Clinical trial NCT00118209
Conditions: Large B Cell Lymphoma
Sponsor: Alliance for Clinical Trials in Oncology
Start date: 2005-05-01; Completion date: 2021-11-15
Enrollment: 524 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial studies rituximab when given together with two different combination chemotherapy regimens to compare how well they work in treating patients with diffuse large B-cell non-Hodgkin's lymphoma. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy 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. Giving rituximab together with combination chemotherapy may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective when given with rituximab in treating diffuse large B-cell non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying rituximab when given together with two different combination chemotherapy regimens to compare how well they work in treating patients with diffuse large B-cell lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare the event-free survival of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone (R-CHOP) versus dose-adjusted (DA-) etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, and rituximab (EPOCH-R) chemotherapy in untreated cluster of differentiation (CD)20 positive (+) diffuse large B-cell lymphomas.

II. To develop a molecular predictor of outcome of R-CHOP and DA-EPOCH-R chemotherapy using molecular profiling.

SECONDARY OBJECTIVES:

I. To compare the response rates, overall survival and toxicity of R-CHOP versus DA-EPOCH-R.

II. To define the pharmacogenomics of untreated diffuse large B-cell lymphoma (DLBCL) and correlate clinical parameters (toxicity, response, survival outcomes and laboratory results) with molecular profiling.

III. To assess the use of molecular profiling for pathological diagnosis. IV. To identify new therapeutic targets using molecular profiling. V. To perform a comprehensive analysis of somatic alterations to the tumor genome and to understand which genomic alterations are somatically acquired by the tumor and which are encoded in the germ line of the patient.

VI. To identify biomarkers of response to chemotherapy by fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging that are predictive of histopathologic remissions and survival in patients with stage I (mediastinal), II, III, or IV untreated DLBCL.

VII. To evaluate the use of semiquantitative measurements of FDG uptake in defining FDG-PET/CT based biomarkers of response to chemotherapy in patients with DLBCL.

VIII. To determine whether FDG-PET/CT measurements of tumor response after the second cycle of chemotherapy can predict clinical response.

IX. To establish a standardized protocol for FDG-PET/CT image acquisition. X. To determine additional FDG-PET/CT parameters (e.g., the ratio of tumor maximum standard uptake value \[SUVmax\] to liver SUVmean; SUVs corrected for body surface area and lean body mass; nuclear medicine physician's assessment) and evaluate their utility in refining FDG-PET/CT based biomarkers of response to therapy.

XI. To evaluate inter-institutional reproducibility of FDG-PET/CT measurements for this indication.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Arms: arm 1: Patients receive the following treatment:

* Rituximab 375 mg/m\^2 IV infusion on Day 1 prior to CHOP chemotherapy
* Cyclophosphamide 750 mg/m\^2 IV on Day 1
* Doxorubicin 50 mg/m\^2 IV on Day 1
* Vincristine 1.4 mg/m\^2 IV (2 mg cap) on Day 1
* Prednisone 40 mg/m\^2/day PO on Days 1-5
* filgrastim or pegfilgrastim as defined in the protocol

Required ancillary medications is administered during all cycles as defined in the protocol.

Cycles will be repeated every 21 days for 6 treatment cycles. Restaging will occur after Cycles 4 and 6. arm 2: Patients receive the following treatment:

Cycle 1 Doses:

* Rituximab 375 mg/m\^2 IV infusion on Day 1 prior to EPOCH chemotherapy
* Doxorubicin 10 mg/m\^2/day CIVI on Days 1-4
* Etoposide 50 mg/m\^2/day CIVI on Days 1-4
* Vincristine 0.4 mg/m\^2/day (no cap) CIVI on Days 1-4 (total 1.6 mg/m2 over 96 hours)
* Cyclophosphamide 750 mg/m\^2 IV on Day 5 (following completion of 96 hour infusions)
* Prednisone 60 mg/m\^2 PO BID on Days 1-5
* Administer filgrastim 480 mcg subcutaneous daily from Day 6 until ANC \> 5000 after the nadir (nadir usually between Days 10-12) or for 10 days (Days 6-15) if the ANC is not being monitored, during every cycle.

Doses for subsequent cycles will be determined by the absolute neutrophil (ANC) or platelet nadir from the previous cycle.

Required ancillary medications are administered during all cycles as defined in the protocol.

Cycles will be repeated every 21 days for a maximum of 6 cycles. Restaging will occur after Cycles 4 and 6.
Interventions: intervention 1: rituximab intervention 2: cyclophosphamide intervention 3: doxorubicin intervention 4: vincristine intervention 5: prednisone intervention 6: etoposide intervention 7: filgrastim intervention 8: pegfilgrastim
Intervention descriptions: intervention 1: IV intervention 2: IV intervention 3: IV or CIVI intervention 4: IV or CIVI intervention 5: oral intervention 6: CIVI intervention 7: IV intervention 8: IV

Protocol documents:
Prot_SAP_000.pdf: 
Activation Date: 05/02/05 
Includes Update #18 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
CALGB 50303/CTSU 50303 
PHASE III RANDOMIZED STUDY OF R-CHOP V. DOSE-ADJUSTED EPOCH-R WITH MOLECULAR PROFILING IN 
UNTREATED DE NOVO DIFFUSE LARGE B-CELL LYMPHOMAS 
 
As of Update #14, enrollment on CALGB 50303 will be limited to institutions and patients participating in the 
required imaging companion study CALGB 580603. 
 
Study Chairs 
Nancy L. Bartlett, MD 
Andrew D. Zelenetz, MD, PhD 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Co-Chairs 
 
 
 
 
 
 
 
Pathology Co-Chair 
Imaging Co-Chair 
 
 
 
 
 
 
Lymphoma Committee Chair 
SWOG Co-Chair 
 
 
 
 
 
 
 
PET Committee Chair 
Imaging Committee Chair 
 
 
 
 
 
 
 
Faculty Statisticians 
 
 
 
 
 
 
Staff Statistician 
 
 
Data Manager 
Protocol Coordinator 
 
 
 
 
 
 
Participating Organizations: ALLIANCE/Alliance for Clinical Trials in Oncology, SWOG/SWOG, ECOG-
ACRIN/ECOG-ACRIN Cancer Research Group, NRG/NRG Oncology 
Version Date: 02/15/2018 
1 
Update #18 


CALGB 50303 
Alliance Protocol Operations Program Office 
 
 
 
Alliance Statistics and Data Center 
 
 
Adverse Event Reporting 
 
CAEPR for rituximab appears in Section 15.1 
Alliance Patient Registration 
 
 
 
Alliance Biorepository at Ohio State University 
 
 
Alliance Imaging Core Lab at IROC Ohio 
 
 
 
 
Alliance Pharmacy Contact 
 
Alliance Nursing Contact 
 
Medidata RAVE® iMedidata portal 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Institutions not aligned with the Alliance will participate through the CTSU mechanism as outlined below and 
detailed in the CTSU logistical appendix 
• 
The study protocol and all related forms and documents must be downloaded from the protocol-specific Web page 
of the CTSU Member Web site located at https://www.ctsu.org. 
• 
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU logistical appendix 
for specific instructions and documents to be submitted. 
• 
Patient enrollments will be conducted by the CTSU. Refer to the CTSU logistical appendix for specific instructions 
and forms to be submitted. 
• 
Data management will be performed by the Alliance. Case report forms (with the exception of patient enrollment 
forms), clinical reports, and transmittals must be sent to the Alliance unless otherwise directed by the protocol. Do 
not send study data or case report forms to the CTSU Data Operations. 
• 
Data query and delinquency reports will be sent directly to the enrolling site by the Alliance (generally via e-mail but 
may be sent via fax or postal mail). Please send query responses and delinquent data to Alliance and do not copy the 
CTSU Data Operations. Query responses should be sent to the Alliance via postal mail (no transmittal form needs to 
accompany response). Each site should have a designated CTSU Administrator and Data Administrator and must keep 
their CTEP AMS account contact information current. This will ensure timely communication between the clinical site 
and the Alliance Statistics and Data Center. 
 
The pharmacogenetic component of this study is conducted as part of the NIH Pharmacogenetics Research Network, 
which is funded through a separate U01 mechanism (see http://www.nigms.nih.gov/Initiatives/PGRN/ for details).
Version Date: 02/15/2018 
2 
Update #18 


CALGB 50303 
PHASE III RANDOMIZED STUDY OF R-CHOP V. DOSE-ADJUSTED EPOCH-R WITH MOLECULAR PROFILING IN 
UNTREATED DE NOVO DIFFUSE LARGE B-CELL LYMPHOMAS 
Schema Page 1 of 2 
Eligibility Criteria: 
Required Initial Laboratory Values* 
Histologically documented de novo stage I mediastinal (thymic) DLBCL or  
ANC 
≥ 1000/µL 
any stage II, III, or IV DLBCL. 
Platelets 
≥ 100,000/µL 
Patients must have one of the following WHO histologic subtypes without 
Creatinine  
≤ 1.5 mg/dL 
evidence of indolent histological features in the tissue biopsy or bone  
 or CrCl 
≥ 50 cc/min 
marrow: 
Total Bilirubin 
≤ 2 mg/dL** 
1. CD20+ diffuse large B-cell lymphoma (includes morphological variants: centroblastic; 
immunoblastic; T-cell/histiocyte rich; and anaplastic). 
 
2. CD20+ mediastinal (thymic) large B-cell lymphoma 
*Unless attributable to non-Hodgkin 
3. CD20+ intravascular large B-cell lymphoma 
lymphoma 
No prior cytotoxic chemotherapy or rituximab (see Section 4.2) 
**Unless attributable to Gilbert’s  
Age ≥ 18 years. 
Disease 
 
ECOG Performance Status 0-2. 
 
 
No active ischemic heart disease or congestive heart failure (see Section 4.5). 
 
No known lymphomatous involvement of the CNS (see Section 4.6). 
 
 
No known HIV disease (see Section 4.7). 
 
 
Non pregnant and non-nursing (see Section 4.8). 
 
 
Patients with active medical processes (e.g., uncontrolled bacterial or viral infection, bleeding) not related to their 
lymphoma should be excluded. 
 
TREATMENT OVERVIEW 
 
CALGB 580603: REQUIRED FDG-PET/CT Imaging Companion (see Section 8.0) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 
A frozen tumor biopsy equivalent to a minimum of 4 at least 16 gauge needle cores is an important component of this study (see repeat 
tissue biopsy guidance in Section 4.1 and Section 5.4.1). Patients without adequate frozen material should have a biopsy performed to 
obtain material. If a biopsy is performed and does not yield adequate material, the patient is still eligible for the study. Patients who do 
not have a tissue site that can be safely biopsied may be enrolled only if permission is granted in writing (e-mail) by the Study Chairs 
(Drs. Wilson or Zelenetz) or their designees. 
† 
Baseline PET/CT for patients registered to the optional FDG-PET/CT Imaging Companion (CALGB 580603) is preferred prior to the 
CALGB 50303 baseline excisional biospsy and ≤ 30 days prior to the start of therapy. 
‡ 
For patients registered to the optional FDG-PET/CT Imaging Companion (CALGB 580603), PET/CT of abd/chest/pelvis will be 
collected at baseline, post-Cycle 2, and post-Cycle 6 (see Section 8.3). 
 
No concurrent radiation therapy will be permitted on study except for isolated CNS lesions. Patients who receive radiation to any site other 
than the CNS will be inevaluable. Patients with parenchymal CNS lesions should receive whole brain radiation and will only be considered 
treatment failures if the systemic disease progresses. 
The use of epoetin is allowed at the discretion of the investigator. It is recommended that epoetin not be used in this protocol unless hemoglobin 
is ≤ 10 g/dL, and that it be held or the dose modified for hemoglobin > 12 g/dL. 
R
E
G
I 
S
T
R
A
T
I
O
N
*
R
A
N
D
O
M
I
Z
A
T
I
O
N 
C1     C2      C3      C4       C5      C6 
Arm A: R-CHOP 
Arm B: DA-EPOCH-R 
C1      C2       C3      C4       C5      C6 
Stage 
Stage 
Treatment 
completed 
Treatment 
completed 
0          3         6         9        12        15      18 
Time Line (Weeks) 
C = Cycle = 21 days 
PET/CT 
CALGB 580603 ‡
PET/CT 
CALGB 580603 ‡
Baseline PET/CT † 
CALGB 580603
Version Date: 02/15/2018 
3 
Update #18 


CALGB 50303 
PHASE III RANDOMIZED STUDY OF R-CHOP V. DOSE-ADJUSTED EPOCH-R WITH MOLECULAR PROFILING IN UNTREATED 
DE NOVO DIFFUSE LARGE B-CELL LYMPHOMAS 
Schema Page 2 of 2 
 
Arm A: R-CHOP (see Section 7.1) 
Dose reductions for subsequent cycles will be determined by the occurrence of grade 4 neutropenia or febrile neutropenia (see Section 9.1.1). 
• 
Rituximab 375 mg/m2 IV infusion on Day 1 prior to CHOP chemotherapy. 
• 
Cyclophosphamide 750 mg/m2 IV on Day 1. 
• 
Doxorubicin 50 mg/m2 IV on Day 1. 
• 
Vincristine 1.4 mg/m2 IV (2 mg cap) on Day 1. 
• 
Prednisone 40 mg/m2/day PO on Days 1-5. 
• 
Begin filgrastim or pegfilgrastim if grade 4 neutropenia (ANC < 500/µL) or febrile neutropenia (ANC < 500/µL + fever ≥ 38.5°C [101°F] 
sustained for more than one hour) develops on the previous cycle. Administer filgrastim 480 mcg subcutaneous daily from Day 2 until ANC 
> 5000 after the nadir (nadir usually between Days 10-12) or for 10 days (Days 2-11) if the ANC is not being monitored, or pegfilgrastim 6 
mg SubQ on Day 2 (may be delayed up to two days for convenience of scheduling due to holidays, weekend, etc.). 
 
Required ancillary medications administered during all cycles: 
• 
Omeprazole 20 mg/day PO (or equivalent) 
• 
Stimulant laxative/stool softener (e.g., Pericolace®) 2 tablets PO BID and adjusted as necessary for constipation (prevention). 
• 
Lactulose 20 g PO Q 6 hours PRN until resolution or institutional preference for treatment of constipation. 
• 
Acetaminophen 650 mg PO and diphenhydramine 50-100 mg IV or PO 30-60 minutes prior to rituximab. 
• 
Hepatitis B surface Ag+ patients receive lamivudine 100 mg/day PO until 8 weeks past last chemotherapy. 
 
Patients with (1) ≥ 2 extranodal sites and elevated LDH, or (2) bone marrow involvement by large cell lymphoma will receive CNS prophylaxis 
consisting of intrathecal methotrexate 12 mg on Day 1 (or Day 2) of Cycles 3, 4, 5, and 6. 
 
Cycles will be repeated every 21 days for 6 treatment cycles. Restaging will occur after Cycles 4 and 6. 
 
Arm B: DA-EPOCH-R (see Section 7.2) 
Cycle 1 Doses: 
• 
Rituximab 375 mg/m2 IV infusion on Day 1 prior to EPOCH chemotherapy. 
• 
Doxorubicin 10 mg/m2/day CIVI on Days 1-4. 
• 
Etoposide 50 mg/m2/day CIVI on Days 1-4. 
• 
Vincristine 0.4 mg/m2/day (no cap) CIVI on Days 1-4 (total 1.6 mg/m2 over 96 hours). 
• 
Cyclophosphamide 750 mg/m2 IV on Day 5 (following completion of 96 hour infusions). 
• 
Prednisone 60 mg/m2 PO BID on Days 1-5. 
• 
Administer filgrastim 480 mcg subcutaneous daily from Day 6 until ANC > 5000 after the nadir (nadir usually between Days 10-12) or for 
10 days (Days 6-15) if the ANC is not being monitored, during every cycle. 
 
Doses for subsequent cycles will be determined by the absolute neutrophil (ANC) or platelet nadir from the previous cycle (see Section 
7.2.3). 
 
Required ancillary medications administered during all cycles: 
• 
Cotrimoxazole DS 1 tablet three times weekly (or equivalent if allergic). 
• 
Omeprazole 20 mg/day PO (or equivalent) 
• 
Stimulant laxative/stool softener (e.g., Pericolace®) 2 tablets PO BID and adjusted as necessary for constipation (prevention). 
• 
Lactulose 20 g PO Q6 hours PRN until resolution or institutional preference for treatment of constipation. 
• 
Acetaminophen 650 mg PO and diphenhydramine 50-100 mg IV or PO 30-60 minutes prior to rituximab. 
• 
Hepatitis B surface Ag+ patients receive lamivudine 100 mg/day PO until 8 weeks past last chemotherapy. 
 
Patients with (1) ≥ 2 extranodal sites and elevated LDH, or (2) bone marrow involvement by large cell lymphoma will receive CNS prophylaxis 
consisting of intrathecal methotrexate 12 mg on Day 1 (or Day 2) of Cycles 3, 4, 5, and 6. 
 
Cycles will be repeated every 21 days for a maximum of 6 cycles. Restaging will occur after Cycles 4 and 6. 
 
Version Date: 02/15/2018 
4 
Update #18 


CALGB 50303 
Guide to Companion Study Registration 
 
 
The following table is meant to assist clinical research associates in companion study registration and, if 
applicable, sample procurement. 
 
