Clinical trial NCT02561273
Conditions: Anaplastic Large Cell Lymphoma, ALK-Negative Anaplastic Large Cell Lymphoma, ALK-Positive Hepatosplenic T-Cell Lymphoma Peripheral T-Cell Lymphoma, Not Otherwise Specified Stage II Angioimmunoblastic T-cell Lymphoma Stage II Enteropathy-Associated T-Cell Lymphoma Stage III Angioimmunoblastic T-cell Lymphoma Stage III Enteropathy-Associated T-Cell Lymphoma Stage IV Angioimmunoblastic T-cell Lymphoma Stage IV Enteropathy-Associated T-Cell Lymphoma
Sponsor: University of Nebraska
Start date: 2015-09-28; Completion date: 2020-11-01
Enrollment: 54 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects and best dose of lenalidomide when given together with combination chemotherapy and to see how well they work in treating patients with newly diagnosed stage II-IV peripheral T-cell non-Hodgkin's lymphoma. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lenalidomide may stop the growth of peripheral T-cell non-Hodgkin's lymphoma by blocking the growth of new blood vessels necessary for cancer growth. Giving combination chemotherapy with lenalidomide may be a better treatment for peripheral T-cell non-Hodgkin's lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the safety and efficacy of lenalidomide in combination with standard induction therapy (CHOEP- cyclophosphamide, doxorubicin \[doxorubicin hydrochloride\], etoposide, vincristine \[vincristine sulfate\] and prednisone) in patients with newly diagnosed stage II, III and IV peripheral T-cell lymphoma not otherwise specified (NOS), anaplastic large cell lymphoma (anaplastic lymphoma receptor tyrosine kinase \[ALK\] negative) (ALK positive if International Prognostic Index \[IPI\] 3, 4, or 5), angioimmunoblastic T-cell lymphoma, enteropathy associated T-cell lymphoma or hepatosplenic gamma delta T-cell lymphoma.

II. To establish the maximum tolerated dose of lenalidomide in combination with CHOEP chemotherapy. (Phase I) III. To assess the efficacy (complete response rate) of this combination. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate overall response rate (complete response \[CR\] + partial response \[PR\]) of the combination of lenalidomide and CHOEP chemotherapy.

II. To evaluate the safety and tolerability of the regimen. III. To assess the 2 year progression free survival (PFS) and overall survival (OS) using this regimen.

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

Patients receive cyclophosphamide intravenously (IV), doxorubicin hydrochloride IV and vincristine sulfate IV on day 1, etoposide IV over 30-60 minutes on days 1-3, prednisone orally (PO) on days 1-5, and lenalidomide PO on days 1-10. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients responding after 6 courses of treatment may then undergo an autologous stem cell transplant or receive maintenance lenalidomide at the discretion of the physician or patient choice as follows:

TRANSPLANT: Patients undergo autologous stem cell transplant per standard of care.

MAINTENANCE LENALIDOMIDE: Patients receive lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Arms: arm 1: Patients receive cyclophosphamide IV, doxorubicin hydrochloride IV and vincristine sulfate IV on day 1, etoposide IV over 30-60 minutes on days 1-3, prednisone PO on days 1-5, and lenalidomide PO on days 1-10. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients responding after 6 courses of treatment may then undergo an autologous stem cell transplant or receive maintenance lenalidomide at the discretion of the physician or patient choice as follows:

TRANSPLANT: Patients undergo autologous stem cell transplant per standard of care.

MAINTENANCE LENALIDOMIDE: Patients receive lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Autologous Hematopoietic Stem Cell Transplantation intervention 2: Cyclophosphamide intervention 3: Doxorubicin Hydrochloride intervention 4: Etoposide intervention 5: Laboratory Biomarker Analysis intervention 6: Lenalidomide intervention 7: Peripheral Blood Stem Cell Transplantation intervention 8: Prednisone intervention 9: Vincristine Sulfate
Intervention descriptions: intervention 1: Undergo autologous stem cell transplant intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Correlative studies intervention 6: Given PO intervention 7: Undergo peripheral blood stem cell transplant intervention 8: Given PO intervention 9: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol Title: A Phase I/II Trial of CHOEP Chemotherapy plus 
Lenalidomide as Front Line Therapy for Patients with Stage II, III and IV 
Peripheral T-Cell Non-Hodgkin’s Lymphoma  
 
Senior National Collaborative Investigator:    
Stephen M. Ansell, M.D. 
 
 
 
 
 
Professor of Medicine 
Mayo Clinic 
200 First Street SW 
Rochester MN 55905 
 
 
 
 
 
Phone (507) 284 0923 
 
 
 
 
 
E-mail: ansell.stephen@mayo.edu  
 
Junior National Collaborator Investigator:   
 
Matthew A. Lunning , D.O.  
 
 
 
Assistant Professor of Medicine  
987680 Nebraska Medical Center 
 
 
 
 
 
Omaha, NE 68198-7680  
 
 
 
 
 
Phone (402) 559-5166  
 
 
 
 
 
FAX (402) 559-6520 
 
 
 
 
 
e-mail: mlunning@unmc.edu  
 
UNMC Secondary Investigators: 
 
 
Julie M. Vose, M.D., M.B.A 
James O. Armitage, M.D. 
Philip J. Bierman, M.D. 
 
 
 
 
 
R. Gregory Bociek, M.D. 
 
Multi-site Participation:   
IRB Approved Sites: 
 
 
 
 
 
 
Ranjana Advani, M.D. 
 
 
 
 
 
Stanford University School of Medicine 
 
 
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
 
Stanford, CA 94305-5821 
 
 
 
 
 
Phone (650) 725-6456 
 
 
 
 
 
E-mail: radvani@stanford.edu 
 
Mary Jo Lechowicz, M.D. 
Emory University/Winship Cancer Institute 
1365-C Clifton Road NE 
Atlanta, GA  30322 
Email:  mlechow@emory.edu 
 
Steven Horwitz, M.D. 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 
Email: horwitzs@mskcc.org 
 


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Bradley Haverkos, M.D., MPH 
University of Colorado Cancer Center 
Anschutz Medical Campus 
1665 Aurora Ct, MS F754 
Aurora, CO 80045 
 
Jasmine Zain, M.D. 
City of Hope National Medical Center 
1500 East Duarte Road MOB 3 
Duarte, CA 91010 
 
 
Neha Mehta-Shah, M.D. 
Washington University School of Medicine 
660 South Euclid Ave 
St. Louis, MO 63110 
Email: Mehta-n@wustl.edu 
 
Hun Lee, MD 
The University of Texas, MD Anderson Cancer Center 
1515 Holcombe Blvd Unit 429 
Houston, Tx 77030-4000 
Email: hunlee@mdanderson.org  
 
 
 
Pathology/Biospecimens:  
Andrew Feldman M.D. Ph.D. 
 
 
 
 
 
 
Associate Professor of Pathology 
Mayo Clinic – Hilton Building 8 
Rochester MN 55905 
 
Biostatistician: 
 
 
Jane Meza, Ph.D. 
 
Lenalidomide: 
Celgene Reference Number: RV-CL-PTCL-PI-003858 
 
 
 
IND _ Exemption #124144___________ 
 
 
Protocol Date: 
Version 1.0  
Dated 21August2014 
 
Version 2.0 
Dated 07November2014 
 
Version 3.0 
Dated 20June2016 
 
Version 4.0 
Dated 28Oct2016 
 
Version 5.0 
Dated 14Mar2017 
 
Version 6.0 
Dated 30Jul2018 
 
Version 6.1 
Dated 17Jan2020 
 
 
 
 
 
 
 
 


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INDEX:  
 
 
 
 
 
 
 
 
Page  
 
Schema  
 
 
 
 
 
 
 
 
4  
Abstract  
 
 
 
 
 
 
 
 
5  
1.0 – Objectives  
 
 
 
 
 
 
 
6  
2.0 - Background, Significance, and Preliminary Studies  
 
7  
3.0 - Eligibility Criteria  
 
 
 
 
 
 
10  
4.0 - Registration Procedures  
 
 
 
 
 
13  
5.0 – Treatment Plan  
 
 
 
 
 
 
17  
6.0 - Measurement of Effect  
 
 
 
 
 
32  
7.0 - Study Parameters  
 
 
 
 
 
 
37  
8.0 - Drug Formulation and Procurement   
 
 
 
40  
9.0 - Toxicity Reporting Guidelines  
 
 
 
 
52  
10.0 - Statistical Considerations  
 
 
 
 
 
60  
11.0 - Records to be Kept   
 
 
 
 
 
63  
12.0 - Patient Consent form Statement  
 
 
 
 
64  
13.0 – References   
 
 
 
 
 
 
67  
14.0 – Data Collection forms 
 
 
 
 
 
69 
Appendix A – Karnofsky Performance Scale  
 
 
 
71  
Appendix B – BSA and Creatinine Clearance Calculation  
 
72  
Appendix C – Eligibility Checklist   
 
 
 
 
73  
Appendix D – Medwatch SAE Reporting Form  
 
 
 
76 
Appendix E -  Oral, Sublingual, and/or Buccal Route Medication  
           Adherence Standard Procedure 
  
Example:  Medication Diary (Form A)                                77 
Appendix F-   Blood and Tissue Sample Processing and Shipping 
                       for Cytokine Level Studies    
 
 
            79 
Appendix G – Risks of Fetal Exposure, Pregnancy Testing Guidelines  
 
 
and Acceptable Birth Control Methods                              81 
 


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SCHEMA 
 
 
 
 
 


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ABSTRACT  
 
Title: A Phase I/II Trial OF CHOEP Chemotherapy Plus Lenalidomide as Front Line 
Therapy for Patients with Stage II, III and IV Peripheral T-Cell Lymphoma 
This is a multi-center phase I/II dose escalation study testing the feasibility, 
tolerability and efficacy of lenalidomide in combination with CHOEP chemotherapy 
(cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone) as front line 
therapy for patients with stage II, III and IV peripheral T-Cell lymphoma (PTLC) not 
otherwise specified (NOS), anaplastic large cell lymphoma (ALK negative) (ALK 
positive if IPI 3, 4, or 5), angioimmunoblastic T-cell lymphoma, enteropathy 
associated T-cell lymphoma or hepatosplenic gamma delta T-cell lymphoma. In the 
phase I portion of the trial, a 3+3 dose escalation design will be used to determine 
the optimal dose of lenalidomide that can be administered with CHOEP. The primary 
endpoint of the phase I portion of the study is to determine the maximum tolerated 
dose (MTD) of lenalidomide given with CHOEP chemotherapy. This will be followed 
by a phase II portion of the study in which patients will be treated with CHOEP in 
combination with lenalidomide at the dose defined in the phase I portion of the study. 
In the Phase I and II portions of the trial, patients will be treated with the combination 
for 6 cycles. Responding patients will then receive either an autologous stem cell 
transplant and no further therapy, or maintenance lenalidomide therapy either until 
disease progression or for a maximum of 12 cycles (1 year). Therapy will be based 
on physician or patient choice. The primary endpoint of the phase 2 portion of the 
study is efficacy, defined as complete response (CR) rate after 6 cycles. Secondary 
endpoints of both phases of the trial will be assessment of toxicity, overall response 
rate (ORR), progression free survival (PFS), PFS rate at 2 years, and overall survival 
(OS). 
 
 
 
 


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1.0  
STUDY OBJECTIVES  
 
1.1 
Primary Objective  
 
1.1.1  To assess the safety and efficacy of lenalidomide in combination with 
standard induction therapy (CHOEP - cyclophosphamide, doxorubicin, 
etoposide, vincristine and prednisone) in patients with newly 
diagnosed stage II, III and IV peripheral T-Cell lymphoma not 
otherwise specified (NOS), anaplastic large cell lymphoma (ALK 
negative) (ALK positive if IPI 3, 4, or 5), Nodal PTCL with TFH 
phenotype or angioimmunoblastic T-cell lymphoma, enteropathy 
associated T-cell lymphoma or hepatosplenic gamma delta T-cell 
lymphoma. 
 
1.1.2  Phase I trial: To establish the maximum tolerated dose of 
lenalidomide in combination with CHOEP chemotherapy. 
 
1.1.3  Phase II trial: To assess the efficacy (complete response rate) of this 
combination. 
 
1.2  
Secondary Objectives  
 
1.2.1 To evaluate overall response rate (CR+PR) of the combination of 
lenalidomide and CHOEP chemotherapy. 
 
1.2.2 To evaluate the safety and tolerability of the regimen.  
 
1.2.3 To assess the 2 year progression free survival (PFS) and overall 
survival (OS) using this regimen.  
 
 
 
 


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2.0  
BACKGROUND, SIGNIFICANCE, and PRELIMINARY STUDIES  
  
2.1 
Treatment of peripheral T-cell lymphoma.  
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare disorders 
that result from clonal proliferation of mature post-thymic lymphocytes 1,2. In Western 
countries, PTCL makes up 5% to 10% of all non-Hodgkin's lymphoma cases and 
typically affects adults 3,4. Most of the histologically distinct subsets share an 
aggressive clinical behavior, poor response to conventional chemotherapy, and poor 
long-term survival 5,6. There is no current consensus on standard therapy for patients 
with newly-diagnosed PTCL 7. Anthracycline-containing regimens such as CHOP 
(cyclophosphamide, doxorubicin, vincristine, and prednisone) are commonly used 
but frequently result in an inadequate response or a lack of durable remission 8. 
High-dose chemotherapy and ASCT have been used as consolidation, but many 
patients still experience disease relapse 9.  Furthermore, many high-dose 
chemotherapy studies have been retrospective and included only patients who 
actually received high-dose chemotherapy. This may overestimate the role of high-
dose chemotherapy as first-line therapy because 30% or more of T-cell lymphoma 
patients progress or do not achieve an adequate response with conventional 
chemotherapy and thus will not proceed to high-dose chemotherapy and ASCT 10,11. 
Improvements in initial therapy in this group of diseases are clearly needed. 
 
2.2  
CHOEP chemotherapy as initial therapy for peripheral T-cell lymphoma.  
CHOP chemotherapy has been a standard treatment for PTCL 8. Prospective and 
retrospective studies have reported complete response rates of 40-60%, when ALK+ 
anaplastic large cell lymphoma (ALCL) patients were omitted, with a 5-year overall 
survival of 35-45% in this patient group 12,13. Efforts to improve the outcome with 
CHOP chemotherapy have evaluated adding etoposide to the combination. The 
German High-Grade Non-Hodgkin Lymphoma Study Group analyzed patients 
treated with CHOP (cyclophosphamide, doxorubicin, vincristine, 
prednisone/prednisolone) or CHOP plus etoposide (CHOEP) for 6-8 cycles 14. The 3-
year event-free survival (EFS) and overall survival were 41.1% and 53.9% for PTCL-
NOS (n = 70), 50.0% and 67.5% for angioimmunoblastic lymphoma (AITL; n = 28), 
and 45.7% and 62.1% for ALK- ALCL (n = 113). For patients ≤ 60 years, the addition 
of etoposide to CHOP improved the 3-year EFS (75.4% versus 51.0%, p = .003). In 
patients > 60 years, however, a benefit for etoposide was not seen14. 
 
2.3 
Lenalidomide in the treatment of T-cell lymphoma.  
Lenalidomide is an immunomodulatory agent that has demonstrated clinical efficacy 
in several hematologic malignancies. Lenalidomide has several hypothesized 
mechanisms of action, including direct cytotoxicity to tumor cells 15,16, and 
immunomodulatory effects such as cytokine modulation 17 and enhanced natural 
killer and T-cell function 18. In addition, lenalidomide alters the tumor cell 
microenvironment to discourage the growth of tumor cells and inhibit the mitogenic 
signaling that supports tumor cells in the bone marrow, both by overcoming the 
protective role of bone marrow stromal cells 18 and through anti-angiogenic 
properties 20. Lenalidomide has proven efficacy in the treatment of several 


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hematologic malignancies, including chronic lymphocytic leukemia 21, multiple 
myeloma 22, and myelodysplastic syndrome 23. 
Two phase II trials have recently demonstrated clinical activity of lenalidomide in 
patients with T-cell lymphoma 24,25. In a Canadian trial of 24 relapsed patients, the 
overall response rate was 30% (7 of 23); all were partial responses 24. Two patients 
had stable disease for ≥5 cycles. Responses were seen in anaplastic, 
angioimmunoblastic, and peripheral T-cell unspecified histologies. The median PFS 
was 96 days (range, 8-696+ days) and the median OS was 241 days (range, 8-696+ 
days). This study was updated at the 2013 American Society of Hematology Annual 
meeting and the results of 39 eligible patients were reported 25. The ORR of all 
patients was 10/39 (26%); 3 (8%) were complete responses and 7 were partial 
responses. Responses occurred in anaplastic, angioimmunoblastic, and PTCL-NOS 
histologies. Three additional patients had SD ≥5 cycles. The median OS was 12 
months (range <1-69+ months), median PFS was 4 months (range, <1-50+ months) 
and the median DoR was 13 months (range 2-37+ months), including 5 responses 
lasting greater than 1 year.  
The study also enrolled patients with untreated T-cell lymphoma who were not 
candidates for combination chemotherapy. The ORR of this subpopulation of 
previously untreated patients who were not eligible for combined chemotherapy 
(n=8) was 43%, median OS was 22 months (range, <1-38+ months), median PFS 
was 2 months (range, <1-38+ months), and median DoR was 21 months (range 5-
28+ months).  
In a separate recent multicenter French trial 26, 54 relapsed or refractory PTCL 
patients were treated and an overall response rate of 22% was seen (11% CR). The 
median PFS was 2.5 months and the median duration of response was 3.6 months. 
Lenalidomide was felt to exhibit single agent activity and combination approaches 
were recommended.  
In most of these studies, 25 mg of lenalidomide was given for 21 days every 4 
weeks. In the proposed trial in which lenalidomide will be combined with CHOEP 
chemotherapy, this dose is not likely to be achieved. We plan to escalate the 
lenalidomide to a maximum of 20 mg for 10 days very 3 weeks. In the maintenance 
portion of the study, our goal is to have patients remain on the drug. A flat lower 
dose of 10 mg for 21 days every 4 weeks will be administered.   
 
2.4 
Phase I/II Study of CHOEP-21 in combination with lenalidomide. 
An initial phase I dose escalation portion of the study will be done testing the 
feasibility and tolerability of lenalidomide in combination with standard CHOEP 
chemotherapy. We will use a 3+3 dose escalation design (see dose level escalation 
table in treatment details section) to determine the optimal dose of lenalidomide that 
can be administered with CHOEP.  
This will be followed by a phase II portion of the study in which patients with 
peripheral T-cell lymphoma will be treated with CHOEP in combination with 
lenalidomide at the dose defined in the phase I portion of the study. Patients will be 
treated with the combination every 21 days (+/- 2 days) for 6 cycles. The primary 
efficacy endpoint of the phase 2 portion of the study is complete response rate after 
6 cycles. 


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Responding patients will then receive either an autologous stem cell transplant and 
no further therapy, or maintenance lenalidomide therapy either until disease 
progression or for a maximum of 12 cycles (1 year). The decision between transplant 
or maintenance therapy will be based on physician or patient choice. While there are 
no data on maintenance lenalidomide in PTCL patients, previous studies using 
lenalidomide continued the drug to progression 25,26. It this therefore anticipated that 
lenalidomide will well tolerated for 1 year in those who select maintenance therapy. 
 
