Before receiving each 
treatment, you will be asked about any new problems that may have occurred since your last visit.  
While on this study you will receive at least two cycles of treatment unless it causes too many bad side effects. 
Each cycle is 28 days. If your disease stays the same or is helped you will continue to receive study treatment and 
if your disease gets worse you will be taken off study treatment. You will take lenalidomide by mouth on 
specified days each cycle as indicated by your study doctor. You will also take dexamethasone once weekly and 
aspirin daily or another form of anticoagulation medication as prescribed by your study doctor. Swallow 
lenalidomide capsules whole with water at the same time each day. Do not break, chew or open the capsules.  
If you miss a dose of the medications, take them as soon as you remember on the same day. If you miss taking 
your dose for the entire day, take your regular dose the next scheduled day (do NOT take double your regular 
dose to make up for the missed dose). Please contact the study staff right away if you inadvertently take more 
than your usual dose of either drug.  
If you take more than the prescribed dose of lenalidomide you should seek emergency medical care if needed and 
contact study staff immediately. 


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Females of childbearing potential that might be caring for you should not touch the lenalidomide capsules or 
bottles unless they are wearing gloves. 
You will be given a diary to record when you take your study drugs. Between each cycle of treatment you will be 
seen by your physician to check if the treatment is having any benefit or whether you are having any bad effects 
from the treatment. During each of these visits, you will have blood and urine tests.  
Day 1 of Cycles 1-4:  
•  
Physical Exam 
•  
Routine blood and urine tests 
•  
Counseling about pregnancy precautions, risks of fetal exposure and other risks  
•  
Pregnancy test (only for females of childbearing potential)  
Day 6 of Cycle 1 (For select participants in Phase II part of study only): 
•  
5cc (about 1 teaspoon) of blood will be drawn at the following time points after you have taken 
your medication on Day 6 of Cycle 1: 0 (pre-dose), 30 minutes, 1 hour, 1 and ½ hours, 2 hours, 
3 hours, 4 hours, 6 hours, 8 hours, and 24 hours at all dose groups. Blood may also be drawn at 
48 hours and 72 hours for participants with severe renal impairment or on dialysis.  
Weekly during Cycles 1-4: 
•  
Pregnancy test every week for the first 28 days (only for females of childbearing potential)  
•  
Routine blood work  
At the End of Cycle 4: 
•  
Physical Exam 
•  
Routine blood and urine tests 
•  
Bone marrow biopsy and aspirate (removal of bone marrow with a needle and syringe)   
•  
Bone survey (x-ray) 
Day 1 of Each Additional Cycle: 
• 
Physical Exam 
•  
Routine blood and urine tests 
•  
Counseling about pregnancy precautions, risks of fetal exposure and other risks  
•  
Pregnancy test every 28 days while on therapy (only for females of childbearing potential)  
Day 1 of Cycle 9 or End of Treatment:  
• 
Physical Exam 
•  
Routine blood and urine tests 
• 
Bone survey (x-ray)  
•  
Bone marrow biopsy and aspirate (removal of bone marrow with a needle and syringe) 
• 
Counseling about pregnancy precautions, risks of fetal exposure and other risks  
•  
Pregnancy test every 28 days while on therapy, the end of your treatment with lenalidomide, 
and 28 days after the last dose of lenalidomide (only for females of childbearing potential)  
Post-Treatment Procedures 
Once you are no longer receiving study medication, or if you withdraw from the study at any time, you will be 
asked to return to be followed. You will be asked about new problems that have happened since your last visit. 
 


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HOW LONG WILL I BE IN THE STUDY? 
You may get treatment as long as your disease continues to respond. You will be followed every 6 months once 
you have stopped treatment. We would like to keep track of your medical condition for up to 3 years from the 
time you begin treatment on this study so researchers can watch your health status and look at the long-term 
effects of the treatment. 
Your doctor may decide to take you off this study if your multiple myeloma does not improve or if side effects of 
treatment would make it unsafe to continue. You will be informed of new developments that might affect your 
participation in the study. 
You may stop participating at any time. However, if you decide to stop participating in the study, we encourage 
you to talk to your doctor first. 
WHAT ARE THE RISKS OF THE STUDY? 
While on this study, you are at risk for the side effects listed below. Everything possible will be done to prevent 
or reduce any discomfort or risk. Your doctor may alter schedules and doses of your therapy if necessary to 
reduce side effects. You may experience all, some or none of the side effects listed. There also may be other side 
effects that the researchers cannot predict. Side effects may appear shortly after receiving the drug or may appear 
years later. Many side effects may disappear after the drugs are stopped. Other side effects may be long lasting, 
permanent or fatal.  
Other drugs may be given to make side effects less serious and uncomfortable. You will be asked to contact your 
study doctor for any problems or questions that arise at any time during your treatment, so that treatment can be 
started to prevent or decrease serious problems. 
Risks and side effects related to the drugs you will be given in this study include:  
Lenalidomide (Revlimid®) 
Likely risks of lenalidomide (events occurring greater than 20% of the time)  
• 
Fatigue or feeling tired 
• 
Neutropenia or a decrease in white blood cells that can make you more prone to infections  
• 
Thrombocytopenia or a decrease in platelets which can cause you to bruise or bleed easily 
and/or may require platelet transfusion 
• 
Constipation or difficulty moving your bowels 
• 
Diarrhea or loose/frequent bowel movements 
Less likely risks of lenalidomide (events occurring in between 3 to 20% of the time) 
• 
Anemia or a decrease in red blood cells that can cause tiredness which may require red blood 
cell transfusion 
• 
Nausea 
• 
Loss of appetite 
• 
Back pain 
• 
Joint pain 
• 
Muscle cramps 
• 
Swelling of the arms and legs 
• 
Problems falling asleep or staying asleep 


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• 
Fever 
• 
Cough 
• 
Shortness of breath or difficulty catching your breath 
• 
Upper respiratory infection 
• 
Rash 
• 
Itching and dry skin 
• 
Lack or loss of strength 
• 
Dizziness 
• 
Headache  
Serious side effects (events occurring less than 3% of the time) 
• 
Neutropenia associated with a fever 
• 
Pulmonary embolism or blood clot in or around the lungs 
• 
Deep vein thrombosis or blood clots in a larger blood vessel 
• 
Atrial fibrillation or irregular heartbeat 
• 
Progression of the disease being studied including multiple myeloma 
• 
Pneumonia or an infection of the lungs 
• 
Sepsis or an infection of the blood 
• 
Dehydration 
• 
Kidney failure which can cause changes in the amounts of chemicals in your blood which can 
cause irregular heartbeats, muscle twitching, seizures, and/or death. 
Rare cases of the following events have been reported (events occurring less than 1% of the time) 
• 
Angioedema – an allergic skin disease characterized by patches of swelling involving the skin 
and/or the lining of your nose, mouth, and gastrointestinal tract. 
• 
Anaphylaxis- serious potentially life-threatening type of allergic reaction that may cause 
breathing difficulty, dizziness, low blood pressure, and loss of consciousness. 
• 
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis – serious allergic skin reactions 
that begin as a rash in one area and later cover more of the body leading to detachment of the 
top layer of skin (could be body-wide). Medical journals have reported patients with allergic 
skin reaction with thalidomide who also developed the same type of reaction with 
lenalidomide. 
• 
Tumor Lysis Syndrome (TLS) – metabolic problems can occur during or without treatment of 
cancer. These complications are caused by the break-down products of dying cancer cells and 
include hyperkalemia (high potassium), hyperphosphatemia (high phosphorus), hyperuricemia 
and hyperuricosuria (high uric acid in the blood and urine), hypocalcemia (low calcium), and 
consequent acute uric acid nephropathy and acute renal failure (kidney damage).  
• 
Tumor Flare Reaction – a condition that can involve increase in the size of the cancerous 
lymph nodes, rash and slight fever. 
• 
Rhabdomyolysis – a serious condition involving the destruction of skeletal muscle that can 
lead to kidney failure. Signs and symptoms include dark, red, or cola-colored urine and muscle 
tenderness, stiffness, aching (myalgia) or weakness. 
• 
Increase in blood levels of lipase due to inflammation of pancreas gland. 
Occasional adverse events such as atrial fibrillation (irregular heartbeat), myocardial infarction (heart attack), and 
congestive heart failure (condition where the heart becomes weak and cannot pump enough blood to the rest of 
the body) have been reported with the use of lenalidomide. 