Frozen Tumor Biopsy (see 
Section 5.4.1) 
Whole Blood For 
Pharmacogenomics (see Section 
5.4.2) 
If “yes,” register to substudy 
CALGB 60405. 
* Please note that model informed consent questions are mapped to the CALGB registration 
system. As a result, it is highly recommended that the wording and order of the model informed 
consent questions be retained in order to facilitate patient registration. 
FDG-PET/CT Images 
(see Section 8.0) 
Registration to FDG-PET 
imaging study CALGB 580603 
is required at time of patient 
registration to CALGB 50303. 
Consent Question*: 
None. Required of all 
patients with accessible 
tissue (see Section 4.1) 
As of Update 14, 
participation in the 
imaging correlative 
study is required. 
Additional Registration 
Required?  No 
Additional 
Registration 
Required?  Yes 
Additional 
Registration 
Required?  Yes 
Consent Question*: 
Consent Question #1: “I 
agree that my blood may be 
used for the genetic research 
studies described above” 
Kind of Submission 
Version Date: 02/15/2018 
5 
Update #18 


CALGB 50303 
TABLE OF CONTENTS 
1.0 INTRODUCTION .............................................................................................................................. 9 
1.1 BACKGROUND .................................................................................................................................. 9 
1.2 RITUXIMAB-CHOP REGIMENS ...................................................................................................... 10 
1.3 DA-EPOCH-RITUXIMAB REGIMENS ............................................................................................. 10 
1.4 MOLECULAR PROFILING ................................................................................................................ 13 
1.5 RADIOTHERAPY CONSOLIDATION AND CNS PROPHYLAXIS .......................................................... 15 
1.6 ANALYSIS OF CANDIDATE GENETIC POLYMORPHISMS AND TREATMENT RESPONSE ................... 17 
1.7 COMPREHENSIVE ANALYSIS OF SOMATIC ALTERATIONS TO THE TUMOR GENOME ..................... 17 
1.8 FDG-PET ASSESSMENT IN DLBCL ............................................................................................... 19 
1.9 STUDY RATIONALE AND SUMMARY .............................................................................................. 21 
1.10 
INCLUSION OF WOMEN AND MINORITIES .................................................................................. 21 
2.0 OBJECTIVES .................................................................................................................................. 22 
2.1 PRIMARY OBJECTIVES .................................................................................................................... 22 
2.2 SECONDARY OBJECTIVES............................................................................................................... 22 
3.0 ON-STUDY GUIDELINES ............................................................................................................. 22 
4.0 ELIGIBILITY CRITERIA ............................................................................................................. 23 
4.1 DOCUMENTATION OF DISEASE....................................................................................................... 23 
4.2 PRIOR TREATMENT ........................................................................................................................ 24 
4.3 AGE ≥ 18 YEARS. ............................................................................................................................ 24 
4.4 ECOG PERFORMANCE STATUS 0-2................................................................................................ 24 
4.5 CARDIAC FUNCTION....................................................................................................................... 24 
4.6 LYMPHOMATOUS ........................................................................................................................... 24 
4.7 HIV STATUS ................................................................................................................................... 24 
4.8 PREGNANCY AND NURSING STATUS .............................................................................................. 24 
4.9 ACTIVE MEDICAL PROCESSES ........................................................................................................ 24 
4.10 
REQUIRED INITIAL LABORATORY VALUES*: ............................................................................ 24 
5.0 REGISTRATION/RANDOMIZATION, DATA SUBMISSION, HISTOLOGIC REVIEW 
AND SPECIMEN SUBMISSION FOR CORRELATIVE STUDIES .................................................. 25 
5.1 REGISTRATION/RANDOMIZATION .................................................................................................. 25 
5.2 DATA SUBMISSION ......................................................................................................................... 27 
5.3 HISTOLOGIC REVIEW ..................................................................................................................... 30 
5.4 SPECIMEN SUBMISSION FOR CORRELATIVE STUDIES .................................................................... 30 
6.0 REQUIRED DATA .......................................................................................................................... 32 
6.1 CALGB 580603 FDG-PET/CT IMAGING REQUIREMENTS ............................................................ 34 
7.0 TREATMENT PLAN ...................................................................................................................... 35 
7.1 ARM A (R-CHOP TREATMENT [7]) ............................................................................................... 35 
7.2 ARM B (DA-EPOCH-R TREATMENT [20]) .................................................................................... 37 
8.0 FDG-PET/CT IMAGING COMPANION (CALGB 580603)....................................................... 39 
8.1 INSTITUTION APPROVAL PROCEDURES FOR FDG-PET/CT IMAGING COMPANION....................... 39 
8.2 PROCEDURES FOR FDG-PET/CT IMAGING .................................................................................... 41 
8.3 FDG-PET/CT IMAGING ACQUISITION ........................................................................................... 41 
8.4 POST-TREATMENT STUDY PET/CT SCANS (CYCLES 2 AND 6) ...................................................... 42 
Version Date: 02/15/2018 
6 
Update #18 


CALGB 50303 
8.5 FDG-PET/CT DATA ARCHIVING, STORAGE, AND SUBMISSION .................................................... 43 
8.6 TRAINING FOR FDG-PET/CT DATA ACQUISITION AND HANDLING ............................................. 44 
8.7 CALGB IMAGING CORE LAB PROCESSING AND STORAGE ........................................................... 45 
8.8 INTERPRETATION OF POSITIVE POST-TREATMENT SCANS AND IMPLICATIONS OF PET IMAGES 
FOR PROGRESSIVE DISEASE .................................................................................................................... 48 
8.9 PET/CT SCAN REIMBURSEMENT ................................................................................................... 49 
9.0 DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY .......................................... 49 
9.1 ARM A (R-CHOP) DOSE MODIFICATIONS ..................................................................................... 49 
9.2 ARM B (DA-EPOCH-R) DOSE MODIFICATIONS ........................................................................... 51 
9.3 DOSE MODIFICATION FOR OBESE PATIENTS.................................................................................. 52 
10.0 
DRUG FORMULATION, AVAILABILITY, AND PREPARATION ................................... 53 
10.1 
DOXORUBICIN HCL (ADRIAMYCIN PFS™, ADRIAMYCIN RFS™, RUBEX®) ........................... 53 
10.2 
ETOPOSIDE (VEPESID®, EPIDOPHYLLOTOXIN, VP-16) ............................................................. 54 
10.3 
VINCRISTINE SULFATE (VCR, LEUROCRISTINE SULFATE, ONCOVIN®, VINCASAR PFS) ........... 55 
10.4 
CYCLOPHOSPHAMIDE (CYTOXAN®; NEOSAR®) ......................................................................... 56 
10.5 
PREDNISONE (DELTASONE, MISCELLANEOUS) .......................................................................... 56 
10.6 
RITUXIMAB ................................................................................................................................ 57 
10.7 
FILGRASTIM (G-CSF; R-MET HUG-CSF; GRANULOCYTE COLONY STIMULATING FACTOR; 
NEUPOGEN®) .......................................................................................................................................... 58 
10.8 
PEGFILGRASTIM (NEULASTA®) ................................................................................................. 58 
10.9 
METHOTREXATE (MTX, FOLEX) ............................................................................................... 59 
11.0 
ANCILLARY THERAPY ........................................................................................................... 59 
11.1 
SUPPORTIVE CARE ..................................................................................................................... 59 
11.2 
HORMONES AND OTHER CHEMOTHERAPEUTIC AGENTS ........................................................... 60 
11.3 
EPOETIN ..................................................................................................................................... 60 
12.0 
CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE ....................................... 60 
12.1 
DEFINITIONS OF RESPONSE [61] ................................................................................................ 60 
12.2 
RESPONSE ASSESSMENT TABLE ................................................................................................ 61 
12.3 
CRITERIA FOR FDG-PET RESPONSE .......................................................................................... 62 
13.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY .............................................. 62 
13.1 
DURATION OF TREATMENT........................................................................................................ 62 
13.2 
EXTRAORDINARY MEDICAL CIRCUMSTANCES .......................................................................... 62 
14.0 
STATISTICAL CONSIDERATIONS ....................................................................................... 63 
14.1 
CLINICAL ENDPOINTS ................................................................................................................ 63 
14.2 
INTERIM ANALYSIS .................................................................................................................... 64 
14.3 
MOLECULAR CHARACTERIZATION STUDIES ............................................................................. 64 
14.4 
STUDY SIZE REQUIREMENTS TO ACHIEVE PHARMACOGENETIC GOALS .................................. 66 
14.5 
OVERVIEW OF FDG-PET/CT STUDY (CALGB 580603) ........................................................... 67 
15.0 
ADVERSE EVENT REPORTING (AER) ................................................................................ 70 
15.1 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST (CAEPR) FOR RITUXIMAB 
(NSC 687451) ......................................................................................................................................... 72 
16.0 
REFERENCES ............................................................................................................................. 76 
Version Date: 02/15/2018 
7 
Update #18 


CALGB 50303 
APPENDIX I ..... CANCER TRIALS SUPPORT UNIT (CTSU) PARTICIPATION PROCEDURES
 
83 
APPENDIX II CALGB 580603 PET/CT INSTRUMENT TECHNICAL SPECIFICATIONS 
FORM 
88 
APPENDIX III .............................................. CALGB 580603 IMAGING SITE PERSONNEL FORM
 
93 
 
Version Date: 02/15/2018 
8 
Update #18 


CALGB 50303 
1.0 
INTRODUCTION 
1.1 
Background  
Approximately 55,000 cases of non-Hodgkin lymphoma (NHL) are diagnosed yearly in the 
United States. Diffuse large B-cell lymphoma (DLBCL) comprises 25-30% of these cases, and 
represents a significant public health issue; it is the single most common lymphoma in the United 
States with over fifteen thousand new cases each year and a rising incidence. Although 
potentially curable, only 35% of patients achieve a durable complete remission with standard 
CHOP chemotherapy, and most of the remaining patients die of their disease [1]. Because of the 
curative potential of DLBCL, advances in treatment will have a significant impact on patient 
survival and quality of life. Indeed, a 15% increase in cure will save over 2000 additional lives 
annually with attendant savings in medical costs, social productivity and patient suffering. 
Investigators have worked to develop alternative regimens that reduce toxicity, permit dose 
intensification, and circumvent tumor cell resistance. Strategies to improve chemotherapy have 
been mostly unsuccessful. The second and third generation regimens–m-BACOD, ProMACE-
CytaBOM and MACOP-B and high dose therapy with stem cell transplantation–strategies 
empirically modeled on the Goldie-Coldman and Dose Intensity hypotheses, have not improved 
survival compared to standard “CHOP” based treatment [1-3]. 
Several recent reports suggest some advances in the chemotherapy treatment of aggressive 
lymphomas, but are open to interpretation. A randomized comparison of ACVBP, a high-dose 
CHOP variant, and standard CHOP in 708 patients aged 61 to 69 years with aggressive NHL 
and at least one adverse prognostic factor in the age-adjusted international prognostic index (IPI) 
was recently published [4]. At 5 years, the ACVBP and CHOP groups had an event-free survival 
(EFS) of 39% and 29% (p=0.005), respectively, and an overall survival of 46% and 38% 
(p=.036), showing an improved outcome for ACVBP. The results indicate, however, that some 
of the benefit of ACVBP may lie in its better control of central nervous system (CNS) disease. 
Because both arms had a similar rate of complete remission (CR) with 58% in the ACVBP and 
56% in the CHOP groups, much of the benefit in the ACVBP arm was due to an improvement 
in disease-free survival (DFS) due in part to a lower rate of CNS progression (9 patients vs. 26 
patients) in the ACVBP compared to the CHOP arm (p=.004). Importantly, only patients in the 
ACVBP group received intrathecal CNS prophylaxis as well as intravenous methotrexate, which 
likely improved control of occult CNS lymphoma. 
The German Lymphoma Study Group recently reported the preliminary results of a 4-arm 
comparison of 14- and 21-day CHOP and CHOEP in younger and older (> 60 years) patients 
with untreated aggressive lymphomas [5,6]. In younger patients with low-risk disease, the 
addition of etoposide (CHOEP) improved overall survival from 74% to 88%, compared to 
CHOP, whereas in older patients with higher risk disease (i.e., at least 1 adverse IPI factor) 
CHOP time intensification (i.e., CHOP-14), compared to CHOP-21, was associated with an 
improved survival (54% v 45%, respectively). One question with these results is the absence of 
an obvious biological basis for the findings. Further insight will have to await publication of 
these results. 
The absence of significant advances in the treatment of aggressive lymphomas over the past 30 
years is a sobering testament to the failure of empirically based clinical research and not 
necessarily to the absence of more effective chemotherapy platforms. Indeed, chemotherapy 
remains the centerpiece of curative therapy for DLBCL, although recent studies indicate the 
importance of targeted agents, such as rituximab. Hence, there is an important need to conduct 
clinical trials using scientifically engineered therapeutics and to assess biological endpoints.  
Version Date: 02/15/2018 
9 
Update #18 


CALGB 50303 
1.2 
Rituximab-CHOP Regimens  
Recent studies suggest that the monoclonal antibody, rituximab (R), directed against the CD20 
B-cell antigen, may increase the efficacy of chemotherapy. In vitro, rituximab has been shown 
to sensitize drug-resistant lymphoma cell lines to chemotherapy. Recent evidence has shown 
that rituximab increases the benefit of CHOP in aggressive CD20+ lymphomas. A randomized 
study of CHOP versus R-CHOP was performed in 197 patients ≥ 60 years old with DLBCL [7]. 
Patients who received R-CHOP had a higher rate of CR compared to CHOP alone; 76% versus 
63%, respectively. With a median follow-up of 2 years, the EFS of R-CHOP and CHOP was 
57% and 38%, respectively, and at 3 years, it was approximately 51% and 38%. Results from a 
phase II study of rituximab and CHOP in untreated aggressive B-cell lymphomas have also been 
reported by Vose et al. [8]. In this study of 33 patients, 61% achieved CR and 90% of patients 
were progression-free, with a median follow-up of 26 months. While the 90% PFS is very 
encouraging, 70% of patients in the series were in the low IPI (0-2) risk group, and at least 21% 
had evidence of a follicular histological pattern. The preliminary results of a phase III trial of 
CHOP-R versus CHOP with a second randomization to maintenance rituximab or observation 
in patients 60 years of age and older with DLBCL were recently presented at the American 
Society of Hematology meetings in 2003 [9]. Although the second randomization confounded 
the study interpretation, the results nevertheless suggested that the addition of rituximab 
improves the outcome of CHOP treatment in DLBCL. Hence, R-CHOP has become the de facto 
new standard for DLBCL, although longer follow-up will be needed to assess accurately the 
impact of rituximab. Of note, however, the benefit of rituximab appears to be principally in 
patients with BCL-2 positive tumors, which is likely a marker for the activated B-cell (ABC) 
subtype of DLBCL [10]. 
1.3 
DA-EPOCH-Rituximab Regimens 
The dose-adjusted (DA) EPOCH regimen was developed based on in vitro and 
pharmacodynamic principles to help overcome drug resistance [11]. In this regimen, 
doxorubicin, vincristine, and etoposide are administered as a 96-hour continuous infusion, and 
cyclophosphamide and prednisone are administered on a bolus schedule. The rationale for the 
administration schedule derived from the laboratory observation that human tumor cell lines, 
including those with a multi-drug resistance phenotype, are more sensitive to cytotoxic natural 
products given for prolonged periods at low concentrations than to the same agents given for 
brief periods at higher concentrations. 
EPOCH was initially developed and tested in 131 patients with relapsed or refractory NHL [12]. 
The response rate in these heavily pre-treated patients was 74% with 24% of patients achieving 
complete remission. Furthermore, among the subset of patients with aggressive histologies, 36% 
achieved complete remissions. Therapy was tolerable with a treatment-related mortality of 2%. 
A study of EPOCH was undertaken to address the role of EPOCH as initial therapy in DLBCL 
[13]. In this trial, the doses of doxorubicin, etoposide and cyclophosphamide were escalated 
20% on every cycle in which the nadir absolute neutrophil count (ANC) exceeded 500/µL, or 
reduced 20% if the ANC was less than 500/µL for more than 2 CBC measurements (CBC 
obtained twice weekly only) or the platelet nadir was < 25,000/µL. The rationale for dose-
adjustment in each patient was based on several factors: 1. Dose intensity has been associated 
with improved outcome in aggressive lymphomas; 2. Small changes in steady state 
concentrations (Css) for infused agents can significantly affect efficacy (i.e., threshold 
concentration); 3. Preliminary pharmacokinetics showed up to a 6-fold variation in Css in 
patients treated with the same dose. 
Fifty patients with untreated de novo DLBCL were enrolled. Patients had a median (range) age 
of 46 (20-88), and IPI distribution of 56% low (0/1/2) and 44% high (3/4/5) risk disease. 
Complete responses (CR) were obtained in 45 patients (92%) and partial responses in 4 patients. 
Version Date: 02/15/2018 
10 
Update #18 


CALGB 50303 
There was no difference in CR rate among the IPI risk groups with 19 of 22 high risk and 26 of 
27 low risk patients achieving CR. With a median follow-up of 62 months, the actuarial 
progression-free survival (PFS) is 70% and overall survival (OS) is 73%. The data have recently 
been updated to a median follow-up of 81 months, and no relapses have occurred since reported 
at a median follow-up of 62 months as shown below [14]. The PFS at 62 months for low and 
high-risk groups are 79% and 58%, respectively, and the OS is 89% and 55%, respectively. 
Dose-adjusted EPOCH was well tolerated with a 8% incidence of fever and neutropenia. 
 
  
 
 
 
 
 
 
 
 
Potential mechanisms of treatment failure, such as bcl-2 and p53 mutation, which are associated 
with apoptosis, and tumor proliferation rate (MIB-1), which is associated with drug sensitivity, 
were assessed by immunohistochemistry [15-18]. Overexpression of bcl-2 was the only factor 
associated with treatment failure in both univariate and multivariate Cox models, with 82% of 
bcl-2 negative and only 50% of bcl-2 positive patients progression-free at 52 months (shown 
below left). Also of interest was the impact of high tumor proliferation on outcome. In contrast 
to findings with CHOP-based regimens, patients with high tumor proliferation (>80%) were less 
likely to progress than patients with lower proliferation rates, although the result did not reach 
statistical significance (p2 = 0.09) (shown below right). These results suggest that dose-adjusted 
EPOCH may produce greater cell kill than CHOP-based regimens. Patients with p53 
overexpression had a higher progression rate, although only survival showed a statistically 
significant association. 
 
 
 
 
 
 
 
 
 
 
 
The dose-adjustment paradigm was developed in an attempt to reduce interpatient variation in 
plasma concentrations of chemotherapy by normalizing dose-rate to neutrophil nadirs. Most 
patients required dose escalations to achieve a neutrophil nadir, with 29% of cycles at ≥ 144% 
0
1
2
3
4
5
6
7
8
20
100
80
60
40
Years on Study 
9
*
*
*
*
*
*
*
o
o
o
o
o
o
o
o
o
Progression-Free (%)
High Risk
Low Risk
p2 = .15
0
1
2
3
4
5
6
7
8
20
100
80
60
40
Years on Study 
9
Progression-Free (%)
*
*
*
o
o
o
o
o
o
o
bcl-2 -
bcl-2 +
p2 = .04
0
1
2
3
4
5
6
7
8
20
100
80
60
40
Years on Study 
9
Progression-Free (%)
MIB-1 ≥80%
MIB-1 < 80%
p2 = .24
*
*
*
*
*
*
o
o
o
o
o
*
*
*
*
*
*
o
o
o
o
o
Overall Survival (74%)
Progression-Free Survival (70%)
Median Follow-up 81 Months 
0
1
2
3
4
5
6
7
8
20
100
80
60
40
Years on Study 
Percent
9
10
CR = 92%
Version Date: 02/15/2018 
11 
Update #18 


CALGB 50303 
of dose level 1 and 5% administered below dose level 1. Of note, the first cycle was more often 
associated with greater hematopoietic toxicity than cycle 2 with 38% of patients requiring dose 
escalations on cycle 3. Over all cycles, the mean dose intensification (DI) for the escalated agents 
were equivalent to the second dose level and were: (mean ± SD: mg/m2/week) 
cyclophosphamide 296 ± 59; etoposide 80 ± 14; doxorubicin 16 ± 2.8. The vincristine DI was 
96% of the planned dose intensity and was (mean ± SD: mg/m2/week) 0.51 ± 0.06.  
The strategy of normalizing dose rate to the neutrophil nadir allows an opportunity to examine 
more accurately the influence of clinical factors on DI. This analysis revealed a significant 
inverse correlation between the DI of all adjusted agents and patient age (etoposide: r = -0.48; 
p2 = 0.0004), but no correlation with any other IPI risk factor, the IPI index itself, or the outcome 
measures of PFS or OS (shown below left) (unpublished observations) [13]. The lower DI with 
age could be explained by decreased hematopoietic tolerance and/or decreased drug metabolism 
in older patients. Preliminary pharmacokinetics (PK) of etoposide in 14 patients receiving dose-
adjusted EPOCH revealed an inverse correlation between age and clearance of free etoposide (r 
= -0.44; p2 = 0.1), suggesting that older patients may achieve higher serum levels than younger 
patients at similar dose rates (shown below left). Additionally, in 6 patients with PK on multiple 
cycles, the clearance of free etoposide increased over each cycle, with an average increase of 
58% between cycles 1 and 6 (Hochberg adjustment for multiple comparisons: p2= 0.02), 
indicating that, in the absence of dose escalation, the actual etoposide serum levels would 
decrease in many patients (shown below right).  
 