 


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3.0  
ELIGIBILITY CRITERIA  
 
3.1 
Inclusion Criteria  
3.1.1  Histologically confirmed new diagnosis of Stage II, III and IV 
Peripheral T-cell Non-Hodgkin’s lymphoma not otherwise specified 
(NOS), Anaplastic large cell lymphoma (ALK negative) (ALK positive if 
IPI 3, 4, or 5), Nodal PTCL with TFH phenotype or 
Angioimmunoblastic T-cell lymphoma, Enteropathy associated T-cell 
lymphoma, Hepatosplenic gamma delta T-cell lymphoma.  
Note: As part of the eligibility criteria review, either the 2008 OR 2016 
WHO classifications of these diagnoses will be recognized and accepted. 
3.1.2  Pathology material: H&E stain and IHC slides or a representative 
FFPE tissue block along with the pathology report from initial 
diagnosis, should be sent to be reviewed, and the diagnosis confirmed 
by Mayo Clinic department (retrospective diagnostic review: treatment 
may commence prior to the Mayo Clinic review).  
3.1.3  No prior therapy with the exception of prior prednisone alone, at the 
discretion of the investigator based on current diagnosis and clinical 
condition. This prednisone treatment will not count toward the 6 cycles 
of treatment given in the study. 
3.1.4  Age 19 years or older (the age of consent in Nebraska); Age 18 years 
or older (applicable to states where the age of majority is 18).  
3.1.5  Expected survival duration of > 3 months.  
3.1.6  Karnofsky Performance Status > 70. (Appendix A)  
3.1.7  Laboratory status as follows:  
• ANC > 1000 cells/mm3, unless cytopenias due to NHL (i.e., bone 
marrow involvement or splenomegaly)  
• Platelet Count > 100,000 /μL or > 75,000 /μL if BM involvement or 
splenomegaly 
• Total bilirubin ≤1.5 x upper normal limit, or ≤ 3 x upper normal limit if 
documented hepatic involvement with lymphoma, or ≤ 5 x upper 
normal limit if history of Gilbert’s Disease.  
• Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 2.5 x upper normal limit (≤ 5 x upper normal limit if 
documented hepatic involvement with lymphoma).  
• Serum creatinine < 2.0 mg/dL or calculated creatinine clearance 
(CrCl) > 45 mL/min (Cockcroft-Gault, Appendix B)  
• PT or INR, and PTT ≤ 1.5 x upper limit of normal unless patient is 
receiving anticoagulants. If patient is on warfarin therapy, levels should 
be within therapeutic range.  
3.1.8  If currently not on anticoagulation medication, willing and able to take 
aspirin (81 or 325 mg) daily. If aspirin is contraindicated, the patient 
may be considered for the study if on therapeutic dose warfarin or low 
molecular weight hep Patients unable to take any prophylaxis are not 


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eligible. 
3.1.9  Patients with measurable disease. Patients with non-measurable but 
evaluable disease may be eligible after discussion with the PI. 
Baseline measurements and evaluations must be obtained within 6 
weeks of registration to the study. Abnormal PET/CT scans will not 
constitute evaluable disease, unless verified by the CT scan portion, 
CT scan, or other appropriate imaging.  
3.1.10  Patients with measurable disease must have at least one objective 
measurable disease parameter. A clearly defined, bi-dimensionally 
measurable defect or mass measuring at least 1.5 cm in diameter on 
the CT portion of a PET/CT or CT scan or MRI (if appropriate) will 
constitute measurable disease. Proof of lymphoma in the liver is 
required by a confirmation biopsy. Skin lesions can be used as 
measurable disease provided bi-dimensional measurements are 
possible. 
3.1.11  All study participants must be registered into the mandatory Revlimid 
REMS™ program, and be willing and able to comply with the 
requirements of the REMS™ program. 
3.1.12  Women must not be pregnant or breast-feeding due to teratogenic 
effects of lenalidomide and chemotherapy.  
• Females of reproductive potential must adhere to the scheduled 
pregnancy testing as required in the Revlimid REMS™ program. 
• All females of childbearing potential must have a blood test within 2 
weeks prior to registration to rule out pregnancy.  
• Pregnancy testing is not required for post-menopausal or surgically 
sterilized women.  
3.1.13  Male and female patients of reproductive potential must agree follow 
accepted birth control measures.  
3.1.14  Patient must be able to adhere to the study visit schedule and other 
protocol requirements.  
3.1.15  Patients must be willing to give written informed consent, and sign an 
institutionally approved consent form before performance of any study-
related procedure not part of normal medical care as noted in 3.1.3 
above; with the exception of 1 cycle of chemotherapy based on current 
diagnosis and clinical condition, with the understanding that consent 
may be withdrawn by the subject at any time without prejudice to 
future medical care.  
3.1.16  No serious disease or condition that, in the opinion of the investigator, 
would compromise the patient’s ability to participate in the study. 
 
 
 
 


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3.2  
Exclusion Criteria 
 
3.2.1 Pregnant or breast feeding females.  
3.2.2  Known seropositive for or active viral infection with human 
immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C 
virus (HCV).  Patients who are seropositive (i.e. hepatitis B core 
antibody positive; quantitative DNA negative) are eligible with 
appropriate prophylaxis. 
3.2.3  Major surgery as defined by the institutional PI within 2 weeks of study 
drug administration.  
3.2.4  Prior malignancies within the past 3 years with exception of 
adequately treated basal cell, squamous cell skin cancer, or thyroid 
cancer; carcinoma in situ of the cervix or breast; prostate cancer of 
Gleason Grade 6 or less with stable PSA levels.  
3.2.5  Patients with a diagnosis of other PTCL subtype histologies other than 
those specified in the inclusion criteria.  Large cell transformation of 
mycosis fungoides is excluded. 
3.2.6  Contraindication to any of the required concomitant drugs or 
supportive treatments, including hypersensitivity to all anticoagulation 
and antiplatelet options, or antiviral drugs.   
3.2.7  Any other clinically significant medical disease or condition laboratory 
abnormality or psychiatric illness that, in the Investigator’s opinion, 
may interfere with protocol adherence or a subject’s ability to give 
informed consent. 
3.2.8 Known hypersensitivity to thalidomide, pomalidomide, or lenalidomide.  
3.2.9 The development of erythema nodosum if characterized by a 
desquamating rash while taking thalidomide, lenalidomide or similar 
drugs. 
3.2.10 Ejection fraction of <45% by either MUGA or ECHO. 
 
NOTE:  
All questions regarding eligibility for UNMC potential subjects should be directed to 
the UNMC Coordinator at 402-559-9053.  
 
All questions regarding eligibility for Participating Site potential subjects should be 
directed to the sponsor PI by contacting the UNMC Fred & Pamela Buffett Cancer 
Center Research Project Coordinator at 402-559-4596. 
 
NOTE: UNMC and Participating Sites should complete the eligibility checklist 
(Appendix C) as source documentation if it has been reviewed, signed, and dated 
prior to registration by the treating physician. The eligibility checklist must be 
accompanied by all other source documents that evidence the subject’s eligibility 
(i.e., dictation, pathology, radiology, laboratory, etc.)  
 
 


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4.0  
REGISTRATION PROCEDURES  
 
Patients, who are referred to the Nebraska Medical Center (NMC) / UNMC, or other 
IRB approved participating sites, with the following histologies: newly diagnosed 
Stage II, III and IV peripheral T-cell non-Hodgkin’s lymphoma not otherwise 
specified(NOS), anaplastic large cell lymphoma (ALK negative) (ALK positive if IPI 3, 
4, or 5), angioimmunoblastic T-cell lymphoma, enteropathy associated T-cell 
lymphoma, hepatosplenic gamma delta T-cell lymphoma may be eligible for this trial.  
Screening eligibility based on standard clinical care will be performed by the treating 
physician at the time of encounter. On initial presentation, a history and physical 
examination are performed, laboratory data obtained, and performance status is 
assessed. Imaging studies obtained include PET/CT; a high-resolution multi-detector 
computed tomography (CT) of the chest, abdomen and pelvis may be necessary if 
measurements cannot be made off the CT portion of the PET/CT. Further imaging 
studies will be obtained as clinically indicated. Pathology material must be reviewed, 
and the diagnosis confirmed by Mayo Clinic pathology department (retrospective) 
(See section 5.7 and Appendix F for details). The patient’s primary oncologist will 
make the decision as to screened eligibility of the candidate based on the eligibility 
criteria listed above, prior to offering consent.  
If the patient is screened as potentially eligible, he/she will then be offered the option 
to participate. An informed consent will be signed by the patient after thorough 
review of the study is completed by the physician and his/her designee.  
Some insurance carrier’s may decline to cover the costs of usual medical care if the 
patient is participating in a clinical trial. The patient will be provided assistance by the 
research nurse coordinator or designated staff in determining if the insurance carrier 
will decline coverage. Insurance carriers may or may not pay for study related 
expenses. The patient can then decide if they wish to participate.  
 
4.1  
Eligibility Verification/Registration:  
 
Before patients are registered to the study, an eligibility checklist (Appendix C) must 
be completed and source documents provided to UNMC to verify the subject meets 
the eligibility criteria.  
 
Date of Enrollment: The date of consent will be considered the date of enrollment. 
Within 24 hours of consent, the following information should be submitted to UNMC 
project coordinator:  
• 
copy of the signed and dated consent form for the subject enrolled in the 
protocol 
• 
Protocol Number  
• 
Patient Identification: Patient initials and site id 
• 
Patient demographics: gender, birth date (mm/dd/yyyy), race, ethnicity, 
insurer information 
 
Registration Date: Eligibility verification and notification of assigned subject number 
(by UNMC) to Participating Sites will be known as the registration date.  


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First study-related Treatment Date: All eligibility criteria do not need to be met until 
the date of the first study related treatment (defined for this protocol as the initiation 
of Cycle 1 CHOEP or as noted in 3.1.3 above; “with the exception prior radiation 
therapy and of 1 cycle of chemotherapy based on current diagnosis and clinical 
condition”.  
Patients will be registered through the sponsor PI by contacting the UNMC Fred & 
Pamela Buffett Cancer Center Research Project Coordinator and the UNMC Fred & 
Pamela Buffett Cancer Center Protocol Review and Monitoring System Office 
(PRMS). All Study personnel from UNMC and non-UNMC IRB approved sites will 
contact the UNMC Research Project Coordinator if a patient appears to meet the 
eligibility criteria. They will email the completed eligibility checklist (Appendix C) and 
de-identified relevant source documents to the Research Project Coordinator, at (ph: 
402-559-4596) to verify the subject meets the eligibility criteria. The eligibility check 
list will be maintained in the study file. If the UNMC Research Project Coordinator 
confirms that the patient meets criteria, and target accrual has not been met, 
approval for the patient will be given. A confirmation of registration will be forwarded 
by the UNMC Research Project Coordinator.  
In the event of an after-hours potential enrollment (i.e., clinic coast time differences), 
or an immediate need-to-treat based on potential subject condition, registration can 
be accomplished by contacting the sponsor PI Dr. Matthew Lunning directly by 
email: mlunning@unmc.edu  (response required) or by phone/pager 402-559-4000 
or 402-888-3837. The UNMC Research Project Coordinator must be notified in order 
to meet UNMC Protocol Review Monitoring System (PRMS) Office requirements.  
 
The UNMC Fred & Pamela Buffett Cancer Center Protocol Review & Monitoring 
System (PRMS) Office Audit Committee defines a Participating Site as: a hospital 
clinic, or other provider of medical services who has agreed to participate in a 
therapeutic trial that has been designed and developed by a University of Nebraska 
Medical Center/Nebraska Medical Center (UNMC/NMC) investigator and is 
sponsored by UNMC.  
The UNMC Research Project Coordinator will provide the following listed information 
to the UNMC Fred & Pamela Buffett Cancer Center PRMS office (obtained from 
participating sites which have local and UNMC IRB approval, and have met all other 
criteria to enroll). The listed information for subjects enrolled at participating sites will 
be provided to the PRMS office within one week of enrollment as applicable:  
o UNMC and Participating Site Protocol Numbers  
o Investigator/Participating Site Identifier (ID)  
o Subject ID: Assigned by UNMC [Site ID followed by subject number 
(##-###)]  
o Consent Date: Date subject signed consent  
o Patient demographics: gender, birth date (mm/dd/yyyy), race, ethnicity 
o Re-consent Date: (If applicable)  
o Ineligibility Status: (If known)  
o Off Study Date: (If applicable)  
 
4.2  
Pathology Requirements  
 


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Pathological materials are to be submitted as indicated in section 3.1.2. “Pathology 
material: H&E stain and IHC slides or a representative FFPE tissue block along with 
the pathology report from initial diagnosis, should be sent to be reviewed, and the 
diagnosis confirmed by Mayo Clinic department (retrospective review)”. Please NOTE: 
the diagnostic H&E slide and IHC slides will be returned after review.  
 
See Biospecimen Section 5.7.1 for details of the required pathological materials for 
retrospective diagnosis.  
 
4.3  
Instructions for Patients Who Do Not Start Assigned Protocol Treatment  
 
If a patient does not receive any assigned protocol treatment, enrollment data will 
still be collected and must be submitted according to the instructions in the protocol. 
Documentation of the reason for not starting protocol treatment should be noted on  
the enrollment forms.  
 
 
4.4  
Requirements for Submitting Regulatory Documents UNMC and 
Participating Institutions:  
 
Before an institution may enroll patients, all site activation criteria must be met by 
submitting required protocol specific regulatory documents to the study project 
manager at UNMC Fred & Pamela Buffett Cancer Center).  
 
 
 


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4.5  
Required Protocol Specific Regulatory Documents  
 
1. Confirmation that the UNMC Team Designee(s) conducted an initial Site 
Visit/Teleconference prior to opening a protocol to accrual at the participating site, 
and that the UNMC and Site PI have documented that questions posed by the Site 
PI regarding the conduct of the protocol have been answered/resolved.  
2. Copy of IRB Informed Consent Document.  
NOTE: Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent document must be 
justified in writing by the investigator and approved by the IRB.  
3. IRB Approval Letter  
NOTE: The above submissions must include the following details:  
• Indicate all sites approved for the protocol under an assurance number.  
• OHRP assurance number of reviewing IRB  
• Full protocol title and number  
• Version Date  
• Type of review (full board vs. expedited)  
• Date of review.  
• Signature of IRB official  
 
 
 
 


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5.0  
TREATMENT PLAN  
 
5.1  
Drug Administration  
 
5.1.1  Body Surface Area (BSA) Calculations  
Dosage calculations will be based on the patient’s BSA, at baseline.  Actual 
height and weight should be used in determining body surface area. 
(Appendix B) Dose adjustments at the beginning of each cycle do not need to 
be made unless there has been a >10% weight gain or loss.  
 
5.1.2  Requirement for Venous Access  
Central venous access is suggested for protocol participation, but not 
mandated. A previously placed central venous access device that is 
functioning properly (free infusion of saline, unimpeded blood return, good 
condition of external appliance, no recent history of device infection or 
thrombosis) can be used. Should the patient require a central venous access, 
an implanted port central venous access device will be placed (e.g. Power 
Port) after appropriate informed consent has been obtained. Other aspects of 
catheter/port management will be in accordance with standard nursing clinic 
central venous port procedures.  
 
5.1.3 Prophylaxis - Pre and post medications as prescribed by the treating 
physician.  
5.1.3.1 CNS prophylaxis: Not required by the protocol. Patients should 
be treated per institutional guidelines  
5.1.3.2 Tumor lysis precaution, per institutional guidelines. Patients 
considered to be at risk for tumor lysis should be well hydrated and 
consider to be treated with allopurinol or a suitable alternative for 12-
24 hours prior to the first infusion of chemotherapy.  
5.1.3.3 Prophylactic Anti-Emetic Premedication:  Standard antiemetic 
prophylaxis will be given per institutional guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.2  
Treatment Schedule. 
 
5.2.1  Phase I Cohort: Lenalidomide plus CHOEP regimen.  
 
NOTE: Patients will receive 6 cycles of therapy before having an autologous 
stem cell transplant or receiving maintenance lenalidomide. Each 
cycle will be 21 days with a +/- 2 day start window. All 10 pills of 
lenalidomide must be taken to be consider eligible for DLT 
assessment for cycle 1; replacement doses if lost/misplaced can be 
obtain if within days (1-10). 
 
DRUG 
DOSE 
FREQUENCY 
# of CYCLES 
Administration 
Cyclophosphamide1 
750 mg/m2 
Day 1 
6 cycles 
IV 
Doxorubicin2 
50 mg/m2 
Day 1 
6 cycles 
IV 
Vincristine3 
1.4 mg/m2 
Day 1 
6 cycles 
IV 
Etoposide4 
100 mg/m2 
Days 1-3 
6 cycles 
IV 
Prednisone 
100 mg 
Days 1-5 
6 cycles 
PO 
Lenalidomide 
 
NOTE: To provide a 
means of ensuring oral 
route of medication 
adherence to subjects 
while participating in this 
clinical trial. Please see: 
Appendix E- Oral, 
Sublingual, and/or 
Buccal Route 
Medication Adherence 
Standard Procedure 
 
As determined 
in phase I, see 
dose escalation 
table (section 
5.3.1)  
Day 1-10 
6 cycles; 
additional 12 
cycles (given 
day 1-21 every 
28 days) or until 
disease 
progression or a 
maximum of 12 
cycles if chooses 
maintenance 
therapy (see 
section 5.2.3.1 
for maintenance 
dosing) 
PO 
Pegfilgrastim 
(Neulasta)6 6mg  
Pegfilgrastim 
(Neulasta) 6mg  
Day 4, 5 or 6 5 6 cycles 
SQ 
Aspirin5  
81mg or 325mg  Daily 
During active 
treatment 
PO 
 
1. Cyclophosphamide dose may be rounded to nearest 50 mg 
2. Doxorubicin dose may be rounded to nearest 5 mg 
3. Vincristine must be capped at 2 mg 
4. Etoposide dose may be rounded to nearest 5 mg. Substituting oral etoposide for intravenous is 
permitted on days 2 and 3 at 200 mg/m2 and must be document in the notes section of 
medication diary in Appendix E 


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5. See Ancillary Treatment section 5.5 regarding anticoagulation recommendations. 
6. Neulasta, on-body injectors are acceptable.  Neupogen can be substituted per institutional 
policy.  One dose per cycle of Neulasta including on-body injectors. 
 
5.2.2 Phase 2 Cohort: Lenalidomide plus CHOEP regimen (at MTD from phase I). 
Patients will receive 6 cycles of therapy. Each cycle will be 21 days with a +/- 2 day 
start window. 
NOTE: Patients will receive 6 cycles of therapy before having an autologous  
stem cell transplant or receiving maintenance lenalidomide. 
 
DRUG 
DOSE 
FREQUENCY 
# of CYCLES 
Administration 
Cyclophosphamide1 
750 mg/m2 
Day 1 
6 cycles 
IV 
Doxorubicin2 
50 mg/m2 
Day 1 
6 cycles 
IV 
Vincristine3 
1.4 mg/m2 
Day 1 
6 cycles 
IV 
Etoposide4 
100 mg/m2 
Days 1-3 
6 cycles 
IV 
Prednisone 
100 mg 
Days 1-5 
6 cycles 
PO 
Lenalidomide 
 
NOTE: To provide a 
means of ensuring oral 
route of medication 
adherence to subjects 
while participating in this 
clinical trial. Please see: 
Appendix E- Oral, 
Sublingual, and/or 
Buccal Route 
Medication Adherence 
Standard Procedure 
 
MTD dose  
Day 1-10 
6 cycles; 
additional 12 
cycles (given day 
1-21 every 28 
days) or until 
disease 
progression if 
chooses 
maintenance 
therapy (see 
section 5.2.3.1 for 
maintenance 
dosing) 
PO 
Pegfilgrastim 
(Neulasta)6 6mg  
Pegfilgrastim 
(Neulasta) 6mg  
Day 4, 5 or 6 
6 cycles 
SQ 
Aspirin5  
81mg or 
325mg  
Daily 
During active 
treatment 
PO 
 
1. Cyclophosphamide dose may be rounded to nearest 50 mg 
2. Doxorubicin dose may be rounded to nearest 5 mg 
3. Vincristine must be capped at 2 mg 
4. Etoposide dose may be rounded to nearest 5 mg.  Substituting oral etoposide for intravenous 
is permitted on days 2 and 3 at 200 mg/m2 and must be document in the notes section of 
medication diary in Appendix E. 
5. See Ancillary Treatment section 5.5 regarding anticoagulation recommendations. 
6. Neulasta, on-body injectors are acceptable.  Neupogen can be substituted per institutional 


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policy.  One dose per cycle of Neulasta including on-body injectors. 
 