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Hematological Toxicity 
Lenalidomide is associated with significant neutropenia (decrease in white blood cells that help fight infection) 
and thrombocytopenia (decrease in platelets that help with blood clotting). You will have your blood counts 
checked frequently when starting treatment with lenalidomide. 
Deep Vein Thrombosis and Pulmonary Embolism 
Lenalidomide has demonstrated an increased risk of deep vein thrombosis [DVT (blood clot in a larger blood 
vessel)] and pulmonary embolism [PE (a blood clot in or around the lungs)] in some people with certain medical 
conditions. The study staff will ask you about any risk factors you may have. [If you have a history of blood clots 
your doctor will prescribe either heparin or coumadin for the first four months of the study treatment. The doctor 
may continue to prescribe the medication or aspirin for the remainder of your course of study treatment. All other 
patients will receive (at the discretion of the treating physician) either oral low–dose aspirin or another treatment 
to prevent blood clotting during study participation.] Patients unable or unwilling to undergo treatment for 
prevention of blood clots will not be eligible to participate in this study. You will be instructed on the signs and 
symptoms of DVT and PE and if symptoms occur you should contact your study doctor promptly. 
Neoplasms Benign, Malignant and Unspecified (including cysts and polyps) 
Reports of progression to Acute Myeloid Leukemia (AML) have been received in MDS studies. It is unclear 
whether lenalidomide increases the risk of AML or if progression merely reflects the natural course of the 
disease. AML is the rapid multiplication of abnormal cells which accumulate in the bone marrow and interfere 
with the production of normal blood cells. AML is a very serious condition which may result in death.  
Second New Cancers 
According to researchers, patients with cancer have a higher risk of developing a second new cancer when 
compared to people without cancer. In clinical studies of newly diagnosed multiple myeloma, a higher number of 
second cancers were reported in patients treated with induction therapy (treatment as first step to reducing 
number of cancer cells) and/or bone marrow transplant then lenalidomide for a long period of time compared to 
patients treated with induction therapy and/or bone marrow transplant then placebo (a capsule containing no 
lenalidomide). Patients should make their doctors aware of their medical history and any concerns they may have 
regarding their own increased risk of other cancers. 
Dexamethasone (DXM)  
Likely risks of dexamethasone (events occurring greater than 20% of the time) 
• 
Stomach and throat ulcers or worsening of any ulcers you had before treatment 
• 
Swelling and pain of the pancreas 
• 
Weight gain around the stomach 
• 
Puffiness (especially in the face) 
• 
Build-up of fluids and a rise in blood pressure 
• 
Possible rise in your blood sugar 
• 
Changes in the blood levels of potassium 
• 
Infection 
 
 


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Less likely risks of dexamethasone (events occurring in between 3 to 20% of the time) 
• 
Muscle weakness 
• 
Brittle bones 
• 
Menstrual changes 
• 
Itching, and other allergic reactions, some severe   
Rare risks of dexamethasone (events occurring less than 3% of the time) 
• 
Mood swings 
• 
Depression 
• 
Trouble sleeping 
• 
Changes in personality 
• 
Seizures 
• 
Dizziness 
• 
Patients who are more likely to get heart disease may have heart failure 
Other Risks and Discomforts 
If any physician other than the study doctor prescribes medication for you for another condition or you are taking 
any over-the-counter medications or vitamins, you must inform the study staff. This is important because the 
interaction of some medications may cause serious side effects. 
Lenalidomide has been shown to increase the level of digoxin in the blood in some patients; please tell your 
doctor if you are taking digoxin. 
The risks of having blood drawn include fainting, bleeding, bruising at the place on your arm where the blood 
was drawn or needle inserted, pain, swelling and rarely, infection or nerve damage. Imaging scans such as chest 
x-ray and bone survey will expose you to low doses of radiation. 
Risks from a Bone Marrow Biopsy 
A bone marrow aspirate is a procedure in which an area of the hip is numbed and a small sample of bone marrow 
is withdrawn. When the local anesthesia (numbing medicine) is given, you may initially feel a burning sensation 
in your skin and bone surface for several seconds. During the procedure, you may temporarily feel pressure 
and/or pain of varying degrees. If necessary, you may ask your doctor for additional local anesthesia or a 
medication to ease your stress. You also may experience bleeding, and/or bruising after the procedure is 
completed and you may experience soreness in the area for a few days afterwards. Rarely, infection can develop. 
Risks Associated with Pregnancy  
Lenalidomide is related to thalidomide. Thalidomide is known to cause severe life-threatening human birth 
defects. Findings from a monkey study indicate that lenalidomide caused birth defects in the offspring of female 
monkeys who received the drug during pregnancy. If lenalidomide is taken during pregnancy, it may cause birth 
defects or death to an unborn baby. Females must not become pregnant while taking lenalidomide. If you are 
female, you agree not to become pregnant while taking lenalidomide. Lenalidomide is present at very low levels 
in human semen of healthy men for three days after stopping the drug according to a study. For some men, such 
as men with kidney problems, lenalidomide may be present in semen for more than three days. Because of the 


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risk of birth defects, all patients taking lenalidomide must read the following statements that apply to them 
according to gender and menopausal status. 
NOTE: If your study utilizes the pregnancy counseling (LCP): All patients must receive, read and agree to 
what is stated in the Lenalidomide Information Sheet. 
Because of this risk, all participants taking lenalidomide must read the following statements that apply to them 
according to gender and menopausal status. 
FOR FEMALES WHO ARE ABLE TO BECOME PREGNANT* 
*(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 (not 
having menstrual cycles due to cancer therapy does not rule out childbearing potential) for at least 24 
consecutive months (for example, has had menses at any time during the preceding 24 consecutive months). 
Please read thoroughly and initial each space provided if you understand each statement 
_____:  I understand that birth defects may occur with the use of lenalidomide. I have been warned by my 
doctor that my unborn baby may have birth defects and can even die, if I am pregnant or become 
pregnant while I am taking lenalidomide. 
_____:  I understand that I must NOT take lenalidomide if I am pregnant, breast-feeding a baby or able to get 
pregnant and not using 2 reliable methods of birth control. 
_____:  If I am having sexual relations with a man, my uterus and/or both ovaries have not been removed, I 
have had at least one menstrual period in the past 24 months and/or my menses stopped due to 
treatment of my disease, I understand that I am able to become pregnant. I must use one highly 
effective method of birth control plus one additional effective method of birth control (contraception) at 
the SAME TIME. 
Highly Effective Methods 
Additional Effective Methods 
Intrauterine device (IUD) 
Latex condom 
Hormonal (birth control pills, injections, implants) 
Diaphragm 
Tubal ligation 
Cervical Cap 
Partner’s vasectomy 
_____:  These birth control methods must be used during the following time periods related to this study: 1) for 
at least 28 days before starting lenalidomide therapy; 2) throughout lenalidomide therapy, including 
interruptions in therapy and 3) for at least 28 days after lenalidomide has been stopped. I must use these 
methods unless I completely abstain from heterosexual sexual contact. If a hormone (birth control pill, 
injection, patch or implant) or IUD method is not medically possible for me, I may use another highly 
effective method or two barrier methods AT THE SAME TIME. 
_____:  I know I must have a pregnancy test done by my doctor within 10 – 14 days and again within 24 hours 
prior to starting lenalidomide therapy, even if I have not had my menses due to treatment of my disease 
or had as little as one menstrual period in the past 24 months. If I have regular or no menstrual cycles, I 
will then have pregnancy tests every week for the first 28 days, then every 28 days while I am taking 
lenalidomide, again when I have been taken off of lenalidomide therapy and then 28 days after I have 
stopped taking lenalidomide. If I have irregular menstrual cycles, I will have pregnancy tests every 
week for the first 28 days, then every 14 days while I am taking lenalidomide, again when I have been 
taken off of lenalidomide therapy, and then 14 days and 28 days after I have stopped taking 
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_____:  I know I must immediately stop taking lenalidomide and inform my doctor, if I become pregnant while 
taking the drug, if I miss my menstrual period or have unusual menstrual bleeding, if I stop using 2 
reliable forms of birth control, or if I think for any reason that I may be pregnant. I must talk to my 
doctor before changing any birth control methods. 
_____:  I am not now pregnant, nor will I try to become pregnant for at least 28 days after I have completely 
finished taking lenalidomide. 
_____:  I understand that lenalidomide will be prescribed only for me. I must not share it with ANYONE, even 
someone that has similar symptoms to mine. It must be kept out of reach of children and should never 
be given to females who are pregnant or able to have children. 
_____:  I agree any unused drug supply will be returned to the research site at each visit.  
_____: I know that I cannot donate blood while taking lenalidomide and for 28 days after stopping 
lenalidomide. 
Study patients who become pregnant will be monitored throughout the pregnancy and will continue to be 
monitored for 30 days after delivery (premature delivery, aborted fetus, full-term pregnancy, or no longer 
pregnant). 
FOR ALL MALES 
Please read thoroughly and initial each space provided if you understand each statement:  
_____:  I understand that birth defects may occur with the use of lenalidomide. I have been warned by my 
doctor that an unborn baby may have birth defects and can even die, if a female is pregnant or becomes 
pregnant while taking lenalidomide. 
_____:  I have been told by my doctor that I must NEVER have unprotected sexual contact with a female who 
can become pregnant. Because lenalidomide is present in semen, my doctor has explained that I must 
completely abstain from sexual contact with females who are pregnant or able to become pregnant, or I 
must use a latex condom every time I engage in any sexual contact with females who are pregnant or 
may become pregnant. I must do this while I am taking lenalidomide, including during times when 
lenalidomide is temporarily stopped, and for 28 days after I permanently stop taking lenalidomide, even 
if I have had a successful vasectomy. 
_____:  I know I must inform my doctor if I have unprotected sexual contact with a female who is pregnant or 
can become pregnant or if I think, for ANY REASON, that my sexual partner may be pregnant. Female 
partners of male patients taking lenalidomide should be advised to call their own physician 
immediately if they get pregnant. 
_____:  I understand that lenalidomide will be prescribed only for me.  I must not share it with ANYONE, even 
someone that has similar symptoms to mine. It must be kept out of reach of children and should never 
be given to females who are able to have children. 
_____:  I agree any unused drug supply will be returned to the research site at each visit.  
_____:  I know that I cannot donate blood, sperm or semen while taking lenalidomide and for 28 days after 
stopping lenalidomide. 
FOR FEMALES THAT ARE NOT ABLE TO BECOME PREGNANT 
Please read thoroughly and initial each space provided if you understand each statement.  
_____:  I understand that birth defects may occur with the use of lenalidomide. I have been warned by my 
doctor that an unborn baby may have birth defects and can even die, if a female is pregnant or becomes 
pregnant while taking lenalidomide. 
_____:  I certify that I am not now pregnant, nor am I of child bearing potential as I have been in a natural 
menopause for at least 24 months (been through the change in life without even 1 menstrual period for 
the past 24 months); or I had my uterus removed (hysterectomy) or had both my ovaries removed 
(bilateral oophorectomy). 