 
 
 
 
 
 
 
 
 
 
These data suggest that the neutrophil nadir can be used as a surrogate to pharmacokinetics for 
normalization of Css. However, the neutrophil nadir will also reflect intracellular mechanisms 
such as drug efflux pumps (e.g., MDR-1), drug metabolism and DNA repair, to name a few.  
These variables all contribute to the variability of tumor response to chemotherapy, and are 
influenced by both germline polymorphisms and mutations within the tumor [19]. Hence, a 
secondary objective of this study will be to investigate the relationship between the 
pharmacogenomics (genetic polymorphisms) of normal mononuclear cells and clinical outcome 
(EFS, OS and toxicity) and tumor microarray. Although exploratory, this may provide important 
insights into the effects of genetic polymorphism on pathways of lymphomagenesis and 
treatment response and toxicity. This will be the first study to assess pharmacogenomics in 
DLBCL.  
The results with dose-adjusted EPOCH demonstrated that the regimen was well tolerated and 
suggested that this novel schedule and pharmacodynamic-based regimen may improve upon 
results achieved with CHOP-based regimens. However, patients with bcl-2+ lymphomas had a 
significantly worse outcome, compared with bcl-2 negative cases, indicating the need for further 
0
200
400
600
800
1000
1200
10
20
30
40
50
60
70
80
Free Etoposide Clearance [ml/min/m
2]
Age (Years) 
r = -0.45
0
200
400
600
800
1000
1200
1400
Free Etoposide Clearance [ml/min/m
2]
 
1
6
5
4
3
2
7
8
Cycle Number
20
18
18
20
18
16
2
2
Version Date: 02/15/2018 
12 
Update #18 


CALGB 50303 
improvement in the regimen. Thus, based upon in vitro evidence showing synergy between 
rituximab and cytotoxic agents, a phase II study of dose-adjusted EPOCH with rituximab (DA-
EPOCH-R) was begun [20]. Preliminary results are available in 76 previously untreated patients 
with CD20+ DLBCL. The median patient age is 48 (range: 12-85) years, median ECOG 
performance status is 1 (range: 0-3), and 36% had high-intermediate or high international 
prognostic index (IPI) scores [14]. Among 71 patients evaluable for response (4 TE; 1 NE), 
complete responses (CR) were achieved in 92%, which is similar to DA-EPOCH alone. At a 
median follow-up of 26 months, the progression-free and overall survivals are both 82%. 
 
 
 
 
 
 
 
 
 
 
Based on the hypothesis that rituximab may help overcome molecular causes of drug resistance, 
it was investigated whether BCL-2 and p53 overexpression are associated with drug resistance 
in DA-EPOCH-R, as had been shown with DA-EPOCH alone. As shown below, BCL-2 no 
longer identified an adverse prognostic group in the DA-EPOCH-R regimen, suggesting that 
rituximab may overcome these pathways of resistance, a result which was confirmed in the 
GELA study of CHOP v R-CHOP [10]. Biologically, BCL-2 is a marker of the activated B-cell 
(ABC) molecular subtype of DLBCL, and this subtype may be the actual target of rituximab. 
 
 
 
 
   
 
 
 
 
 
 
The data on dose-adjusted EPOCH and EPOCH-R suggest these regimens may circumvent the 
limitations of conventional CHOP chemotherapy, but this needs to be ultimately confirmed in a 
randomized trial with R-CHOP. Furthermore, the dose-adjustment strategy has made the 
regimen tolerable in all age ranges and, unlike other approaches, its use is not age dependent. 
1.4 
Molecular Profiling 
Historically, treatment studies have been restrained by histological definitions of cancer. 
Molecular characterization, however, provides the foundation for a biological classification that 
weighs the relevance of tumor heterogeneity [21,22]. Without molecular characterization, the 
Percent
0
20
100
80
60
40
Months on Study 
6
12
18
24
30
Median Follow-up: 2 years
PFS and OS: 79% 
42
36
48
54
60
DA-EPOCH
DA-EPOCH-R
Median Follow-up 60 mos
Median Follow-up 23 mos
BCL-2 – (82%)
BCL-2+ (50%)
0
1
2
3
4
5
6
7
8
20
100
80
60
40
Years on Study 
Percent
p2 = .04
Percent
0
20
100
80
60
40
Months on Study 
6
12
18
24
30
BCL-2+ (83%)
42
36
48
54
60
BCL-2- (71%)
Version Date: 02/15/2018 
13 
Update #18 


CALGB 50303 
clinical evaluation of treatments/drugs may fail to reveal important activity if only a portion of 
the tumors possess the molecular target(s) or pathways affected by the therapy. The 
Lymphoma/Leukemia Molecular Profiling Project at the NCI (LLMPP) has used molecular 
profiling to subdivide the most common type of non-Hodgkin lymphoma, diffuse large B-cell 
lymphoma, into distinct diseases with different responses to anthracyline-based multi-agent 
chemotherapy. Diffuse large B-cell lymphoma (DLBCL) presents a unique opportunity to 
incorporate molecular profiling in a clinical study comparing two treatment strategies that may 
have different molecular pathways of resistance. This trial will assess a new regimen (DA-
EPOCH-R) versus the current standard regimen (R-CHOP) for this common and potentially 
curable lymphoma. Through molecular profiling, it may be possible to identify molecular 
subgroups that are more susceptible to one treatment regimen and will allow the development 
of a molecular prognostic model that may be useful clinically. We believe this study can provide 
proof of principle for the importance of molecular profiling in prospective clinical trials and 
hasten the translation of molecular diagnosis into routine clinical management of cancer 
patients. 
Roughly 35% of patients with DLBCL can be cured by conventional anthracycline-based 
chemotherapy regimens (e.g., CHOP), whereas the others eventually succumb to this disease. 
This clinical heterogeneity suggested that this lymphoma type might encompass several 
molecularly distinct subgroups that differ in their responsiveness to therapy. This hypothesis has 
been confirmed in gene expression profiling studies conducted by the LLMPP, which recently 
analyzed gene expression in 240 retrospectively obtained biopsy specimens of DLBCL and 
correlated gene expression profiles of the tumors with clinical outcome of the patients [23,24]. 
Three broad gene expression subgroups of DLBCL were defined that differed in the expression 
of over 1,000 genes. These subgroups reflected, in part, the cell of origin of the tumors. One 
subgroup, termed germinal center B-cell-like (GCB) DLBCL resembled normal germinal center 
B cells in gene expression whereas another subgroup, termed activated B-cell-like (ABC) 
DLBCL, resembled mitogenically activated blood B cells. A third minor subgroup, termed Type 
3, did not share gene expression features of either GCB or ABC DLBCL and may be 
heterogeneous. Importantly, this gene expression subgroup distinction identified patients with 
distinct clinical outcomes: GCB DLBCL patients had a relatively favorable prognosis, with a 5-
year survival rate of 60%, whereas ABC and Type 3 DLBCL patients had 5-year survival rates 
of 35% and 39%, respectively. One mechanism underlying this differential response to 
chemotherapy may be that GCB DLBCLs, like normal germinal center B-cells, have particularly 
low activity of the NF-kB pathway. This pathway protects cells from apoptosis induced by 
chemotherapy and is constitutively active in ABC DLBCLs, perhaps accounting for their 
relative resistance to CHOP chemotherapy [13]. 
 
 
 
 
 
 
 
 
 
 
Version Date: 02/15/2018 
14 
Update #18 


CALGB 50303 
Additionally, however, further variation in gene expression was found to account for the residual 
clinical heterogeneity within each of the DLBCL subgroups [24]. A systematic search was 
undertaken for individual genes with expression patterns that correlated with overall survival. 
The majority of predictive genes could be classified into four gene expression “signatures” that 
reflected different aspects of tumor cell biology. Most of the genes that predicted poor outcome 
belonged to the proliferation gene expression signature that includes genes that are more highly 
expressed in dividing cells than in quiescent cells.  Many genes that predicted good outcome 
belonged to the germinal center B-cell signature, a finding that reflects the relatively good 
outcome of GCB DLBCL patients. Two other sets of genes that predicted good outcome 
suggested that host immune responses might contribute to curative outcomes following 
chemotherapy. The expression of MHC class II genes in the tumor cells correlated with good 
outcome, suggesting a role for antigen presentation by the tumor cells to infiltrating T 
lymphocytes. Another set of genes that predicted good outcome identified tumors with an 
intense fibrotic reaction characterized by infiltrating macrophage and natural killer cells, and 
may reflect an innate immune response to the tumor. In addition to these four sets of predictive 
genes, a single gene, BMP6, was found to be an independent predictor of poor outcome, and its 
expression may reflect the ability of the lymphoma cells to differentiate towards plasma cells. 
A multivariate predictive model of overall survival was created from 17 genes chosen from the 
different functional groups mentioned above [24]. This gene expression-based outcome 
predictor was able to stratify patients into risk groups with strikingly distinct overall survival 
rates. One half of the patients could be placed in a favorable risk group with a 71% 5-year 
survival rate. One quarter of the patients were in a poor risk group with only a 15% 5-year 
survival rate and the remaining quarter of patients had a 36% 5-year survival rate. Clearly, these 
findings demonstrate the need to identify alternative therapies for those patients in the poorest 
risk groups. 
The results of this study will have important implications for future treatment of DLBCL. 
Clinically, the study will determine if DA-EPOCH-R provides a significant therapeutic advance 
over R-CHOP, and will determine the therapeutic platform for future trials in DLBCL. Because 
DA-EPOCH-R incorporates several unique strategies, including infusional scheduling, 
etoposide use and pharmacodynamics-based dose optimization, the clinical outcome will 
provide some assessment of these strategies. The microarray tissue analyses and 
pharmacogenomics will provide important information. This study will be the first to 
prospectively assess microarray histological diagnosis, which is likely to become an important 
pathological diagnostic tool. The study will develop a molecular prognostic model for each 
regimen, which will provide patient prognostic information, identify patients suitable for novel 
therapy approaches, and will identify potential mechanisms of treatment failure important for 
the rational development of new treatment strategies. Importantly, this study will be the first to 
assess molecular mechanisms of treatment failure with a rituximab-based regimen. It will also 
be the first to prospectively validate the use of microarray in a lymphoma therapeutic trial, thus 
providing proof of principle, and serve as a model for future trials. 
1.5 
Radiotherapy consolidation and CNS prophylaxis 
A salient question is the role of radiation in the treatment of DLBCL. Radiation has been variably 
used in clinical trials for both advanced and early stage disease. Although several studies have 
suggested a benefit for radiation consolidation following CHOP chemotherapy in early stage 
DLBCL, longer follow-up has indicated a higher rate of late relapses among patients who receive 
limited chemotherapy and radiation, with an equivalent PFS and OS [25,26]. Additionally, 
preliminary results of a randomized study of ACVBP versus CHOP followed by radiotherapy 
in low risk localized aggressive lymphoma showed a statistically superior EFS and OS for the 
ACVBP arm, and concluded that ACVBP is superior to CHOP + radiation [27]. Radiation has 
Version Date: 02/15/2018 
15 
Update #18 


CALGB 50303 
also been commonly used following chemotherapy in patients with primary mediastinal 
(thymic) DLBCL (PMLBCL). In a study of 50 patients with PMLBCL initially treated with 
MACOP-B, 66% had a persistently positive gallium scan, suggesting the presence of active 
disease [28]. However, following radiation consolidation, only 19% of patients had a positive 
gallium scan. With a median follow up of 39 months, 80% of all patients were event free. 
Importantly, all patients with a negative gallium after radiation were event free, whereas 60% 
of gallium positive patients relapsed. For comparison, none of the patients with PMLBCL 
treated with DA-EPOCH or DA-EPOCH-R received radiation consolidation. Among 14 
PMLBCL patients treated with DA-EPOCH, PFS and OS were 68% and 79%, respectively, at 
the median follow-up of 81 months; all patients in CR or CRu were gallium negative at the end 
of treatment. Furthermore, among 13 PMLBCL patients treated with DA-EPOCH-R, PFS and 
OS is 93% and 100%, respectively, at the median follow-up of 24 months. Although the patient 
numbers are small, they suggest that rituximab may benefit patients with PMLBCL; a benefit 
which may also extend to patients receiving CHOP chemotherapy. These studies raise the 
question of whether radiation consolidation is necessary in patients with PMLBCL. Although 
radiation appears to benefit patients treated with MACOP-B, this cannot be extended to the DA-
EPOCH or ACVBP regimens. It is also important to recognize that radiation consolidation has 
significant adverse long term side effects, including an increased risk of breast cancer in women 
under 30 years of age (the most common group with PMLBCL), heart disease and other solid 
tumors [29]. Hence, inclusion of PMLBCL patients in this phase III study will provide important 
information on their outcome with rituximab based treatment and in the absence of radiation. 
To provide a measure of safety, all patients with PMLBCL with residual mediastinal 
abnormalities after completion of treatment will receive a PET scan. Patients whose PET scan 
is highly suspicious will undergo biopsy. Patients whose PET scan is equivocal will be followed 
monthly with a PET and/or CT scan and undergo a biopsy if the scan indicates increasing 
abnormalities. Only patients with biopsy proven disease following treatment may receive 
radiation and will be considered treatment failures on the study. 
Radiation consolidation has been variably used in patients with more advanced stage DLBCL, 
but has no clear benefit. The 4-arm studies of CHOP 14/21 and CHOEP 14/21 employed 
radiotherapy consolidation for those patients with initial masses ≥ 7.5 cm, but the studies were 
not designed to assess the role of radiation and its inclusion confounds the interpretation of 
results [5,6]. In contrast, studies employing ACVBP from the GELA group have not included 
radiation consolidation, including those patients with PMLBCL [4]. Similarly, radiation has not 
been used in the DA-EPOCH or DA-EPOCH-R studies. In conclusion, these studies do not 
suggest that radiation consolidation significantly improves the cure of DLBCL. Because the 
clinical and scientific objectives of this phase III study are to compare the efficacy of R-CHOP 
and DA-EPOCH-R and to assess mechanisms of treatment failure, inclusion of radiation 
consolidation would confound the interpretation of results and will not be used in the present 
study. 
Secondary involvement of the central nervous system (CNS) by aggressive B-cell lymphomas 
is an infrequent but nearly always fatal complication [29,30]. Prophylactic treatment reduces the 
incidence of CNS relapse, but increases the toxicity of systemic chemotherapy and is only 
necessary in patients at high risk of CNS spread [4]. This has led to the development of clinical 
risk paradigms to identify patients who might benefit from CNS prophylaxis, but even among 
these patients, only a minority ever develop CNS disease [31,32]. For example, in a study of 
605 newly diagnosed large cell lymphomas, van Besien et al. reported a Kaplan-Meier estimate 
of 17.4% probability of CNS recurrence at 1 year in 93 patients at risk according to their 
multivariate model, which included elevated lactate dehydrogenase (LDH) and more than one 
extranodal disease site [31]. In a randomized study of ACVBP versus CHOP in poor-prognosis 
aggressive lymphoma, there was a significantly higher incidence of CNS failures in the CHOP 
Version Date: 02/15/2018 
16 
Update #18 


CALGB 50303 
arm, where CNS prophylaxis was not performed [4]. These studies indicate that patients at high 
risk of CNS disease may benefit from prophylaxis, and prophylaxis should be used in such 
patients. For this reason, patients treated on the DA-EPOCH and DA-EPOCH-R studies who 
were at high risk of CNS disease received CNS prophylaxis with intrathecal methotrexate. 
Hence, for the phase III study, patients who have a high clinical risk of CNS involvement will 
receive CNS prophylaxis. Patients will be considered to be high risk based on the risk paradigm 
developed by van Besien et al. This includes: 1. patients with 2 or more extranodal disease sites 
and elevated LDH or; 2. any patient with involvement of the bone marrow or testicle by DLBCL. 
1.6 
Analysis of Candidate Genetic Polymorphisms and Treatment Response 
There is increasing evidence suggesting that germline polymorphisms related to the metabolism, 
transport, therapeutic targets and/or therapeutic pathways of anticancer agents might help predict 
therapeutic outcomes [33,34]. The major aim of this effort is to determine the influence of 
candidate gene polymorphisms on toxicity and outcome measures, including event free survival 
(EFS), with the ultimate goal of individualized cancer therapy. 
The primary pharmacogenetic hypothesis will be that the ABCB1 3435 CC genotype is 
associated with decreased EFS in both arms of this study. The ABCB1 gene (ATP Binding 
Cassette Beta 1; also called MDR1), encodes the P-glycoprotein PGP, a transmembrane protein 
involved in human cellular transport [35]. PGP achieves the energy dependant efflux of 
doxorubicin, etoposide, vincristine and prednisone out of target cells [36,37]. While many 
ABCB1 polymorphisms have been studied, the synonymous C to T polymorphism at base 
position 3435 of the ABCB1 has been most strongly associated with drug treatment outcome 
[38]. Individuals with the CC genotype at this position exhibit worse outcomes in response to 
drug therapy for HIV [39], epilepsy [40], and acute myeloid leukemia (receiving an 
anthracycline based regimen) [41]. We therefore hypothesize that patients with the ABCB1 3435 
CC genotype will exhibit decreased EFS relative to patients with the 3435 CT and 3435 TT 
genotypes. 
Secondary hypotheses will also be tested to evaluate the association between the presence of 
variants in candidate genes and measures of both toxicity and outcome in both study arms. 
Assays for genetic variants will be performed for the following genes: CD20 (rituximab), 
TOP2A (doxorubicin, etoposide), TUBB and MAP4 (Vincristine), CYP3A4/3A5 (doxorubicin, 
vincristine, etoposide, prednisone), CYP2C19, ADH1, and ALDH1A1 (cyclophosphamide) and 
NR3C1 (prednisone).  These candidate genes have been chosen based on their potential influence 
on metabolism and activity of the therapeutics used in this study. Additional genes or variants 
of interest might also be explored as new information relevant to the study emerges. 
In addition to specific hypothesis testing for the above candidate genes, this study will also 
provide the framework for analyzing the relationship between genotypes derived from germline 
vs. tumor DNA. As excess tumor DNA will be collected in the pharmacogenomics component 
of this study, we will genotype candidate polymorphisms in DNA derived from both tumor 
tissue and whole blood. This will allow us to assess the accuracy of germline genotypes for 
predicting tumor genotypes, and to determine the relative power of tumor vs. germline 
genotypes for predicting treatment outcome. 
1.7 
Comprehensive Analysis of Somatic Alterations to the Tumor Genome 
Genome sequence characterization is a key to understanding the biology and clinical behavior 
of cancers and to predict the response to therapy. The present study proposes to perform a 
comprehensive analysis of somatic alterations to the tumor genome. To understand which 
genomic alterations are somatically acquired by the tumor and which are encoded in the germ 
line of the patient, it is necessary to compare the genome of a tumor biopsy sample with that of 
a matched sample of normal tissue, such as blood. Included in this analysis will be DNA 
Version Date: 02/15/2018 
17 
Update #18 