 
5.2.3  Maintenance lenalidomide or autologous stem cell transplantation 
Responding patients after 6 cycles of lenalidomide plus CHOEP may then be treated 
either an autologous stem cell transplant and no further therapy, or maintenance 
lenalidomide at 10 mg for 21 days of a 28 day cycle (with a +/- 2 day start window) 
either until disease progression or for a maximum of 12 cycles (1 year). Therapy will 
be based on physician or patient choice. 
 
5.2.3.1 Administration Schedule for lenalidomide maintenance  
 
• Lenalidomide 10 mg PO days 1 through 21 on a 28-day cycle.  
To provide a means of ensuring oral route of medication adherence to subjects while participating in this clinical trial. 
Please see: Appendix E- Oral, Sublingual, and/or Buccal Route Medication Adherence Standard Procedure 
NOTE: The dose of lenalidomide to be given as maintenance therapy 
is a fixed dose of 10mg PO days 1-21 on a 28 day cycle and is 
independent of the dose received in combination with CHOEP 
chemotherapy. 
NOTE: The first cycle of lenalidomide will start 8 weeks (+/- 1 week) 
after day 1 of cycle 6 of induction. Patients who, due to unacceptable 
lab values or other reasons, are unable to start consolidation within 16 
weeks after the start of Cycle 6 of CHOEP/lenalidomide will be 
withdrawn from study treatment. The patient should remain on the 
study and should be followed for subsequent events. 
NOTE: Prior to starting lenalidomide continuation and subsequent 
cycles at time points referenced in study calendar, the ANC must be > 
1000 cells/mm3 (1.0 x 109/L) and the platelet count must be > 75,000 
cells/mm3 (75 x 109/L).   
NOTE: Creatinine clearance (CrCl) should be calculated prior to the 
first dosing of lenalidomide. If CrCl < 30 ml/min, or for patients on 
dialysis, lenalidomide should not be given.  
NOTE: All patients receiving lenalidomide based continuation therapy 
must complete the lenalidomide pill diary for each cycle/dose of 
lenalidomide 
 
Anticoagulation - All subjects receiving lenalidomide maintenance therapy will 
be required to have deep vein thrombosis (DVT) prophylaxis every day 
during lenalidomide therapy. Subjects with a history of a thrombotic vascular 
event are required to have therapeutic doses of low molecular weight heparin 
or warfarin with a goal to maintain an INR between 2.0–3.0. Oral anti-Xa or 
direct thrombin inhibitors are not allowed.  All subjects without a history of a 
thromboembolic event are required to take a daily aspirin (81mg or 325 mg) 
for DVT prophylaxis. Subjects who are unable to tolerate aspirin should 
receive prophylactic doses of low molecular weight heparin therapy or 


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warfarin treatment per institutional policy.  
 
Of note, if patients’ platelets decline to < 50,000/mm3 (50 x 109/L), 
prophylactic anti-coagulation should be stopped (in addition to holding 
lenalidomide as below in Section 5.4). If/when lenalidomide is restarted (with 
return of platelet toxicity to ≤ Grade 2 as in Table 5.4.2 in Section 5.4), then 
prophylactic anti-coagulation should also be restarted. 
5.2.3.2 Hematopoietic Stem Cell Transplantation  
 
Administration of Standard Preparative Regimen (in patients who have 
a CR or PR as per investigator’s discretion) followed by HSCT (as per 
institutional guidelines) regimen optional ex: BEAM  
 
Subjects going on to receive transplant per standard/institutional 
guidelines will only be followed for PFS.  
 
Hematopoietic Stem Cell Collection: Peripheral blood stem cells will be 
collected as per the discretion of the treating physician until an 
adequate number of CD34+ cells/kg have been collected (as per 
existing institutional guidelines).  
 
The timing of stem cell collection will be at the discretion of the treating 
physician and as per institutional guidelines. However, it is 
recommended that delays in administering CHOEP plus lenalidomide 
be avoided. 
 
Suggested optional preparative regimen - BEAM: 
 
 
 
Dose Modifications for Suggested Optional BEAM Regimen -  
The dose of BEAM will remain constant for each subject throughout 
the study. No adjustments in doses for post-screening changes in 
body surface area will be made. 
 
NOTE: The preparative regimen above is a suggested option. The 
exact combination and dosing should be as per institutional standards.  
 
 
 
5.2.3.3 Reason as to why patients do not proceed to transplant:  
 
Physicians will be required to document the reason why patients did 
not proceed to an autologous transplant - i.e., comorbidities, advanced 
age, inability to mobilize, patient decision, and physician decision. 
Day – 6 
Day – 5 
Day - 4 
Day - 3 
Day - 2 
Day - 1 
Day 0 
BCNU  
300mg/m2  
Etoposide 
100mg/m2 
BID  
Cytarabine 
100mg/m2 
BID 
Etoposide 
100mg/m2 
BID  
Cytarabine 
100mg/m2 
BID 
Etoposide 
100mg/m2 
BID  
Cytarabine 
100mg/m2 
BID 
Etoposide 
100mg/m2 
BID  
Cytarabine 
100mg/m2 
BID 
Melphalan  
140mg/m2 
Stem 
Cell 
Infusion  


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5.3  
Phase I dose escalation and determination of MTD. 
5.3.1  Dose escalation of lenalidomide 
 
Dose level 
Dose 
Day of the 21-day cycle 
-1 
Lenalidomide 5 mg 
Day 1-10 
1 (starting dose level) 
Lenalidomide 10 mg 
Day 1-10 
2 
Lenalidomide 15 mg 
Day 1-10 
3 
Lenalidomide 20 mg 
Day 1-10 
 
5.3.1.1  
Three patients will be treated at each dose level and 
observed for a minimum of 3 weeks (1 cycle), to assess 
toxicities, before new patients are treated. Doses will 
not be escalated in any individual patient because of 
the risk of cumulative toxicity. 
5.3.1.2 
Investigators are to contact the UNMC collaborators  
soon as any dose-limiting toxicity occurs. 
 
5.3.2  Definitions of Dose Limiting Toxicity (DLT) 
 
For this protocol, dose-limiting toxicity (DLT) will be defined as follows: an adverse 
event attributed (definitely, probably or possibly related) to the study treatment and 
meeting following criteria with the first cycle  
 
Toxicity 
Definition 
Hematologic 
Either: 
1. PLT <25,000 for ≥7days or platelet nadir <10,000 at 
anytime 
2. Failure to recover counts to PLT ≥ 75,000 and/or ANC 
≥1500 by day 28 after initiation of cycle 1 treatment. 
Infection 
Grade 4 per NCI Common Terminology Criteria for 
Adverse Events v4.0* (life threatening). 
Non-hematologic 
Either: 
1. ≥ grade 3 as per NCI Common Terminology Criteria for 
Adverse Events v4.0* 
2. Any toxicities that caused dose delay of > 1 week of the 
intended next dose 
 
*Grade 3 nausea, vomiting, or diarrhea with maximal supportive treatment(s) will be 
considered dose-limiting. Fatigue and mouth sores that are considered Grade 3 and 
are considered to be due to treatment (definitely, probably, or possibly related) will 
be considered as dose-limiting. 
 
 
 
 


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5.3.3 Maximal Tolerated Dose (MTD) Determination 
 
The MTD in this study will be 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). This will be defined on cycle 1 data; however, toxicity 
data will be collected during all cycles and monitored for cumulative toxicity.  Based 
on the cumulative toxicity data, additional patients may be added to cohorts to 
further investigate and cohorts may not be investigated at the discretion of the 
investigators if a cumulative toxicity signal is seen.  
 
5.3.4 Dose Escalation 
 
5.3.4.1  
Three patients will be treated at a given dose level 
combination and observed at least until day 1 of cycle 
2to assess toxicity. 
5.3.4.2  
If dose-limiting toxicity (DLT) is not seen in any of the 3 
patients, up to 3 new patients will be accrued and 
treated at the next higher dose level (as specified in 
7.21). If DLT is seen in 2 or 3 of 3 patients treated at a 
given dose level, then the next 3 patients will be treated 
at the next lower dose level, if only 3 patients were 
enrolled and treated at this lower dose level. 
5.3.4.3 
If a DLT is seen in 1 of 3 patients treated at a given 
dose level, up to 3 additional patients will be enrolled 
and treated at the same dose level. If DLT is seen in at 
least one of these additional three patients (≥2 of 6), the 
MTD will have been exceeded, and further accrual will 
cease to this cohort. If potentially dose-limiting toxicity 
(DLT) is not seen in any of the three additional patients, 
3 new patients will be accrued and treated at the next 
higher dose level. 
5.3.4.4  
If DLT is observed in at least 2 of 6 patients after 
enrolling 6 patients on a specific dose level, then the 
MTD will have been exceeded and defined as the 
previous dose unless only 3 patients were treated at the 
lower dose level. In that case, 3 additional patients will 
be treated at this lower dose level such that a total of 6 
patients are treated at the MTD to more fully assess the 
toxicities associated with the MTD. 
 
5.3.5  Dose De-escalation from Dose Level 1 
 
If 2 treatment-related DLTs are observed at the starting 
dose level, patients will be accrued to level -1. The 
accrual rules based on observed DLT will be as outlined 
in Section 5.3.4. If 2 treatment-related DLTs are 
observed at dose level -1, the study will be suspended. 
 
5.3.6  If a patient in phase I cohort fails to complete cycle 1 for reasons other 


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than toxicity, the patient will be regarded as non-evaluable and will be 
replaced for DLT assessment but will remain eligible for further toxicity 
and efficacy assessment. 
 
5.4  
Dosage Modification Based on Adverse Events –  
 
Strictly follow the modifications in this table for the first two cycles, until individual 
treatment tolerance can be ascertained. Thereafter, these modifications should be 
regarded as guidelines to produce mild-to-moderate, but not debilitating, side effects. 
If multiple adverse events are seen, administer dose based on greatest reduction 
required for any single adverse event observed. Reductions or increases apply to 
treatment given in the preceding cycle and are based on adverse events observed 
since the prior dose. 
 
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. 
 
NOTE: Patients in whom one or more CHOEP plus lenalidomide study treatment 
agents have been discontinued will remain on study unless all CHOEP plus 
lenalidomide study treatment agents are discontinued. Patients in whom all the 
CHOEP plus lenalidomide study treatment agents were discontinued will proceed to 
event monitoring. 
 
Table 5.4.1 Dose Levels (Based on Adverse Events in Table 5.4.2) 
Dose level 
 
Dose 
Day 
Route 
-1 
Lenalidomide 
5 mg 
Day 1-10 
orally 
1 
Lenalidomide 
10 mg 
Day 1-10 
orally 
2 
Lenalidomide 
15 mg 
Day 1-10 
orally 
3 
Lenalidomide 
20 mg 
Day 1-10 
orally 
 
 
 
 


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Table 5.4.2 Adverse Events and Dose Modifications. 
 
Use Common Terminology Criteria for Adverse Events (CTCAE) v4.0 unless otherwise specified  
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
BASED ON INTERVAL ADVERSE EVENT 
Blood/Bone marrow 
Hematologic nadirs: 
ANC<500 for ≥7 days or 
PLT<25,000 for ≥7 days 
or <10,000 at any time 
Lenalidomide 
/CTX/ADR/ 
etoposide 
 
Decrease lenalidomide to the next lowest 
dose level. If AE reoccurs with subsequent 
cycles, decrease lenalidomide to the next 
lowest dose level etc. If the lowest dose 
level is reached and AE occurs, discontinue 
lenalidomide. If AE occurs after lenalidomide 
discontinued, decrease CTX, etoposide and 
ADR by 25% and follow standard dosing 
guidelines.  
Cardiac General 
Left ventricular systolic 
dysfunction ≥ grade 3 
ADR 
Discontinue ADR.  
Renal/ 
Genitourinary 
Cystitis ≥ grade 2 
CTX 
Omit CTX until resolution of cystitis. 
Decrease CTX 50% of preceding dose for 
next cycle of treatment. If subsequent cycle 
is well tolerated and there is no grade ≥2 
renal/GU adverse events, increase CTX to 
100% of the original dose. 
Neurology 
Neuropathy – motor 
Grade 2 
VCR 
 
Omit VCR until neuropathy < grade 2 and 
resume at 50% dose reduction. 
Neuropathy – motor 
Grade ≥ 3  
Discontinue VCR. 
Neuropathy – sensory 
Grade 3  
Omit VCR until neuropathy <grade 2 and 
resume at 50% dose reduction. 
Neuropathy – sensory 
Grade 4 
Discontinue VCR 
Allergy/Immunology 
Allergic reaction or 
hypersensitivity: 
Grade 2 
Lenalidomide 
 
Omit treatment until ≤ grade 1 and restart 
with prophylaxis. If questions, call study 
chair. 
 
Allergic reaction or 
hypersensitivity: 
Grade 3 
Omit therapy; treat the reaction and restart 
at MD discretion. 
 
Allergic reaction or 
hypersensitivity:  
Grade 4 
If attributable to lenalidomide, discontinue 
treatment with lenalidomide. 
Vascular 
Venous 
thrombosis/embolism 
Grade 3 or 4 
Discontinue lenalidomide. 
ADR-doxorubicin, CTX – cyclophosphamide, VCR - vincristine 
 


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Use Common Terminology Criteria for Adverse Events (CTCAE) v4.0 unless otherwise specified  
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
BASED ON INTERVAL ADVERSE EVENT 
Gastrointestinal 
Nausea/Vomiting ≥ Grade 
3 
Lenalidomide/ 
CHOEP 
 
Maximize antiemetic therapy; if maximized 
antiemetic treatment ineffective, take off 
treatment at physician discretion.  
Mucositis/Stomatitis ≥ 
Grade 2  
ADR 
Decrease ADR by 25% of preceding dose 
for next cycle. If no grade ≥3 GI toxicities in 
subsequent cycle, increase ADR to 100% of 
original dose. 
Constipation grade 2 
 
 
Constipation ≥ grade 3 
Lenalidomide/ 
VCR 
Initiate bowel regimen and continue 
lenalidomide and VCR. 
 
Omit lenalidomide until grade 2, initiate 
bowel regimen and restart lenalidomide. 
Decrease VCR by 25% 
Dermatology/ 
Skin 
Desquamating (blistering 
rash) grade 3 
Lenalidomide 
Omit lenalidomide until ≤ grade 2 and restart 
at next lower dose level. If Lenalidomide 
held for more than 21 days, call study chair. 
Desquamating (blistering 
rash) grade 4 
Discontinue lenalidomide. 
Non desquamating rash 
grade 4 
Discontinue lenalidomide. 
Infection 
 
Infection with 
ANC ≥ 1,000/μL 
 
Lenalidomide/ 
CHOEP 
 
Hold drugs in case of an infection requiring 
IV antibiotics or hospitalization and restart 
when infection is controlled. If dosing is held 
≥ 21 days call study chair.  
 
If adverse event reoccurs on subsequent 
cycles, decrease lenalidomide to next lower 
dose level and consider prophylactic 
antibiotics. If AE re-occurs at this dose level 
call study chair. 
 
Infection with 
ANC < 1,000/μL 
Hold drugs in case of an infection requiring 
IV antibiotics or hospitalization and restart 
when infection is controlled, decrease 
lenalidomide to the next lowest dose level. If 
dosing is held ≥ 21 days call study chair.  
If adverse event reoccurs despite 
discontinuation of lenalidomide, then on 
subsequent cycle reduce CTX by 25%, 
etoposide by 25% and ADR by 25%, 
consider prophylactic antibiotics. If dosing is 
held ≥ 21 days, call study chair. 
 
New or reactivation of viral 
hepatitis  
Discontinue treatment, treat hepatitis.  
ADR-doxorubicin, CTX – cyclophosphamide, VCR - vincristine  
 


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Use Common Terminology Criteria for Adverse Events (CTCAE) v4.0 unless otherwise specified  
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
BASED ON INTERVAL ADVERSE EVENT 
Other non-hematologic 
Grade 3 or 4* 
Lenalidomide/ 
CHOEP 
 
Hold drugs until toxicity has resolved to 
grade 2 or baseline grade then restart drugs.   
If questions, contact the study chair. 
*Nausea and vomiting of grade 3 or 4 after full anti-emetic therapy will then follow dose reduction 
guidelines. 
 
 
Use Common Terminology Criteria for Adverse Events (CTCAE) v4.0 unless otherwise specified  
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
AT TIME OF RETREATMENT 
Blood/Bone marrow 
ANC<1500 
PLT< 75,000 
 
 
 
 
Lenalidomide/ 
CHOEP 
 
Hold drugs. Repeat CBC/diff and if counts 
recover any time before or on d28 to ANC 
≥1500 and PLT ≥75,000 proceed with full 
dose. 
Between days 29-35: 
ANC ≥1500,   PLT 
≥75,000 
Decrease lenalidomide to the next lowest 
dose level, continue 100% CHOEP. If 
lenalidomide at the lowest dose level, 
discontinue.  If not recovered continue to 
hold. 
Day 36 and beyond: 
ANC ≥1500,  
PLT ≥75,000 
Discontinue lenalidomide; resume CHOEP 
with 25% ADR, 25% etoposide and 25% 
CTX dose reduction.  Future dose 
modifications of CHOEP should follow 
standard CHOEP guidelines. 
Other non-hematologic 
Grade ≥ 3* 
 
Hold drugs until toxicity has resolved to 
grade 2 or baseline grade then restart 
lenalidomide at next lower dose level. If 
lenalidomide is at lowest level, discontinue. 
If next cycle is delayed by ≥ 2 weeks, 
contact study chair.  
*Nausea and vomiting of grade 3 or 4 after full anti-emetic therapy will then follow 
dose reduction guidelines. 
ADR-doxorubicin, CTX – cyclophosphamide, VCR - vincristine 
 
 
 
 
 
 


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5.5 
Ancillary Treatment 
 
5.5.1  Patients who are not already on anticoagulation should receive aspirin 
(81 mg or 325 mg) daily. This should be discontinued if platelets are 
<50,000 or if the patient is intolerant of aspirin or develops bleeding 
complications irrespective of the platelet count. If aspirin is 
contraindicated for other reasons – call study chair. 
 
5.5.2  Patients should be considered for proton pump inhibitor while on 
aspirin or other prophylaxis per physician discretion. 
 
5.5.3  Antiemetics may be used at the discretion of the attending physician. 
 
5.5.4  Tumor lysis syndrome prophylaxis should be considered at the 
discretion of the treating physician.  
 
5.5.5  Blood products and growth factors should be utilized as clinically 
warranted and following institutional policies and recommendations. 
Growth colony stimulating factor (GCSF) support will be given with 
each cycle. Treat as needed. 
 
5.5.6  Patients should receive full supportive care while on this study. This 
includes blood product support, antibiotic treatment, and treatment of 
other newly diagnosed or concurrent medical conditions. All blood 
products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be 
recorded in the medical records. 
 
5.5.7  Diarrhea: This could be managed conservatively with anti-diarrheal 
agents such as loperamide. The recommended dose of loperamide is 
4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive 
measures are allowed: hydration, octreotide, and antidiarrheals. 
 