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_____:  I understand that lenalidomide will be prescribed only for me. I must not share it with ANYONE, even 
someone that has similar symptoms to mine. It must be kept out of reach of children and should never 
be given to females who are pregnant or able to have children. 
_____:  I agree any unused drug supply will be returned to the research site at each visit.  
_____: I know that I cannot donate blood while taking lenalidomide and for 28 days after stopping 
lenalidomide. 
ALL PATIENTS 
You will be counseled at least every 28 days during lenalidomide treatment and again one last time when you 
stop taking lenalidomide about not sharing lenalidomide (and other study drugs), the potential risks of fetal 
exposure, abstaining from blood and other donations, and you will be reminded not to break, chew or open 
lenalidomide capsules. You will be provided with the “Lenalidomide Information Sheet for Patients Enrolled in 
Clinical Research Studies” with each new supply of lenalidomide as a reminder of these safety issues. 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
If you agree to take part in this study, there may or may not be direct medical benefit to you. We hope the 
information learned from this study will benefit other patients with multiple myeloma in the future. 
WHAT OTHER OPTIONS ARE THERE? 
You do not have to be in this study to receive treatment for your condition. Your other choices may include: 
• 
Alternative chemotherapy treatments 
• 
Treatment with lenalidomide off study. 
• 
Comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite 
problems and other problems caused by cancer. It does not treat cancer directly, but instead 
tries to improve how you feel. 
You should talk to the researcher and your regular physician about each of your choices before you decide if you 
will take part in this study. 
HOW WILL I KNOW IF THERE IS NEW INFORMATION LEARNED THAT MIGHT AFFECT MY DESIRE TO 
CONTINUE TO PARTICIPATE IN THIS STUDY? 
During the course of the study, your study doctor will let you know about any new information that may affect 
your willingness to remain in the study. If new information is learned that may affect you after the study has been 
completed, you will be contacted by the study doctor. 
WHAT ABOUT CONFIDENTIALITY? 
This study is being conducted by PrECOG, LLC. PrECOG is a not for profit organization that conducts research 
for the Eastern Cooperative Oncology Group (ECOG) Research and Education Foundation. Your doctor has 
agreed to participate in this study as an investigator.  
You have a right to privacy. All information gathered in this study that can be identified with your name would 
remain confidential by state and federal law. Your initials and the study number assigned will be used to identify 
your records specific to the study. Your name will not be placed on any of your blood samples. Your name will 
not be made public in any reports or publications resulting from this study. 


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This study requires the use of your medical information. National data protection regulations give you the right to 
control the use of your medical information. Therefore, by signing this form you specifically authorize your 
medical information to be checked, transferred and processed as follows: the study monitors, auditors and 
inspectors may review your medical information by direct access to your medical records. Study data, including 
your anonymous medical information, may be processed, which means it will be collected, entered into computer 
databases, verified, analyzed, printed and reported as necessary for legitimate scientific purposes. Authorization 
to access your medical records will end upon completion of this clinical trial. You may access your medical 
information as allowed by national law. 
By signing this consent you are hereby authorizing the use and/or disclosure of protected health information to 
certain individuals, including:  
• 
The study investigator (doctor) and study staff at the office/hospital 
• 
PrECOG and/or their authorized representatives 
• 
Government regulatory agencies and/or their authorized representatives (such as the FDA) 
• 
Celgene and/or their authorized representatives 
This may include your original medical record plus any additional specific information recorded or generated 
during the study.  
Your original medical records, plus any additional, study specific information, related to your participation in the 
study, may be required in order to verify study data. Any inspection will be done only under the permitted federal 
and local laws and regulations. These records will not be available to the public. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a summary of 
the results. You can search this Web site at any time. 
WHAT ABOUT COSTS? 
You and/or your health plan will need to pay for all tests and procedures that are part of this study because they 
are needed for your regular medical care. The study drug, lenalidomide, will be provided to you at no cost, and 
the blood samples collected on day 6 of cycle 1 will also be completed at no cost to you for the selected 
participants in the phase II arm of study. However, you or your health care plan will need to pay for the 
dexamethasone. You or your health plan will have to pay for other drugs or treatments which are given to help 
you control side effects. Before you take part in this study, you should call your health insurer to find out if the 
cost of these tests and/or procedures will be paid for by the plan. Some health insurers will not pay for these 
costs. You will have to pay for any costs not covered by your health insurer. 
In the event of injury or illness resulting from this study, emergency medical treatment is available, but it will be 
provided at the usual charge. No funds have been set aside to compensate you in the event of injury. 
You or your insurance company will be charged for continuing medical care and/or hospitalization. 
WILL I BE PAID TO PARTICIPATE IN THIS STUDY? 
You will receive no payment for taking part in this study. 
 
 


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BLOOD SAMPLES FOR FUTURE RESEARCH (PHASE II IN SELECTED PATIENTS) 
Your blood samples will be sent to a central laboratory. The central laboratory can use your blood samples solely 
for research purposes as described in the research study. Your blood samples may be destroyed upon termination 
or expiration of the research study. Your sample will be sent to the central laboratory in a coded format, which 
protects your identity. 
These tests are only for research purposes. You will be told the results of tests that are part of your clinical care, 
but you will not be told the results of the research tests. 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
It is important that you tell your doctor, [investigator’s name(s)]; if you feel that you have been injured because 
of taking part in this study. You can tell the doctor in person or call him/her at [telephone number]. 
You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health 
plan will be charged for this treatment. The study will not pay for medical treatment.   
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
Taking part in this study is voluntary. You may choose not to take part or may leave the study at any time. 
Leaving the study, or choosing not to take part, will not result in any penalty or loss of benefits to which you are 
entitled. 
We will tell you about new information that may affect your health, welfare, or willingness to stay in this study, 
including new information about the safety of the study medications or treatment for your disease. 


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WHAT IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related injury, contact your cancer doctor, at 
Name(s) 
 
 
 
 
 
 
 
 
Telephone Number(s) 
For questions about your rights as a research participant, contact the [NAME OF CENTER] Institutional Review 
Board, which is a group of people who review the research to protect your rights) at ____________________.  
If available, also list a patient representative or other individual who is not on the research team or IRB. 
WHERE CAN I GET MORE INFORMATION? 
You will get a copy of this form. You may talk to your study doctor at any time regarding your participation in 
the study or your treatment. More information on cancer clinical trials can be found through resources of the 
National Cancer Institute (1-800-4-CANCER) or http://www.cancer.gov/clinicaltrials and the National Clinical 
Trials Registry at clinicaltrials.gov. 
 


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CONSENT STATEMENT 
I have read and understand the information describing this medical research study in this consent form. The study 
doctor or study staff have explained this information and answered all of my questions to my satisfaction. I 
voluntarily consent to take part in this study. I authorize the release of my medical records related to this study, 
including my signed consent form, to the Sponsor and their representatives, the Food and Drug Administration 
(FDA), and the IRB. By signing this form I have not given up any of my legal rights as a research participant. I 
understand that, on the day I sign this consent form, I will receive a signed copy of this consent form for my 
records. 
 
 
 
Printed Name of Participant 
  
 
 
 
 
 
Signature of Participant or Legal Representative 
 
Date 
 
 
 
 
Printed Name of Person Explaining Consent 
 
 
 
 
 
 
 
Signature of Person Explaining Consent 
 
Date 
 
PRINCIPAL INVESTIGATOR’S STATEMENT 
I attest that my representative or I discussed this study with the above named participant or legal representative. 
This person had enough time to consider this information, had an opportunity to ask questions, and voluntarily 
agreed to participate in this study. 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 


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Appendix II 
Multiple Myeloma Diagnostic Criteria 
 
 
Standard criteria for a diagnosis of multiple myeloma are as follows (Kyle et al British Journal of 
Haematology. 121(5):749-57, 2003)  
 
Multiple Myeloma 
Monoclonal protein present in serum ≥3 g/dl 
and/or 
Bone marrow clonal plasma cells ≥10% 
 
Myeloma-related organ or tissue impairment (ROTI) 
Calcium 1 mg/dL (0.25 mmol/L) above the upper limit of normal 
Creatinine >2 mg/dL (173 mmol/L) 
Anemia: hemoglobin 2 g/dL below the lower limit of normal  
or hemoglobin <10 d/gL 
Lytic bone lesions or osteoporosis 
 
Asymptomatic myeloma 
Multiple myeloma and absence of ROTI 
 
Symptomatic myeloma 
Multiple myeloma and presence of any ROTI that can be attributed to myeloma. 


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Appendix III ECOG Performance Status Scale  
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5 
Dead. 
 
(Source:  Eastern Cooperative Oncology Group, Robert Comis, M.D., Group Chair) 
 


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Appendix IV Cockcroft-Gault Estimation of Creatinine Clearance (CrCl)  
(Cockcroft, 1976; Luke 1990) 
Males: 
CrCl (mL/min) =               (140 –age) x (weight, kg)__      
                                        72 x (serum creatinine, mg/dL) 
Females: 
CrCl (mL/min) =               (140 –age) x (weight, kg)_   __ x 0.85 
                                      72 x (serum creatinine, mg/dL) 
 
If the patient is >65 y/o and creatinine is <1, use 1 as serum creatinine value to calculate 
the creatinine clearance. 
 