CALGB 50303 
sequencing of all or part of the tumor and normal cell genomes, which can be achieved by 
classical DNA sequencing of individual genes or by utilizing high-throughput DNA sequencing 
technologies. Recently, in diffuse large B cell lymphoma (DLBCL), a number of recurrent 
oncogenic abnormalities have been uncovered by DNA sequencing. These abnormalities track 
with known molecular subtypes of this disease. For example, in the ABC subtype of DLBCL, 
recurrent mutations in CARD11, CD79B, and MYD88 have been described [42-44]. 
Conversely, the GCB DLBCL subtype is characterized by frequent gain-of-function mutations 
of EZH2 [45-47]. 
Other genomic methodologies will be used to assess DNA copy numbers in both tumor and 
normal DNA using, for example, microarrays containing oligonucleotides representing single 
nucleotide polymorphisms (SNPs) and other non-polymorphic regions of the genome. These 
copy number changes also segregate according to the molecular subtype of DLBCL [48]. For 
example, deletion of the INK4A/Arf tumor suppressor locus occurs in roughly one fifth of ABC 
DLBCL cases, but never in GCB DLBCL. Moreover, copy number changes have been 
associated with overall survival in response to CHOP chemotherapy [48]. Specifically, 
INK4A/Arf locus deletions and trisomy of chromosome 3 were both associated with adverse 
survival among patients with ABC DLBCL. 
The activity of the tumor genome will be assessed by profiling the expression levels of mRNAs 
and microRNAs in a tumor biopsy sample using microarray and multiplexed PCR methods. The 
mRNA expression profiling of samples on CALGB 50303 is a primary endpoint of this trial 
since gene expression signatures have been used to identify molecular subtypes of DLBCL and 
to predict therapeutic response [49-51]. In addition, new methods have been developed recently 
to identify new RNA species that are expressed from the genome. For example, digital gene 
expression is based on the high-throughput resequencing of mRNA, an effort that can uncover 
previously unannotated genes and new alternatively spliced isoforms of known genes. This 
effort would be exploratory, aiming to identify new aspects of the biology of DLBCL tumors 
that are related to therapeutic response. In addition, microRNAs have the capacity to identify 
molecular subtypes of DLBCL and can yield additional functional information because of their 
ability to regulate the expression of large repertoire of genes [52-53]. 
The activity of the genome is also dictated by patterns of cytosine DNA methylation. In acute 
myelogenous leukemia, molecular subtypes have been identified by their DNA methylation 
patterns that are biologically and clinically distinct [54-55]. Application to DLBCL revealed the 
de novo methylation of many targets of the polycomb repression complex PRC2, which may 
play an important role in DLBCL given the recurrent mutations in EZH2, a component of this 
complex [56]. 
The technology platforms that are able to interrogate genomic structure and function are 
constantly in flux. Therefore, the exact nature of the methodologies that will be employed will 
be assessed at the time that the samples are collected and ready for analysis. The following are 
technologies that are currently in use for each task. 
Genomic DNA and total RNA will be extracted from tumor and normal samples using a Qiagen 
All-prep kit. MicroRNAs will be extracted from the samples using a Qiagen miRNeasy Mini 
Kit. 
For individual target genes that are recurrently mutated in DLBCL (CARD11, CD79B, MYD88, 
EZH2), classical Sanger sequencing will be performed on PCR amplicons, using primers 
surrounding the known sites of mutation in DLBCL. 
To broadly assess mutation, next generation sequencing (e.g. on an Illumina HiSeq 2000 
platform) will be employed, using a paired end sequencing strategy of libraries constructed from 
tumor and matched normal DNA. DNA will either be sequenced in its entirety from a whole 
genome library or will be first enriched for exonic sequences using the Agilent Sure Select 
Version Date: 02/15/2018 
18 
Update #18 


CALGB 50303 
system, aiming for 30X or 100X average coverage per base, respectively. The sequence 
fragments will be mapped back to genome using the BWA algorithm [57]. Of sequences 
overlapping a particular base pair in the genome, the percent mutant cells greater than 20% with 
a minimum of 25X coverage will be considered as an arbitrary threshold for single nucleotide 
variants (SNVs). SNVs that are not present in the matched normal sample will be considered 
candidate somatic mutations.  
A related technology, RNA-Seq, utilizes RNA from the tumor specimen to create a cDNA 
library for high-throughput sequencing. RNA-seq will be performed using Illumina kits 
followed by high-throughput sequencing on an Illumina HighSeq 2000 machine. The cutoffs for 
coverage and percent mutant calls mentioned above will also be used to identify putative SNVs.  
RNA sequencing will also be used to read out digital gene expression across the genome as 
described [58]. 
MicroRNAs will be profiled using an Illumina kit to construct a library from tumor RNA 
samples and will be sequenced using the Illumina HighSeq 2000 platform. 
Array comparative genomic hybridization (e.g. on Agilent 240K or Affy SNP 6.0 microarrays) 
will be used to assess DNA copy number alterations as described, in both tumor and normal 
genomic DNA [59]. The comparison of these two profiles will yield somatically acquired 
regions of copy number gain and loss. 
Methylated DNA will be immunoprecipitated as described and used to prepare a Illumina 
genomic DNA library, followed by sequencing using the HighSeq 2000 platform [59]. 
1.8 
FDG-PET Assessment in DLBCL 
1.8.1 Oncology Biomarker Qualification Initiative (OBQI) 
In February 2006, the Federal Drug Administration (FDA), National Cancer Institute 
(NCI), and Centers for Medicare and Medicaid Services (CMS) announced the Oncology 
Biomarker Qualification Initiative (OBQI) – an agreement to collaborate on improving the 
development of cancer therapies and the outcomes for cancer patients through biomarker 
development and evaluation. The goal of OBQI is to validate particular biomarkers so that 
they can be used to evaluate new, promising technologies in a manner that will shorten 
clinical trials, reduce the time and resources spent during the drug process, improve the 
linkage between drug approval and drug coverage, and increase the safety and 
appropriateness of drug choices for cancer patients. 
Under the OBQI, biomarker research will be focused in four key areas: standardizing and 
evaluating imaging technologies to see in more detail how treatments are working; 
developing scientific bases for diagnostic assays to enable personalized treatments; 
instituting new trial designs to utilize biomarkers; and pooling data to ensure that key 
lessons are shared from one trial to another. By working with academic and industry 
scientists, as well as professional organizations, the OBQI teams can foster the 
development of key information on biomarkers through clinical trials. 
This CALGB imaging companion to the treatment trial study will be carried out under a 
public-private partnership (PPP) formed by the partners in the OBQI with pharmaceutical 
manufacturers (represented by the Pharmaceutical Manufacturers’ Association [PhRMA]) 
and administered under the auspices of the Foundation of the National Institutes of Health 
(FNIH). The project will be overseen by a Lymphoma FDG-PET Working Group 
comprised of PET experts and oncologists from the NCI, FDA, CALGB, and PhRMA. 
1.8.2 FDG-PET Imaging-Derived Biomarkers 
In oncology, the gold standard clinical trial endpoint is overall survival, which may require 
long-term studies and may be confounded by deaths from causes other than the patient’s 
Version Date: 02/15/2018 
19 
Update #18 


CALGB 50303 
cancer. Over the years, the oncology community and the FDA have come to rely on other 
endpoints that from a scientific perspective are regarded as correlates of clinical benefit. 
These endpoints are objective response (OR), time to progression (TTP), disease-free 
survival (DFS), and progression free survival (PFS). All are determined by biomarkers 
measuring the cancer’s extent. Anatomic imaging using one- or two-dimensional 
measurements to characterize cancers has been used traditionally to make these 
measurements in all aspects of cancer patient management from diagnosis and staging to 
therapy and disease progression. 
However, measurements made using standard anatomic imaging techniques are often 
inadequate for characterizing the cancer, especially for monitoring the effects of drugs that 
do not cause tumor shrinkage or for cancers that progress slowly or metastasize diffusely. 
Newer imaging modalities including volumetric and functional imaging show high promise 
as the basis for characterizing better biomarkers of cancer (reviewed in [69]). In lymphoma, 
FDG-PET has the potential to improve patient management, particularly by signaling the 
need for early therapeutic changes in non-responders (NR) [70-74] and by refining the IWG 
response criteria to better differentiate complete responses (CR), partial responses (PR), and 
complete response with residual mass (CRu, unconfirmed due to residual tumor mass) [68, 
70, 71, 74-76]. Thus, if the utility of FDG-PET as a biomarker can be confirmed in such 
settings, unnecessary chemotherapy may be avoided for some patients and the costs of 
unnecessary long-term follow up reduced. As an early surrogate endpoint for clinical 
benefit, FDG-PET also has the potential to facilitate oncologic drug development by 
shortening phase II trials and detecting clinical benefit earlier in phase III investigations. 
FDG-PET and FDG-PET/CT imaging are increasingly being used in oncology clinical 
trials. However, there are as yet no standardized criteria for PET imaging or established 
procedures detailing transmission, storage, quality assurance, and analysis of PET images. 
This companion trial is one of the first steps toward developing the standardized protocols 
and endpoints that will be needed to move forward [77]. 
1.8.3 CALGB 580603 Companion: Evaluating the Prognostic Utility of PET Scanning in 
Lymphoma 
Considerable evidence supports the association of post-therapy FDG-PET results with 
outcome in lymphoma patients. Specifically, FDG uptake has been a significant early 
predictor of residual or recurrent disease and disease progression, as well as PFS and overall 
survival (OS) [73, 78-83]. FDG-PET is especially useful in differentiating tumor from 
fibrosis within residual radiographic masses [84, 85]. Such masses are present in half (NHL) 
to two-thirds (Hodgkin lymphoma (HL)) of patients, of whom only 25% (NHL) to 30% 
(HL) eventually relapse. In a prospective study of 58 patients (43 with HL) with residual 
masses following treatment, FDG-PET (SUV ≤ 3) predicted recurrence (p = 0.004) and PFS 
(p < 0.00001) [83]. Disease progression was observed after two months in 16/19 versus 3/22 
lymphoma patients with positive and negative FDG-PET results, respectively (p < 0.001) 
[81]. FDG-PET results obtained after the first cycle of chemotherapy in 30 NHL and HL 
patients predicted PFS at 18 months (p ≤ 0.001) [86]. A recent meta-analysis found that 
persistence of FDG-avid lesions after therapy predicted relapse, with up to 100% of patients 
with positive FDG-PET scans experiencing recurrence within two years [87]. Conversely, 
absence of disease by FDG-PET scan is an indicator of a favorable prognosis. Indeed, the 
negative predictive value of FDG-PET was 96% in one study of 81 HL patients [88], and 
several studies have also reported a higher positive predictive value for FDG-PET versus 
conventional imaging modalities [68, 88-90]. Evidence also supports the integration of 
FDG-PET with the IWG response criteria to increase the predictability of outcome [70, 71, 
74-76]. 
Version Date: 02/15/2018 
20 
Update #18 


CALGB 50303 
1.9 
Study Rationale and Summary 
The proposed study is a phase III randomized comparison of R-CHOP, the de facto standard for 
DLBCL, to dose-adjusted (DA)-EPOCH-R, a regimen developed from studies on drug schedule 
and resistance and pharmacokinetics. Importantly, this study will incorporate tumor microarray 
analysis using Affymetrix genome arrays in all patients to identify molecular mechanisms of 
drug resistance, develop molecular prognostic models and to assess microarray tissue diagnosis. 
Microarray is an important new tool, which has altered our understanding of lymphoma biology 
and has important clinical value. An important aim of the microarray is to identify the next 
therapeutic hurdles to allow rational treatment design and this is one of the goals of the proposed 
randomized study. Retrospective microarray results with CHOP-based treatment in DLBCL, for 
example, has already identified that tumor proliferation and the Activated B cell (ABC) 
signature are the most important adverse molecular prognostic hurtles [23]. Results with DA-
EPOCH show that it can abrogate tumor proliferation as an adverse prognostic factor, making 
the testing of DA-EPOCH a rational next step approach based on the microarray. 
Update #02: Change from 8 Cycles to 6 Cycles of Therapy in Treatment Arms 
The necessary number of treatment cycles for R-CHOP and DA-EPOCH-R were based on 
standard practice. In the case of R-CHOP, 6 or 8 cycles have been routinely administered. 
Because the present phase III trial was based on the GELA randomized study of CHOP versus 
R-CHOP for 8 cycles, 8 cycles were selected for the R-CHOP arm of this trial [7, 65]. However, 
a recent large phase III randomized study of CHOP versus R-CHOP for 6 or 8 cycles have 
demonstrated no difference in outcome [66]. On an intent-to-treat basis, there was no difference 
in failure free survival between 6 cycles (n=414) and 8 cycles (n=413) of R-CHOP (p=0.23). 
Furthermore, an analysis of the GELA study shows the potential for increased cardiac toxicity 
with R-CHOP, which would be impacted by 8 versus 6 treatment cycles [65]. Specifically, there 
was a higher incidence of deaths among patients in complete remission that received R-CHOP 
compared to CHOP. Although the authors attributed this disparity to the higher number of 
patients in complete remission in the R-CHOP arm that would be at risk of dying, further 
consideration may be warranted. A general estimate of the risk of dying in remission at 5 years, 
calculated from the number of patients who died in remission and those who were event free, 
yields 8% (5/60) and 15% (17/113) for the CHOP and R-CHOP arms, respectively. Furthermore, 
there was a trend toward a higher incidence of death in remission from cardiac disease among 
R-CHOP (9/17) compared to CHOP (0/5) patients (p2=0.054; Fisher’s exact test). These findings 
indicate that 6 cycles of R-CHOP is equivalent to 8 cycles and hence are likely to be associated 
with lower cardiac toxicity. 
DA-EPOCH-R was developed to administer 2 cycles beyond stable disease (defined as < 30% 
reduction in bi-dimensional measurements between the end of cycles 4 and 6) for a minimum of 
6 cycles. Based on this paradigm, over 85% of patients have only required 6 cycles [13,67]. No 
comparative trial has been performed to determine if the additional 2 cycles are even necessary 
in this small minority of patients and this paradigm was based on general accepted practices that 
had not been validated in a randomized study. 
Based on the evidence from a randomized study of R-CHOP for 6 versus 8 cycles, there is no 
evidence that 8 cycles is necessary and may be more toxic. Hence, effective with Update #02, 
the treatment plan was modified to administer a total of 6 cycles of treatment in both arms of the 
trial. This change should not affect the study outcome given the low number of patients accrued 
and have reached > 4 cycles (approximately 5 patients). 
1.10 
Inclusion of Women and Minorities 
It is the intent of the Alliance to enroll patients regardless of gender or race. In the development 
of this protocol, the possibility of inherent gender or racial/ethnic differences in treatment 
Version Date: 02/15/2018 
21 
Update #18 


CALGB 50303 
response has been considered. Although lymphocytic lymphomas are more common in males 
than females and the incidence is higher in whites than in blacks, data derived from prior studies 
involving human subjects, other relevant research, and subjective observation support the 
conclusion that there is no evidence which would require gender or racial/ethnic subgroupings 
and a commensurate sample size change. However, detailed analysis of the data will include 
these as well as other parameters examined for responsiveness to either regimen. 
2.0 
OBJECTIVES  
2.1 
Primary Objectives 
2.1.1 To compare the event-free survival of R-CHOP versus DA-EPOCH-R chemotherapy in 
untreated CD20+ diffuse large B-cell lymphomas.  
2.1.2 To develop a molecular predictor of outcome of R-CHOP and DA-EPOCH-R chemotherapy 
using molecular profiling. 
2.2 
Secondary Objectives 
2.2.1 To compare the response rates, overall survival and toxicity of R-CHOP versus DA-
EPOCH-R. 
2.2.2 To define the pharmacogenomics of untreated DLBCL and correlate clinical parameters 
(toxicity, response, survival outcomes and laboratory results) with molecular profiling. 
2.2.3 To assess the use of molecular profiling for pathological diagnosis. 
2.2.4 To identify new therapeutic targets using molecular profiling. 
2.2.5 To perform a comprehensive analysis of somatic alterations to the tumor genome and to 
understand which genomic alterations are somatically acquired by the tumor and which are 
encoded in the germ line of the patient. 
2.2.6 To identify biomarkers of response to chemotherapy by FDG-PET/CT imaging that are 
predictive of histopathologic remissions and survival in patients with stage I (mediastinal), 
II, III, or IV untreated DLBCL. 
2.2.7 To evaluate the use of semiquantitative measurements of FDG uptake in defining FDG-
PET/CT based biomarkers of response to chemotherapy in patients with DLBCL. 
2.2.8 To determine whether FDG-PET/CT measurements of tumor response after the second cycle 
of chemotherapy can predict clinical response. 
2.2.9 To establish a standardized protocol for FDG-PET/CT image acquisition. 
2.2.10 To determine additional FDG-PET/CT parameters (e.g., the ratio of tumor  SUVmax to 
liver SUVmean; SUVs corrected for body surface area and lean body mass; nuclear 
medicine physician’s assessment) and evaluate their utility in refining FDG-PET/CT based 
biomarkers of response to therapy. 
2.2.11 To evaluate inter-institutional reproducibility of FDG-PET/CT measurements for this 
indication. 
3.0 
ON-STUDY GUIDELINES 
All relevant medical and other considerations should be taken into account when deciding whether 
this protocol is appropriate for a particular patient. To maximize patient safety, patients should be 
treated on this protocol only at centers having ready access to blood product support and adequately 
Version Date: 02/15/2018 
22 
Update #18 