If diarrhea is severe (requiring intravenous rehydration) and/or 
associated with fever or severe neutropenia (grade 3 or 4), broad-
spectrum antibiotics must be prescribed. Patients with severe diarrhea 
or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
 
 


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5.6  
Assessments  
 
5.6.1  Course Assessment Schedule  
 
A dedicated CT response assessment will be done after cycles 2. A PET/CT scan is 
done at the end of therapy to confirm the response.  
 
PET/CT is preferred as part of the initial staging evaluation.  Dedicated CT is 
necessary if measurements cannot be made for the CT portion of the PET/CT. 
PET/CT is optional after initial response evaluation and at the end of cycle 6.  If the 
patient elects to undergo autologous transplant at D+100 response evaluation with 
CT or PET/CT is at the discretion of the investigator but PET/CT would be preferred 
if not in a CR after cycle 6. 
 
A restaging bone marrow biopsy may be done if a staging bone marrow biopsy was 
previously positive or if symptoms suggest involvement. Restaging may also include 
MRI; if clinically indicated. (See Section 7.0.)  
 
Patients with stable disease after 6 cycles are off study. Patients with progressive 
disease (PD) at any time are off study and will discontinue study treatment.  
 
Patients achieving PR/CR after 6 courses, and if transplant eligible, as per 
investigator’s discretion, proceed to HDT per institutional guidelines (See Section 
5.2.3.2).  
 
Patients achieving PR/CR after 6 courses, and who are not transplant eligible or 
elect not to proceed to autologous transplant, as per investigator’s discretion, 
proceed to maintenance therapy with lenalidomide either until disease progression 
or for a maximum of 12 cycles (1 year).  (See Section 5.2.3).  
 
NOTE: Assessments during the first year after completing 6 cycles of CHOEP plus 
lenalidomide should be as per section 7.0. Assessments in year 2 post transplant or 
at the completion of maintenance therapy is per institutional guidelines. 
 
5.6.2  Post Trial Assessments  
 
Patients who go off study treatment at any time during the trial will be followed for 30 
days after the last day of treatment or until other disease-related treatment begins. 
For all patients, drug-related SAEs and AEs will be followed until baseline or ≤ grade 
1 levels. Patients who responded or maintained stable disease during the study will 
be followed for date of disease progression. Patients will be assessed after cycle 2 
and 6 as outlined in treatment plan as well as at 100 days and 1 year post 
transplant. Patients may refuse to participate in the post-trial assessments. 
 
 
 


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5.7  
Biospecimens  
 
One 6 mL EDTA tube will be collected for serum, plasma and DNA at 
baseline, and after study treatment completion (4-6 weeks after cycle 6 day1). 
Serum and plasma will be used to measure serum cytokines. Any leftover 
serum, plasma and DNA specimens will be stored until the end of the study..  
 
5.7.1  Required Pathological Materials for Retrospective Diagnosis  
 
Baseline standard of care diagnostic pathology samples will be done as 
clinically indicated. Pathological materials are to be submitted as indicated in 
sections 3.1.2 and 4.2. “Pathology material: H&E stain and IHC slides or a 
representative FFPE tissue block along with the pathology report from initial 
diagnosis,), should be sent to be reviewed, and the diagnosis confirmed by 
Mayo Clinic department (retrospective diagnostic review: treatment may 
commence prior to the Mayo Clinic review)”.  
 
Please NOTE: the diagnostic H&E slide and IHC slides will be returned after review.  
 
Initial diagnostic materials should be submitted within 1 month of patient 
registration. A copy of the pathology report should be sent when the sample 
is shipped. 
 
5.7.2  Correlative Studies Related to the Research - Plasma Cytokines and 
DNA analysis 
Rationale: Recent data have suggested that increased levels of serum or 
plasma cytokines pretreatment correlate with prognosis in patients with 
lymphoma. We wish to determine whether the proposed treatment 
combination results in changes in the cytokine profile. 
Method: We will measure the plasma levels of a variety of inflammatory 
cytokines, using a multiplex ELISA. Thirty cytokines, including pro-
inflammatory, Th1 and Th2 associated cytokines, will be analyzed for each 
time point. Multiple cytokine analysis kits will be used. Assays will be run in 
duplicate according to the manufacturers’ protocol. Data will be collected 
using the Luminex system and data analysis will be performed using a 
multiplex expression analysis software platform such as the MasterPlex QT or 
Bio-Plex system. A five-parameter regression formula will be used to 
calculate the sample concentrations from the standard curves and a change 
of 50% from the baseline value will be considered significant. 
EDTA Tube Processing: Centrifuge for 15 minutes at room temperature at 
1500 RPM within 30 minutes of collection. For cytokine analysis – Remove 
and aliquot the top 2 ml of plasma from the EDTA tube. Store 1 ml aliquots in 
two (2) properly labeled polypropylene tubes for cryopreservation. Store 
samples in the freezer at ≤ -20°C until they are shipped for analysis.  
For DNA analysis – Remove and aliquot the top 1 ml of cells from the EDTA 
tube. Store the 1 ml aliquot in a properly labeled polypropylene tube for 


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cryopreservation. Store the sample in the freezer at ≤ -20°C until it is shipped 
for analysis. 
Shipping: All specimens pathology and EDTA serum and DNA samples are to 
be sent to the Mayo Clinic, to the contact and address listed below. Send 
blood samples overnight on ice Monday through Thursday only; do not send 
the day before a holiday. (See Appendix F) 
 
Please contact Tammy Price-Troska, Hematology Research, at (507) 284-
3805, or  
pricetroska.tammy@mayo.edu, to advise of planned shipments, and to 
discuss appropriate procedures in the event a sample collection must be 
drawn on a Friday or before a holiday.   
 
Shipping Address:  
Tammy Price-Troska 
Hematology Research – Stabile 6-13 
Mayo Clinic 
200 First Street SW 
Rochester MN 55905 
Phone: (507) 284-3805 
Email:  pricetroska.tammy@mayo.edu    
 
 


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6.0  
MEASUREMENT OF EFFECT  
 
6.1 
Response to therapy  
 
Response to therapy will be classified as complete response (CR), partial 
response (PR), stable disease (SD), progressive disease (PD), early death, 
or not evaluable. Response to therapy will be determined after cycles 2 and 6 
as outlined in treatment plan.  
 
Patients with a global deterioration of health status requiring permanent 
discontinuation of study treatment (taken off study) without objective evidence 
of disease progression will be counted as progressive disease. Every effort 
should be made to document the objective progression even after 
discontinuation of treatment. Deaths will be counted as treatment failure.  
 
Patients will be analyzed with respect to overall survival (OS) and 
progression-free survival (PFS). Overall survival is defined as time from the 
first chemotherapy administered on trial until death from any cause. For 
subjects who are still alive at the time of the study analysis or are lost to 
follow-up, survival will be censored at the last recorded date that the subject 
was known to be alive. Progression-free survival is defined as time from 
therapy until relapse, progression, or death from any cause. Response will be 
determined by the principal investigator or the co-principal investigators.  
 
CR rate is at the end of 6 cycles of the CHOEP/lenalidomide. 
 
Definitions for clinical response for patients with lymphoma are from the 
Cheson et al. Revised Response Criteria for Malignant Lymphoma27. Lymph 
node measurements should be taken from CT, CT portion of the PET/CT if 
possible, or MRI scans where applicable.  Measurement of lymphadenopathy 
will be determined by adding the sum of the products of the maximal 
perpendicular diameters of measured lesions (SDP).  Measurable extranodal 
disease should be assessed in a manner similar to that for nodal disease. For 
these recommendations, the spleen is considered nodal disease. Disease 
that is only assessable (eg, pleural effusions, bone lesions) will be recorded 
as present or absent only, unless, while an abnormality is still noted by 
imaging studies or physical examination, it is found to be histologically 
negative. 
 
Response is based on both the CT component of PET/CT taking into 
consideration avidity of targets, CT alone, or MRI where applicable.  


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Response criteria, modified from Cheson et al. 2007 27. Peripheral T-cell lymphomas are 
considered FDG avid. 
 
Response 
Category 
Definition 
Nodal Masses 
Spleen, liver 
Bone Marrow 
CR 
Disappearance 
of all evidence of 
disease. 
Mass of any size 
permitted if PET 
negative; 
Deauville 3 or 
less  
 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared 
on repeat biopsy; 
if indeterminate 
by morphology, 
immunohistoche
mistry should be 
negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
50% decrease 
in SPD of up to 6 
largest dominant 
masses; no 
increase in size 
of other nodes 
and 
one or more PET 
positive 
(Deauville 4) at 
previously 
involved site 
50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or spleen 
Irrelevant if 
positive prior to 
therapy; cell type 
should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
PET positive 
(Deauville 4) at 
prior sites of 
disease and no 
new sites on CT 
or PET 
 
 
Relapse/ 
Progressive 
disease 
Any new lesion 
or increase by 
50% of 
previously 
involved sites 
from nadir 
Appearance of a 
new lesion(s) > 
1.5 cm in any 
axis, 50% 
increase from 
nadir in SPD of 
more than one 
node, or 50% 
increase in 
longest diameter 
of a previously 
identified node > 
1 cm in short 
axis. 
The lesions 
referred to above 
are required to 
be PET positive 
(Deauville 5). X 
lesion by 
> 50% increase 
from nadir in the 
SPD of any 
previous lesions 
New or recurrent 
involvement 


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PET/CT are not 
to be considered 
progression 
unless biopsy 
confirmed  
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron 
emission tomography; CT, computed tomography; PR, partial remission; SPD, sum of 
the product of the diameters; SD, stable disease; PD, progressive disease. 
 
 


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6.2 
Complete Response (CR) 
 
6.2.1 Complete disappearance of all detectable clinical evidence of disease 
and definitely disease-related symptoms if present before therapy. 
 
6.2.2 T-cell lymphomas are FDG-avid lymphomas: in patients with no 
pretreatment PET/CT scan or when the PET/CT scan was positive 
before therapy, a post-treatment residual mass of any size is permitted 
as long as it is PET negative (Deauville 3 or less). 
 
6.2.3 The spleen and/or liver, if considered enlarged before therapy on the 
basis of a physical examination, CT scan, or CT portion of the PET/CT 
should not be palpable on physical examination and should be 
considered normal size by imaging studies, and avid nodules related 
to lymphoma should disappear or should acquire a Deauville score of 
3 or less. However, determination of splenic involvement is not always 
reliable because a spleen considered normal in size may still contain 
lymphoma, whereas an enlarged spleen may reflect variations in 
anatomy, blood volume, the use of hematopoietic growth factors, or 
causes other than lymphoma.  Therefore residual splenomegaly if felt 
not to be avid by PET/CT at subsequent response evaluation Similarly, 
other organs considered to be enlarged before therapy due to 
involvement by lymphoma, such as liver and kidneys, must have 
decreased in size. 
 
6.2.4 If the bone marrow was involved by lymphoma before treatment, the 
infiltrate must have cleared on repeat bone marrow biopsy. The biopsy 
sample on which this determination is made must be adequate (with a 
goal of > 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample 
that is negative by immunohistochemistry but that demonstrates a 
small population of clonal lymphocytes by flow cytometry will be 
considered a CR until data become available demonstrating a clear 
difference in patient outcome.  
 
6.3 
Criteria for Partial Response (PR). The designation of PR requires all of the 
following: 
 
6.3.1 At least a 50% decrease in sum of the product of the diameters (SPD) 
of up to six of the largest dominant nodes or nodal masses. These 
nodes or masses should be selected according to all of the following:  
• 
they should be clearly measurable in at least 2 
perpendicular dimensions 
• 
if possible they should be from disparate regions of the body 
• 
they should include mediastinal and retroperitoneal areas of 
disease whenever these sites are involved 
 
 
6.3.2 No increase should be observed in the size of other nodes, liver, or 
spleen. 


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6.3.3 Splenic and hepatic nodules must regress by 50% in their SPD or, for 
single nodules, in the greatest transverse diameter.  
 
6.3.4 With the exception of splenic and hepatic nodules, involvement of 
other organs is usually assessable and no measurable disease should 
be present. 
 
 
6.3.5 Bone marrow assessment is irrelevant for determination of a PR if the 
sample was positive before treatment. However, if positive, the cell 
type should be specified\.Patients who achieve a CR by the above 
criteria, but who have persistent morphologic bone marrow 
involvement will be considered partial responders.  
 
 
When the bone marrow was involved before therapy and a clinical CR 
was achieved, but with no bone marrow assessment after treatment, 
patients should be considered partial responders. 
 
 
6.3.6 No new sites of disease should be observed. 
 
 
6.3.7 For patients with no pretreatment PET/CT scan or if the PET/CT scan 
was positive before therapy, the post-treatment PET/CT should be 
positive in at least one previously involved site and considered a 
Deauville 4. 
 
6.4 
Criteria for Stable Disease (SD) 
6.4.1  A patient is considered to have SD when he or she fails to attain the 
criteria needed for a CR or PR (see above), but does not fulfill those 
for progressive disease (see below).  
6.4.2  The PET should be positive at prior sites of disease with no new areas 
of involvement on the post-treatment PET/CT Deauville 4.  
6.5 
Relapsed Disease (after CR)/Progressive Disease (after PR, SD):  
Lymph nodes should be considered abnormal if the long axis is more than 1.5 
cm regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 
cm, it should only be considered abnormal if its short axis is more than 1.0. 
Lymph nodes 1.0 x 1.0 cm will not be considered as abnormal for relapse 
or progressive disease.  
 
 
6.5.1 Appearance of any new lesion more than 1.5 cm in any axis during or 
at the end of therapy, even if other lesions are decreasing in size. 
Increased FDG uptake in a previously unaffected site should only be 
considered relapsed or progressive disease after confirmation with 
other modalities. In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign. Thus, 
a therapeutic decision should not be made solely on the basis of the 
PET/CT without histologic confirmation. 


UNMC IRB#511-14 Protocol Version 6.1 Dated 01-17-2020  
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6.5.2 At least a 50% increase from nadir in the SPD of any previously 
involved nodes, or in a single involved node, or the size of other 
lesions (eg, splenic or hepatic nodules). To be considered progressive 
disease, a lymph node with a diameter of the short axis of less than 1.0 
cm must increase by 50% and to a size of 1.5 x 1.5 cm or more than 
1.5 cm in the long axis. 
 
 
 
6.5.3   At least a 50% increase in the longest diameter of any single 
previously identified node more than 1 cm in its short axis.  
 
 
6.5.4   Lesions should be PET positive if observed in a typical FDG-avid 
lymphoma or the lesion was PET positive before therapy unless the 
lesion is too small to be detected with current PET/CT systems (< 1.5 
cm in its long axis by CT).  
 
 
 
 
 


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7.0  
STUDY PARAMETERS - Test Schedule for both Phase 1 and 2 patients 
  
 
Active Monitoring Phase 
 
 
Combination treatment 
Post-transplant or during 
maintenance therapy 
Tests and procedures 
≤ 14 days 
prior to 
day 1 of 
cycle 1 
Prior to ( -2 days) 
subsequent 
treatment (cycles 2-
6) 
During 
interval 
between 
cycles 
After completion of 
therapy (4-6 
weeks after  day 1 
of cycle 6) 
Every 3 months for year 117 
History and exam, weight,  
X 
X 
 
X 
X 
Adverse event assessment 
X 
X 
 
X 
X 
Height, Karnofsky Scale PS 
X 
 
 
 
 
Registered in the Revlimid 
REMS™  program 
X14 
X14 
X14 
X14 
Monthly14 
Serum or urine pregnancy 
test1 
X1 
X1 
X1 
X1 
 
Tumor tissue sample for 
confirmation of diagnosis 
X2 
 
 
 
 
Hematology group 
 CBC (HgB, WBC, 
Differential, PLT) 
X 
X 
Weekly 
X 
X 
Chemistry group 
Total bilirubin, AST, Alkaline 
Phosphatase, LDH, 
Creatinine, Sodium, 
Potassium, Calcium 
X 
X 
 
X 
X 
Direct bilirubin, PT/INR4, PTT 
X 
 
 
 
 
HIV HBV, HCV screen 
X3 
 
 
 
 
Tumor 
Measurement/Evaluation of 
indicator lesions (CT chest, 
X12 
Before cycle 3 
 
X 
X16 


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Active Monitoring Phase 
 
 
Combination treatment 
Post-transplant or during 
maintenance therapy 
Tests and procedures 
≤ 14 days 
prior to 
day 1 of 
cycle 1 
Prior to ( -2 days) 
subsequent 
treatment (cycles 2-
6) 
During 
interval 
between 
cycles 
After completion of 
therapy (4-6 
weeks after  day 1 
of cycle 6) 
Every 3 months for year 117 
abdomen, pelvis; other CT 
and/or MRI when indicated)10 
PET/CT scan 
X15 
Before cycle 311 
 
X5 
 
Bone marrow aspirate and 
biopsy (unilateral or bilateral) 
X13 
Before cycle 36 
 
X6 
 
Electrocardiogram 
X15 
 
 
 
 
Left ventricular function 
measurement 
X7, 15 
 
 
 
 
Cerebrospinal fluid analysis 
X8 
 
 
 
 
Research blood samples R 
XR 
 
 
XR 
 
 
1.  Pregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) is a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Screening pregnancy tests must 
occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled 
within 7 days as required by Revlimid REMS™ ).  Per protocol inclusion criteria, screening pregnancy test must be serum; all 
other testing can be serum or urine. Female subjects must either commit to continued abstinence from heterosexual intercourse 
or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE 
SAME TIME, at least 28 days before she starts taking lenalidomide.  FCBP must also agree to ongoing pregnancy testing.  Men 
must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy (see 
Appendix G: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).  
2.  Central review of pathology is required for confirmation of diagnosis. Completion of central pathology review is not required prior 
to registration for patients; however materials for central review must be submitted within 1 month after registration.  


UNMC IRB#511-14 Protocol Version 6.1 Dated 01-17-2020  
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3.   Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV; see eligibility) or 
hepatitis C virus (HCV).  Actual testing is not mandatory for participation in this trial. Patients who are seropositive because of 
hepatitis B virus vaccine are eligible. 
4.  PT/INR assessment frequency for patient on coumadin per investigator discretion to keep in therapeutic range 
5.  If positive after the completion of cycle 6, a biopsy of PET positive area may be done at MD discretion.  
6.  Repeat bone marrow only required to confirm CR if initial bone marrow or post cycle 2 bone marrow was positive.  
7.  MUGA or ECHO. 
8.  A lumbar puncture and cytologic examination of the cerebrospinal fluid is not required, but should be performed if clinically 
indicated. 
9.   Pathology material: H&E stain and IHC slides or a representative FFPE tissue block from initial diagnosis 
 
. Please NOTE: the diagnostic H&E slide and IHC slides will be returned after review.  
.  
10. Measurements can be done off the CT images of a PET/CT; however a dedicated CT or MRI; must be done by dedicated CT if 
that demonstrates the lesion more clearly.  The image number should be included with the measurements. If there are questions, 
call the UNMC collaborative investigator. 
11. PET/CT is mandatory pre- and post-treatment.  It is optional after 2 cycles; however, if PET/CT is used for the measureable 
lesion then it should be strongly considered before cycle 3.   
12. Imaging must be done ≤ 6 weeks prior to study registration. 
13. Bone marrow must be done ≤ 6 weeks prior to study registration. 
14. For patients receiving maintenance lenalidomide - All unused lenalidomide must be returned as instructed through the Revlimid 
REMS™  program. 
15. Must be done ≤ 28 days prior to study registration. 
16. A PET/CT scan should be considered a D+100 post autologous transplant.  If PET negative CR then CT may be substituted per 
investigator choice.  The interval should remain every 3 months (+/- 14 days until 1 year post transplant.  In patients who do not 
undergo autologous transplant a PET/CT if not achieved a PET/CT CR or CT can be substituted for PET negative CR should  be 
done every 3 months (+/-14 days) for 1 year after completing the 6 cycles of CHOEP plus lenalidomide. Imaging thereafter is at 
the discretion of the treating physician. 
17. Follow up in year 2 and beyond is as per institutional guidelines. 
R.  Research funded study.  Please note, if a subject is unable to complete study treatment through cycle 6, then the research 
sample after completion of cycle 6 would not be collected. 
 