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Appendix V 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has the effect 
of the lenalidomide on human eggs and sperm. 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 female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive 
months (e.g., 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 
(e.g., all females of childbearing potential must be counseled concerning the following risks and 
requirements prior to the start of lenalidomide study therapy): 
• 
She understands the potential teratogenic risk to the unborn child 
• 
She understands the need for effective contraception, without interruption, 28 days before starting 
lenalidomide, throughout the entire duration of lenalidomide treatment, including dose interruptions, 
and for 28 days after the end of lenalidomide 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 lenalidomide 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: 
• 
Females of childbearing potential comply with the conditions for pregnancy risk minimization, 
including confirmation that she has an adequate level of understanding, and acknowledge the 
aforementioned requirements 
• 
Females NOT of childbearing potential acknowledge that she understands the hazards and necessary 
precautions associated with the use of lenalidomide 
• 
Male patients taking lenalidomide acknowledge that he understands that traces of lenalidomide have 
been found in semen, that he understands the potential teratogenic risk if engaged in sexual activity 
with a female of childbearing potential, and that he understands the need for the use of a condom even 
if he has had a vasectomy, if engaged in sexual activity with 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 intercourse during the 
following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) 
throughout the entire duration of lenalidomide treatment; 3) during dose interruptions; and 4) for at least 
28 days after lenalidomide 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:   
o Highly effective methods: 
 
Intrauterine device (IUD) 
 
Hormonal (birth control pills, injections, implants) 
 
Tubal ligation 
 
Partner’s vasectomy 
o Additional effective methods: 
 
Male condom 
 
Diaphragm 
 
Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking 
lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a patient is 
currently using combined oral contraception the patient should switch to one of the effective method 
listed above. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined 
oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with 
dexamethasone. 


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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 lenalidomide 
Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting 
lenalidomide. The first pregnancy test must be performed within 10-14 days prior to the start of 
lenalidomide and the second pregnancy test must be performed within 24 hours prior to the start of 
lenalidomide. The patient may not receive lenalidomide until the Investigator has verified that the results 
of these pregnancy tests are negative. 
Male Patients: 
Must agree to practice complete abstinence or agree to use a condom during sexual contact with pregnant 
females or females of childbearing potential throughout the entire duration of lenalidomide treatment, 
during dose interruptions and for at least 28 days following lenalidomide discontinuation, even if he has 
undergone a successful vasectomy. 
During study participation and for 28 days following lenalidomide discontinuation  
Female Patients: 
• 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 28 
days of lenalidomide treatment, including dose interruptions, and then every 28 days throughout the 
remaining duration of lenalidomide treatment, including dose interruptions, at lenalidomide 
discontinuation, and at Day 28 following lenalidomide discontinuation. If menstrual cycles are 
irregular, the pregnancy testing must occur weekly for the first 28 days of lenalidomide treatment, 
including dose interruptions, and then every 14 days throughout the remaining duration of 
lenalidomide treatment, including dose interruptions, at lenalidomide discontinuation, and at Day 14 
and Day 28 following lenalidomide discontinuation. 
• 
At each visit, the Investigator must confirm with the FCBP that she is continuing to use two reliable 
methods of birth control at each visit during the time that birth control is required. 
• 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted 
at a minimum of every 28 days throughout the entire duration of lenalidomide treatment, including 
dose interruptions. 
• 
If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide must be 
immediately discontinued. 


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• 
Pregnancy testing and counseling must be performed if a patient misses her period or if her pregnancy 
test or her menstrual bleeding is abnormal. Lenalidomide treatment must be temporarily discontinued 
during this evaluation. 
• 
Females must agree to abstain from breastfeeding during study participation and for at least 28 days 
after lenalidomide discontinuation. 
Male Patients: 
• 
Must practice complete abstinence or use a condom during sexual contact with pregnant females or 
females of childbearing potential throughout the entire duration of lenalidomide treatment, during 
dose interruptions and for at least 28 days following lenalidomide discontinuation, even if he has 
undergone a successful vasectomy. 
• 
Counseling about the requirement for condom use during sexual contact with females of childbearing 
potential and the potential risks of fetal exposure must be conducted at a minimum of every 28 days 
throughout the entire duration of lenalidomide treatment, including dose interruptions. 
• 
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 lenalidomide to another person and to return any unused 
capsules to the Investigator at the end of treatment. 
• 
Female patients should not donate blood during therapy and for at least 28 days following 
discontinuation of lenalidomide. 
• 
Male patients should not donate blood, semen or sperm during therapy or for at least 28 days 
following discontinuation of lenalidomide. 
• 
Only enough lenalidomide for one cycle of therapy may be dispensed with each cycle of therapy. 
 


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Appendix VI Education and Counseling Guidance Document 
 
Protocol Number: PrE1003________________________________________________ 
Patient Name (Print): __________________ DOB: _____/_____/_____ (mm/dd/yyyy) 
Female:  ⁯  
If female, check one: 
FCBP (Female of Childbearing Potential): sexually mature female who: 1) has not undergone a 
hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both 
ovaries) or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not 
rule out childbearing potential) for at least 24 consecutive months (e.g., has had menses at any time 
during the preceding 24 consecutive months) 
⁯ NOT FCBP 
Male: 
⁯ 
To be completed prior to each dispensing of lenalidomide. 
 
Do Not Dispense lenalidomide if: 
• 
The patient is pregnant. 
• 
No pregnancy tests were conducted for a FCBP. 
• 
The patient states she did not use TWO reliable methods of birth control (unless practicing 
complete abstinence of heterosexual intercourse) [at least 28 days prior, during dose 
interruption, and 28 days after discontinuation of lenalidomide]. 
 
FCBP: 
 
1. 
I verified that the required pregnancy tests performed are negative. 
 
2. 
I counseled FCBP regarding the following: 
• 
Potential fetal harm: If lenalidomide is taken during pregnancy, it may cause birth defects or 
death to any unborn baby. Females are advised to avoid pregnancy while taking lenalidomide. 
The teratogenic potential of lenalidomide in humans cannot be ruled out. FCBP must agree not to 
become pregnant while taking lenalidomide. 
• 
Using TWO reliable methods of birth control at the same time or complete abstinence from 
heterosexual intercourse [at least 28 days prior, during dose interruption and 28 days after 
discontinuation of lenalidomide]. 
• 
Continuation of TWO reliable methods of birth control or complete abstinence if therapy is 
interrupted. 
• 
That even if she has amenorrhea she must comply with advice on contraception 


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• 
Use of one highly effective method and one additional method of birth control AT THE SAME 
TIME. The following are examples of highly effective and additional effective methods of 
contraception: 
o Highly effective methods: 
 
Intrauterine device (IUD) 
 
Hormonal (birth control pills, injections, implants) 
 
Tubal ligation 
 
Partner’s vasectomy 
o Additional effective methods: 
 
Male condom 
 
Diaphragm 
 
Cervical Cap 
• 
Pregnancy tests before and during treatment, even if the patient agrees not to have reproductive 
heterosexual intercourse. Two pregnancy tests will be performed prior to receiving study drug, 
one within 10-14 days and the second within 24 hours of the start of lenalidomide. 
• 
Frequency of pregnancy tests to be done: 
o Every week during the first 28 days of this study and a pregnancy test every 28 days during 
the patient’s participation in this study if menstrual cycles are regular or every 14 days if 
cycles are irregular. 
o If the patient missed a period or has unusual menstrual bleeding. 
o When the patient is discontinued from the study and at day 28 after study drug 
discontinuation if menstrual cycles are regular. If menstrual cycles are irregular, pregnancy 
tests will be done at discontinuation from the study and at days 14 and 28 after study drug 
discontinuation. 
• 
Stop taking lenalidomide immediately in the event of becoming pregnant and to call their study 
doctor as soon as possible. 
• 
NEVER share lenalidomide with anyone else. 
• 
Do not donate blood while taking lenalidomide and for 28 days after stopping lenalidomide. 
• 
Do not breastfeed a baby while participating in this study and for at least 28 days after study drug 
discontinuation. 
• 
Do not break, chew, or open lenalidomide capsules. 
• 
Return unused lenalidomide to the investigator. 
 
3. 
Provide Lenalidomide Information Sheet to the patient. 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
108 
 
FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR AT LEAST 24 
CONSECUTIVE MONTHS, A HYSTERECTOMY, OR BILATERAL OOPHORECTOMY): 
 
1. 
I counseled the female NOT of child bearing potential regarding the following: 
• 
Potential fetal harm (Refer to item #2 in FCBP) 
• 
NEVER share lenalidomide with anyone else. 
• 
Do not donate blood while taking lenalidomide and for 28 days after stopping lenalidomide. 
• 
Do not break, chew, or open lenalidomide capsules 
• 
Return used lenalidomide capsules to the Investigator. 
2. 
Provide Lenalidomide Information Sheet to the patient. 
 
MALE: 
 
1. 
I counseled the Male patient regarding the following: 
• 
Potential fetal harm (Refer to item #2 in FCBP). 
• 
To engage in complete abstinence or use a condom when engaging in sexual intercourse 
(including those who have had a vasectomy) with a female of childbearing potential, while taking 
lenalidomide, during dose interruptions and for 28 days after stopping lenalidomide. 
• 
Males should notify their study doctor when their female partner becomes pregnant and female 
partners of males taking lenalidomide should be advised to call their healthcare provider 
immediately if they get pregnant 
• 
NEVER share lenalidomide with anyone else. 
• 
Do not donate blood, semen or sperm while taking lenalidomide and for 28 days after stopping 
lenalidomide. 
• 
Do not break, chew, or open lenalidomide capsules. 
• 
Return unused lenalidomide capsules to the investigator. 
 