CALGB 50303 
staffed to care for the severely neutropenic patient. Physicians should consider the risks and benefits 
of any therapy and, therefore, only enroll patients for whom the agents administered are appropriate. 
Although they will not be considered as formal eligibility criteria, as part of this decision-making 
process physicians should recognize that the following may increase the risk to the patient entering 
this protocol: 
• 
Other serious illnesses which would limit survival to < 2 years, or a psychiatric condition which 
would prevent compliance with treatment or informed consent. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin cancers. 
Patients are not considered to have a “currently active” malignancy if they have completed 
therapy and are considered by their physician to be at less than 30% risk of relapse within one 
year. 
• 
Patients with severe active medical processes (e.g., active uncontrolled bacterial or viral 
infection, bleeding, etc.) not related to their lymphoma should be excluded. 
• 
All patients must be screened for hepatitis B infection before starting treatment (see Section 6.0). 
Those patients who test positive for hepatitis B should be closely monitored for evidence of active 
HBV infection and hepatitis during and for several months after rituximab treatment, and should 
be managed as indicated (see Sections 7.1.1 and 7.2.1). 
4.0 
ELIGIBILITY CRITERIA 
As of protocol update #14, the PET/CT imaging companion study CALGB 580603 will be required 
of all patients enrolling onto the treatment study CALGB 50303. Participation on CALGB 580603 
will no longer be optional in order to participate in CALGB 50303.  
4.1 
Documentation of Disease 
Histologically documented de novo CD20+ DLBCL with stage II, III or IV disease. Stage I 
primary mediastinal (thymic) DLBCL is also eligible. Patients with an underlying low-grade 
lymphoma, such as a transformed lymphoma or low-grade lymphoma in the bone marrow, are 
not eligible. Diagnosis should be based on an adequate tissue sample, including open biopsy or 
core needle biopsy. Needle aspiration for primary diagnosis is unacceptable. Patients must have 
one of the following WHO [21] classification subtypes:  
• 
Diffuse large B-cell lymphoma (includes morphological variants: centroblastic; 
immunoblastic; T-cell/histiocyte rich; and anaplastic). 
• 
Mediastinal (thymic) large B-cell lymphoma 
• 
Intravascular large B-cell lymphoma 
Note: Failure to submit a pathology block within 60 days of patient registration will be 
considered a major protocol violation (see Section 5.3). 
Fresh (frozen) tumor biopsy must be available or attempted (see repeat tissue biopsy guidance 
below and Section 5.4). A frozen tumor biopsy equivalent to a minimum of four at least 16 
gauge needle cores is an important component of this study. Patients without adequate frozen 
material should have a biopsy performed to obtain material. If a biopsy is performed and does 
not yield adequate material, the patient is still eligible for the study. If a biopsy cannot be done 
safely, the patient may still be eligible for the study if permission is granted in writing (e-mail) 
by the Study Chairs (Drs. Wilson or Zelenetz) or their designees. 
Drs. Wilson or Zelenetz may be consulted to discuss situations involving invasive biopsy 
procedures that may pose an increased risk to the patient. 
NOTE: THIS STUDY DOES NOT ALLOW CONCURRENT RADIATION UNLESS A 
PATIENT HAS A DOCUMENTED CNS TREATMENT FAILURE WITH NO SYSTEMIC 
FAILURE. PLEASE DO NOT ENROLL A PATIENT YOU MIGHT WISH TO RADIATE. 
Version Date: 02/15/2018 
23 
Update #18 


CALGB 50303 
4.2 
Prior Treatment 
No prior cytotoxic chemotherapy or rituximab. Patients may be entered if they have received 
prior limited field radiation therapy or a short course of glucocorticoids (< 10 days) for an urgent 
local disease complication at diagnosis (e.g., cord compression, SVC syndrome). Patients who 
have received chemotherapy for prior malignancies are not eligible.  
4.3 
Age ≥ 18 years. 
4.4 
ECOG Performance Status 0-2. 
4.5 
Cardiac Function 
No active ischemic heart disease or congestive heart failure. If there is suspicion of cardiac 
disease, a cardiac ejection fraction must show LVEF > 45%, but the study is not required.  
4.6 
Lymphomatous 
No known lymphomatous involvement of the CNS. A lumbar puncture prior to study is 
not required in the absence of neurological symptoms. 
4.7 
HIV Status 
No known HIV disease. Patients with a history of intravenous drug abuse or any other behavior 
associated with an increased risk of HIV infection should be tested for exposure to the HIV 
virus. The mechanism of disease in patients with HIV may be different from de novo diffuse 
large B cell lymphoma. Additionally, the immunocompromised state of patients with HIV 
infection may result in more extensive dose reductions than intended for the intensive 
therapeutic regimens used in this study. Therefore, patients who test positive or who are known 
to be infected are not eligible. An HIV test is not required for entry on protocol, but is required 
if the patient is perceived to be at risk. 
4.8 
Pregnancy and Nursing Status 
Non pregnant and non-nursing. Treatment would expose an unborn child to significant risks. 
Women and men of reproductive potential should agree to use an effective form of 
contraception. 
4.9 
Active medical processes 
Patients with active medical processes (e.g., uncontrolled bacterial or viral infection, bleeding) 
not related to their lymphoma should be excluded. 
4.10 
Required Initial Laboratory Values*: 
ANC 
≥ 1000/µL 
Platelets 
≥ 100,000/µL 
Creatinine 
≤ 1.5 mg/dL or creatinine clearance ≥ 50 cc/min.  
Total Bilirubin 
≤ 2 mg/dL** 
* 
Unless attributable to non-Hodgkin lymphoma 
** Unless a history of Gilbert’s Disease 
Version Date: 02/15/2018 
24 
Update #18 


CALGB 50303 
5.0 
REGISTRATION/RANDOMIZATION, DATA SUBMISSION, HISTOLOGIC REVIEW AND SPECIMEN 
SUBMISSION FOR CORRELATIVE STUDIES 
5.1 
Registration/Randomization 
5.1.1 Registration/Randomization Requirements 
5.1.1.1 
Informed Consent 
The patient must be aware of the neoplastic nature of his/her disease and willingly 
consent after being informed of the procedure to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, side effects, risks, and discomforts. 
Human protection committee approval of this protocol and of its consent form are 
required. 
5.1.1.2 
Fresh (frozen) Tumor Biopsy  
A fresh (frozen) tumor biopsy must be available or attempted (see guidance for 
repeat tissue biopsy in Section 4.1). A frozen tumor biopsy equivalent to a minimum 
of 4 at least 16 gauge needle cores is an important component of this study (see Section 
5.4.1). Patients without adequate frozen material should have a biopsy performed to 
obtain material. If a biopsy is performed and does not yield adequate material, the 
patient is still eligible for the study. If a biopsy cannot be done safely, the patient may 
still be eligible for the study if permission is granted in writing (e-mail) by the Study 
Chairs (Drs. Wilson or Zelenetz) or their designees. 
5.1.1.3 
Pharmacogenomic Correlative Science Companion 
All participating institutions must ask patients for their consent to participate in 
CALGB 60405 (see Section 5.1.2 “Registration to Companion Studies”), although 
patient participation is optional. See Section 5.4.2 for instructions for the collection 
and shipment of samples for pharmacogenomics. 
5.1.1.4 
FDG-PET/CT Companion Study (CALGB 580603): Institutional Approval 
Procedures 
As of protocol update #14, participation in the PET/CT imaging companion study 
CALGB 580603 is required of all patients enrolling onto the treatment study CALGB 
50303. Starting on August 1, 2012, registration will be limited to patients and 
institutions participating in CALGB 580603. Participation in CALGB 580603 will no 
longer be optional in order to participate in CALGB 50303. Please note: if a PET/CT 
scan has already been performed for clinical evaluation, it may be possible to submit 
the scan as the baseline image for the correlative study CALGB 580603. Please contact 
the Imaging Co-Chair to determine suitability for submission as a baseline image. 
Institutions must be approved to participate in the FDG-PET/CT companion to this 
protocol (see Section 8.1).  
The following documentation is required to participate in CALGB 580603: 
1) Submit to the Imaging Core Laboratory: 
• 
PET Instrument Technical Specifications Form (Appendix II) 
• 
Imaging Site Personnel Form (Appendix III) 
Institutional approval to participate in this imaging companion is contingent upon 
receipt of this documentation. 
Version Date: 02/15/2018 
25 
Update #18 


CALGB 50303 
5.1.2 CALGB Registration/Randomization Procedures 
Registration and randomization will be accepted only through CALGB Main Member 
institutions, at-large members, selected affiliate institutions, and CCOPs. Registration and 
randomization must occur prior to the initiation of therapy. 
Confirm eligibility criteria (Section 4.0). Complete the Registration Worksheet. Either fax 
the worksheet to 
 or call the CALGB Registrar (
, Monday-
Friday, 9:00 AM – 5:00 PM, Eastern Time) with the following information: 
Study 
Name of group (CALGB) 
Name of institution where patient is being treated 
Name of treating physician 
Name of treating physician or responsible CRA 
Other group patient ID #, if applicable 
CALGB patient ID #, if applicable 
Patient’s initials (last initial, first initial, middle initial) 
Patient’s Social Security #, date of birth, and hospital ID # 
Patient’s gender 
Patient’s race 
Patient’s height, in centimeters (optional) 
Patient’s weight, in kilograms (optional) 
CTC performance status (if required by CDUS) 
Type of insurance (method of payment) 
Disease, type and stage, if applicable 
Patient’s Postal Code, if applicable 
Treatment start date 
Date of signed consent 
Date of HIPAA authorization 
Patient demographics, if applicable 
Companion studies, if applicable (see below) 
Eligibility criteria met (no, yes) 
 
When the patient is registered, a patient identification number will be generated. Please write 
the number in your records. Registration to any mandatory or optional companion studies 
will be done at the same time as registration to the treatment study. Registration to both 
treatment and companion studies will not be completed if eligibility requirements are not 
met for all selected trials (treatment and companions). Please see “Registration to 
Companion Studies” below. 
After registration is complete the patient may be randomized. Once the randomization is 
complete, note the patient's treatment assignment in your records. 
The Main Member Institution and registering institution will receive a Confirmation of 
Randomization. Please check for errors. Submit corrections in writing to the Alliance 
Statistics and Data Center, 
 
 
Registration to Companion Studies 
Within CALGB 50303 there are two sub-studies. The sub-studies included within CALGB 
50303 are: 
• 
Pharmacogenomics in CALGB 50303 (CALGB 60405) 
Version Date: 02/15/2018 
26 
Update #18 


CALGB 50303 
• 
FDG-PET/CT Imaging in CALGB 50303 (CALGB 580603) 
As of protocol update #14, the PET/CT imaging companion study CALGB 580603 will be 
required of all patients enrolling onto the treatment study CALGB 50303. Starting on August 
1, 2012, registration will be limited to patients and institutions participating in CALGB 
580603. Participation in CALGB 580603 will no longer be optional in order to participate 
in CALGB 50303. Please note: if a PET/CT scan has already been performed for clinical 
evaluation, it may be possible to submit the scan as the baseline image for the correlative 
study CALGB 580603. Please contact the Imaging Co-Chair to determine suitability for 
submission as a baseline image. 
These embedded companion studies must be offered to all patients enrolled on CALGB 
50303. Patients may opt not to participate on CALGB 60405, however the imaging 
companion study 580603 is required.  
The rationales for performing the correlative science substudies are discussed in Sections 1.6 
and 1.8. If a patient answers “yes” to “I agree that my blood may be used for the genetic 
research studies described above” (Question #1) in the model consent, they have consented 
to participate in the correlative science pharmacogenomic substudy. Patients should be 
registered to CALGB 60405. Although it is preferable that patients be registered to CALGB 
60405 at the same time they are registered to CALGB 50303, registration to CALGB 60405 
may occur up to 60 days following registration to the treatment trial. Samples should be 
submitted according to the instructions in Section 5.4.2. If the institution is approved to 
participate in CALGB 580603 (see Section 8.1 for approval procedures) and the patient 
consents to participate in the treatment study CALGB 50303, then they have consented to 
participate in the correlative science FDG-PET/CT imaging correlative study. Patients 
should be registered to CALGB 580603. Images should be submitted according to the 
instructions in Section 8.5. 
5.2 
Data Submission 
As of Update #18 to the protocol, this study will use Medidata Rave® for remote data capture 
(RDC) of all future data collection. All data originally received by the Alliance and Statistics 
and Data Center (SDC) (either electronically using the “Print and/or Submit to CALGB” button 
[i.e. Teleform form] or by mail) has been transferred to Medidata Rave ® and can be accessed 
via the Medidata Rave ® system. If necessary, data originally submitted to the SDC 
electronically (or by mail) can be amended via the Medidata Rave ® system. 
The Rave system can be accessed through the iMedidata portal at 
 
For additional information regarding account setup or training, please visit the training section 
of the Alliance website. Forms should be submitted in compliance with the table below, and a 
copy of the All Forms Packet can be downloaded from the Alliance and CTSU websites. 
Site personnel with Rave roles assigned on the appropriate roster may receive a study invitation 
e-mail from iMedidata. To accept the invitation, site users must log into the Select Login 
 using their CTEP-IAM user name and password, and 
click on the “accept” link in the upper right-corner of the iMedidata page. Please note, site users 
will not be able to access the study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the iMedidata screen. Personnel 
who did not receive an invitation should contact the Alliance Service Center. 
Users who have not previously activated their iMedidata/Rave account at the time of an initial 
site registration approval for a study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website’s Rave tab under the Rave Resource Materials heading (Medidata Account Activation 
Version Date: 02/15/2018 
27 
Update #18 


CALGB 50303 
and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the 
CTSU Help Desk at 
 or by e-mail at 
. 
 
Version Date: 02/15/2018 
28 
Update #18 


CALGB 50303 
Form 
 
Submission Schedule 
 
 
 
C-1319 
CALGB 50303 On-Study Form 
 
C-1321 
Lymphoma Measurement Form 
 
C-1332 
Tumor Biopsy Specimen Submission Form 
Within one week of registration. 
C-1333 
Pharmacogenomic Sample Submission Form* 
 
 
 
 
 
Pathology Reports 
 
 
 
 
C-1331 
Copy of C-1331 & Block to Alliance 
Biorepository at OSU 
Within 60 days of registration. See Section 5.3. 
 
 
 
C-1323 
Chemotherapy Dose Form 
Every cycle while on therapy. 
 
 
 
C-1627 
50303 PET and CT Measurement Form** 
As of protocol update #14, submission is 
required: 
Prior to therapy; post-Cycle 2; and post-Cycle 6 
per Section 8.3. 
 
 
 
C-1657 
50303 Imaging Adjunctive Data Sheet** 
Prior to therapy; post-Cycle 2; and post-Cycle 6 
per Section 8.3. 
 
 
 
C-1322 
CALGB 50303 Follow-Up Form 
Every 2 cycles while on therapy, then q3 months 
for 2 years, then q6 months for 5 years from study 
registration, at relapse, and at death. 
 
 
 
C-1320 
CALGB 50303 Treatment Form 
Every 2 cycles while on therapy. 
C-1324 
CALGB 50303 Adverse Event Form 
 
 
 
C-1321 
Lymphoma Measurement Form 
Post-Cycle 4; post-Cycle 6; q3 months for 2 
years, then q6 months for 5 years from study 
registration, and at relapse. 
 
 
 
C-1001 
New Primary Malignancy Form 
At time of new primary malignancy. 
 
 
 
C-1742 
CALGB: Confirmation of Lost to Follow-up Form 
Follow form directions. 
C-2089 
CALGB 50303 Consent for Additional Genomic 
Research Studies †† 
Only for patients already enrolled on study prior 
to Update #12 (4/15/2011); submit once patient 
has read the Addendum to the Model Consent 
and answered Question #6.  
† 
Submit legible copies of all institutional pathology, immunophenotyping, and baseline CT scan reports documenting 
diagnosis. 
‡ 
Submit legible copies of all pathology, immunophenotyping, and CT scan reports documenting response and/or 
progression. 
* 
Patient may be enrolled on pharmacogenomic correlative science study (CALGB 60405) as many as 60 days after 
enrollment on CALGB 50303. 
** Send forms to the Imaging Core Laboratory and the Alliance Statistics and Data Center. See Section 8.5 for image 
submission. 
†† Submit only for patients already enrolled on study prior to Update #12 (4/15/2011), NOT those who are new patients 
on study. For patients already enrolled on study, submit C-2089 once the patient has read the Addendum to the 
Model Consent, answered Question #6, and provided a signature. (New patients being enrolled onto CALGB 50303 
will also receive the Addendum to the Model Consent, answer Question #6, and provide a signature, but their 
answers to Question #6 are to be recorded within the registration system.) 
Version Date: 02/15/2018 
29 
Update #18 


CALGB 50303 
5.3 
Histologic Review 
Submission of either a nodal or extranodal biopsy from the original diagnosis is required. 
An adequate specimen of tissue must be available for central review of morphology, 
architecture and appropriate immunohistochemical stains to confirm the diagnosis. 
Diagnosis should be based on an adequate tissue sample, including open biopsy or core 
needle biopsy. Needle aspiration for primary diagnosis is unacceptable. 
Within 60 days of registration, send a formalin-fixed, paraffin-embedded block of well-fixed 
lymphoma tissue containing adequate material for histologic confirmation of diagnosis.  Please 
label the block with the CALGB patient ID number, institution, date of acquisition, protocol 
number, and tissue source.  A block at least 2 cm x 1 cm x 0.5 cm is preferable, although smaller 
is acceptable if no other block is suitable. If only one block exists, and the tissue is sufficiently 
large, it is acceptable to split the block into two and submit one. Contact Dr. Eric Hsi (216-444-
5230) with questions. Submit the labeled block and a copy of the pathology report (include 
consultative pathology reports, if available), CT scan report(s), and a copy of the completed 
Lymphoma Pathology Submission Form C-1331 to the Alliance Biorepository at Ohio State 
University (ABOSU). 
Alliance Biorepository at Ohio State University 
 
 
 
 
 
 
 
Failure to submit a pathology block within 60 days of patient registration will be considered a 
major protocol violation. Send the original C-1331 form to the Alliance Statistics and Data 
Center. 
The Alliance has instituted special considerations for the small percentage of institutions whose 
policies prohibit the release of any blocks. If, due to institutional policy, a block cannot be sent, 
please call the Alliance Biorepository at OSU at 
 to obtain a protocol for 
submission of representative tissue from your institution. 
5.4 
Specimen Submission for Correlative Studies 
A frozen tumor biopsy equivalent to a minimum of 4 at least 16 gauge needle cores is an 
important component of this study. Patients without adequate frozen material should have a 
biopsy performed to obtain material. If a biopsy is performed and does not yield adequate 
material, the patient is still eligible for the study. If a biopsy cannot be done safely, the 
patient may still be eligible for the study if permission is granted in writing (e-mail) by the 
Study Chairs (Drs. Wilson or Zelenetz) or their designees. 
All participating institutions must ask patients for their consent to participate in the additional 
pharmacogenomic companion substudy in CALGB 50303, although patient participation in the 
pharmacogenomic study is optional (see Section 5.4.2). Instructions for the collection and 
shipment of samples are detailed below. 
Samples shipped from Alliance institutions should be logged and shipped via the CALGB 
LabTrak application. All samples should be labeled with the CALGB patient ID, CALGB 
protocol number (CALGB 50303), institution, date of acquisition, and tissue source. Instructions 
for the procurement and shipping of samples are included below.  
Version Date: 02/15/2018 
30 
Update #18 