 


 
8.0  
DRUG FORMULATION AND PROCUREMENT 
 
8.1  
Lenalidomide (Revlimid®, CC-5013, CDC-501) 
 
Please consult the most current Investigator’s Brochure and package insert 
for complete drug information. 
 
8.11  Background: Lenalidomide has a wide range of effects, including the 
inhibition of hematopoietic tumor cell proliferation, the enhancement of 
T cells and natural killer (NK) cell activity, the modulation of stem cell 
differentiation, the inhibition of angiogenesis, and the inhibition of 
inflammation. 
 
8.12  Formulation: For clinical study, lenalidomide is provided as 1.25-, 2.5-, 
5-, 10-, 15-, 20-, and 25-mg capsules for oral administration. Each 
capsule contains lenalidomide as the active ingredient and the 
following inactive ingredients: anhydrous lactose, microcrystalline 
cellulose, croscarmellose sodium, and magnesium stearate.  
 
Placebo capsules for the 1.25-, 2.5-, 5-, 10-, 15-, 20-, and 25-mg 
lenalidomide capsules are available for use in blinded studies. Each 
placebo capsule visually matches the drug product. 
 
The lenalidomide and placebo capsules are supplied in push-through 
blister foil or tamper-evident, child-resistant, opaque, high-density 
polyethylene (HDPE) containers with HDPE caps. 
 
8.13  Preparation and storage: Lenalidomide should be stored at room 
temperature, between 59 and 86ºF (15-30ºC). The drug should be 
stored away from direct sunlight. 
 
8.14  Administration: Capsules are administered by mouth daily with water. 
Patients should not break, chew or open the capsules. 
 
8.15  Pharmacokinetic information: 
a) Absorption – Lenalidomide is rapidly absorbed following oral 
administration to subjects with multiple myeloma or MDS, with 
maximum plasma concentrations occurring between 0.5 and 6 hours 
post-dose. Co-administration with a high-fat and high-calorie meal in 
healthy subjects reduced the extent of absorption, resulting in an 
approximately 20% decrease in AUC and 50% decrease in Cmax in 
plasma. In the pivotal MM and MDS registration trials where the 
efficacy and safety were established for lenalidomide, the drug was 
administered without regard to food intake. Thus, lenalidomide can be 
administered with or without food. Multiple dosing (up to 100 mg BID) 
did not cause marked drug accumulation. Systemic exposure (AUC) of 
lenalidomide in MM and MDS patients with normal or mild renal 
function (CLcr ≥ 60 mL/min) is approximately 60% higher as compared 
to young healthy male subjects. 
b) Distribution – In vitro (14C)-lenalidomide binding to plasma proteins 


UNMC IRB#511-14 Protocol Version 6.1 Dated 01-17-2020  
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binding to plasma proteins is approximately 30%. 
c) Metabolism – Lenalidomide undergoes limited metabolism. 
Unchanged lenalidomide is the predominant circulating component in 
humans. Two identified metabolites are hydroxy-lenalidomide and N-
acetyl-lenalidomide; each constitutes less than 5% of parent levels in 
circulation. 
d) Excretion – Elimination is primarily renal. Approximately 65% to 
85% of lenalidomide is eliminated unchanged through urinary 
excretion in subjects with normal renal function. The half-life of 
elimination is approximately 3 to 4 hours at the clinically relevant 
doses (5 to 50 mg/day). Steady-state levels are achieved within 4 
days. 
 
8.16  Potential Drug Interactions: Results from human in vitro metabolism 
studies and nonclinical studies show that lenalidomide is neither 
metabolized by nor inhibits or induces the cytochrome P450 pathway 
suggesting that lenalidomide is not likely to cause or be subject to 
P450-based metabolic drug interactions in man. In vitro studies 
demonstrate that lenalidomide is not a substrate of multidrug 
resistance proteins MRP1, MRP2, or MRP3 or a substrate of organic 
anion and cation uptake transporters OAT1, OAT3, OATP1B1 or 
OCT1. In vitro, lenalidomide is a substrate, but is not an inhibitor of P-
glycoprotein (Pgp). Patients taking concomitant therapies such as 
erythropoietin stimulating agents or estrogen containing therapies may 
have an increased risk of venous thromboembolism (VTE). Periodic 
monitoring of digoxin plasma levels is recommended due to increased 
Cmax and AUC with concomitant lenalidomide therapy. Close 
monitoring of PT and INR is recommended in multiple myeloma 
patients taking concomitant warfarin. 
 
8.17  Known potential toxicities: 
 
Pregnancy Warning: Lenalidomide is structurally related to 
thalidomide, a known human teratogen. Therefore, in an effort to 
prevent to the greatest extent possible any chance of fetal exposure, 
lenalidomide is available through a controlled distribution program, 
specifically a pregnancy prevention program called REMS™ . It is 
contraindicated in women who are or may become pregnant. Female 
subjects of childbearing potential are required to submit to regular 
pregnancy testing, and to agree to use effective forms of birth control 
as outlined in study protocols. Male subjects, even those who have 
had a vasectomy, must agree to use a condom during sexual contact 
with a pregnant woman or a woman who can become pregnant. 
 
Very Common AEs (≥ 10%): peripheral edema, fatigue, insomnia, 
fever, dizziness, headache, pruritus, rash, dry skin, hyperglycemia, 
hypokalemia, diarrhea, constipation, nausea, weight loss, dyspepsia, 
anorexia, taste perversion, abdominal pain, urinary tract infection, 
thrombocytopenia, neutropenia, anemia, myelosuppression, muscle 
cramp, weakness, arthralgia, back pain, tremor, paresthesia, limb 


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pain, blurred vision, naso-pharyngitis, cough, dyspnea, pharyngitis, 
epistaxis, upper respiratory infection, pneumonia. 
Common (≥ 1% and < 10%): edema, deep vein thrombosis, 
hypertension, chest pain, palpitation, atrial fibrillation, syncope, 
hypoesthesia, pain, depression, bruising, cellulitis, erythema, 
hypothyroidism, hypomagnesemia, hypocalcemia, vomiting, 
xerostomia, loose stools, dysuria, leukopenia, febrile neutropenia, 
granulocytopenia, lymphopenia, pancytopenia, ALT increased, 
myalgia, rigors, peripheral neuropathy, sinusitis, rhinitis, bronchitis, 
pulmonary embolism, respiratory distress, hypoxia, pleural effusion, 
pneumonitis, pulmonary hypertension, night sweats, diaphoresis, and 
sepsis. 
 
Uncommon, limited to important or life-threatening (< 1%): acute 
febrile neutropenia, dermatitis, acute leukemia, acute myeloid 
leukemia (AML), adrenal insufficiency, angioedema, atrial flutter, 
azotemia, Basedow’s disease, biliary obstruction, blindness, bone 
marrow depression, bradycardia, brain edema, cardiac failure, 
cardiogenic shock, cardiomyopathy, cardiopulmonary arrest, 
cerebrovascular accident, CHF, cholecystitis, chondrocalcinosis, 
chronic obstructive airway disease, circulatory collapse, coagulopathy, 
colonic polyp, dehydration, delirium, diabetes mellitus, diabetic 
ketoacidosis, diverticulitis, dysphagia, encephalitis, erythema 
multiforme, Fanconi syndrome, gout, hematuria, hemolysis, hemolytic 
anemia, hemorrhage, hepatic failure, hepatitis, herpes virus infection, 
hyperbilirubinemia, hypernatremia, hypersensitivity, hypoglycemia, 
hypotension, infection, interstitial lung disease, intestinal perforation, 
intracranial hemorrhage, ischemia, ischemic colitis, 
leukoencephalopathy, liver failure, abnormal liver function tests, lung 
cancer, lung infiltration, lymphoma, MI, myopathy, neutropenic sepsis, 
orthostatic hypotension, pancreatitis, peripheral ischemia, 
pseudomembranous colitis, pulmonary edema, refractory anemia, 
renal calculus, renal failure, renal mass, renal tubular necrosis, 
respiratory failure, secondary primary malignancies (AML, HL), septic 
shock, serum creatinine increased, skin desquamation, small bowel 
obstruction, spinal cord compression, splenic infarction, Stevens-
Johnson syndrome, stomatitis, supraventricular arrhythmia, 
tachyarrhythmia, thrombophlebitis, toxic epidermal necrolysis, troponin 
I increased, tumor lysis syndrome (TLS), tumor flare reaction (TFR), 
urinary retention, urosepsis, urticaria, ventricular dysfunction, and 
wheezing. 
 
The following additional adverse reactions have been reported in 
Celgene sponsored clinical studies and are considered by the 
company to be possibly related to the administration of lenalidomide: 
granulocytopenia, cataract, vision blurred, abdominal pain upper, dry 
mouth, gastrointestinal motility disorder, toothache, fall, herpes 
simplex, influenza, rhinitis, hyperuricemia, hypophosphatemia, iron 
overload, musculoskeletal pain, dysgeusia, headache, paresthesia, 
dry skin, hyperhidrosis, and pruritus. 


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Please refer to the Investigator Brochure for a more comprehensive 
list of treatment-emergent adverse events. 
 
8.18  Drug procurement:  
 
Lenalidomide (Revlimid®) will be provided to research subjects for the 
duration of their participation in this trial at no charge to them or their 
insurance providers.  Lenalidomide will be provided in accordance with 
the  Celgene Corporation’s Revlimid REMS™ program.  Per standard 
Revlimid REMS™  program requirements, all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial, and 
all research subjects enrolled into this trial, must be registered in, and 
must comply with, all requirements of the Revlimid REMS™  program. 
Only enough lenalidomide for one cycle of therapy will be 
supplied to the patient each cycle. 
Any unused lenalidomide should be returned for disposition in 
accordance with the Revlimid REMS™ program. 
 
Pregnancy Testing: Females must follow pregnancy testing 
requirements as outlined in the Revlimid REMS™  program material. 
 
8.19  Nursing Guidelines: 
8.191  Myelosuppression is dose-dependent and reversible with 
treatment interruption and/or dose reduction. Monitor CBC 
w/diff regularly. Instruct patient to report any unusual bruising 
or bleeding (thrombocytopenia); signs and symptoms of 
infection (neutropenia); and energy conserving lifestyle 
(anemia). 
 
8.192  Lenalidomide can have thrombotic adverse events (i.e DVT 
and PE). Instruct patient to report any limb swelling or pain, and 
to seek medical attention for shortness of breath or chest pain. 
 
8.193  Because of the potential for birth defects patients should be 
instructed in effective methods of birth control. Female patients 
should use 2 forms of birth control during treatment and for 4 
weeks after discontinuing therapy. Males must be instructed to 
use a latex condom during any sexual contact with a woman of 
child bearing potential (even if they have had a vasectomy), 
because it is unknown if lenalidomide is present in semen. 
 
8.194  Patents may experience pruritus, rash and dry skin. Because of 
the rare risk of Steven’s Johnson Syndrome, patients should 
immediately report any rash to their provider. 
8.195  Drug may cause hyperglycemia. Patients with diabetes or 
impaired fasting glucose may need to have their glucose levels 
monitored more closely. 
 
8.196  Gastrointestinal side effects (diarrhea, constipation, nausea, 


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dyspepsia, anorexia, etc) are commonly seen. Manage patent 
symptomatically and monitor for effectiveness. 
 
8.197  Patients may experience myalgias, arthralgias, and other 
generalized pain. Administer analgesics as ordered and 
monitor for their effectiveness. 
 
8.198  Upper respiratory symptoms (naso-pharyngitis, cough, 
epistaxis, etc.) can be seen. Manage symptomatically and 
monitor for effectiveness. 
 
8.2  
Cyclophosphamide (Cytoxan, CTX, Neosar®) 
 
8.21  Preparation and storage: Injectable powder is stored at room 
temperature. The temperature is not to exceed 90°F. Reconstituted 
parenteral solutions are stable for 24 hours at room temperature or six 
days if refrigerated. Dissolve the 100 mg, 200 mg, 500 mg, 1 gm, and 
2 gm vials in 5, 10, 25, 50, and 100 mL of sterile water, respectively, 
resulting in a solution of 20 mg/mL. Shake vials vigorously and warm 
slightly in lukewarm water to facilitate the dissolving of crystals. The 
lyophilized form is more easily solubilized. Cyclophosphamide should 
be administered according to standard CHOEP regimen. 
 
8.22  Known potential toxicities: Myelosuppression, hemorrhagic cystitis, 
alopecia, nausea, and vomiting are all common, SIADH is dose–
related (more common with single doses > 2 gm/m2), cardiac (if dose 
level 2 gm/m2). Secondary leukemia, liver dysfunction, headaches, 
dizziness, interstitial pulmonary fibrosis, cardiac necrosis may occur. 
Anaphylaxis is rare. 
 
8.23  Drug procurement: Commercially available for injection in 100 mg, 200 
mg, 500 mg, 1 gm and 2 gm vials. 
 
8.24 Nursing guidelines 
8.241  Leukopenia nadir occurs 8-14 days after administration and 
recovery is usually 18-25 days. Monitor CBC. 
 
8.242  Instruct patient to drink 2-3 liters of fluid per day for 2-3 days 
following treatment and to void frequently, not greater than 
every three hours to facilitate emptying the bladder of drug. 
 
8.243  Instruct patient to report any urinary urgency, frequency, 
dysuria, or hematuria. 
 
8.244  Advise patient of possible strong metallic taste associated with 
Cytoxan and suggest hard candy with a strong flavor 
(cinnamon, peppermint) to alleviate it. 
 
8.245  Administer antiemetics as necessary to minimize nausea and 
vomiting, which usually occurs 6-8 hours after administration. 


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8.246  Report and record any complaint of lightheadedness, facial 
“heat sensation”, or diaphoresis during administration. 
 
8.247  Corticosteroids, phenothiazine, imipramine, and allopurinol may 
inhibit Cytoxan metabolism and modify its effect. They may 
also increase bone marrow suppression.  
 
8.3 
Etoposide (VePesid®, Toposar®, VP16) 
 
8.31 
Background: Etoposide has been shown to delay transit of cells 
through the S phase and arrest cells in late S or early G2 phase. The 
drug may inhibit mitochondrial transport at the NADH dehydrogenase 
level or inhibit uptake of nucleosides into HeLa cells. It is a 
topoisomerase II inhibitor and appears to cause DNA strand breaks. 
Etoposide does not inhibit microtubular assembly. 
 
8.32 
Formulation: Commercially available for injection as: Injection, 
solution: 20 mg/mL (5 mL, 25 mL, 50 mL)  
 
8.33 
Preparation, storage, and stability: Refer to package insert for 
complete preparation and dispensing instructions. Store intact vials at 
room temperature of 25ºC (77ºF); do not freeze. Protect from light. 
Etoposide should be diluted to a concentration of 0.2-0.4 mg/mL in 
D5W or NS for administration. Diluted solutions have concentration-
dependent stability; more concentrated solutions have shorter stability 
times. Precipitation may occur with concentrations >0.4 mg/mL. 
Following dilution 0.9% Sodium Chloride or D5W to concentrations of 
0.2-04 mg/mL, then drug is chemically stable for 96 and 24 hours at 
room temperature respectively.  
 
8.34 
Administration:  Refer to the treatment section for specific 
administration instructions. Administer standard doses over at least 
30-60 minutes to minimize the risk of hypotension. 
 
8.35 
Pharmacokinetic information: 
Distribution: Vd: 7-171 L/m2; poor penetration across the blood-
brain barrier; CSF concentrations <5% of plasma concentrations 
Protein binding: 94% to 98% 
Metabolism: Hepatic via CYP3A4 and 3A5, to various 
metabolites. 
Half-life elimination: Terminal 4-11 hours 
Excretion: Urine (56%; 45% as unchanged drug) within 120 
hours; feces (44%) within 120 hours 
 
8.36 
Potential Drug Interactions: 
Metabolism/Transport Effects: Substrate of  CYP1A2 (minor), 
CYP2E1 (minor), CYP3A4 (major), P-glycoprotein; Inhibits 
CYP2C9 (weak), 3A4 (weak)  


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Ethanol/Herb/Nutraceutical Interactions: Avoid ethanol (may 
increase GI irritation). Avoid concurrent St John’s wort; may 
decrease etoposide levels. 
 
8.37 
Known potential adverse events: Consult the package insert for 
the most current and complete information.  
U.S. boxed warning: Severe dose-limiting and dose-related 
myelosuppression with resulting infection or bleeding may occur. 
 
Common known potential toxicities, > 10%:   
Dermatologic: Alopecia 
Gastrointestinal: Nausea/vomiting, anorexia, diarrhea 
Hematologic:  Leukopenia, thrombocytopenia, anemia 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Hypotension 
Gastrointestinal: Stomatitis, abdominal pain 
Hepatic: Hepatic toxicity 
Neuromuscular & skeletal: Peripheral neuropathy 
Miscellaneous: Anaphylactic-like reaction 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Amenorrhea, blindness (transient/cortical), cyanosis, 
extravasation, facial swelling, hypersensitivity, hypersensitivity-
associated apnea, interstitial pneumonitis, laryngospasm, 
maculopapular rash, metabolic acidosis, MI, mucositis, optic 
neuritis, perivasculitis, pruritus, pulmonary fibrosis, radiation-
recall dermatitis, rash, seizure, Stevens-Johnson syndrome, 
tongue swelling, toxic epidermal necrolysis, weakness 
 
8.38 
Drug procurement:  Commercial supplies. Pharmacies or clinics 
shall obtain supplies from normal commercial supply chain or 
wholesaler. 
 
 
8.39 
Nursing guidelines 
 
 
 
8.391 
Monitor CBC.  Neutropenia may be severe.  Instruct 
patients to report any sign/symptoms of infection to the 
health care team. 
 
 
 
 
8.392 
Rare myocardial infarctions have been reported in 
patients who have received prior mediastinal XRT.  
Instruct patient to report any chest pain, or racing of 
the pulse to the health care team immediately.  
 
 
 
 
8.393 
Advise patient of possible mild, reversible alopecia. 
 
 
 
 
8.394 
A rapid infusion may cause hypotension and/or allergic 
reaction; administer medication over 30-60 minutes 
and monitor VS during administration. 


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8.395 
Drug is a radiosensitizer and irritant.  Assess IV 
patency before and throughout infusion.  Patients who 
have received prior radiation may experience radiation 
recall.  Assess skin in these areas and monitor closely.  
Instruct patient to report any rash or skin changes to 
the health care team immediately. 
 
 
 
 
8.396 
Anaphylaxis is rare but has been observed.  
Symptoms may include hypotension, bronchospasm, 
fever, or chills.  Have the anaphylaxis tray available. 
 
 
 
 
8.397 
Nausea and vomiting are usually mild.  However the 
incidence is increased with oral administration.  Pre-
medicate with antiemetics as ordered and monitor for 
their effectiveness.  
 
 
 
 
8.398 
Instruct patient in importance of maintaining adequate 
hydration to avoid hyperuricemia. 
 
 
 
 
8.399a Monitor liver function tests. 
 
 
 
 
8.399b Etoposide solution is oil based and settles to bottom of 
bag or drip chamber.  Be sure to agitate bag to avoid 
reaction to concentrated solution.  Reaction would 
include flushing, shortness of breath, back pain, and 
anxiety. 
 
 
 
 
8.399c Advise patient that facial flushing is common and may 
occur even after administration. 
 