2. 
Provide Lenalidomide Information Sheet to the patient. 
 
Investigator/Counselor Name (Print): ____________________  
 (circle applicable) 
 
Investigator/Counselor Signature: _______________________ Date: _____/_____/_____ 
(circle applicable) 
 
**Maintain a copy of the Education and Counseling Guidance Document in the patient records** 
 
August 2009 (Global PPP version date) 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
109 
 
 
Appendix VII Lenalidomide Information Sheet 
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES  
Please read this Lenalidomide Information Sheet before you start taking lenalidomide and each 
time you get a new supply, since there may be new information. This Lenalidomide Information 
Sheet does not take the place of an informed consent to participate in clinical research or talking 
to your study doctor or healthcare provider about your medical condition or your treatment.   
What is the most important information I should know about lenalidomide? 
1. 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. Preliminary findings from a monkey study 
appear to indicate that lenalidomide caused birth defects in the offspring of female 
monkeys who received the drug during pregnancy. 
If you are a female who is able to become pregnant: 
• 
Do not take lenalidomide if you are pregnant or plan to become pregnant 
• 
for 28 days before starting lenalidomide 
• 
while taking lenalidomide  
• 
during dose interruptions of lenalidomide  
• 
for 28 days after stopping lenalidomide  
• 
Stop taking lenalidomide if you become pregnant during lenalidomide 
treatment 
• 
Do not breastfeed while taking lenalidomide 
• 
You must have pregnancy testing done at the following times: 
• 
within 10 – 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) 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
110 
 
• 
You must practice complete abstinence 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  
• 
and for 28 days after stopping lenalidomide 
• 
The study doctor will be able to advise you where to get additional advice on 
contraception. 
• 
If you suspect you are pregnant at any time during the study, you must stop 
lenalidomide immediately and immediately inform your study doctor. The study 
doctor will report all cases of pregnancy to Celgene Corporation.  
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 male: 
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.   
• 
Male patients must practice complete abstinence or must use a condom during 
sexual intercourse with a pregnant female or a female that can become pregnant 
(including those who have had a vasectomy): 
- While you are taking lenalidomide  
- During dose interruptions of lenalidomide  
- For 28 days after you stop taking lenalidomide   
• 
Male patients should not donate sperm or semen while taking lenalidomide 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 Celgene Corporation. 
2. Lenalidomide restrictions in sharing lenalidomide and donating blood: 
• 
Do not share lenalidomide with other people. It must be kept out of the reach of 
children and should never be given to any other person. 
• 
Do not give blood while you take lenalidomide and for 28 days after stopping 
lenalidomide.  


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
111 
 
• 
Do not break, chew, or open lenalidomide capsules. 
• 
You will get no more than a 28-day supply of lenalidomide at one time. 
• 
Return unused lenalidomide capsules to your study doctor. 
Additional information is provided in the informed consent form and you can ask your 
study doctor for more information. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
112 
 
Name ______________________  
 
 
 
 
 
 
 
 
 
 
PrECOG Patient ID Number: ______________  
 
 
 
Cycle No. ________ 
 
Appendix VIII Lenalidomide Days 1 to 21 MEDICATION DIARY 
 
Please complete this diary on a daily basis. Write in the amount of the dose of lenalidomide, 
dexamethasone and aspirin that you took in the appropriate “Day” box. 
 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily dose, 
please write in “0”, but remember to take your prescribed dose at the next regularly scheduled time. Do 
not make up any missed doses of lenalidomide or dexamethasone. 
 
If you are on dialysis, on the days you undergo dialysis take lenalidomide and/or dexamethasone after 
your dialysis treatment. 
 
*Warfarin or low molecular weight heparin can be substituted in place of Aspirin at MD discretion. Discuss with 
your doctor. 
 
Week of: _________________________ 
 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
My next scheduled visit is: ______________________________________________________________ 
If you have any questions, please call: ______________________________________________________ 
Patient Signature: _________________________________ Date: ______________________ 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
113 
 
Name ______________________  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PrECOG Patient ID Number: ______________  
 
 
 
Cycle No. ________ 
 
Appendix IX Lenalidomide Every Other Day MEDICATION DIARY 
 
Please complete this diary on a daily basis. Write in the amount of the dose of lenalidomide, 
dexamethasone and aspirin that you took in the appropriate “Day” box. 
 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily dose, 
please write in “0”, but remember to take your prescribed dose at the next regularly scheduled time. Do 
not make up any missed doses of lenalidomide or dexamethasone. 
 
If you are on dialysis, on the days you undergo dialysis take lenalidomide and/or dexamethasone after 
your dialysis treatment. 
 
*Warfarin or low molecular weight heparin can be substituted in place of Aspirin at MD discretion. Discuss with 
your doctor. 
 
Week of: _________________________ 
 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
My next scheduled visit is: ______________________________________________________________ 
If you have any questions, please call: ______________________________________________________ 
Patient Signature: _________________________________ Date: _______________________ 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
114 
 
Name ______________________  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PrECOG Patient ID Number: ______________  
 
 
 
Cycle No. ________ 
 
Appendix X 
Lenalidomide Two Times Weekly MEDICATION DIARY 
 
Please complete this diary on a daily basis. Write in the amount of the dose of lenalidomide, 
dexamethasone and aspirin that you took in the appropriate “Day” box. 
 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily dose, 
please write in “0”, but remember to take your prescribed dose at the next regularly scheduled time. Do 
not make up any missed doses of lenalidomide or dexamethasone. 
 
If you are on dialysis, on the days you undergo dialysis take lenalidomide and/or dexamethasone after 
your dialysis treatment. 
 
*Warfarin or low molecular weight heparin can be substituted in place of Aspirin at MD discretion. Discuss with 
your doctor. 
 
Week of: _________________________ 
 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Lenalidomide 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
My next scheduled visit is: ______________________________________________________________ 
If you have any questions, please call: ______________________________________________________ 
Patient Signature: _________________________________ Date: _______________________ 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
115 
 
Appendix XI Eligibility Checklist 
 
 
 Pt Initials:   ___   ___   ___                Study Personnel: ____________________________ 
                       F      M       L                 Date of Evaluation: ___/___/____ 
 
NOTE:  Phase I Only – Prior to discussing protocol entry with the patient AND prior to 
registering in eDC, call PrECOG to ensure that a place on the protocol is open to the patient. 
 
INCLUSION CRITERIA 
 
Age ≥18. 
Birth Date: _____/_____/_____                       
  Documentation in patient record 
 
Diagnosed with previously treated multiple myeloma (please see Appendix II for definition of 
myeloma). 
Date of Diagnosis: _____/_____/______      
  Documentation in patient record 
 
Patients must have measurable disease assessed by one of the following ≤21 days prior to 
registration: 
  Serum monoclonal protein ≥1 g by protein electrophoresis 
  >200 mg of monoclonal protein in the urine on 24 hour electrophoresis 
 Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum 
immunoglobulin kappa to lambda free light chain ratio 
  Monoclonal bone marrow plasmacytosis ≥30% (evaluable disease). 
NOTE:  If both serum and urine m-components are present, both must be followed in order to 
evaluate response. 
  Documentation in patient record 
 
All previous cancer therapy including chemotherapy, radiation, hormonal therapy and surgery, 
must have been discontinued ≥2 weeks prior to registration. 
Type of treatment: ________________________________________________________ 
  End date of treatment: _____/_____/_____   
  Documentation in patient record 
 
ECOG Performance Status 0, 1 or 2 (see Appendix III). 
PS  
  0  
  1  
  2  (must document in patient record) 
 
Acceptable organ and marrow function ≤21 days prior to registration as defined below: 
Laboratory test date __ __/__ __/__ __ __ __. 
• Absolute neutrophil count ≥1000 cells/mm³. Absolute neutrophil count = ______. 
• Platelet count ≥75,000 cells/mm³. Platelet count = ______. 
Laboratory test date __ __/__ __/__ __ __ __. 
• Total bilirubin ≤2 mg/dL. Total bilirubin = ______. 
• AST (SGOT) and ALT (SGPT) ≤3 x ULN. 
AST (SGOT) = ______. AST (SGOT) ULN = ______. 
ALT (SGPT) = ______. ALT (SGPT) ULN = _______. 
Laboratory test date __ __/__ __/__ __ __ __._ 
• Renal impairment at baseline as measured by serum creatinine clearance (CrCl) ≤60 mL/min 
≤21 days prior to registration (see Appendix IV). CrCl = ______. 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
116 
 
 
 Pt Initials:   ___   ___   ___                Study Personnel: ____________________________ 
                       F      M       L                 Date of Evaluation: ___/___/____ 
 
   Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy 
test with a sensitivity of at least 25 mIU/mL within 10 – 14 days and again within 24 hours 
prior to starting Cycle 1 of lenalidomide 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 V: Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods, AND Appendix VI: Education and Counseling Guidance 
Document. 
 
  Not a woman of childbearing potential or male. 
  Woman of childbearing potential - Negative pregnancy test date __ __/__ __/__ __ __ __ 
 
* A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy 
or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer 
therapy does not rule out childbearing potential) for at least 24 consecutive months (e.g., has had menses at 
any time in the preceding 24 consecutive months). 
 
Able to take required prophylactic anticoagulation (see Section 9.4). 
  Documentation in patient record 
 
Ability to understand and the willingness to sign a written informed consent document. 
Consent Date: _____/_____/_____  
  Consent in patient record 
 
Only applies to selected subjects registered at Mayo Clinic to the Phase II component.  
Patient willing to provide blood samples for research purposes (see Sections 4.0 and 14.0). 
NA 
   OR   Phase II Mayo Subject   
  Yes    
  NA (required # of pts already met). 
 