CALGB 50303 
5.4.1 Fresh (Frozen) Tumor Biopsy Sample (ALL PATIENTS) 
• 
Fresh (Frozen) Tumor Biopsy Sample Procurement 
Contact one of the following individuals to obtain shipping packages: 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shipping packages will be sent to each participating institution. To ensure timely arrival 
of shipping packages, place a request for multiple packages (at least 2 more than is 
needed) at the time of local IRB review. Packages will consist of the following items: 
(1) 
Fresh (Frozen) Tumor Biopsy Sample Procurement Instructions 
(1) 
Styrofoam Box 
(1) 
Cardboard Box 
(1) 
Biohazard Labeled Ziplock Bag 
(10)  
2 mL cryopreservation screw cap tube 
Each package should be used to mail only one set of samples from a single patient. DO 
NOT CONSOLIDATE SAMPLES FROM MULTIPLE PATIENTS INTO A 
SINGLE BOX. 
Remove the collection tubes from the styrofoam container. Label all tubes with the 
CALGB patient ID number, CALGB protocol number, institution, date of acquisition, 
and tissue source. 
Use the 2 mL cryotubes to collect tumor samples. A minimum of a hundred milligrams 
(100 mg) of tissue should be provided. This corresponds to a minimum of 4 core needle 
biopsy specimens (16 gauge needle at least) or an excisional biopsy that is at least 100 
cubic mm in volume (i.e., the size of a pea). Fill the Nunc tubes 2/3 full and use as many 
Nunc tubes as necessary. REMOVE ALL LIQUID FROM SAMPLE BEFORE 
FREEZING. Immediately preserve by freezing in dry ice or liquid nitrogen and 
transfer them from the liquid nitrogen or dry ice container, to a -70°/-80° C freezer 
(preferable), or to a -20°C freezer for storage until time of shipment. 
• 
Fresh (Frozen) Tumor Biopsy Sample Shipment 
Note: Must have patient identification number before shipping sample. Place all 
tubes with samples into the styrofoam box filled with at least 2 lbs. of dry ice. Position 
the tubes so that they are roughly in the center of the container (i.e., surrounded by dry 
ice). Remember: ONE PATIENT SAMPLE SET PER “ZIPLOCK” BAG/BOX. 
Complete the Tumor Biopsy Specimen Submission Form (C-1332) and place in the 
document compartment of the waterproof “Ziplock” plastic bag. Place in the styrofoam 
box. Send a copy of Form C-1332 to the Alliance Statistics and Data Center. 
Tape the styrofoam box. Put the box inside the provided cardboard box. Close with tape. 
Affix a FedEx label. Make a note of the air bill number on the FedEx label. Please mail 
overnight on a Monday through Thursday so shipment will arrive during the week. 
After mailing, send an e-mail to:  
 with the subject: “URGENT: 
CALGB 50303 Fresh/Frozen Biopsy Sample Sent” indicating the DAY, TIME, 
INSTITUTION, CALGB PATIENT ID NUMBER AND AIR BILL NUMBER OF 
THE PACKAGE in which the sample set was mailed. Mail the samples to: 
 
 
 
Version Date: 02/15/2018 
31 
Update #18 


CALGB 50303 
 
 
Questions or problems with sample procurement or shipment should be directed to the 
following individuals: 
 
 
 
 
 
 
 
 
  
 
Institutions without access to CALGB LabTrak application for shipping samples should send 
an e-mail to 
 with the subject “URGENT. CALGB 50303 
Fresh/Frozen Biopsy Sample Sent” indicating the day, time, institution, CALGB patient ID 
number, and the airbill number of the package in which the sample was sent. Questions or 
problems with sample procurement may be directed to the individuals identified above. 
Please note: it is necessary to submit CALGB form C-1332 in order to receive 
reimbursement, regardless of whether biopsy was successful. In this instance, complete form 
C-1332 and indicate that biopsy specimen does not accompany the form, and fax it to 
 
 as well as to the Alliance Statistics and Data Center, Data 
Operations. Reimbursement for sample procurement will not be made for patients who are 
exempted from the biopsy requirement. 
5.4.2 Pharmacogenomic Sample (Must be offered to all patients enrolled on CALGB 50303) 
• 
Pharmacogenomic Sample Procurement 
Prior to initiation of therapy obtain 2 EDTA (purple top) tubes of peripheral blood (each 
containing approximately 10 mL) for pharmacogenetic studies. A mailing label should 
be completed that contains the CALGB patient ID number, CALGB protocol number, 
institution, date of sample acquisition, sample collection time point (prior to initiation 
of therapy), tissue source, and sample purpose (i.e., CALGB 50303 Pharmacogenetic 
Sample). 
• 
Pharmacogenomic Sample Shipment 
Samples should be shipped on a cold/gel pack in an approved container using an express 
courier. Ship samples to: 
 
 
 
 
 
 
 
 
A copy of the 50303 Pharmacogenomic Specimen Submission Form (C-1333) should 
accompany all samples sent to the ABOSU. Note: If specimen is sent on Friday, 
CHECK SATURDAY DELIVERY on the FEDERAL EXPRESS INVOICE. Also, 
send a copy of the completed forms to the Alliance Statistics and Data Center at the time 
of shipment. 
 
6.0 
REQUIRED DATA 
Guidelines for Pre-Study Testing 
Version Date: 02/15/2018 
32 
Update #18 


C A L G B 5 0 3 0 3  
T o be c o m plete d wit hi n 1 6 D A Y S bef ore re gistrati o n: 
-  All bl o o d w or k 
-  Hist or y a n d p h ysical 
T o be c o m plete d wit hi n 2 8 D A Y S bef ore re gistrati o n: 
- A n y X -ra y, sca n of a n y t y pe or ultras o u n d w hic h is utilize d f or t u m or meas ure me nt 
T o be c o m plete d wit hi n 4 2 D A Y S bef ore re gistrati o n:  
-  A n y baseli ne e xa ms use d f or scree ni n g, i.e., E K G, L V E F or M U G A 
- A n y X -ra y, sca n of a n y t y pe or ultras o u n d of u ni n v ol ve d or ga ns w hic h is n ot utilize d f or t u m or 
meas ure me nt; b o ne marr o w bi o ps y a n d as pirate.  
 
 
 
D a y 1  
At   
P ost - 
 
Pri or 
t o 
B et w ee n  
of E ac h  
Ti me of  
Tre at me nt  
Tests & O bser v ati o ns  
St u d y  
C ycles  
C ycle ‡  
Rest a gi n g *  
F oll o w -u p * *  
Hist or y & Pr o gress N otes  
X  
 
X  
X  
X  
P h ysical E xa mi nati o n  
X  
 
X  
X  
X  
P ulse, Bl o o d Press ure  
X  
 
X  
X  
X  
Hei g ht/ W ei g ht/ B o d y S urface Area  
X  
 
A  
 
 
P erf or ma nce Stat us ( E C O G)  
X  
 
X  
X  
X  
T u m or Meas ure me nts  
X  
 
B  
X  
X  
Dr u g T o xicit y Assess me nt  
 
 
X  
X  
X  
St u dies  
 
 
 
 
 
C B C, Diff, Platelets  
X  
2 x/ wee k †  
X  
X  
X  
Ser u m Creati ni ne, B U N  
X  
 
X  
 
 
A S T, Al k P h os, Bilir u bi n, L D H  
X  
 
X  
X  
 
T otal Pr otei n, Al b u mi n  
X  
 
 
 
 
HI V  ser olo g y (if necessar y, se e Secti o n  4. 7 ) 
X  
 
 
 
 
Ser u m of uri ne 
H C G
 
G  
 
 
 
 
E K G  
X  
 
 
 
 
L V E F  (ec h o  or  M U G A)  (if  necessar y,  see 
Secti o n 4. 5 ) 
X  
 
 
 
 
H B S A g a n d ser ol o g y  
X, E  
 
 
 
 
Fres h T u m or Bi o ps y ( Secti o n  5. 4. 1 ) 
X  
 
 
 
 
P har mac o ge n o mic Sa m ple (se e Secti o n 5. 4. 2 ) 
X  
 
 
 
 
St a gi n g  
 
 
 
 
 
C T/ M RI Sca n C hest, A b d, P el vis  
X  
 
 
X  
X  
B o ne Marr o w As pirate & Bi o ps y  
X  
 
 
C  
 
Hea d sca n ( M RI preferre d) & C S F e xa m, if 
ris k fact ors 
F 
 
 
 
 
P E T Sca n ( C A L G B 5 0 3 0 3)  
 
 
 
D  
D  
Hist ol o gic Re vie w  
X  
 
 
 
 
‡ 
Pre -re gistrati o n  tests,  o bser vati o ns,  a n d  la b  st u dies  c o m plete d  wit hi n  7  da ys  pri or  t o  t he  first  da y  of  C ycle  1 
treat me nt nee d n ot be re peate d. La bs a n d p h ysical e xa m ma y be o btai ne d wit hi n 4 8 h o urs pri or t o treat me nt f or 
all ot her c ycles.  
* 
I n Ar ms A a n d B, resta ge aft er C ycles 4 a n d 6. 
* *  E ver y 3 m o nt hs f or 2 years, t he n q 6 m o nt hs u ntil 5 years fr o m st u d y re gistrati o n or rela pse ( w hic he ver occ urs 
first). 
† 
T wice wee kl y (e. g., o n M o n d a y & T h urs da y or T ues da y & Fri da y) t o ass ure t hat c o u nts are c hec ke d e ver y t hree -
f o ur da ys. T he t wice -w ee kl y m o nit ori n g is re q uire d f or Ar m B ( D A -E P O C H -R) o nl y.  
A 
T he wei g ht at C ycle 1 s h o ul d be use d f or d ose calc ulati o ns f or all c ycles, u nless t here is a ≥ 1 0 % c ha n ge o ver a 
peri o d of o ne c ycle. If a wei g ht c ha n ge ≥1 0 % occ urs, d oses s h o ul d be recalc ulate d a n d t he ne w d ose use d fr o m 
t hat ti me f or war d. 
B 
If accessi ble t o p h ysical e xa mi nati o n, please rec or d meas ure me nts o n Da y 1 of eac h c ycle. 
C 
If b o ne marr o w i nitiall y p ositi ve, re peat t o c o nfir m a c o m plete res p o nse. 
Versi o n Date: 0 2 /1 5/ 2 0 1 8  
3 3  
U p date # 1 8 


CALGB 50303 
D 
PET scan is recommended at end of treatment in patients who achieve CRu. If positive, biopsy site. If 
borderline positive, biopsy site OR follow closely with repeat PET and CT scan monthly as indicated to 
assess sites. Contact Study Chair for guidance concerning “borderline” PET positivity. If scans show 
progression, perform a biopsy. NO patient will be considered to have failed treatment based on a positive 
PET scan alone.  
E 
All patients must be screened for hepatitis B infection before starting treatment. Carriers of hepatitis B should be 
closely monitored for evidence of active HBV infection and hepatitis during and for several months after 
rituximab treatment. 
F 
Patients with (1) ≥ 2 extranodal sites and elevated LDH, or (2) bone marrow involvement by large cell lymphoma 
will receive CNS prophylaxis according to Sections 7.1.3 (Arm A) or 7.2.3 (Arm B). 
G 
In women of childbearing potential 
6.1 
CALGB 580603 FDG-PET/CT Imaging Requirements 
As of protocol update #14, the PET/CT imaging companion study CALGB 580603 will be 
required of all patients enrolling onto the treatment study CALGB 50303. Participation on 
CALGB 580603 will no longer be optional in order to participate in CALGB 50303. Please 
note: if a PET/CT scan has already been performed for clinical evaluation, it may be possible 
to submit the scan as the baseline image for the correlative study CALGB 580603. Please contact 
the Imaging Co-Chair to determine suitability for submission as a baseline image. 
Tests & Observations 
Prior to 
Study 
Day of FDG-
PET/CT 
Imaging 
Post-Cycle 2 
Post-Cycle 6 
Blood glucose 
X 
X 
 
 
Height/Weight/Body 
Surface Area 
X 
X 
 
 
 
 
 
 
 
Staging and Imaging 
 
 
 
 
PET/CT Scan‡ 
X 
X 
A 
B 
Biopsy 
 
 
 
C 
‡ Baseline PET/CT scan preferred prior to the CALGB 50303 baseline excisional biopsy and≤ 30 days 
prior to start of therapy (see Section 8.3). If a PET/CT scan has already been performed for clinical 
evaluation, please contact the Imaging Co-Chair to determine suitability for submission as a baseline 
image. 
A To be performed 17-21 days post-Cycle 2 therapy and 0-4 days prior to start of Cycle 3. 
B To be performed post-Cycle 6 (3-8 weeks after last dose of chemotherapy). At Cycle 6, if PET is 
positive, but CT negative, another PET/CT scan will be performed after 2-3 months. 
C If PET remains positive after the second post-Cycle 6 PET/CT scan, the site should be biopsied to 
determine histopathology. If a PET/CT scan shows progression, results will be provided to treating 
physician to assist in further evaluation of the patient, and the site should be biopsied to document 
active disease. Patients with a 4+ positive PET scan after Cycle 6 may undergo biopsy immediately at 
treating physician’s discretion. No patient will be considered to have failed treatment based on a 
positive PET scan alone. 
Version Date: 02/15/2018 
34 
Update #18 


CALGB 50303 
7.0 
TREATMENT PLAN 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient’s lymphoma. 
No radiation therapy will be permitted on study except for isolated CNS lesions. Patients who receive 
radiation to any site other than the CNS will be inevaluable. Patients with parenchymal CNS lesions 
should receive whole brain radiation and will only be considered treatment failures if the systemic 
disease progresses. 
Patients must begin treatment within seven days of registration/randomization. Patients will be 
randomized to either Arm A (R-CHOP) or Arm B (DA-EPOCH-R). 
All patients must be screened for hepatitis B infection before starting treatment. Those patients who 
test positive for hepatitis B should be closely monitored for evidence of active HBV infection and 
hepatitis during and for several months after rituximab treatment, and should be managed as indicated 
(see Sections 7.1.1 and 7.2.1). 
Institutions must be approved to participate in the optional FDG-PET/CT companion CALGB 
580603 (see Section 8.1). 
7.1 
Arm A (R-CHOP Treatment [7]) 
7.1.1 Required Ancillary Medications 
• 
Omeprazole 20 mg/day PO (or equivalent).  
• 
Stimulant laxative/stool softener (e.g., Pericolace®) 2 tablets PO BID (adjusted as 
necessary) or institutional preference for prevention of constipation. 
• 
Lactulose 20 g PO Q 6 hours PRN until resolution or institutional preference for 
treatment of constipation. 
• 
Acetaminophen 650 mg PO and diphenhydramine 50-100 mg IV or PO 30 to 60 minutes 
prior to starting each rituximab infusion. 
• 
Hepatitis B surface Ag+ patients receive lamivudine 100 mg/day PO until 8 weeks past 
last chemotherapy.  
7.1.2 R-CHOP Chemotherapy 
• 
Rituximab 375 mg/m2 IV infusion on Day 1 prior to CHOP chemotherapy. See Section 
10.10 for dose rate information. 
• 
Cyclophosphamide 750 mg/m2 IV Day 1 
• 
Doxorubicin 50 mg/m2 IV Day 1  
• 
Vincristine 1.4 mg/m2 (2 mg cap) IV Day 1  
• 
Prednisone 40 mg/m2/day PO on Days 1-5 
• 
Begin filgrastim or pegfilgrastim if grade 4 neutropenia (ANC < 500/µL) or febrile 
neutropenia (ANC < 500/µL + fever 38.5° (101°F) lasting for more than one hour) 
developed on the previous cycle. Administer filgrastim 480 mcg subcutaneous daily 
from Day 2 until ANC > 5000 after the nadir (nadir usually between Days 10-12) or for 
10 days (Days 2-11) if the ANC is not being monitored, or pegfilgrastim 6 mg 
subcutaneous on Day 2 (may be delayed up to two days for convenience of scheduling 
due to holidays, weekend, etc.). 
• 
Repeat cycles every 21 days. To begin a cycle, ANC must be ≥ 1500/µL and platelets 
≥ 100,000/µL. Delay cycle by up to 2 weeks if these values are not met on Day 1 of 
cycle. Contact the Study Chair if delay is greater than two weeks. 
Version Date: 02/15/2018 
35 
Update #18 


CALGB 50303 
7.1.3 CNS Prophylaxis and Treatment 
7.1.3.1 
CNS Prophylaxis 
Patients with (1) ≥ 2 extranodal sites and elevated LDH, or (2) bone marrow 
involvement by large cell lymphoma will receive CNS prophylaxis consisting of 
intrathecal methotrexate 12 mg on day 1 (or day 2) of Cycles 3, 4, 5, and 6. 
7.1.3.2 
Treatment of CNS Disease 
• 
Treatment of CNS Disease 
If the CSF is cytologically positive at the time CNS prophylaxis is scheduled to 
begin (Cycle 3), the patient should receive active treatment of the CSF with 
methotrexate (see below). If this treatment either is not tolerated or found to be not 
effective, then cytarabine alone or in combination with methotrexate may be used. 
Additionally, a brain MRI should be obtained and radiation consolidation 
administered at the end of chemotherapy if there are parenchymal lesions. 
• 
CNS Induction Treatment 
CNS induction treatment will be administered twice per week for two weeks 
beyond negative cytology with a minimum of 4 weeks of treatment. CNS induction 
may consist of one of the following: 
- Intrathecal methotrexate 12 mg or intraventricular (via Ommaya) methotrexate 6 
mg  
OR 
- Intrathecal or intraventricular (via Ommaya) cytarabine 70 mg 
OR 
- Intrathecal methotrexate 12 mg + cytarabine 30 mg + hydrocortisone 15 mg or 
intraventricular (via Ommaya) methotrexate 6 mg + cytarabine 30 mg + 
hydrocortisone 15 mg 
• 
CNS Consolidation Treatment 
CNS consolidation will consist of the same treatment as induction, but 
administered weekly x 6. 
• 
CNS Maintenance Treatment 
CNS maintenance will consist of the same treatment as induction, but administered 
monthly x 4. 
If CNS treatment must be modified due to unforeseen circumstances or 
investigator preference, please consult with the Alliance Study Chair. 
7.1.4 Restaging and Treatment Duration 
Perform PET/CT scan post-Cycle 2 and after Cycles 4 and 6. Repeat CT/MRI scans at site(s) 
of initial involvement. If initial bone marrow biopsy is positive, a bone marrow examination 
should be repeated at each restaging point until it is negative and then no further biopsy is 
necessary. Patients will receive a maximum of 6 cycles. 
Submit PET/CT scan documentation post-Cycle 6. If patient is PET positive but CT negative, 
then repeat PET/CT scan 2-3 months later and submit documentation (see Section 8.3). 
Version Date: 02/15/2018 
36 
Update #18 