 
 
 
8.399d Monitor INR closely in patients on warfarin therapy, as 
etoposide may increase prothrombin (PT) time. 
 
8.399e May increase the toxicity of methotrexate or 
cyclosporine (cytotoxicity) when given concurrently. 
 
8.4  
Doxorubicin (ADR) 
8.41  Preparation and storage: Doxorubicin RDF intact vials are stable 
protected from light at room temperature. Doxorubicin PFS vials must 
be refrigerated. 
 
Reconstituted solutions are stable for 24 hours at room temperature 
and 48 hours under refrigeration. The doxorubicin RDF 150 mg 
multidose vial is stable after reconstitution for 7 days at room 
temperatures or 15 days if refrigerated and protected from sunlight. It 
is not necessary to further dilute. This avoids long infusion times and 
the risk of extravasation. Dilution takes place when administered 
through a rapidly flowing IV line. Doxorubicin should be administered 
according to standard R-CHOEP regimen. 


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8.42  Known potential toxicities: 
 
8.421  Hematologic: Leukopenia (dose-limiting), also 
thrombocytopenia and anemia. This treatment nadir is usually 
10-14 days with recovery in 21 days. 
 
8.422  Dermatologic: Alopecia, usually complete, hyperpigmentation 
of nail beds and dermal creases, radiation recall. 
 
8.423  Gastrointestinal: Nausea and vomiting, sometimes severe, 
anorexia, diarrhea, mucositis. 
 
8.424 Cardiovascular: Arrhythmias, thrombosis/embolism, ECG 
changes, rarely sudden death. Congestive heart failure due to 
cardiomyopathy related to total cumulative dose, risk is greater 
with doses greater than 550 mg/m2, mediastinal irradiation, 
preexisting cardiac disease, advanced age, risk is reduced with 
weekly or continuous infusion regimens. 
 
8.425 Other: Red discoloration of urine, fever, anaphylactoid reaction, 
may enhance cyclophosphamide cystitis or mercaptopurine 
hepatotoxicity, secondary AML/MDS (risk is uncommon, but 
may be increased when given in combination with an alkylating 
agent, especially if one or both are given at higher than 
standard doses. 
 
8.426  Local effects: Vesicant if extravasated; flush along vein, facial 
flush. 
 
8.43  Availability: Commercially available as powder for injection in 10, 20, 
50, 100, 150 mg vials, and as 2 mg/ml solution for injection in 10, 20, 
50, and 200 mg vials. 
 
8.44  Nursing guidelines:  
.441  Check CBC and platelet counts. Monitor for signs of infection, 
bleeding, and anemia. 
 
8.442  Advise patient that their urine may turn pink in color for 
approximately 24 hours after administration of the drug. 
8.443  Doxorubicin is a vesicant. Check IV potency before and 
frequently during administration. If extravasation occurs, refer 
to institutional extravasation policy. 
 
8.444  Hair loss occurs 2-4 weeks after initial injection and can be 
complete. Regrowth begins 2-3 months after discontinuation. 
 
8.445  Beware of doxorubicin “flare” that can occur during 
administration. The reaction consists of an erythematous streak 
up the vein receiving the infusion. Adjacent veins may also 


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demonstrate red streaks. Urticaria and pruritus can be 
associated with the reaction. The use of corticosteroids and/or 
antihistamines has been helpful. 
 
8.446  Administer antiemetics to minimize nausea and vomiting. 
 
8.447  Assess for alterations in mucous membranes. Stomatitis occurs 
within 7-10 days after injection. It begins with burning sensation 
and can progress to ulceration, which can last 3 days. Carafate 
slurry may be useful. Adequate nutritional counseling is 
important. Topical anesthetics such as viscous xylocaine can 
be used symptomatically. 
 
8.448  Advise patient that there is often significant malaise and fatigue 
1-2 weeks after injection. 
 
8.449a Doxorubicin may potentiate toxicity of other antineoplastic 
therapies. It has reportedly exacerbated cyclophosphamide- 
(Cytoxan, CTX) induced hemorrhagic cystitis. 
 
8.449b Assess heart and lung sounds. Monitor vital signs (resting 
pulse). Be alert to early signs of cardiotoxicity, i.e., dyspnea, 
steady weight gain, nonproductive cough, arrhythmias, 
tachycardia, and pulmonary rales. 
 
8.449c Document cumulative dose, which should not exceed 
maximum cumulative dose. 
 
8.449d Advise patient of probable facial flushing for several hours after 
drug administration, especially if given quickly. 
 
8.5  
Vincristine (VCR) 
 
8.51  Preparation and storage: Vincristine is stored in the refrigerator. No 
preparation is required. Vincristine should be administered according 
to the standard CHOEP regimen.  
 
 
 
8.52 Known potential toxicities: 
 
8.521  Hematologic: Rarely leukopenia (mild), rarely 
thrombocytopenia, and anemia. 
 
8.522 Dermatologic: Alopecia, skin and soft tissue damage if 
extravasated (the manufacturer recommends subcutaneous 
injection of hyaluronidase and application of heat to help 
disperse the drug), rash. 
 
8.523  Gastrointestinal: Nausea, rarely vomiting, constipation, 


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abdominal cramps, anorexia, and diarrhea. Fatal ascending 
paralysis follows intrathecal administration. 
 
8.524  Hepatic: Elevation of AST and ALT (mild and transient). 
 
8.525  Neurologic: Peripheral neuropathy (loss of deep tendon 
reflexes, paresthesias, paralysis), autonomic neuropathy 
(constipation, paralytic ileus, urinary retention, orthostasis), 
ataxia, myalgias, cortical blindness, headache, seizures. 
 
8.526  Pulmonary: Bronchospasm (acute shortness of breath), more 
common when administered with mitomycin. 
 
8.527  Ocular: Diplopia, ptosis, photophobia, cortical blindness (see 
neurologic), and optic atrophy. 
 
8.528  Other: Severe pain in the jaw, pharynx, bones, back, and limbs 
following injection, syndrome of inappropriate antidiuretic 
hormone (SIADH), fever, rarely pancreatitis. 
 
8.529  Cardiovascular: Thrombosis/embolism. 
 
8.53  Availability: Commercially available in a concentration of 1 mg/ml in 1, 
2, and 5 mg vials and 1 mg and 2 mg syringes. 
 
8.54 Nursing guidelines: 
8.541  Check IV patency before and frequently during administration. 
Vincristine is a vesicant. If extravasation occurs, refer to 
agency extravasation policy. 
 
8.542  Evaluate the patient for numbness and tingling in fingertips 
and toes, clumsiness of hands, and difficulty walking. 
 
8.543  Monitor bowel function and encourage use of stool softeners. 
 
8.544  Symptoms of cranial nerve neuropathy may develop several 
weeks after drug administration and take 10–12 months to 
resolve. 
8.6  
Prednisone (PRED) 
 
8.61 
 Preparation and storage: The drug is stored at room temperature in a 
dry place.  
 
8.62 Known potential toxicities: 
 
8.621  Hematologic: Leukocytosis. 
 
8.622  Gastrointestinal: Nausea, vomiting, anorexia, increased 
appetite and weight gain, peptic ulcer. 
 


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8.623  Dermatologic: Rash, skin atrophy, facial hair growth, acne, 
facial erythema, and ecchymosis. 
 
8.624 Genitourinary: Menstrual changes (amenorrhea, menstrual 
irregularities) 
 
8.625  Neurologic: Insomnia, muscle weakness, euphoria, psychosis, 
depression, headache, vertigo, and seizures. 
 
8.626 Cardiovascular: Fluid retention and edema, hypertension, 
hyperkalemia. 
 
8.627  Ocular: Cataracts, increased intraocular pressure, and 
exophthalmos. 
 
8.628  Metabolic: Hyperglycemia decreased glucose tolerance, 
aggravation or precipitation of diabetes mellitus, adrenal 
suppression, and cushingoid syndrome. 
 
8.629  Other: Osteoporosis (and resulting back pain), serious 
infections including herpes zoster, varicella zoster, fungal 
infections, pneumocystis carinii, tuberculosis, muscle wasting. 
 
8.63  Availability: Commercially available in 1, 2.5, 5, 10, 20, 25, and 50 mg 
tablets. Vincristine is also available as 1 mg/ml oral solution and syrup, 
and as a 5 mg/ml oral solution. 
 
8.64 Nursing guidelines: 
8.641  Instruct patient to report any abdominal pain, GI bleeding (i.e., 
tarry stools, vomiting coffee-ground material, etc.) to health 
care team immediately since active peptic ulceration is a 
toxicity that requires dose modification. Antacid therapy may be 
employed. 
 
8.642 Instruct patient to take prednisone after and close to meals. To 
prevent sleep disruption and restlessness, avoid taking 
prednisone at bedtime. A mild sedative may be needed. 
8.643  Monitor CBC and glucose levels. 
 
8.644  Educate patient concerning potential mood changes. 
 
8.645  Gradual tapering of doses should be employed after long-term 
use.  
 
9.0  
TOXICITY REPORTING GUIDELINES  
 
The reporting is only for lenalidomide-CHOEP “study medication,” until 30 days after 
last administration of study medication.  
 
No transplant related AE’s will be recorded or reported.  


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NOTE: Problems related to insurance coverage for UNMC potential subjects or 
enrolled subjects will be reported to the IRB as they are encountered.  
 
This protocol will comply with monitoring and adverse event reporting requirements 
of the UNMC Fred & Pamela Buffett Cancer Center Data Monitoring plan. The 
protocol will adhere to the institutional and FDA guidelines for the toxicity reporting. 
 
All patients will be closely followed for toxicity from the time of informed consent until 
30 days after last administration of study medication. Adverse event and serious 
adverse events will be followed until baseline or ≤ grade 1 levels. Toxicity will be 
assessed using the revised NCI CTCAE version 4.02.  
 
All adverse events will be followed to a satisfactory conclusion. Serious adverse 
events should be followed until resolution, death, or until no further improvement is 
reasonably expected. Deaths occurring within 30 days of study treatment regardless 
of relationship will be reported to the UNMC IRB and UNMC DSMC. 
 
In addition to complying with all applicable regulatory reporting laws and regulations, 
all serious adverse events and toxicities will be reported to the University of 
Nebraska Medical Center, Institutional Review Board (IRB), participating sites own 
IRB and Fred & Pamela Buffett Cancer Center Data and Safety Monitoring 
Committee (DSMC). 
 
Definitions:  
Adverse Event  
An adverse event (AE) is defined as any untoward medical occurrence in a subject 
or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not the event is considered causally 
related to the use of the product.  
 
An elective surgery or procedure that is scheduled to occur during a study will not be 
considered an adverse event if the surgery or procedure is being performed for a 
pre-existing condition and the surgery or procedure has been planned before study 
entry. However, if the pre-existing condition deteriorates unexpectedly during the 
study (e.g., the surgery is performed earlier than planned), then the deterioration of 
the condition for which the elective surgery or procedure is being done will be 
considered an adverse event.  
 
An adverse event can result from use of the drug as stipulated in the protocol or 
labeling, as well as from accidental or intentional overdose, drug abuse, or drug 
withdrawal. Any worsening of a pre-existing condition or illness is considered an 
adverse event. Laboratory abnormalities and changes in vital signs are considered 
to be adverse events if they result in discontinuation from the study, necessitate 
therapeutic medical intervention, meet protocol specific criteria (see Section 5.0, 
Treatment Plan) and/or if the investigator considers them to be adverse events. In 
general, if a laboratory abnormality or change in vital sign is associated with a 


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specific diagnosis that is being reported concurrently as an adverse event (e.g. 
elevated creatinine with renal failure or sinus tachycardia in febrile neutropenia) the 
findings that support the diagnosis do not need to be reported as separate adverse 
events unless the investigator feels it is appropriate.  
 
Treatment-emergent Adverse Event  
Treatment-emergent adverse event is defined as any adverse event with onset or 
worsening from the time that the first dose of study drug is administered until 30 
days after the final dose of study drug is administered.  
 
Unexpected Adverse Event  
An unexpected adverse event is any adverse drug event that is not listed in the 
current labeling/Investigator’s Brochure. This includes events that may be 
symptomatically and pathophysiologically related to an event listed in the labeling, 
but differ from the labeled event because of greater severity or specificity. For 
example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the labeling only referred to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the labeling only listed cerebral 
vascular accidents. “Unexpected,” as used in this definition, refers to an adverse 
drug experience that has not been previously observed (i.e., included in the labeling) 
rather than from the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product.  
 
Serious Adverse Event  
A serious adverse event is one that at any dose (including overdose) and regardless 
of causality that:  
• 
Results in death  
• 
Is life-threatening1  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity2  
• 
Is a congenital anomaly or birth defect  
• 
Is an important medical event3  
• 
Pregnancy  
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 
expedited reporting is appropriate in situations where none of the outcomes 
listed above occurred. Important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed 
in the definition above should also usually be considered serious. Examples 
of such events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or 


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drug abuse. A new diagnosis of cancer during the course of a treatment 
should be considered as medically important. 
 
9.1  
Adverse Event Reporting and Definitions Per University of Nebraska 
Medical Center, IRB and Fred & Pamela Buffett Cancer Center Data and 
Safety Monitoring Committee (DSMC) and Celgene Drug Safety and 
Surveillance 
This protocol will adhere to all institutional guidelines for adverse event 
reporting. Adverse events will be evaluated using the NCI Common 
Terminology Criteria for Adverse Events (CTC-AE) version 4.02.  
 
9.1.1  IRB REPORTING  
All internal serious adverse events (AE) must be reported to the local IRB 
promptly per institutional policy  and in no case later than two (2) business 
days following PI notification that the event occurred if the principal 
investigator determines that conditions A, B, and C are met:  
a. The AE is unexpected, AND  
b. The AE is related to, or possibly related to, the drug, biologic, device, or 
other research intervention, AND  
c. The AE is more than minor in nature which is defined as requiring treatment 
from a health professional.  
 
All unexpected, internal, fatal AEs must be reported promptly to the local IRB 
per institutional policy, but no later than 24 hours following PI 
notification that the event occurred. If documentation is still pending, 
the IRB office must be notified by a telephone call or e-mail.  
All expected, internal, fatal AEs (i.e., due to progressive disease or which 
reflect a risk currently found in the consent form) must be reported to 
the local IRB per institutional policy no later than ten (10) business days 
following PI notification that the event occurred.  
9.1.2  FRED & PAMELA BUFFETT CANCER CENTER DATA AND SAFETY 
MONITORING COMMITTEE (DSMC) REPORTING  
 
All adverse events > grade 3 (expected or unexpected, regardless of attribution) will 
be reported to the University of Nebraska Medical Center, Fred & Pamela 
Buffett Cancer Center Data and Safety Monitoring Committee (DSMC) in 
accordance with DSMC guidelines.  
Attribution of AE: The likelihood of relationship of the AE to the study drugs will be 
determined by the investigator based on the following definitions:  
Not related: The subject was not exposed to the study treatment or another cause is 
obvious.  
Probably not related: The AE is most likely explained by another cause, and the 
time of occurrence of the AE is not reasonably related to the study treatment. 
  
Possibly related: Study treatment administration and AE occurrence reasonably 
related in time, and the AE is explained equally well by causes other than 
study treatment, or treatment administration and AE occurrence are not 
reasonably related in time, but the AE is not obviously a result of other 
causes.  
 


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Probably related: Study treatment administration and AE occurrence are 
reasonably related in time, and the AE is more likely explained by study 
treatment than by other mechanisms.  
 
Definitely related: There occurrence and timing of the AE are clearly attributable to 
the study treatment.  
 
Severity Grade of AE. The severity of events reported on the AE case report 
form will be determined by the principal investigator according the NCI 
Common Toxicity Criteria (CTC version 4.02).  
 
AEs will be collected from the time the subject signs the consent form and 
ending 30 days following the final chemotherapy. All AEs will be followed until 
resolution or a cause is identified. Prescription medication taken to relieve 
symptoms of the AE will be recorded in addition to the outcome.  
 
AEs judged by the investigator as not related or probably not related to the 
treatment will NOT be followed beyond the 30 days after the final 
chemotherapy.  
 
Transplant related Adverse Experiences (AE’s) or Serious Adverse 
Experiences (SAE’s) will NOT be collected.  
 
Copies of the AE report will be submitted to the IRB as indicated in Section 
9.1.1.  
 
Detailed policy and procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html 
 
9.1.3  FOOD AND DRUG ADMINISTRATION (FDA) REPORTING  
 
This study has been determined by the FDA to be IND Exempt.  The participating 
site investigator may utilize the FDA MedWatch Form (Appendix D) for the reporting 
of serious adverse events and follow up information to those events to meet Celgene 
reporting requirements. The form can be found at the following URL:  
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM04
8334.pdf The SAE information will be routed to the UNMC PI who will further 
evaluate the SAE.  
 
SAE reporting instructions are reiterated and further outlined in the Participating Site 
Study Manual.  
 
Additionally, serious adverse events will be reported to CELGENE, the IRB, SRC, 
Audit Committee and the Data Safety Monitoring Committee by the Investigator as 
described further within Section 9.0.  
 
9.1.4 CELGENE REPORTING REQUIREMENTS: 
 
All adverse experience reports must include the patient number, age, sex, weight, 
severity of reaction (e.g. mild, moderate, severe), relationship to drug (e.g. probably 


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related, unknown relationship, definitely not related), date and time of administration 
of test medications and all concomitant medications, and medical treatment 
provided.   The investigator is responsible for evaluating all adverse events to 
determine whether criteria for “serious” and as defined above are present.  The 
investigator is responsible for reporting adverse events to Celgene as described 
below. 
 
Serious Adverse Event (SAE) Reporting -  
 
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 
• 
Suspected positive pregnancy 
 
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 expedited reporting is appropriate in 
situations where none of the outcomes listed above 
occurred.  Important medical events that may not be 
immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other 
outcomes listed in the definition above should also 
usually be considered serious.  Examples of such 
events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug 
dependency or drug abuse.  A new diagnosis of cancer 
during the course of a treatment should be considered 
as medically important.  
Expedited reporting by investigator to Celgene 
 


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For the purpose of regulatory reporting, Celgene Drug Safety will determine the 
expectedness of events of being related to lenalidomide based on the Investigator 
Brochure.  In the United States, all suspected unexpected serious adverse reactions 
(SUSARs) will be reported in an expedited manner in accordance with 21 CFR 
312.32. 
 
 
Serious adverse events (SAE) are defined above.  The investigator must inform 
Celgene in writing using a Celgene SAE form or MEDWATCH 3500A form (see 
Appendix D) of any SAE within 24 hours of being aware of the event.  The written 
report must be completed and supplied to Celgene by facsimile within 24 hours/1 
business day.  The initial report must be as complete as possible, including an 
assessment of the causal relationship between the event and the investigational 
product(s).  Information not available at the time of the initial report (e.g., an end date 
for the adverse event or laboratory values received after the report) must be 
documented on a follow-up report.  A final report to document resolution of the SAE 
is required.  The Celgene tracking number (RV-CL-PTCL-PI-003858) and the 
institutional protocol number should be included on SAE reports (or on the fax cover 
letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE 
report to Celgene should be attached to the SAE and retained with the patient 
records. 
 