If previously received lenalidomide, demonstration of clinical response of any duration or stable 
disease with progression-free interval of ≥ 6 months from the start of that therapy. 
  N/A –or- 
 Previously received lenalidomide with clinical response of: __________________________ 
 
  Start date of treatment: _____/_____/_____  
  End date of treatment: _____/_____/_____   
  Documentation in patient record 
 
 
 
 
 
 
 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
117 
 
 
EXCLUSION CRITERIA 
 
Concurrent use of other anti-cancer agents or treatments. 
NOTE:  Growth factors and bisphosphonates are allowed as medically indicated. Steroids may 
be used with an equivalency of up to 20 mg Prednisone per day as long as dose has not been 
adjusted upwards in past 2 weeks prior to study registration. 
  N/A  
  Documentation in patient record 
 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, 
uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
  N/A  
  Documentation in patient record 
 
Any of the following as this regimen may be harmful to a developing fetus or nursing child: 
• Pregnant women 
• Breast-feeding women 
• Men or women of childbearing potential or their sexual partners who are unwilling to 
employ adequate contraception (condoms with spermicidal agent, diaphragm, birth control 
pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or 
abstinence, e.g..) 
  N/A  
  Documentation in patient record 
 
HIV-positive patients on combination antiretroviral therapy (because of the potential for 
pharmacokinetic interactions with lenalidomide). 
NOTE:  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. 
  N/A  
  Documentation in patient record 
 
 
Known hypersensitivity to thalidomide or other immunomodulary drugs (IMiDs®). 
  N/A  
  Documentation in patient record 
 
History of Stevens-Johnson syndrome characterized by a desquamating rash while taking 
thalidomide or similar drugs. 
  N/A  
  Documentation in patient record 
 
Other active malignancy with the exception of non melanoma skin cancer or in situ cervical or 
breast cancer. 
  N/A  
  Documentation in patient record 
 
Concurrent radiation therapy, except for palliation of a single painful bone lesion or fracture. 
  N/A  
  Documentation in patient record 
 


PrECOG Protocol Number: PrE1003 
IND Number: 103014 
Confidential 
Date: 3/28/2011 
 
 
118 
 
 
Appendix XII Investigator's Statement 
 
1. 
I have carefully read this protocol entitled “A Phase I/II Study of the Tolerability of 
Lenalidomide and Low Dose Dexamethasone in Previously Treated Multiple 
Myeloma Patients with Impaired Renal Function, Version 6.0 dated 3/28/2011” 
(Protocol number PrE1003) and agree that it contains all the necessary information 
required to conduct the study. I agree to conduct the study as outlined in the protocol. 
 
2. 
I agree to conduct this study according to the moral, ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki, the principles of GCP 
as described in 21 CFR and any applicable local requirements. 
 
3. 
I understand that this trial will not be initiated without approval of the appropriate 
Institutional Review Board, and that all administrative requirements of the governing body 
of the institution will be complied with fully. 
 
4. 
Informed written consent will be obtained from all participating patients in accordance with 
institutional and FDA requirements as specified in Title 21, Code of Federal Regulations, 
Part 50. 
 
5. 
I understand that my signature on the electronic Case Report Form indicates that I have 
carefully reviewed each page and accept full responsibility for the contents thereof. 
 
6. 
I understand that the information presented in this study protocol is confidential, and I 
hereby assure that no information based on the conduct of the study will be released 
without prior consent from PrECOG, LLC unless this requirement is superseded by the 
Food and Drug Administration. 
 
 
Principal Investigator: 
 
PI Name: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site Name: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of PI:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date of Signature: 
 
 
\ 
 
 
\ 
 
 
 
 
 
 
 
 
 
MMM 
 
 
DD  
 
YYYY 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan  
PrECOG/Pr1003 
Version 1/ 26 January 2017 
 
 
1 
 
 
 
 
 
Statistical Analysis Plan 
 
Study code 
Pr1003 
 
Version 
 1 
 
Date 
 26 January 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Phase I/II Study of the Tolerability of Lenalidomide and Low 
Dose Dexamethasone in Previously Treated Multiple Myeloma 
Patients with Impaired Renal Function. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
PrECOG/Pr1003 
Version 1/ 26 January 2017 
 
 
2 
 
 
 
 
 
DOCUMENT:
Statistical Analysis Plan
PROTOCOL
Number:
Pr1003
Title:
A Phase I/II Study of the Tolerability of Lenalidomide and Low 
Dose Dexamethasone in Previously Treated Multiple Myeloma 
Patients with Impaired Renal Function.
SAP STATUS
Final
SAP VERSION DATE
27 January 2017 (Version 1)
SPONSOR:
PrECOG  
PREPARED BY:
 
, Inc. 
 
 






Statistical Analysis Plan  
PrECOG/Pr1003 
Version 1/ 26 January 2017 
 
 
5 
 
 
 
 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................. 1 
1. LIST OF ABBREVIATIONS ............................................................................................ 7 
2. INTRODUCTION ........................................................................................................ 9 
2.1. Objective of the Statistical Analysis Plan .................................................................. 9 
3. STUDY OBJECTIVES ................................................................................................... 9 
3.1. Primary Objective .................................................................................................. 9 
3.2. Secondary Objectives ........................................................................................... 10 
4. STUDY DESIGN ........................................................................................................ 10 
4.1. General Study Design and Plan .............................................................................. 10 
4.2. Study Population ................................................................................................. 11 
4.3. Treatment Administration .................................................................................... 11 
5. EFFICACY MEASUREMENTS ...................................................................................... 11 
5.1. Response and Progression .................................................................................... 11 
5.2. Other Efficacy Measurements ............................................................................... 11 
6. SAFETY MEASUREMENTS ........................................................................................ 11 
6.1. Adverse Events .................................................................................................... 12 
6.2. Physical Examination and Medical History ............................................................. 12 
6.3. Electrocardiogram ................................................................................................ 12 
6.4. Clinical Laboratory Assessments ............................................................................ 12 
7. LENALIDOMIDE PHARMACOKINETIC MEASUREMENTS .............................................. 12 
8. GENERAL STATISTICAL CONSIDERATIONS ................................................................. 13 
8.1. Determination of Sample Size ............................................................................... 13 


Statistical Analysis Plan  
PrECOG/Pr1003 
Version 1/ 26 January 2017 
 
 
6 
 
 
 
 
8.2. Methodology ....................................................................................................... 13 
8.3. Handling of Dropouts or Missing Data ................................................................... 13 
8.4. Endpoints ............................................................................................................ 14 
8.4.1. Primary Endpoint ............................................................................................... 14 
8.4.2. Secondary Endpoints .......................................................................................... 14 
8.5. Analysis Populations ............................................................................................ 14 
8.5.1. Intention-to-Treat (ITT) Population ...................................................................... 15 
8.5.2. Safety Population ............................................................................................... 15 
8.6. Efficacy Analysis ................................................................................................... 15 
8.6.1. Primary Efficacy Analysis .................................................................................... 15 
8.7. Safety Analysis ..................................................................................................... 15 
8.7.1. Demographics and Baseline Characteristics .......................................................... 15 
8.7.2. Prior and Concomitant Medications ..................................................................... 16 
8.7.3. Adverse Events .................................................................................................. 16 
8.7.4. Physical Examination and Medical History ............................................................ 16 
8.7.5. Electrocardiogram data ...................................................................................... 17 
8.7.6. Clinical Laboratory Data ...................................................................................... 17 
9. SUMMARY OF CHANGES FROM PROTOCOL-SPECIFIED ANALYSES .............................. 17 
10. REPORTING CONVENTIONS .................................................................................... 17 
11. REFERENCES ......................................................................................................... 19 
12. TABLES, FIGURES, AND LISTINGS ............................................................................ 19 
 
 


Statistical Analysis Plan  
PrECOG/Pr1003 
Version 1/ 26 January 2017 
 
 
7 
 
 
 
 
1.   LIST OF ABBREVIATIONS 
Abbreviation or special 
term 
Explanation 
AE(s) 
Adverse event(s) 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CR 
Complete response 
CRF 
Case report form 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
H 
Hour(s) 
HCG 
Human Chorionic Gonadotropin 
HepC 
HIPAA 
Hepatitis C antibody 
Health Information Portability and Accountability Act 
HIV 
Human immunodeficiency virus antibody 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IND 
IRB 
ITT 
LDH 
Investigational New Drug 
Institutional Review Board 
Intent-to-treat 
Lactate dehydrogenase 
Max 
Maximum 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MID 
Minimum intolerable dose 
min 
Minimum 
MIP 
Molecular inversion probe 
MR 
Modified Release 


Statistical Analysis Plan  
PrECOG/Pr1003 
Version 1/ 26 January 2017 
 
 
8 
 
 
 
 
Abbreviation or special 
term 
Explanation 
N 
NDA 
Number of observations 
New Drug Application 
PaR 
Partial response  
pCR 
Pathologic complete response 
PD 
Progressive disease 
PK 
Pharmacokinetic(s) 
PR 
PR wave complex 
PT 
Prothrombin time 
PTH 
QD 
QID 
Parathyroid hormone 
Once daily 
Four times daily 
QDS 
Quality Data Services, Inc. 
QRS 
QRS wave complex 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
sCR 
Stringent Complete response 
SD 
Standard deviation 
SGOT 
Serum glutamic-oxaloacetic transaminase (same as AST) 
SGPT 
Serum glutamic-pyruvic transaminase (same as ALT) 
SOP 
Standard Operating Procedure 
SD 
SE 
Standard deviation 
Standard error 
TEAE 
Treatment Emergent Adverse Event 
TSH 
US 
Thyroid-stimulating hormone 
United States 
VGPR 
Very good partial response 
WBC 
White blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 


Statistical Analysis Plan  
PrECOG/Pr1003 
Version 1/ 26 January 2017 
 
 
9 
 
 
 
 
2.   INTRODUCTION 
2.1.   Objective of the Statistical Analysis Plan 
This statistical analysis plan (SAP) describes the planned analysis of the safety and efficacy data from this 
study.  A detailed description of the planned tables, figures and listings (TFLs) to be presented in the 
Clinical Study Report (CSR) is provided in the accompanying TFL template document. The analyses for 
the lenalidomide pharmacokinetics (PK) of plasma samples collected during cycle 1 day 6 (phase II) will 
be reported in a separate report.  
The intent of this document is to provide guidance for the analysis of data related to safety and efficacy 
to describe any applicable statistical procedures.  In general, the analyses come directly from the 
protocol, unless they have been modified by agreement between the Sponsor and Quality Data Services, 
Inc. (QDS).  A limited amount of information concerning this study (e.g., objectives, study design) is 
summarized to help the reader interpret the accompanying TFL templates.  That information is not a 
synopsis of the study and does not require review or approval because it is simply extracted from the 
protocol.  Attached signatures indicate approval of the statistical analysis sections of the SAP, as well as 
accompanying TFL templates.  These sections must be agreed upon prior to database lock.  When the 
SAP and TFL templates are agreed upon and finalized, they will serve as the template for a portion of 
this study’s CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified.  If additional analyses are required to supplement the 
planned analyses described in this SAP, they may be performed and will be identified in the appropriate 
section of the CSR.  Any substantial deviations from this SAP will be agreed upon between the sponsor 
and QDS.  Deviations from this SAP, both substantial and non-substantial, will be documented in the 
CSR.  Any updates to their respective analyses, study designs, and TFL presentations after this SAP is 
finalized and approved will be documented in a running Note to the SAP document. 
Various outputs may be required during the conduct of this trial which will necessitate the production of 
some but not all of the Figures, Summary Tables and Key Data Tabulations detailed in this document.  
The SAP will not be updated to reflect these potential changes. 
3.   STUDY OBJECTIVES 
3.1.   Primary Objective 
The primary objectives of this study are:  
 
Phase I: To establish the maximum tolerated dose of lenalidomide in each of three groups of 
myeloma patients with impaired renal function. 
 