CALGB 50303 
7.2 
Arm B (DA-EPOCH-R Treatment [20]) 
7.2.1 Required Ancillary Medications 
• 
Cotrimoxazole DS 1 tablet three times weekly (or equivalent if allergic). 
• 
Omeprazole 20 mg/day PO (or equivalent). 
• 
Stimulant laxative/stool softener (e.g., Pericolace®) 2 tablets PO BID (adjusted as 
necessary) or institutional preference for prevention of constipation. 
• 
Lactulose 20 g PO Q6 hours PRN until resolution or institutional preference for 
treatment of constipation. 
• 
Acetaminophen 650 mg PO and diphenhydramine 50-100 mg IV or PO 30 to 60 minutes 
prior to starting each rituximab infusion. 
• 
Hepatitis B surface Ag+ patients receive lamivudine 100 mg/day PO until 8 weeks past 
last chemotherapy.  
7.2.2 Dose-Adjusted EPOCH-R Chemotherapy 
All patients initiate therapy at Dose Level 1 of DA-EPOCH-R shown below. Subsequent 
treatment doses are determined by hematological toxicity experienced on the previous cycle 
according to the dose-adjustment paradigm in Section 9.2. Dose adjustment is based on 
measurements of twice weekly CBC only (e.g., Monday and Thursday, or Tuesday and 
Friday), even if additional CBCs are obtained. 
Cycle 1 Doses 
• 
Rituximab 375 mg/m2 IV infusion on Day 1 prior to EPOCH chemotherapy. See Section 
10.10 for dose rate information. 
• 
Doxorubicin 10 mg/m2/day CIVI on Days 1-4 (total 40 mg/m2 over 96 hours) 
• 
Etoposide 50 mg/m2/day CIVI on Days 1-4 (total 200 mg/m2 over 96 hours) 
• 
Vincristine 0.4 mg/m2/day (no cap) CIVI on Days 1-4 (total 1.6 mg/m2 over 96 hours) 
• 
Cyclophosphamide 750 mg/m2 IV on Day 5 (following completion of 96 hour infusions) 
• 
Prednisone 60 mg/m2 PO BID on Days 1-5 
• 
Administer 
filgrastim 
480 
mcg 
subcutaneous 
daily 
from 
Day 
6 
until 
ANC > 5000 after the nadir (nadir usually between Days 10-12) or for 10 days (Days 6-
15) if the treating physician is not actively monitoring the required twice-weekly 
CBC/differential/platelets, during every cycle. 
Note: DA-EPOCH-R dosing has only been validated using filgrastim. Pegfilgrastim has 
different kinetics of neutrophil recovery and its use may adversely affect dosing and 
reduce disease cure rates. Use of pegfilgrastim (6 mg subcutaneous Day 6) must be 
approved by the Study Chair and will only be approved if the patient cannot receive 
filgrastim. 
• 
Repeat cycles every 21 days. To begin a cycle, ANC must be ≥ 1000/µL and platelets ≥ 
100,000/µL. Delay cycle by up to 2 weeks if these values are not met on Day 1 of cycle. 
Filgrastim may be used for several days to increase ANC. Contact the Study Chair if 
delay is greater than two weeks. 
Version Date: 02/15/2018 
37 
Update #18 


CALGB 50303 
7.2.3 CNS Prophylaxis and Treatment 
7.2.3.1 
CNS Prophylaxis 
Patients with (1) ≥ 2 extranodal sites and elevated LDH, or (2) bone marrow 
involvement by large cell lymphoma will receive CNS prophylaxis consisting of 
intrathecal methotrexate 12 mg on day 1 (or day 2) of Cycles 3, 4, 5, and 6. 
7.2.3.2 
Treatment of CNS Disease 
• 
Treatment of CNS Disease 
If the CSF is cytologically positive at the time CNS prophylaxis is scheduled to 
begin (Cycle 3), the patient should receive active treatment of the CSF with 
methotrexate (see below). If this treatment either is not tolerated or found to be not 
effective, then cytarabine alone or in combination with methotrexate may be used. 
Additionally, a brain MRI should be obtained and radiation consolidation 
administered at the end of chemotherapy if there are parenchymal lesions. 
• 
CNS Induction Treatment 
CNS induction treatment will be administered twice per week for two weeks 
beyond negative cytology with a minimum of 4 weeks of treatment. CNS induction 
may consist of one of the following: 
- Intrathecal methotrexate 12 mg or intraventricular (via Ommaya) methotrexate 6 
mg  
OR 
- Intrathecal or intraventricular (via Ommaya) cytarabine 70 mg 
OR 
- Intrathecal methotrexate 12 mg + cytarabine 30 mg + hydrocortisone 15 mg or 
intraventricular (via Ommaya) methotrexate 6 mg + cytarabine 30 mg + 
hydrocortisone 15 mg 
• 
CNS Consolidation Treatment 
CNS consolidation will consist of the same treatment as induction, but 
administered weekly x 6. 
• 
CNS Maintenance Treatment 
CNS maintenance will consist of the same treatment as induction, but administered 
monthly x 4. 
If CNS treatment must be modified due to unforeseen circumstances or 
investigator preference, please consult with the Alliance Study Chair. 
7.2.4 Restaging and Treatment Duration for DA-EPOCH-R 
If institution and patient are participating in the optional imaging companion study (CALGB 
580603), perform PET/CT scan post-Cycle 2. Otherwise, restage patients after Cycles 4 and 
6. Patients will receive a maximum of 6 cycles. Repeat CT/MRI scans at site(s) of initial 
involvement. If initial bone marrow biopsy is positive, a bone marrow examination should 
be repeated at each restaging point until it is negative, and then no further biopsy is 
necessary. 
Version Date: 02/15/2018 
38 
Update #18 


CALGB 50303 
If institution and patient are participating in the optional imaging companion study, submit 
PET/CT scan documentation post-Cycle 6. If patient is PET positive but CT negative, then 
repeat PET/CT scan 2-3 months later and submit documentation (see Section 8.3). 
8.0 
FDG-PET/CT IMAGING COMPANION (CALGB 580603) 
As of protocol update #14, the PET/CT imaging companion study CALGB 580603 will be required 
of all patients enrolling onto the treatment study CALGB 50303. Participation on CALGB 580603 
will no longer be optional in order to participate in CALGB 50303. Please note: if a PET/CT scan 
has already been performed for clinical evaluation, it may be possible to submit the scan as the 
baseline image for the correlative study CALGB 580603. Please contact the Imaging Co-Chair to 
determine suitability for submission as a baseline image. 
If the CT scan for the PET/CT imaging companion (CALGB 580603) is performed with (a) both oral 
and IV contrast with contrast enhancement in the arterial and/or portal venous phase; (b) is at least a 
2-slice CT; and (c) is acquired with at least 40-60 mAs and CT scans are obtained with contiguous 
sections with a maximum of 5 mm slice thickness, then the pre-study and post-Cycle 6 PET/CT scan 
alone will suffice for patients enrolled on both CALGB 50303 and the PET/CT imaging companion. 
8.1 
Institution Approval Procedures for FDG-PET/CT Imaging Companion 
Prior to enrollment of patients, institutions must be approved by the Alliance Imaging Core Lab 
at IROC Ohio. Institutions will be responsible for evaluating PET/CT scans as they do for 
clinical care, while the Alliance Imaging Core Laboratory will be responsible for the 
standardized central imaging reads and the quantitative SUV analyses. 
8.1.1 FDG-PET/CT Equipment 
All institutions participating in the FDG-PET/CT imaging companion are required to have 
a hybrid PET/CT scanner. All PET/CT scanners manufactured by General Electric, Philips, 
and Siemens meet the technical specifications of this companion. If an institution uses a 
scanner not listed above, the Imaging Core Laboratory must approve the equipment. For 
information regarding whether the PET/CT scanner to be used complies with this protocol, 
contact the Alliance Imaging Core Laboratory. Institutional approval for participation in 
the imaging companion is contingent upon submission of the PET/CT Instrument 
Technical Specifications Form (Appendix II) to the Imaging Core Laboratory (see 
Section 5.1.1.4). 
8.1.2 Institution FDG-PET/CT Imaging Approval 
The Alliance Imaging Core Lab at IROC Ohio will adhere to the ACRIN criteria for PET 
imaging approval procedures. In order for an institution to be approved to participate in this 
FDG-PET/CT companion, they are required to submit two de-identified test patient studies, 
as well as a submission of a uniform phantom image for technical and quality review by the 
Alliance Imaging Core Laboratory (see Section 8.1.3 below). After approval, the 
participating institution will be provided with an institution-specific (equipment-specific) 
instruction manual that details all components of the image acquisition and reconstruction 
throughout the study. The Imaging Core Laboratory will continue to verify that the 
acquisition and reconstruction performed at the participating sites are in compliance with 
set guidelines. 
Institutional approval for participation in the imaging companion is contingent upon 
submission of the PET/CT Instrument Technical Specifications Form (Appendix II) to 
the Imaging Core Laboratory. 
8.1.3 Approval Procedures for PET/CT Imaging 
Approval requirements for the optional imaging companion CALGB 580603 are equivalent 
to ACRIN credentialing procedures for PET/CT imaging. 
Version Date: 02/15/2018 
39 
Update #18 


CALGB 50303 
Each institution must submit FOR ALL PET/CT instruments utilized: 1) Two test patient 
studies; 2) Uniform phantom data (with the SUV measurement of the phantom); and 3) 
PET/CT Instrument Technical Specifications Form (Appendix II). Each institution must 
also submit the Imaging Site Personnel Form (Appendix III) to the Imaging Core 
Laboratory. 
1) 
Two test patient studies 
Images of two unidentified patients shall consist of three volume or multi-slice files as 
follows: a) Whole body CT from PET/CT scanner; b) Whole body (torso) emission 
with attenuation correction (A/C); and c) Whole body (torso) emission without A/C. 
2) 
Uniform phantom images 
Water-fillable uniform phantom: The phantom must be filled with water, and a known 
amount of F-18 (either as fluoride or as FDG) should be injected into the phantom. The 
activity injected should be determined by measurement of the syringe before and after 
the injection in a properly calibrated dose calibrator. The injected activity should be 
chosen to result in an activity concentration similar to that encountered in clinical FDG 
imaging (i.e., 1-1.5 mCi of F-18 should be added to the 6,283 mL phantom; 2 mCi for 
the 9,293 mL phantom). After thoroughly mixing the phantom, the phantom must be 
scanned with the same protocol used for the patient imaging. The images also must be 
reconstructed with the same algorithm and filters used for patient imaging. A circular 
or elliptical region of interest (ROI) covering most of the interior of the phantom must 
be drawn over all slices, and the average SUV and standard deviation must be measured 
and reported in the PET/CT Instrument Technical Specifications Form (Appendix II). 
The expected SUV for the uniform phantom is 1.0 and the acceptable range is 0.9 to 
1.1. 
(Alternatively) Ge-68/Ga-68 calibration phantom: This phantom can readily be 
scanned with the same protocol used for patient imaging. The assay date and activity 
from the calibration certificate of this phantom must be reported on the PET/CT 
Instrument Technical Specifications Form (Appendix II). The images must be 
reconstructed with the same algorithm and filters used for patient imaging. A circular 
or elliptical ROI covering most of the interior of the phantom must be drawn over all 
slices, and the average SUV and standard deviation must be measured and reported in 
the PET Instrument Technical Specification form. The expected SUV for the uniform 
phantom is 1.0 and the acceptable range is 0.9 to 1.1. 
3) 
PET/CT Instrument Technical Specifications Form 
The PET/CT Instrument Technical Specifications Form may be found in Appendix II. 
Please fax, e-mail, or send this form to: 
 
 
 
 
 
 
 
 
 
Version Date: 02/15/2018 
40 
Update #18 


CALGB 50303 
8.2 
Procedures for FDG-PET/CT Imaging 
8.2.1 Patient Preparation 
Patients should avoid any strenuous exercise for 24 hours prior to the PET/CT scan. Patients 
with poorly controlled diabetes (based on HbA1C) will be excluded. Patients must fast for 
≥ 4 hours prior to the injection of FDG, and must have a fasting blood glucose level ≤ 200 
mg/dL prior to FDG injection. However, an attempt will be initially made to control the 
blood glucose level, which will require the rescheduling of the injection. If the glucose level 
cannot be controlled (i.e., the blood glucose still exceeds 200 mg/dL), the patient will not 
be included in the FDG-PET/CT imaging companion. Patients should be adequately 
hydrated with plain water. Weight (kg), height (cm), and blood glucose (mg/dL) will be 
measured and recorded prior to the injection of FDG. 
Sedation (alprazolam, 0.5-1 mg, po, 30 minutes pre-FDG injection) is allowed, but not 
mandatory and should be used consistently by the patient for all scans. Filgrastim, 
pegfilgrastim, and epoetin are known to affect FDG uptake, and so their use by the patient 
should be recorded. 
Patients should wait in a warm room to avoid false positive brown fat FDG uptake. Patients 
will rest comfortably in a quiet room during the FDG uptake period. 
FDG will be synthesized and prepared in accordance with the institution’s standard 
procedures or obtained from a commercial supplier. 
8.2.2 FDG Dosing and Administration 
The administered activity of FDG should be based on the PET/CT scanner manufacturer’s 
recommendation. The recommended FDG dose is 0.14-0.21 mCi/kg. The actual FDG dose 
should be a bolus of 8-20 mCi, followed by a saline flush (per institutional procedure). A 
dose at the higher end of the range is recommended, if feasible, with appropriate reduction 
in the per kilogram dose for heavier patients (in accordance with the manufacturer’s 
recommendation). The effective FDG dose injected and time of injection should be 
documented on CALGB form C-1657 (50303 Imaging Adjunctive Data Sheet). 
8.3 
FDG-PET/CT Imaging Acquisition 
The FDG-PET/CT Imaging protocol must be followed exactly for every examination and for 
every patient. Any changes must be approved in advance by the Imaging Core Laboratory 
 and changes will be documented in  
a revised Technical PET Site Manual. It is highly suggested that the baseline exam is available 
for comparison at the time of the follow-up examination. 
The following PET/CT images will be collected digitally for evaluation and archival: 
• 
Baseline (preferred ≤ 30 days prior to start of therapy and before baseline excisional biopsy). 
If an eligible patient has a baseline PET/CT scan after the baseline excisional biopsy, the 
biopsied site must be excluded from quantitative evaluation. Please contact the Imaging 
Core Laboratory with questions. For qualified local sites participating in the evaluation of 
semi-quantitative PET parameters, study-specific baseline scans are required; 
• 
17-21 days after the beginning of Cycle 2 therapy and 0-4 days prior to start of Cycle 3; 
• 
Post-Cycle 6 (3-8 weeks after last dose of chemotherapy); 
• 
Any PET/CT image obtained post-Cycle 6. 
Whole body emission acquisition at both pre-therapy (baseline) and post-therapy (Cycles 2 and 
6) MUST start 60 (± 10) minutes after FDG injection. The starting time will be recorded. Oral 
and/or IV contrast is optional. The field of view is to encompass the region between the base of 
the skull and the mid-thighs, but the entire head or distal lower extremities should be included 
Version Date: 02/15/2018 
41 
Update #18 


CALGB 50303 
if these are known sites of disease at baseline. Patient will be scanned supine with arms 
positioned comfortably above the head, if possible. It is critical that follow-up emission scans 
be performed in an identical way to the baseline scan, with the same scanner, same scan 
direction (skull to thighs or thighs to skull), and consistent arm positioning (arms up or 
arms down). The interval between FDG injection and initiation of emission scanning should be 
the same as the baseline scan (no more than a ± 10 minute difference). All emission scans should 
be started between 50-70 minutes after injection of FDG. Preferably, schedule the patient for 
both baseline and follow-up scans at the same time of day (AM or PM) to improve 
reproducibility. Patient should empty his/her bladder immediately before the acquisition of 
images. 
For baseline scans, if the start time of the PET emission acquisition is outside of the protocol 
time window (60 ± 10 minutes post-injection), a non-compliance notification will be sent to the 
institution and the Alliance Imaging Committee. The Imaging Core Laboratory will coordinate 
with the Imaging Committee to decide whether or not (a) the patient should be included in 
follow-up studies, and if yes, (b) if the follow-up emission scans should be performed identically 
to the baseline scan in which the uptake time departed from the protocol, or if an adjustment will 
be necessary. The Imaging Core Laboratory will notify the institution of the decision and the 
case-specific procedure required for follow-up exams on that specific patient. 
If emission scans in follow-up exams are not performed identically to the baseline scan 
according to the protocol or to the decision by the Alliance Imaging Committee in a case of an 
accepted deviation, the same procedure outlined in the paragraph above will be used to clarify 
the acceptance of such an examination. 
For the emission scanning, the acquisition should be performed in 2D or 3D mode in accordance 
with the manufacturer’s recommendations defined in the Technical PET Site Manual. The 
emission scanning must be consistent between examinations and bed positions. The duration of 
acquisition for emission data should be in accordance with the manufacturer’s recommendations 
and the data must be corrected for scatter, random events, and dead-time losses using the 
manufacturer’s recommended procedure defined in the Technical PET Site Manual. Images 
should be attenuation corrected using CT data (note that if IV contrast is used, blood FDG SUV 
may be altered; therefore attenuation correction must be done without contrast). 
The patient will empty his/her bladder again immediately following PET/CT imaging. 
8.4 
Post-Treatment Study PET/CT Scans (Cycles 2 and 6) 
The post-treatment PET/CT scans are to be done according to the same specifications described 
in Section 8.0. The post-treatment PET/CT scans should be done on the same scanner within the 
same qualified institution used for the baseline PET. If there is a need to change the scanner, the 
institution must notify the Imaging Core Laboratory. 
The first post-treatment PET/CT scan will be done 17-21 days after completion of Cycle 2 of 
chemotherapy, and 0-4 days prior to initiation of Cycle 3 chemotherapy. 
The final post-treatment PET scan will be done at 3-8 weeks after the completion of Cycle 6 in 
order to allow for resolution of post-treatment inflammatory effects that can cause false positive 
PET scan results. If the patient is unable to complete six cycles of chemotherapy, a PET/CT scan 
should be performed at a similar interval after the last treatment. 
Each post-treatment PET/CT scan will be read and interpreted together with the baseline 
PET/CT scan and knowledge of other relevant clinical information. There will be a separate 
central review by the Imaging Core Laboratory. 
Version Date: 02/15/2018 
42 
Update #18 