 
 
Pregnancies 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject is 
on lenalidomide, or within 28 days of the subject’s last dose of lenalidomide, are 
considered immediately reportable events. Lenalidomide is to be discontinued 
immediately. The pregnancy, suspected pregnancy, or positive pregnancy test must 
be reported to Celgene Drug Safety immediately by facsimile or email using the 
Pregnancy Initial Report Form. The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for 
further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and 
must notify Celgene Drug Safety immediately about the outcome of the pregnancy 
(either normal or abnormal outcome) using the Pregnancy Follow-up Report Form.  If 
the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE. If the 
abnormal outcome meets any of the serious criteria, it must be reported as an SAE 
to Celgene Drug Safety immediately by facsimile, or other appropriate method, 
within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the IP should also be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate 


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method, within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form.  
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taking lenalidomide should notify the Investigator, and the 
pregnant female partner should be advised to call their healthcare provider 
immediately. 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: 
(908) 673-9115 
E-mail: drugsafety@celgene.com 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
 
 
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an 
annual report is provided to the FDA within 60-days of the IND anniversary date.  21 
CRF 312.33 provides the data elements that are to be submitted in the report.  The 
Annual Report should be filed in the study's Regulatory Binder, and a copy provided 
to Celgene Corporation as a supporter of this study as follows. 
 
 
Celgene Corporation 
 
Attn: Medical Affairs Operations 
 
Connell Corporate Park  
 
400 Connell Drive Suite 700 
 
Berkeley Heights, NJ  07922 
 
 
9.2 Auditing  
 
The UNMC Fred & Pamela Buffett Cancer Center Scientific Review Committee 
(SRC) will review this protocol on at least an annual basis.  
 
This study will undergo audit on at least a quarterly basis by the UNMC Fred & 
Pamela Buffett Cancer Center Audit Committee.  
 
For participating site(s) that are NCI Cancer Centers, the protocol specific finding of 
the participating site’s Audit Committee will be submitted to the UNMC Audit 
Committee for review on a schedule to be determined by the UNMC Audit 
Committee. For participating site(s) that are not NCI Cancer Centers, the audit 
process will be established by the UNMC Audit Committee on a site-by-site basis. 
All adverse events whether internal or external, will be reported to the UNMC Fred & 


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Pamela Buffett Cancer Center Data and Safety Monitoring Committee (DSMC) as 
noted in Section 9.1.2. In its initial review, the DSMC will make a recommendation 
for the frequency of DSMC monitoring based on an assessment of risk associated 
with study-associated therapy, per DSMC policy.  
 
Detailed policy and procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html.  
 
9.3 Monitoring  
 
9.3.1  Various methods will be implemented by the sponsor (UNMC) to 
exchange information with participating sites:  
 
• Site Initiation/Orientation  
• Regular Teleconferences including group wide progress within the 
agenda  
• Investigator meetings as feasible (remote or TBA, possibly in 
conjunction with larger meetings)  
• Email distributions/reports as needed  
• Celgene, Lenalidomide Safety Updates (Sent direct to site PI from 
Celgene)  
 
 
 
9.3.2  Ongoing safety monitoring for all the subjects in this study:  
 
All participating sites are required to execute a data compliance policy agreement. 
UNMC will monitor the data of participating sites in adherence to applicable research 
regulations, the protocol, and the policy agreement. De-identified source documents 
which support data entered must be provided to the sponsor by mail, fax, or 
electronic means for centralized compliance monitoring. 
 
10.0  STATISTICAL CONSIDERATIONS  
 
This study will determine the efficacy and toxicity of a combination of lenalidomide 
and CHOEP in patients with peripheral T-cell lymphoma.  In phase I, a standard 3+3 
study design will be effective in determining the MTD.  In phase II, a Simon two-
stage design with an interim analysis will be utilized to determine the complete 
response rate. The intent to treat analysis will be conducted for all eligible patients 
(Please refer to Section 10.6 Evaluable Patient).  
 
10.1 
Primary Objective  
Phase 1 part: Determine the maximum tolerated dose (MTD). 
Phase 2 part: Complete response (CR) rate 
 
10.2  Secondary objectives 
Toxicity assessment, Overall response rate (ORR), Progression free survival 
(PFS), PFS rate at 2 years, and overall survival (OS). 
 
10.3  Efficacy Endpoints 


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Overall response rate (ORR) and progression free survival (PFS) 
 
10.4    Sample Size 
 
Total:  54 patients - Per Group:  Up to 20 in phase I, 34 in phase II 
 
 
This study is expected to require a minimum of 9 and a maximum of 18 
evaluable patients in the phase I dose escalation. (If a patient in phase I 
cohort fails to complete cycle 1 for reasons other than toxicity, the patient will 
be regarded as non-evaluable and will be replaced.) An additional 31 
evaluable patients will be accrued in the phase II portion.  It is anticipated that 
5 additional patients will be accrued (2 phase I, 3 phase II) to account for 
ineligibility, cancellation, major treatment violation, or other reasons.  
Therefore, the overall sample size will be a maximum of 54 patients.  
 
10.5  Stopping Rules 
 
In the phase I portion of the study, the DLT criteria will be used to halt dose 
escalation and confirm safety of the MTD.  In the phase II portion, a Simon 
two-stage design with an interim analysis will be utilized. The interim analysis 
will be conducted after the first 19 patients are evaluable for response, where 
at least 9 complete responses must be seen to continue accrual. 
 
10.6  Evaluable Patient  
 
If a patient in phase I cohort fails to complete cycle 1 for reasons other than 
toxicity, the patient will be regarded as non-evaluable for toxicity and will be 
replaced. 
 
Every patient who fulfills all aspects of patient eligibility who receives at least 
2 cycles of chemotherapy will be evaluable for the response endpoint. 
Patients with a global deterioration of health status requiring permanent 
discontinuation of study treatment (taken off study) without objective evidence 
of disease progression will be counted as progressive disease. Every effort 
should be made to document the objective progression even after 
discontinuation of treatment. Deaths will be counted as treatment failure. CR 
rate is at the end of the lenalidomide-CHOEP (6 cycles).  
Every patient who fulfills all aspects of patient eligibility who receives a partial 
or complete cycles of chemotherapy will be evaluable for toxicity after cycle 1 
in the phase I and evaluable for efficacy if remains without prior evidence of 
progression of disease. Any exclusion, for any reason, must be specified by 
the responsible investigator on the flow sheets. 
 
10.7 
Primary Analysis  
 
Phase I: 
 
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 


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new patients). A dose level must have a total of 6 patients treated with ≤1 
DLTs seen to be called the MTD. 
 
Toxicity Profile: 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 CTC standard 
toxicity grading. Hematologic toxicity measures of thrombocytopenia, 
neutropenia, and leukopenia will be assessed using continuous variables as 
the outcome measures (primarily nadir) as well as categorization via CTC 
standard toxicity grading. Overall toxicity incidence as well as toxicity profiles 
by dose level and patient will be explored and summarized. Frequency 
distributions, graphical techniques and other descriptive measures will form 
the basis of these analyses. 
 
Phase II:   
 
The primary endpoint of this trial is the proportion of complete responses. A 
success is defined to be an objective status of CR after completion of 6 
cycles of treatment.  All patients meeting the eligibility criteria who have 
signed a consent form and have begun treatment will be evaluable for 
response.  The proportion of successes will be estimated by the number of 
successes divided by the total number of evaluable patients. A 95% 
confidence interval for the true overall CR rate will be calculated according to 
the method of Duffy and Santner. 28 
 
The toxicity profile will be further assessed based on phase II patients. 
 
The ORR will be estimated by the total number of patients who achieve a PR 
or CR at the end of six cycles of treatment divided by the total number of 
evaluable patients. Exact binomial 95% confidence intervals for the true ORR 
will be calculated. 
 
The progression-free survival (PFS) time is defined as the time from 
registration to progression or death due to any cause. The distribution of PFS 
will be estimated using the method of Kaplan-Meier. 28   The PFS rate at 2 
years will be estimated.  A 2-year PFS rate of 60% will be considered of 
interest. 
 
The overall survival time is defined as the time from registration to death due 
to any cause.  The distribution of overall survival will be estimated using the 
method of Kaplan-Meier. 29   
 
10.8  Statistical Power Calculation 
 
In the phase II portion, a Simon optimum two-stage design will be utilized to 
assess the efficacy and tolerability of the combination of lenalidomide-
CHOEP in patients with peripheral T-cell lymphoma.  The primary endpoint is 
complete response rate, where a success is defined to be an objective status 
of CR at the end of 6 cycles of treatment.  We are interested in testing the null 
hypothesis that the CR rate in this population is 40%.  The study will have 9% 


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Type I error and 85% power to detect an effective treatment using a two-
stage design with an interim analysis based on a Simon optimum design.30 If 
the true proportion of patients who achieve a complete response is at least 
60% versus the null hypothesis that the true complete response rate is at 
most 40%.  The 6 patients treated at the MTD in phase I will also be included 
in the phase II portion.  An additional 13 or 31 evaluable patients will be 
enrolled for up to 37 evaluable patients overall in the phase II portion.  An 
interim analysis will be conducted after the first 19 patients are evaluable for 
response, where at least 9 successes must be seen to continue accrual.  
Accrual will however continue while the interim analysis is performed. For the 
final analysis, if 18 or fewer successes are observed in all 37 evaluable 
patients accrued, we will consider this regimen ineffective in this patient 
population.  If 19 or more successes are observed, this will be considered 
sufficient evidence that this treatment may be recommended for further 
testing in subsequent studies.   
 
 
 
 


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11.0  RECORDS TO BE KEPT  
 
Information regarding the actual treatments, adverse effects, radiographic and 
laboratory information, and pathology are to be recorded on appropriate forms. See 
attached Data forms. De-identified source documents which support data entered 
must be provided to the sponsor by mail, fax, or electronic means for centralized 
compliance monitoring. Serious adverse events, when noted, will be recorded on site 
via the standard serious adverse effects form.  
 
11.1 Quality assurance:  
Complete records must be maintained in a research chart on each patient 
treated on the protocol. These records should include primary documentation 
(e.g., lab. report slips, X-ray reports, scan reports, pathology reports, 
physician notes, etc.) which confirm that:  
- The patient met the eligibility criteria.  
- Signed informed consent was obtained prior to treatment.  
- Treatment was given according to protocol (dated notes about doses 
given & reasons for any dose modifications).  
- Toxicity was assessed according to protocol (laboratory report slips, 
etc.).  
- Response was assessed according to protocol (x-ray, scan, lab 
reports, dated notes on measurements & clinical assessment, as 
appropriate).  
 
11.2 Electronic Data Capturing (EDC) System 
 
Data will be stored electronically for this study on the Forte secure server.  Data 
forms will not differ from the paper versions with the exception of an electronic 
format containing the UNMC Fred & Pamela Buffett Cancer Center and Forte 
logo. 
 
Forte EDC provides for remote data collection that meets FDA 21 CFR Part 11 
requirements as well as HIPAA and other regulatory requirements designed to 
enhance data security and protect patient confidentiality. Authorized users log 
into Forte through a secure connection and must provide a valid username, 
password, and database ID.    This data may be made available to the public at 
large. 
 
 
 
 
12.0  PATIENT CONSENT  
 
12.1  Human Subjects Research Protection Training  
All personnel involved in this research project will have completed the OHRP-
approved computer based training course on the Protection of Human 
Research Subjects. All clinical and correlative research included in this 
application will have approval by the institutional review board.  


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12.2  Study Population  
Patients are from all socio-economic groups and will be entered into the study 
without bias with respect to gender or race. Attempts will be made to recruit 
minorities. No vulnerable subjects will be included in the study.  
 
12.3  Sources of Material  
Pathology material (as stated in Section 5) must be reviewed, and the 
diagnosis confirmed by Mayo Clinic pathology department (retrospectively) as 
outlined in the protocol. 
 
12.4  Recruitment and Informed Consent  
Patients with histologically confirmed new diagnosis of Stage II, III and IV 
Peripheral T-cell Non-Hodgkin lymphoma (PTCL) not otherwise specified 
(NOS), Anaplastic large cell lymphoma (ALK negative), Angioimmunoblastic 
T-cell lymphoma, Enteropathy associated T-cell lymphoma, Hepatosplenic 
gamma delta T-cell lymphoma for whom this therapy would be appropriate 
will be available for recruitment. These patients will be informed of the nature 
of this study, and will be asked to participate on a voluntary basis after 
informing them of the possible risks and benefits of the study. A number of 
public registries may be accessible to health care providers and prospective 
subjects as listed below.  
National Library of Medicine - http://clinicaltrials.gov (NCT02561273) 
National Cancer Institute - http://www.cancer.gov (NCI-2015-00088)  
 
12.5  Subject Competency  
Subjects will be eligible to participate in the study only if they are competent 
to give informed consent. A subject that the investigators judges to be 
incompetent will not be enrolled.  
 
12.6  Process of Informed Consent  
If the patient chooses to be a participant in this study, informed consent will 
be obtained by the investigators. The study and procedures involved 
including the risks will be explained in detail to each subject. It will be clearly 
explained to the subject that this is a research study and that participation is 
entirely on a voluntary basis. Subjects will be given the option to discuss the 
study with a family member, friend, counselor or, another physician. The 
participating investigators will be available to discuss the study with them.  
 
12.7  Subject/Representative Comprehension  
When the process of informed consent is completed, the subject will be asked 
to state in his/her own words, the purpose of the study, the procedures that 
will be carried out, potential risk, potential benefits to the subject, the 
alternatives and the right to withdraw from the study. If there is any indication 
that a given subject's comprehension is anything less than accurate, the 
points of confusion will be discussed and clarified.  


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12.8  Information Purposely Withheld.  
The results of the tests done solely for research purposes will not be 
disclosed to the subject. No other information will be purposely withheld from 
the subject.  
 
12.9  Potential Benefits of the Proposed Research to the Subjects  
It is hoped that the use of protocol therapy in this patient population may 
result in tumor shrinkage or stabilization of disease.  
 
12.10  Potential Benefits to Society.  
Information obtained from this study may help other cancer patients by 
Identifying proper doses of lenalidomide used in combination with an 
established cancer drugs, CHOEP.  
 
12.11  Potential Risks  
The use of multiagent cytotoxic chemotherapy is associated with numerous 
potential risks. Multiagent chemotherapy is considered to be a valid treatment 
option for patients with advanced malignancies. It is believed the treatment 
option outlined in the study will not pose significant additional risks compared 
to conventional treatment that might consist of other chemotherapy drugs 
given alone or in combination.  
 
12.12  Therapeutic Alternatives  
If patients choose not to participate in this study they may elect to receive 
standard therapy as per their primary oncologist, which may include other 
chemotherapy drugs given alone or in combination.  
 
 
12.13  Risk/Benefit Relationship  
Although there are inherent risks involved because of the use of 
chemotherapy agents, the risk is considered to be acceptable in the setting of 
cancer.  
 
12.14  Consent Form Documents  
No information will be purposely withheld from the patients. The consent 
document used in this study will include the adult consent document. See 
attached consent form 
 
 
 
 


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13.0  REFERENCES  
 
1.  
Lopez-Guillermo A, Cid J, Salar A, et al: Peripheral T-cell lymphomas: Initial 
features, natural history, and prognostic factors in a series of 174 patients 
diagnosed according to the R.E.A.L. Classification. Ann Oncol 9:849-855, 
1998 
2.  
Harris NJ, Jaffe ES, Armitage JO: Lymphoma classification: From REAL to 
WHO and beyond, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: 
Principles and Practice of Oncology Updates. Philadelphia, PA, Lippincott-
Raven, 1999, pp 1-14 
3.  
Ascani S, Zinzani PL, Gherlinzoni F, et al: Peripheral T-cell lymphomas: 
Clinico-pathologic study of 168 cases diagnosed according to the R.E.A.L. 
classification. Ann Oncol 8:583-592, 1997 
4.  
Anderson JR, Armitage JO, Weisenburger DD: Epidemiology of the non-
Hodgkin’s lymphomas: Distributions of the major subtypes differ by 
geographic locations—Non-Hodgkin’s Lymphoma Classification Project. Ann 
Oncol 9:717-720, 1998 
5.  
Dearden CE, Foss FM: Peripheral T-cell lymphomas: Diagnosis and 
management. Hematol Oncol Clin North Am 17:1351-1366, 2003 
6.  
Horwitz SM: Management of peripheral T-cell non-Hodgkin’s lymphoma. Curr 
Opin Oncol 19:438- 443, 2007 
7.  
National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines 
in Oncology: Non- Hodgkin’s Lymphoma, V. 2, 2011 
8.  
Vose J, Armitage J, Weisenburger D, et al: International peripheral T-cell and 
natural killer/T-cell lymphoma study: Pathology findings and clinical 
outcomes. J Clin Oncol 26:4124-4130, 2008 
9.  
Reimer P: Impact of autologous and allogeneic stem cell transplantation in 
peripheral T-cell lymphomas. Adv Hematol 2010:320624, 2010 
10.  
Reimer P, Rüdiger T, Geissinger E, et al. Autologous stem cell 
transplantation as first-line therapy in peripheral T cell lymphomas: results of 
a prospective multicenter study. J Clin Oncol 2009;27(1):106-113  
11.  
Mercadal S, Briones J, Xicoy B, et al. Intensive chemotherapy (high-dose 
CHOP/ESHAP regimen) followed by autologous stem cell transplantation in 
previously untreated patients with peripheral T-cell lymphoma. Ann Oncol 
2008;19:958-963 
12.  
Reimer P, Schertlin T, Rüdiger T, et al. Myeloablative radiochemotherapy 
followed by autologous peripheral blood stem cell transplantation as first-line 
therapy in peripheral T-cell lymphomas: first results of a prospective 
multicenter study. Hematology Journal. 2004;5(4):304–311. 
13.  
Sonnen R, Schmidt WP, Müller-Hermelink HK, Schmitz N. The International 
Prognostic Index determines the outcome of patients with nodal mature T-cell 
lymphomas. British Journal of Haematology. 2005;129(3):366–372. 
14.  
Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of mature T-
cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma 
treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study 
Group. Blood. 2010 Nov 4;116(18):3418-25. 
15.  
Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs 
overcome drug resistance of human multiple myeloma cells to conventional 
therapy. Blood. 2000; 96: 2943-2950. 


UNMC IRB#511-14 Protocol Version 6.1 Dated 01-17-2020  
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16.  
Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by 
immunomodulatory thalidomide analogs in human multiple myeloma cells: 
therapeutic implications. Blood. 2002; 99: 4525-4530. 
17.  
Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and 
T cell activation by 2 distinct classes of thalidomide analogues that are potent 
inhibitors of TNF-alpha. J Immunol. 1999; 163: 380-386. 
18.  
Chang DH, Liu N, Klimek V, et al. Enhancement of ligand-dependent 
activation of human natural killer T cells by lenalidomide: therapeutic 
implications. Blood. 2006; 108: 618-621. 
19.  
Lin YC, Shun CT, Wu MS, et al. A novel anticancer effect of thalidomide: 
inhibition of intercellular adhesion molecule-1-mediated cell invasion and 
metastasis through suppression of nuclear factor-kappaB. Clin Cancer Res. 
2006; 12: 7165-7173. 
20.  
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: 56-63. 
21.  
Chanan-Khan A, Miller KC, Musial L, et al. Clinical efficacy of lenalidomide in 
patients with relapsed or refractory chronic lymphocytic leukemia: results of a 
phase II study. J Clin Oncol. 2006; 24: 5343-5349. 
22.  
Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for 
relapsed multiple myeloma in North America. N Engl J Med. 2007; 357: 2133-
2142 
 
23.  
List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic 
syndrome with chromosome 5q deletion. N Engl J Med. 2006; 355: 1456-
1465. 
24.   
Dueck G, Chua N, Prasad A, et al. Interim report of a phase 2 clinical trial of 
lenalidomide for T-cell non-Hodgkin lymphoma. Cancer. 2010 Oct 
1;116(19):4541-8. 
25. 
Toumishey E, Prasad A, Dueck GS, et al. Final Report Of a Phase II Clinical 
Trial Of Lenalidomide Monotherapy For T-Cell Lymphoma. American Society 
of Hematology Annual meeting, 2013, abstract 4376. 
26.  
Morschhauser F, Fitoussi O, Haioun C, et al. A phase 2, multicentre, single-
arm, open-label study to evaluate the safety and efficacy of  single-agent 
lenalidomide (Revlimid®) in subjects with relapsed or refractory peripheral T-
cell non-Hodgkin lymphoma: The EXPECT trial. Eur J Cancer. 2013 
Sep;49(13):2869-76. 
27.  
Cheson BD, Pfistner B, Juweid ME, et al. International Harmonization Project 
on Lymphoma. Revised response criteria for malignant lymphoma. J Clin 
Oncol. 2007 Feb 10;25(5):579-86. 
28.  
Duffy D, Santner T: Confidence intervals for a binomial parameter based on 
multistage tests. Biometrics 1987, 43:81- 93. 
29.  
Kaplan E, Meier P: Nonparametric estimation for incomplete observations. J 
Am Stat Assoc 1958; 53:457-481. 
30.  
Simon R: Optimal two-stage designs for phase II clinical trials. Controlled 
Clinical Trials 1989; 10:1-10. 
 