 
Phase II: To assess the efficacy of lenalidomide and low dose dexamethasone given in  
combination across the three groups of myeloma patients with impaired renal function. 
 


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3.2.   Secondary Objectives 
The secondary objectives of this study are:  
 
To describe the overall survival, progression-free survival, duration of response, and time to 
treatment failure of myeloma patients with impaired renal function treated with lenalidomide 
and dexamethasone; 
 
 
To evaluate the safety profile of lenalidomide given in combination with weekly dexamethasone 
in myeloma patients with impaired renal function; 
 
 
To describe renal function over time and to evaluate the safety profile of a onetime increase in 
lenalidomide dose at least 2 cycles after start of treatment due to improved renal function; and 
 
 
To determine the pharmacokinetics of lenalidomide administration in myeloma patients with 
impaired renal function.  
 
4.   STUDY DESIGN 
4.1.   General Study Design and Plan 
This phase I/II study involves three single arm phase I trials designed to determine the MTD and toxicity 
of lenalidomide in the treatment of multiple myeloma in three groups of patients defined by renal 
dysfunction. Once an MTD is determined within a group, an additional 15 patients will be accrued within 
the group and treated with the MTD as part of the phase II study to assess efficacy of lenalidomide and 
dexamethasone in the treatment of multiple myeloma. The 6 phase I patients treated at the MTD plus 
15 additional patients accrued in each group will be combined (total = 63 patients) to assess efficacy 
using a one-stage design. 
 
The first phase I study enrolls patients with moderate renal dysfunction (Group A); the second one 
enrolls patients with severe renal dysfunction (Group B); and the third one enrolls patients with ESRD 
renal dysfunction (Group C). Groups A, B, and C have a maximum of 3, 4, and 4 dose levels respectively. 
The MTD for each group will be determined concurrently. 
 
 
 
 
 
 


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4.2.   Study Population 
Sixty-three, 18 years or older, patients who meet all inclusion and exclusion criteria as stated in the 
Section 3 of the study protocol, will be eligible to participate in this study.  
Upon determination that a patient meets eligibility criteria, the patient will be registered in the study.  
4.3.   Treatment Administration 
Patients must not start protocol treatment prior to registration. Treatment should begin ≤ 7 working 
days of registration. 
Dexamethasone will be given at a fixed dose of 40 mg by mouth once weekly on a 28 day treatment 
cycle. If a dose of dexamethasone is missed, it is up to the treating physician whether the dose should 
be made up. In addition, continuing dexamethasone if lenalidomide is stopped is also at the discretion of 
the treating physician. 
5.   EFFICACY MEASUREMENTS  
Efficacy measurements include complete response (CR), stringent complete response (sCR), very good 
partial response (VGPR), and partial response (PR).   
5.1.   Response and Progression  
Criteria for response and progression are listed in tables 11.2 (page 41) and 11.5 (pages 42 and 43) of 
the study protocol. 
5.2.   Other Efficacy Measurements 
ECOG performance status will be assessed at pre-study and at day 1, end of cycle 4, day 1 of each 
additional cycle and at day 1 of cycle 9 or at the end of treatment. 
6.   SAFETY MEASUREMENTS 
Safety will be evaluated by  
 
 
Clinical laboratory tests,  
 
 
Physical examination findings,   
 
 
Vital signs measurements, and  
 
 
By the documentation of concomitant medications and adverse events.  


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6.1.   Adverse Events 
Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing 
medical condition in a patient administered a medicinal product in a clinical investigation and which 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a product (investigational or marketed), whether or not 
considered related to the product (investigational or marketed). Following written consent to 
participate in the study, the collection of AEs/SAEs should begin at the initiation of therapy, unless 
related to a protocol related procedure. 
 
Following written consent to participate in the study, the collection of AEs/SAEs should begin at the 
initiation of therapy, unless related to a protocol related procedure. 
 
The categories and definitions of severity used for this clinical trial’s AEs are defined in the NCI’s 
Common Terminology Criteria (CTCAE) Version 4.0.  
Categories ‘Definite’, ‘probable’ and ‘possible’ are considered study drug related. Categories ‘not likely’ 
and ‘not related’ are considered not study drug-related. 
AEs should be followed to resolution or stabilization, and reported as SAEs if they become serious. 
6.2.   Physical Examination and Medical History 
Physical examination findings will be collected at screening, day 1 of cycles 1 through 4, end of cycle 4, 
day 1 of each additional cycle, and at day 1 of cycle 9 or end of treatment. 
All physical examination findings must be recorded in the patient’s source documents and in the 
patient’s CRF.  
Medical history will also be collected prior to registration. 
6.3.   Electrocardiogram 
12-lead ECG will be obtained within 21 days prior to registration.  
6.4.   Clinical Laboratory Assessments 
Clinical laboratory tests will be collected at screening, day 1 of cycles 1 through 4, end of cycle 4, day 1 
of each additional cycle and day 1 of cycle 9 or end of treatment.  
7.   LENALIDOMIDE PHARMACOKINETIC MEASUREMENTS 
The pharmacokinetic sampling will only apply to selected Mayo Clinic patients who are registered in the 
Phase II portion of this clinical investigation. 5cc of blood will be drawn on Day 6 of Cycle 1: 0 (pre-dose), 
0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hour at all dose groups and at 48 and 72 hour for patients in Group B with 
severe renal impairment or in Group C on dialysis.  


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8.   GENERAL STATISTICAL CONSIDERATIONS 
This section will go into detail about the statistical approaches and methodology for this study analysis.  
Statistical analysis and programming of tables and listings will be conducted by QDS, using SAS® Release 
9.2 (SAS Institute Inc., Cary, North Carolina, USA).  After the TFLs are approved as final, SAS programs 
used to perform statistical analyses and generate analysis datasets and TFLs will be archived in 3 formats 
(ASCII, .PDF, and .SAS); the analysis SAS Datasets will archived in XPT format created using SAS PROC 
COPY. 
Analyses for the pharmacokinetic parameters are not included in the statistical analysis plan. 
8.1.   Determination of Sample Size 
Phase I: For Group A, the study may involve a maximum of 18 patients (6 for each of the 3 dose levels) 
but would likely require 15 patients (3 at the first dose level, 6 for the dose level prior to the MTD, and 6 
at the MTD). For Group B, the study may involve a maximum of 24 patients (6 for each of the 4 dose 
levels) but would likely require 18 patients (3 at the first 2 dose levels, 6 for the dose level prior to the 
MTD, and 6 at the MTD). For Group C, the study may involve a maximum of 24 patients (6 for each of 
the 4 dose levels) but would likely require 18 patients (3 at the first 2 dose levels, 6 for the dose level 
prior to the MTD, and 6 at the MTD).  
 
Phase II: Each group will accrue an additional 15 patients at the MTD.  
 
Overall:  The study needs a maximum of 111 patients, and an expected number of 96 patients. 
 
In addition, the protocol allows replacement of patients in phase I who withdraw before completing 
cycle 1 for reasons other than toxicity. 
 
8.2.   Methodology 
Continuous data will be summarized with the following descriptive statistics: number of observations 
(n), mean, standard deviation (SD), median, minimum (min), and maximum (max). Categorical data will 
be summarized with frequencies and percentages. 
In general, listings will be presented by patient.  Tables will be presented by renal impairment group 
relative to specific patient populations. 
 
8.3.   Handling of Dropouts or Missing Data 
All attempts will be made to prevent any missing values.  Missing or invalid data will be treated as 
missing, not imputed. 


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No data imputation will be done for safety parameters except for the adverse events (AEs) with missing 
starting date.  If the AE onset date is unknown, then the date of first study treatment will be used for 
classification of AEs that were experienced following administration of study drug. 
8.4.   Endpoints 
8.4.1.   Primary Endpoint 
The primary endpoint is the proportion of patients who have at least a partial response to treatment. A 
partial response or better will be considered synonymous with “success”, unless specified otherwise. 
The 6 patients treated at the recommended dose level (MTD) within each group will be included in the 
analysis for this portion of the study. The efficacy population will include the 63 patients across groups 
and include all patients meeting eligibility criteria who signed a consent form and began treatment.  
8.4.2.   Secondary Endpoints 
In this section:  
 
 
Survival time is defined as the time from registration to death due to any cause.  
 
 
Progression-free survival time is defined as the time from registration to the earliest date of 
documentation of disease progression. If a patient dies without a documentation of disease 
progression the patient will be considered to have had disease progression at the time of their 
death. If the patient is declared to be a major treatment violation, the patient will be censored 
on the date the treatment violation was declared to have occurred. In the case of a patient 
starting treatment and then never returning for any evaluations, the patient will be censored for 
progression on day 1 post-registration.  
 
 
Duration of response is defined for all eligible, treated patients who have achieved a partial 
response or better as the date at which the patient’s earliest objective status is first noted to be 
either a partial response or better to the earliest date progression is documented. 
 