 
 


UNMC IRB#511-14 Protocol Version 6.1 Dated 01-17-2020  
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14.0 Data Forms  
Attached  
 
 


UNMC IRB#511-14 Protocol Version 6.1 Dated 01-17-2020  
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Appendix A. Karnofsky Scale for Performance Status 
 
Scale (%)  
Description  
 
100  
Normal; no complaints  
90  
Able to carry on normal activities; minor signs or symptoms of disease  
80  
Normal activity with effort  
70 
Cares for self. Unable to carry on normal activity or to do active work  
60  
Requires occasional assistance but able to care for most of needs  
50  
Requires considerable assistance and frequent medical care  
40  
Disabled; requires special care and assistance  
30  
Severely disabled; hospitalization indicated though death not imminent  
20  
Very sick. Hospitalization is necessary. Active supportive treatment 
necessary  
10  
Moribund  
0  
Dead  
 
Reference: Karnofsky DA, et al. Cancer 1:634-656, 1948.  
 
 


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Appendix B: Body Surface Area and Creatinine Clearance Calculations 
 
 
Body surface area (BSA) should be calculated using a standard nomogram that 
yields the following results in meters squared (m2)  
 
 
 
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as 
follows:  
 
CrCl (ml/min) =  
(140-age) (actual wt in kg)  
72 x serum creatinine (mg/dl)  
 
For females use 85% of calculated CrCl value.  
 
 
 
 
 
 


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Appendix C: Eligibility checklist 
 
Date Completed: 
 
Institution:  
Patient ID#:  
Checklist Version #4.0 
 Dated: 03-14-17 
 
IRB# 511-14   Title: A Phase I/II Trial of CHOEP Chemotherapy plus 
Lenalidomide as Front Line Therapy for Patients with Stage II, III and IV 
Peripheral T-Cell Non-Hodgkin’s Lymphoma  
Celgene Reference #: RV-CL-PTCL-PI-003858 PI: Matthew Lunning, MD 
Waiver #: 
Inclusion Criteria:  Response should be YES 
Yes    No      N/A 
1. Histologically confirmed new diagnosis of Stage II, III and IV Peripheral T-cell Non-
Hodgkin’s lymphoma not otherwise specified (NOS), Anaplastic large cell lymphoma (ALK 
negative) (ALK positive if IPI 3, 4, or 5), Nodal PTCL with TFH phenotype or 
Angioimmunoblastic T-cell lymphoma, Enteropathy associated T-cell lymphoma, 
Hepatosplenic gamma delta T-cell lymphoma. 
Note: As part of the eligibility criteria review, either the 2008 OR 2016 WHO 
classifications of these diagnoses will be recognized and accepted. 
[  ]     [  ] 
 
Diagnosis: _________ 
 
Source documenting: 
_______________________ 
2. Pathology material: H&E stain and IHC slides or a representative FFPE tissue block along 
with the pathology report from initial diagnosis sent to be reviewed, and the diagnosis 
confirmed by Mayo Clinic department (retrospective diagnostic review: treatment may 
commence prior to the Mayo Clinic review).  
[  ]     [  ]  
3. No prior therapy with the exception of prior prednisone alone, at the discretion of the 
investigator based on current diagnosis and clinical condition.  
This prednisone treatment will not count toward the 6 cycles of treatment given in the study. 
[  ]     [  ]       [  ] 
Source documenting: 
_______________________ 
4. Age 19 years or older (the age of consent in Nebraska); Age 18 years or older (applicable 
to states where the age of majority is 18). 
[  ]     [  ]  
DOB: ______________ 
5. Expected survival duration of > 3 months. 
[  ]     [  ]  
Source documenting: 
_______________________ 
6. Karnofsky Performance Status > 70. (Appendix A) 
[  ]     [  ]  
Source documenting: 
_______________________ 


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7. Laboratory status as follows (Please enter values OR WNL, as appropriate): 
_________________ANC > 1000 cells/mm3, unless cytopenias due to NHL (i.e., bone marrow 
involvement or splenomegaly) 
__________________ Platelet Count > 100,000 /μL or > 75,000 /μL if BM involvement or 
splenomegaly 
___________________ Total bilirubin ≤1.5 x upper normal limit, or ≤ 3 x upper normal limit if 
documented hepatic involvement with lymphoma, or ≤ 5 x upper normal limit if history 
of Gilbert’s Disease 
___________________ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤ 2.5 x upper normal limit (≤ 5 x upper normal limit if documented hepatic involvement 
with lymphoma) 
___________________ Serum creatinine < 2.0 mg/dL or calculated creatinine clearance (CrCl) 
> 45 mL/min (Cockcroft-Gault, Appendix B) 
________________ PT or INR, and PTT ≤ 1.5 x upper limit of normal unless patient is receiving 
anticoagulants. If patient is on warfarin therapy, levels should be within therapeutic 
range 
[  ]     [  ]  
 
Source documenting: 
_______________________ 
8. If currently not on anticoagulation medication, willing and able to take aspirin (81 or 325 
mg) daily.  
If aspirin is contraindicated, the patient may be considered for the study if on therapeutic dose warfarin or 
low molecular weight heparin. Patients unable to take any prophylaxis are not eligible. 
[  ]     [  ]   
 
Source documenting: 
_______________________ 
9. ___Patient with measurable disease.  
___Patient with non-measurable but evaluable disease may be eligible after discussion 
with the PI.  
Baseline measurements and evaluations must be obtained within 6 weeks of registration to the study. 
Abnormal PET/CT scans will not constitute evaluable disease, unless verified by the CT scan portion, CT scan, 
or other appropriate imaging. 
[  ]     [  ]   
 
Source documenting: 
_______________________ 
10. Patient with measurable disease must have at least one objective measurable disease 
parameter.  
A clearly defined, bi-dimensionally measurable defect or mass measuring at least 1.5 cm in diameter on the 
CT portion of the PET/CT or CT scan or MRI (if appropriate) will constitute measurable disease. Proof of 
lymphoma in the liver is required by a confirmation biopsy. Skin lesions can be used as measurable disease 
provided bi-dimensional measurements are possible. 
[  ]     [  ]        [  ] 
Source documenting: 
_______________________ 
11. Patient must be registered into the mandatory Revlimid REMS™  program, and be willing 
and able to comply with the requirements of the REMS™  program. 
[  ]     [  ]   
Source documenting: 
_______________________ 
12. Women must not be pregnant or breast-feeding due to teratogenic effects of 
lenalidomide and chemotherapy.  
_____________ Female of reproductive potential must adhere to the scheduled pregnancy 
testing as required in the Revlimid REMS™  program 
___________ Female of childbearing potential must have a blood test within 2 weeks prior 
to registration to rule out pregnancy 
____________ Pregnancy testing is not required for post-menopausal or surgically sterilized 
women 
[  ]     [  ]   
[  ] 
 
Source documenting: 
_______________________ 
13. Male and female patient of reproductive potential must agree follow accepted birth 
control measures. 
[  ]     [  ]   
14. Patient must be able to adhere to the study visit schedule and other protocol 
requirements. 
[  ]     [  ]   


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15. Patient must be willing to give written informed consent, and sign an institutionally 
approved consent form before performance of any study-related procedure not part of 
normal medical care as noted in number 3 above; with the exception of 1 cycle of 
chemotherapy based on current diagnosis and clinical condition, with the understanding 
that consent may be withdrawn by the subject at any time without prejudice to future 
medical care. 
[  ]     [  ]   
Date Consent signed: 
_______________________ 
16. No serious disease or condition that, in the opinion of the investigator, would 
compromise the patient’s ability to participate in the study.  
[  ]     [  ]   
Exclusion Criteria: Response should be NO 
Yes    No      N/A 
1.    Pregnant or breast feeding female.  
[  ]     [  ]   
 
2.    Known seropositive for or active viral infection with human immunodeficiency virus 
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).   
         Patients who are seropositive because of hepatitis B virus vaccine is eligible. A patient who is hepatitis 
B core antibody +; quantitative DNA (PCR) negative is eligible if appropriate prophylaxis is planned 
[  ]     [  ]  
Source documenting: 
_______________________   
3.    Major surgery within 2 weeks of study drug administration. 
[  ]     [  ] 
Source documenting: 
_______________________   
4.    Prior malignancy within the past 3 years with exception of adequately treated basal cell, 
squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or breast; 
prostate cancer of Gleason Grade 6 or less with stable PSA levels. 
[  ]     [  ]  
Source documenting: 
_______________________   
5.    Diagnosis of other PTCL histologies other than those specified in the inclusion criteria. 
[  ]     [  ]   
 
6.    Contraindication to any of the required concomitant drugs or supportive treatments, 
including hypersensitivity to all anticoagulation and antiplatelet options, or antiviral 
drugs. 
[  ]     [  ]   
 
7.    Any other clinically significant medical disease or condition laboratory abnormality or 
psychiatric illness that, in the Investigator’s opinion, may interfere with protocol 
adherence or a subject’s ability to give informed consent. 
[  ]     [  ]   
 
8.     Known hypersensitivity to thalidomide or lenalidomide. 
[  ]     [  ]   
9.    The development of erythema nodosum if characterized by a desquamating rash while 
taking thalidomide, lenalidomide or similar drugs. 
[  ]     [  ]   
10.  Ejection fraction of <45% by either MUGA or ECHO.  
[  ]     [  ]      
Source documenting: 
_______________________ 
NOTE: All questions regarding eligibility for potential subjects should be directed to the UNMC Research Project Manager at 402-559-4596   
Eligibility: 
[  ] Patient satisfies all criteria    
                            [  ] Patient not formally eligible, but admitted to this study because (state reason): 
 
Patient Initials:  __________MR or Study ID#______________ 
ELIGIBILITY reviewed and confirmed.  
                                                                 Site Investigator Signature _______________________Date_____________   
                                                                   Printed Name of Investigator:  __________________________ 
 
ELIGIBILITY reviewed and confirmed.  
                                                        Principal Investigator Signature _______________________Date_____________        
                                                                    Printed Name of Investigator:  __________________________ 
 


UNMC IRB#511-14 Protocol Version 6.1 Dated 01-17-2020  
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Appendix D: FDA MEDWATCH form 
 
Available on-line at 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM04
8334.pdf  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix E: 
Oral, Sublingual, and/or Buccal Route  
Medication Adherence Standard Procedure 
 
PURPOSE 
To provide a means of ensuring oral, sublingual and/or buccal routes of 
medication adherence to subjects while participating in a clinical trial. 
1. A physician’s order will be completed by study subjects or representative 
for oral, sublingual and/or buccal administration per IRB approved 
protocol. 
2. To ensure the consistent and safe administration of medications not given 
under the direct supervision of study staff (at home), there will be a 
“Medication Information Sheet” and a diary to document times of drug 
administration. 
3. To record medication adherence Study staff will document results of 
medication reconciliation and or medication return in the subject’s chart. 
4. Maintain documentation of medications returned or sent to for destruction 
(if applicable).  
PROCEDURE 
1. Subjects will be given a monthly “Medication Diary”.  The diary will have a 
place for the subject to record the time that the medication(s) were taken. 
(See Form A for example) 
 
2. The research nurse will review the subject’s “Medication Diary” for 
adherence to the study regimen for oral medication administration. 
Adherence will be noted in the subject’s chart.  All unused Revlimid® 
(lenalidomide) capsules should be returned to the research center for 
disposition in accordance with the Revlimid REMS TM program.  If any study 
drug is lost or damaged, its disposition should be documented in the 
source documents.   
 
 
 
 
 
 
 
 
 
 
 
 
Medication Diary (Form A)   


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Medication Lenalidomide Diary 
CYCLE_______________ Date__________ 
 
Your prescribed dose is _________________. 
   If you miss a dose please add the comment “missed dose” on the corresponding date. 
   If your Study Doctor has asked you to change your dose, please add the new dosage on the corresponding 
date. 
  Return all study drug bottles, any unused drug and completed diaries to the Study Coordinators at the 
study site. 
 
Sunday 
Monday 
Tuesday Wednesday Thursday 
Friday 
Saturday 
Date:_________ 
Revlimid®  at: 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
  
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
 Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
 Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
  
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
Date:_________ 
Revlimid®  at: 
_______AM / PM 
  
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
  
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
  
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
  
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
  
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
  
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Date:_________ 
Revlimid®  at: 
 
_______AM / PM 
 
Notes: 
 
 
 
 


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Appendix F: 
Blood and Tissue Sample Processing and Shipping 
Description of Sample Collection:  
One 6 mL EDTA tube will be collected for serum, plasma and DNA at 
baseline, and at re-staging. The serum, plasma and DNA specimens will be 
stored until the end of the study. The tumor biopsy at the time of diagnosis 
will be reviewed and slides returned to sites after review. (See protocol 
section 5.7 for details) No therapeutic intervention will be undertaken and the 
results of these studies will not have any influence on the medical management 
of the subjects.  
Facility 
Sample 
Contact Person(s) 
Date and 
Time Points 
Hematology 
Research  
Mayo Clinic 
 
 
Pathology 
material: H&E 
stain and IHC 
slides or a 
representative 
FFPE tissue 
block along 
with the 
pathology 
report from 
initial 
diagnosis,  
 
Please NOTE: 
the diagnostic 
H&E slide and 
IHC slides will 
be returned 
after review.  
 
Tammy Price-Troska 
Phone: (507) 284-3805 
Email:  pricetroska.tammy@mayo.edu  
Shipping Address: 
Hematology Research – Stabile 6-13 
Mayo Clinic 
200 First Street SW 
Rochester MN 55905 
  Diagnostic   
Baseline Tissue 
Date: 
___/___/____ 
Submit within 1 
month of patient 
registration. A copy 
of the pathology 
report should be 
sent when the 
sample is shipped. 
 
Diagnostic H&E 
slide and IHC 
slides will be 
returned 
 
Provide Return 
Shipping 
contact, 
address and 
phone # :  
 
 
 
 
Hematology 
Research  
Mayo Clinic 
 
Research 
blood 
specimen: 
One 6 mL 
EDTA tube at 
baseline and 
at re-staging. 
EDTA Tube 
Processing: 
Centrifuge for 15 
minutes at room 
temperature at 
1500 RPM within 
30 minutes of 
collection. For 
cytokine analysis 
– Remove and 
aliquot the top 2 
ml of plasma 
Tammy Price-Troska 
Phone: (507) 284-3805 
Email:  pricetroska.tammy@mayo.edu    
 
Shipping Address: 
Hematology Research – Stabile 6-13 
Mayo Clinic 
200 First Street SW 
Rochester MN 55905 
 
 Baseline 
Blood 
      Sample  
Date: 
___/___/____ 
 
  Re-staging  
Blood 
Sample 
Date: 
___/___/____ 
 


UNMC IRB#511-14 Protocol Version 6.1 Dated 01-17-2020  
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from the EDTA 
tube. Store 1 ml 
aliquots in two 
(2) properly 
labeled 
polypropylene 
tubes for 
cryopreservation. 
Store samples in 
the freezer at ≤ -
20°C until they 
are shipped for 
analysis.  
For DNA analysis 
– Remove and 
aliquot the top 1 
ml of cells from 
the EDTA tube. 
Store the 1 ml 
aliquot in a 
properly labeled 
polypropylene 
tube for 
cryopreservation. 
Store the sample 
in the freezer at ≤ 
-20°C until it is 
shipped for 
analysis. 
 
 Please 
contact 
Tammy 
Price-Troska, 
Hematology 
Research, 
at 
(507) 
284-3805, 
orpricetroska.tammy@mayo.edu, to advise of planned shipments, and to discuss appropriate procedures.   
 
 
 


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Appendix G: 
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 embryo fetal development study in animals indicates that 
lenalidomide produced malformations in the offsprings 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.  
All study participants must be registered into the mandatory Revlimid REMS TM 
program, and be willing and able to comply with the requirements of Revlimid REMS 
TM program. 
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 for at least 24 consecutive months (i.e., 
has had menses at any time in the preceding 24 consecutive months).  
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.  
• Females NOT of childbearing potential acknowledge that she understands 
the hazards and necessary precautions associated with the use of 
lenalidomide.  
• Male subjects taking lenalidomide acknowledge that he understands that 
traces of lenalidomide have been found in semen, that he understands the 
potential or pregnant female, if engaged in sexual activity with a female of 
childbearing potential or pregnant female, 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 or pregnant female.  
 
Contraception 


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Females of childbearing potential (FCBP)† must agree to use two reliable forms 
of contraception simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods related to this study: 1) 
for at least 28 days before starting lenalidomide; 2)throughout the entire duration 
of lenalidomide; and 3) 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: 
• Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants) 
o Tubal ligation 
o Partner’s vasectomy 
• Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
 Because of the increased risk of venous thromboembolism in subjects with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive 
pills are not recommended.  If a subject is currently using combined oral 
contraception the subject 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.  
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 subjects with 
neutropenia.  
Pregnancy testing 
 
Medically supervised pregnancy tests with a minimum sensitivity of 50mIU/mL must 
be performed for females of childbearing potential, including females of 
childbearing potential who commit to complete abstinence, as outlined below.                                  
 
                                                        
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
 
 


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Before starting study drug:   
Female Subjects   
• FCBP must have two (2) negative pregnancy tests (sensitivity of at least 
50 mIU/mL) prior to prescribing lenalidomide.  The first pregnancy test 
must be performed within 10-14 days prior to prescribing lenalidomide and 
the second pregnancy test must be performed within 24 hours prior to 
prescribing lenalidomide.  The subject may not receive lenalidomide until 
the Investigator has verified that the results of these pregnancy tests are 
negative. 
 
Male Subjects   
• Must agree to use a latex condom during sexual contact with females of 
childbearing potential while participating in the study and for at least 28 
days following discontinuation from the study even if he has undergone a 
successful vasectomy.  
During study participation and for 28 days following discontinuation from 
the study: 
Female Subjects   
• 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.  
• If pregnancy or a positive pregnancy test does occur in a study subject, 
lenalidomide must be immediately discontinued.  Pregnancy testing and 
counseling must be performed if a subject misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide 
treatment must be discontinued during this evaluation. 
• Female must agree to abstain from breastfeeding during study 
participation and for at least 28 days after lenalidomide discontinuation.  
Male Subjects 


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• Must practice complete abstinence or use a condom during sexual contact 
with pregnant female 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.  If pregnancy or a positive pregnancy 
test does occur in the partner of a male study subject during study 
participation, the investigator must be notified immediately.  
• Male subjects should not donate semen or sperm during therapy or for at 
least 28 days following discontinuation of lenalidomide.  
Additional precautions 
• Subjects should be instructed never to give lenalidomide to another 
person. 
• Subjects should not donate blood during therapy and for at least 28 days 
following discontinuation of lenalidomide. 
• Only enough lenalidomide for one cycle of therapy may be prescribed with 
each cycle of therapy. 
• Any unused lenalidomide must be returned as instructed through Revlimid 
REMS TM program.