 
Time to treatment failure is defined to be the time from registration to the date at which the 
patient is removed from treatment due to progression, adverse events, or refusal. If the patient 
is considered to be a major treatment violation or is taken off study as a nonprotocol failure, the 
patient will be censored on the date they are removed from treatment. 
 
The failure time distributions for the secondary endpoints defined above will be estimated using Kaplan-
Meier methods. 
 
8.5.   Analysis Populations 
This section is designed to identify the characteristics that are necessary for inclusion in particular 
populations defined for the purpose of analysis.  


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8.5.1.   Intent-to-Treat (ITT) Population 
The intention-to-treat (ITT) population is defined to include all patients as randomized.  
8.5.2.   Safety Population 
The safety population is defined as all patients treated with at least one dose of trial therapy. All safety 
data collected up to the end of the study (i.e., through the last follow-up evaluation) are included in the 
safety analysis. 
8.5.3.   Efficacy Population 
The efficacy population is defined as all eligible patients who received at least one dose of trial therapy.  
Patients who do not have an efficacy evaluation will be included and will be classified as unevaluable. 
8.6.   Efficacy Analysis 
8.6.1.   Primary Efficacy Analysis 
The proportion of successes will be estimated by the number of successes divided by the total number 
of patients in the efficacy population. Eligible, treated patients who are unevaluable for response will be 
included in the denominator when estimating the proportion of successes. 95% Confidence intervals for 
the true success proportion will be calculated according to exact two-stage binomial confidence 
intervals. (Atkinson and Brown, 1985) Secondary analyses include estimation of the proportion of 
successes with 95% confidence intervals for each group. 
8.7.   Safety Analysis 
The safety evaluations include AEs, clinical laboratory assessments, vital signs with weight, and physical 
examination. 
 
The results of this study will be reported using summary tables, figures, and data listings. Continuous 
variables will be summarized using mean, SD, median, minimum, and maximum.  Categorical variables 
will be summarized by presenting the number (frequency) and percentage in each category.  
If any screening safety data is repeated, the measurement taken closest to dosing will be used in the 
analysis as pre-study baseline.  If any post-dose safety data is repeated the measurement taken first at 
the particular visit in question will be used in the analysis. 
8.7.1.   Demographics and Baseline Characteristics 
Demographic data (e.g. age, gender, race, height, screening body weight, etc.) will be listed for the ITT 
population.  Data will be summarized descriptively (number of patients, mean, SD, median, minimum, 
and maximum within the efficacy population, overall and by renal impairment group).  
Pre-study (i.e., screening and Baseline) data will be listed for the ITT population.  When appropriate, 
tabular summaries of incidence (frequencies) of events/abnormalities or descriptive statistical 


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summaries (number of patients, mean, SD, median, minimum, and maximum) will be presented within 
the efficacy  population, overall and by renal impairment group. 
8.7.2.   Prior and Concomitant Medications 
The use of prior and concomitant medications taken will be recorded on the CRFs.  Prior and 
concomitant therapies will be coded to a World Health Organization Drug Dictionary (WHO-DD) term.  A 
by-patient listing of prior and concomitant medication use will be included in the CSR.  
Prior medications are all doses taken prior to the first dose of study medication.  Concomitant 
medications are all doses taken after the first dose of study medication.  If any medications were started 
prior to dosing and were continued after dosing they will be shown in the listings as prior but will be 
included in the concomitant summary table.  
The use of concomitant medications will be summarized by renal impairment group for the safety 
population.  In each of these summary tables, the number and percentage of patients taking each 
medication will be presented by ATC Classification. 
8.7.3.   Adverse Events 
Adverse events will be assessed in the safety population. 
TEAEs are those that occur after administration of the first study dose until completion of the follow up 
evaluations. In the case where the start date of the AE is unknown, it will be assumed to be treatment-
emergent. Treatment-emergent AEs (TEAEs) will be summarized by system-organ-class (SOC) and 
preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA®). The frequency of 
patients who experience TEAEs will be summarized overall cycle. Patients, having the same AE more 
than once per group, will be counted once for each PT and once within each SOC.  
All AEs are listed by patient, including non-treatment-emergent (i.e., pre-dosing or post-dosing) AEs, if 
applicable. Separate patient data listings are provided for patients who experience treatment-emergent 
SAEs, TEAEs leading to early termination from the study, or fatal TEAEs. 
Additional summary tables will display the number of patients with treatment-emergent AEs by 
maximum intensity, treatment-emergent AEs by strongest relationship to study drug, and treatment-
emergent AEs that led to premature discontinuation of study classified by renal impairment group, 
system organ class and preferred term. The total number of all treatment-emergent AEs, serious TEAEs, 
TEAEs by maximum severity, treatment-related TEAEs, TEAEs leading to discontinuations, and TEAEs 
leading to death will also be summarized by renal impairment group. 
CTC Version 4.0 will be used. 
8.7.4.   Physical Examination and Medical History 
Physical examination data will be summarized using frequencies for each visit, Body System, and result 
by baseline, day 1, end of cycle 4, day 1 of each additional cycle and day 1 of cycle 9 or end of treatment 
for the safety population. The incidence of abnormalities at each visit for each Body System will be 


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summarized by frequency counts. A by-patient listing of all physical examination data will be displayed. 
Unscheduled visits will only be displayed in the listings. 
Medical history data will be presented with a by-patient listing. 
8.7.5.   Electrocardiogram data 
A by-patient listing of all ECG data at pre-study will be displayed.   
8.7.6.   Clinical Laboratory Data 
Numeric clinical laboratory data will be summarized using descriptive statistics.  Non-numeric laboratory 
tests will be summarized separately using frequency counts on unique responses.  Individual change 
from baseline in lab values will be calculated and summarized descriptively. The incidence of treatment-
emergent graded abnormalities (shown as High, Low, or Abnormal depending on the test) at each visit 
for each laboratory test will be summarized by frequency counts.  Listings of abnormal laboratory results 
will be produced, showing normal ranges, out-of-range flags, and toxicity grades. 
All clinical laboratory data with normal ranges, out-of-range flags, and toxicity grades will be listed by 
patient. Unscheduled visits will only be displayed in the listings. 
9.   SUMMARY OF CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
No changes are planned.  
10.   REPORTING CONVENTIONS 
The mean and median will be displayed to one decimal place greater than the original value and the 
standard deviation will be displayed to two decimal places greater than the original value. All statistical 
programming and analyses will be performed using SAS® Release 9.2 (SAS Institute Inc., Cary, North 
Carolina, USA). 
The following standards will be used in the data presentation: 
 
Section 14 tables should be in landscape format.  Output should adhere to US / International 
Conference on Harmonization (ICH) margins and should not require changes for European page size.  
For item 14 tables, a blank row will separate the header from the content of the table listing.  For 
tables that have “n (%)”, the placement should be centered below “N=xx” in the column header.  
Frequency tables will be center justified.  Descriptive statistics will be decimal aligned.   
 
Percentages presented in in-text tables should be rounded to one decimal using the SAS rounding 
function.  If “%” is part of the column heading, do not repeat the “%” sign in the body of the table.  
Unless specified otherwise, “%” should reflect the total population of the treatment groups.  Any 
deviation from that should be part of the footnote.  For 0 counts, leave the corresponding 
percentage blank. 
 
The format for minimum and maximum should be “Min, Max”.  SD should be the default for 
representing scale, unless standard error has been specified.  Standard deviation should be 


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abbreviated as “SD”, and presented next to the mean value, without any +/- sign.  The SD should 
have one additional decimal place beyond that of the mean (e.g. mean has one decimal place, SD 
should have two). 
 
 “N” will represent the entire treatment group for the population group being analyzed, while “n” 
will represent a subset of the treatment group.  For tables with population designated as a row 
heading, “N” should be used (i.e. tables where all participant data is not available for every variable 
within a treatment group).  As a guideline, if the number is used in a denominator it should be 
presented as “N”.  If the number is used in the numerator, it should be presented as an “n”. 
 
The heading should consist of four lines.  Line 1:  Sponsor identifier.  Line 2:  Protocol identifier.  Line 
3: blank line.  Line 4:  Table/Appendix number  Table Title – Population.  The title for in-text tables 
should begin with the Table/Appendix number. 
 
All data listings will be sorted by Patient Number and time point (if applicable). 
 
The date format for all dates is DDMMMYYYY.  
A solid line should appear both above and below the column headings of a table.  A solid line should 
appear at the end of the table or at the bottom of each page if the table extends to more than one page.  
Footnotes should start after the bottom solid line. 
 
 


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11.   REFERENCES 
References are provided in the protocol.  
Atkinson, E. N., and Brown, B. W. (1985). Confidence limits for probability of response in multistage 
phase II clinical trials. Biometrics, 41, 741-744. 
12.   TABLES, FIGURES, AND LISTINGS 
See separate template document.


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DOCUMENT HISTORY 
 
Version Date
 By
Summary of Changes
26JAN2017
Updated names of signatories 
 
 
 
 
 
 
 


Amendment for PrE1003 SAP (20130507 PRECOG10003 SAP V0.3.pdf) 
July 13, 2015 
 
Per communication with PrE1003 study statistician 
 confirmed that “the efficacy 
analysis was to be done among 63 patients who were treated at the MTD (Maximum Tolerated Dose) 
across all groups.”  
 confirmation email comes through PrECOG study contact 
 sending to QDS 
on July 09, 2015 5:04pm (with subject PrE1003 SAP and Mocks). 
As an amendment, the following sentences (underline) are added to further clarify the “eligible 
patients” in the definition of Efficacy Population at SAP 8.5.3: 
The efficacy population is defined as all eligible patients who received at least one dose of trial therapy. 
Patients who do not have an efficacy evaluation will be included and will be classified as unevaluable. 
Once patients reached their Maximum Tolerated Dose (MTD), they are eligible patients for efficacy 
population.