CALGB 50303 
In addition to the tumor SUV and background SUV determinations described below (see Section 
8.7.4), an overall PET response scale will be reported for each patient, and the presence of any 
new lesions will be recorded and a confidence assessment indicated. The scale is as follows: 
Negative 
0 No abnormal activity (tumor cold compared with background) 
1+ 
Minimal activity (tumor less than background) 
2+ 
Equivocal (tumor = background) 
Positive 
3+ 
Moderately increased activity (tumor greater than background; i.e., greater than 
ABP) 
4+ 
Markedly increased activity (tumor much greater than background) 
After completion of standard chemotherapy, 
(1) Are there new foci of FDG activity (yes/no)? 
(2) Are these judged to represent lymphoma (yes/no)? 
8.5 
FDG-PET/CT Data Archiving, Storage, and Submission 
The complete PET/CT scan will be submitted to the Imaging Core Laboratory in digital DICOM 
format as defined in the Technical PET Site Manual. BMP files, JPG files, or hard copies 
(films) are not acceptable. The raw data of the entire study should be saved until the scan is 
accepted by the Imaging Core Laboratory. De-identify the patient data using institutional 
procedures to remove patient name and medical record number while preserving the CALGB 
ID number and protocol number. The de-identified digital images may be burned to a CD or 
transferred to a PC based system. The following complete data sets must be sent: 1) 
Transmission CT data; 2) emission data with attenuation correction; and 3) emission data 
without attenuation correction. 
Data may be transferred by 1) FTP transfer or 2) mail/express courier transfer. 
1) FTP Transfer: Any FTP software can be used to initiate access to the secure FTP Server of 
the Imaging Core Laboratory. The standard FTP access information will be provided separately 
through the specific trial e-mail 
, per the request by 
participating sites before their first data submission. 
Once you have access to the main data directory of the FTP server at the Imaging Core 
Laboratory, create a folder using the CALGB 50303 Subject Identifier assigned to the image 
data set you wish to FTP (upload). Then create another sub-folder with the date of the exam 
(YYYYMMDD), followed by the abbreviation of the study performed (PET, CT). Upload 
(copy) the imaging files to the appropriate sub-directory (the imaging files can be exported as a 
single file series). Once the upload is complete, you must send an e-mail to the Imaging Core 
Laboratory at 
 to inform them that the images have 
been uploaded from your institution. Please include the CALGB patient ID number and the 
date of the scan. 
2) Shipment/Mail Transfer: If FTP data transfers cannot be achieved, the de-identified images 
in digital DICOM format should be burned to a CD and mailed to the Imaging Core Laboratory. 
Please submit only one patient’s images per CD, with the patient’s CALGB ID number, study 
types (i.e., PET/CT baseline, post-Cycle 2, post-Cycle 6, or any other follow-up study), date of 
scans, date of first study treatment, and name of submitting institution. Alternatively, where 
institutional information systems allow, the images can be e-mailed to the Alliance Imaging 
Core Laboratory at the Ohio State University. 
Version Date: 02/15/2018 
43 
Update #18 


CALGB 50303 
Submit these data to: Alliance Imaging Core Laboratory 
 
 
 
 
 
 
Once the image acquisition has been completed, the entire study (complete PET/CT data in 
digital DICOM format), along with CALGB form C-1657 (50303 Imaging Adjunctive Data 
Sheet), must be submitted to the Imaging Core Laboratory within no more than 3 business days. 
Institutions must send C-1657 to the Alliance Statistics and Data Center, Data Operations. 
Please note that it is optional to submit the CALGB form C-1627 (50303 PET and CT 
Measurement Form). If C-1627 is submitted, it should be submitted to the Imaging Core 
Laboratory and the Alliance Statistics and Data Center, Data Operations at the same time as 
CALGB form C-1657 (50303 Imaging Adjunctive Data Sheet). 
If there are any difficulties or questions concerning the FDG-PET/CT data submission, please 
contact the Imaging Core Laboratory. 
The Alliance Imaging Core Laboratory will acknowledge receipt of the imaging data via e-mail 
confirmation to the institution within one business day of receipt. The data will be reviewed for 
quality (see Section 8.7.2). After completion of the quality check, another e-mail assessing the 
protocol compliance will be sent to the institution. 
8.6 
Training for FDG-PET/CT Data Acquisition and Handling 
As part of the approval process, the Imaging Core Laboratory will train the technologists and 
responsible imaging physicians for the institutions in all aspects of patient handling, image 
acquisition, and image transfer. The Imaging Core Laboratory will use a virtual site visit concept 
based on WebEx that can facilitate communication on any computer that has access to the 
Internet. Outlined below is the WebEx conference information that will be included in the 
institution-specific manual. 
WebEx conferencing allows the simultaneous display of images/text/help instructions (desktop 
presentations/desktop applications, such as Power Point) in a secure manner to participating sites 
to any computer with Internet access. For a WebEx conference, computers must have broadband 
Internet access and users must have the authority to download a WebEx client. For another level 
of safety and quality, the Imaging Core Laboratory will use a CALGB call-in number that should 
preferably be used from a conference phone if there is more than one participant from your 
location. 
The Imaging Core Laboratory will create a video stream that includes didactic information and 
training for technologists on any of the institution-specific issues. This information can be 
accessed at any time and/or downloaded at the institution for viewing. Furthermore, the Imaging 
Core Laboratory will offer a training course/workshop on a needed basis that can be attended by 
site personnel. 
The Imaging Core Laboratory will train intra- and inter-institutional image readers using other 
independent data sets including imaging data import/export using the Workstations; image 
integrity/completeness check with the support of software tools; PET/CT fusion; ROI/VOI 
placements; SUV calculation. 
Version Date: 02/15/2018 
44 
Update #18 


CALGB 50303 
The readers will be benchmarked against a gold standard established for those images by a 
consensus assessment of the experienced nuclear medicine physicians selected by the Imaging 
Committee, to include the protocol Imaging Co-Chair. Readers will be required to assess their 
consistency in assessment at least every six months. Furthermore, a web-based training module 
for nuclear medicine attendings reading trial studies will be developed. The Imaging Core 
Laboratory will not provide basic skills, but a dedicated training on all assessment aspects of 
this trial. 
8.7 
CALGB Imaging Core Lab Processing and Storage 
8.7.1 HIPAA Compliance 
The image data sets must be sent in a HIPAA-compliant manner. Upon receipt, the Imaging 
Core Laboratory will verify that the images are de-identified and contain the trial and 
CALGB patient ID. In the case that they do contain patient private information, the Imaging 
Core Laboratory will issue a non-compliance statement to the institution and will de-identify 
the submitted data sets. The Imaging Core Laboratory will work in a completely de-
identified manner and will use study and patient identification alpha-numerics according to 
CALGB procedures. 
8.7.2 Quality Assurance and Quality Control of PET/CT Images 
During institutional approval, institution-specific manuals will be established. All submitted 
PET/CT images will be reviewed regarding technical specifications such as dosage, timing, 
acquisition, and reconstruction, and that they are compliant with the protocol. Any non-
compliance or discrepancies will be reported in the quality assessment and compliance 
review. This procedure will be performed for every submitted data set and will occur within 
72 hours upon receipt of the data set at the Alliance Imaging Core Lab at IROC Ohio. The 
quality of the PET/CT systems will be verified on a daily and monthly basis. The review of 
the institution- and equipment-specific quality management, including daily quality 
assurance set-up and compliance to the policies, will be established at the approval 
assessment and verified on an ongoing basis. 
If, at the approval review of the institution, the Imaging Core Laboratory determines that 
there are insufficient quality standard operating procedures established for the site, it will 
propose that established procedures for the specific equipment type, based upon the 
manufacturer’s recommendation and established guidelines, be used. If at any time the 
institution is deemed to be non-compliant, a non-compliance statement will be issued and a 
remedy procedure suggested. If an institution does not remedy quality compliance concerns, 
the Imaging Core Laboratory will revoke the approval of the institution. The institution 
would then become ineligible for participation in the FDG-PET/CT companion until 
resolution of the defined issues. Imaging Core Laboratory guidelines will be in alignment 
with the ACRIN guidelines. 
The quality of each PET/CT image will be assessed in three steps: 1) confirmation that 
images have been received and are electronically accessible; 2) image review for 
completeness and image quality by an experienced research associate or technologist who 
will have access to staff nuclear medicine physicians in case of questions; and 3) review of 
images and post-processing results by an experienced staff member (nuclear medicine 
physician or radiologist). All ROI and calculation steps will be electronically documented 
and the quantitative data transferred into the trial database. 
There are two components regarding readability of images. One is the technical readability 
(e.g., the images are in a DICOM format, which is a requirement, or in a data format of any 
of the three major equipment vendors: General Electric, Philips, and Siemens). The other 
aspect is the image quality. As described above, every data set received will be reviewed 
Version Date: 02/15/2018 
45 
Update #18 


CALGB 50303 
regarding compliance to the acquisition and reconstruction protocol. Patient images that 
show artifacts due to patient motion, extravasation of radiotracer, or other technical issues, 
including non-compliance of the timeline, will be identified as such during the quality 
compliance review and reported as compliant/non-compliant or acceptable/unacceptable to 
the institution. 
Submitted images will be classified as “optimal” if they are compliant with all acquisition, 
reconstruction, and quality criteria without showing any artifacts. The classification 
“readable but not optimal” will be reserved for those images which are compliant in the 
essential components, but are sub-optimal due to patient motion or non-detrimental 
deviation from the expected performance. The classification “not readable” will be used for 
any other cases that cannot be characterized in the other two categories (i.e., no evaluable 
lesions; too much motion; wrong body location; data broken; images incomplete; non-
DICOM image formats, such as JPEG images, bitmap images, screen-captured images, 
scanned films or hardcopies, etc.) and that are non-compliant. 
An initial QA check will be performed within 72 hours by the Imaging Core Laboratory 
upon receipt of each imaging study from the sites. The imaging studies will be stratified as 
(1) optimal, (2) readable but not optimal, and (3) not readable, based upon predetermined 
rules. Imaging studies that are not readable will be communicated to the site and Imaging 
Co-Chair by the Imaging Core Laboratory and will be encouraged to be immediately 
repeated. Imaging studies that are readable but not optimal will be discussed with the 
Imaging Co-Chair to decide upon status in the analysis. It may be that these studies are 
included in the qualitative analysis, but not semiquantitative analysis. 
Strict enforcement of compliance and quality assessment is necessary in order to ensure the 
highest quality of the data collected in this trial. The assessment of every submitted study 
and image within 72 hours of submission to the Imaging Core Laboratory regarding 
compliance and quality enables not only the appropriate third party review, but also a timely 
notification about non-compliance to the institution and the Alliance. The Imaging Core 
Laboratory will copy non-compliance notices to the Alliance Imaging Committee and the 
Alliance Statistics and Data Center, and it will support the institution to ensure that 
compliance is achieved through appropriate measures. The Imaging Core Laboratory will 
propose remedy options that will include expected timelines and will revoke the institutional 
approval if compliance is not achieved within reasonable timelines. Any such action will be 
coordinated with the Alliance Imaging Committee. 
For non-compliant images: If images received by the Imaging Core Laboratory are not able 
to be analyzed (i.e., no evaluable lesions; data broken; images incomplete; non-DICOM 
image formats, such as JPEG images, bitmap images, screen-captured images, scanned films 
or hardcopies) and these potential problems cannot be resolved, then the following scenarios 
may apply: 
a) 
If the problem occurs with the baseline images, then an imaging quality check 
report will be sent to both the institution and the Alliance Imaging Committee 
Leadership, in which the Imaging Core Laboratory will suggest that the baseline 
scans be rescheduled/reperformed, as well as that the imaging data be 
retransmitted. Otherwise, if the patient has been in follow-up studies, then the 
Alliance Imaging Committee Leadership will decide whether and how the patient 
can be included in the analyses. 
b) 
If the problem occurs with the Cycle 2 images, but the baseline images are 
compliant, then an inquiry will be sent to the Alliance Imaging Committee 
Leadership to decide if the patient will be included in follow-up studies. If so, an 
imaging quality check report will be sent to both the institution and the Alliance 
Version Date: 02/15/2018 
46 
Update #18 


CALGB 50303 
Imaging Committee Leadership in which the Imaging Core Laboratory will remind 
the institution to avoid these problems in the follow-up scans and to provide 
DICOM-formatted imaging data for Cycle 6 and post-Cycle 6 images. 
c) 
If the problem occurs with the Cycle 6 images, but both baseline and Cycle 2 
images are compliant, then an inquiry will be sent to the Alliance Imaging 
Committee Leadership to decide if the patient will be included in any follow-up 
studies. If so, then an imaging quality check report will be sent to both the 
institution and the Alliance Imaging Committee Leadership in which the Imaging 
Core Laboratory will remind the institution to avoid these problems in post-Cycle 
6 scans. Otherwise, if the Cycle 2 images were also non-compliant, then an 
imaging quality check report will be sent to both the institution and the Alliance 
Imaging Committee Leadership, and the Alliance Imaging Committee Leadership 
will decide if the patient will be excluded from further post-Cycle 6 PET/CT scans. 
If the images received are analyzable, then an imaging quality check report will be 
sent to both the institution and the Alliance Imaging Committee Leadership, and 
the Alliance Imaging Committee Leadership will decide if the analysis for the 
patient is to be finished by the Imaging Core Laboratory. 
Summary Reports: The Imaging Core Laboratory will generate a monthly summary report 
for each institution that will report on the number of cases submitted, specification of images 
received, quality assurance failures and queries outstanding, and details of reconciliation 
processes in terms of images received/acquired, the quality/compliance assessment, etc. In 
addition to these institution-specific reports, the Imaging Core Laboratory will create 
summary reports for the entire trial, including recruitment quality status and number of non-
compliance queries. The Imaging Core Laboratory will submit quarterly and yearly reports 
to the Lymphoma FDG-PET Working Group (including experts from the NCI, FDA, 
Alliance, and PhRMA), the Imaging Co-Chair, and the Alliance Statistics and Data Center. 
8.7.3 Imaging Core Laboratory Image Reconstruction and Analysis 
Image reconstruction (i.e., an interactive reconstruction method with preference for OSEM 
reconstruction, 8 subsets, 2 iterations, followed by smoothing with a 6 mm 3-D Gaussian 
kernel) will be performed using the manufacturer-recommended parameters and specified 
in the Technical PET Site Manual. Both visual/qualitative and semi-quantitative (SUV) PET 
data analysis will be performed. 
Both visual/qualitative and semi-quantitative (SUV) PET/CT data analysis will be 
performed locally by the sites, as well as by the Alliance Imaging Committee in 
collaboration with the Imaging Core Laboratory. Data analysis of the study endpoints will 
be 
based 
on 
readings 
by 
three 
qualified 
independent 
nuclear 
medicine 
physicians/radiologists, selected by the Imaging Committee. Readings will be performed 
according to procedures outlined by the FDA imaging reports and will consist of two 
independent reads. Any discordance (defined by endpoints in the imaging analysis plan) 
will be adjudicated by a third independent nuclear medicine physician/radiologist. The 
adjudicator can only select one of the two initial independent reads, as outlined by FDA 
independent read documentation. Quantitative assessments (e.g., tumor location, tumor size, 
ROI/VOI information, SUV, etc.) will be electronically documented (screen captured from 
the Workstation) independently and used for determining consensus of readings, as well as 
inter-observer variability. Both Cycle 6 and Cycle 2 endpoints are dichotomous, and so will 
be determined by consensus of two or three readings. If an eligible patient has a baseline 
PET/CT scan after the baseline excisional biopsy, the biopsied site must be excluded from 
quantitative evaluation. Please contact the Imaging Core Laboratory with questions. 
Version Date: 02/15/2018 
47 
Update #18 


CALGB 50303 
8.7.4 Institutional & Imaging Core Laboratory Determination of Tumors and SUVs 
Tumor Selection: Up to six tumor masses > 2 cm will be selected for analysis at baseline, 
and their locations and size (length and width) will be defined. Tumor dimensions will be 
determined in a single plane on the transverse CT image where the tumor appears largest. 
The maximum dimension (length) should be measured, followed by the width, which should 
be perpendicular to the length. Tumor #1 will be the tumor site with highest SUVmax; the 
others will be selected in descending order of SUV. Location and dimensions of the index 
tumors will be determined at baseline and at all subsequent PET/CT scans. For post-
treatment assessment of lesions other than the six index lesions, see Section 8.8. 
SUVs: SUVs for the study endpoints will be calculated using decay-corrected administered 
dose and uncorrected body weight. SUVs will be calculated at baseline and at all subsequent 
PET/CT scans. These procedures are described briefly below. 
Tumor SUVmax: For the purposes of this study, the primary SUVs for calculation and 
reporting will be the SUVmax within each of the index (up to 6) tumor volumes. This will 
be determined by the nuclear medicine physician visually identifying the region or regions 
on the PET images that qualitatively appear to have the most intense FDG uptake and that 
correspond to known tumor based on other data (e.g., CT scan). SUVmax should be 
determined on the transverse slice where the tumor visually appears the brightest, as well as 
on several adjacent slices above and below, to be certain that the reported maximum is 
correct. Determinations will be made on a 128 x 128 image matrix size image. VOIs can be 
placed where the tumor visually appears the brightest by 3-D ellipse/spherical or 3-D 
isosurface tools. 
Prints of the image and the SUV cursor should be acquired and retained for source 
documentation. As noted above, for the purposes of this protocol, up to six lesions will be 
analyzed. The one with the highest SUVmax will be reported as lesion #1; the others should 
be identified in descending order of SUV. 
ABP SUVmean: Place the ROI on a transverse image or the spherical VOI with a 1 cm oval 
in the middle third of the aorta, well away from the edge. Take the mean SUV of the 
ROI/VOI. 
Liver SUVmean: Place the ROI on a transverse image (a 3-5 cm long by 2 cm irregular 
region) or the spherical VOI (a 3-5 cm long by 2 cm irregular volume) through the mid liver 
with relative uniform intensities, which excludes the central hilum of the liver. Take the 
mean SUV of the ROI/VOI. 
Other SUV data will be determined. As noted above, SUVs obtained and used for the 
endpoints of this study will be based on body weight and will not be corrected for body 
surface area or other measures of patient size/shape. However, patient height data will be 
collected, and exploratory analysis of SUV corrected for body surface area and lean body 
mass will be performed to determine whether this correction provides more useful data than 
conventional, uncorrected SUV. 
8.8 
Interpretation of Positive Post-Treatment Scans and Implications of PET Images for 
Progressive Disease 
At Cycle 6, if a scan is PET positive but CT negative, another PET/CT scan will be performed 
after 2-3 months. If PET remains positive, the PET-positive site(s) should be biopsied to 
determine histopathology, if feasible, or additional follow-up PET scans should be performed 
until the activity resolves or is stable for six months or longer. If a PET scan shows progression, 
results will be provided to the treating physician to assist in further evaluation of the patient. No 
patient will be considered to have failed treatment based on a positive PET scan alone. 
Version Date: 02/15/2018 
48 
Update #18 


CALGB 50303 
PET/CT results obtained post-Cycle 2 will not be provided to treating physicians during the 
course of the trial, since these data are exploratory in nature and their utility in patient 
management is unknown. Exceptions are the rare occurrences of any results suggesting the 
presence of progression or life-threatening disease. These data will be provided to the treating 
physician as soon as possible after they are obtained to aid the further evaluation of the patient. 
8.9 
PET/CT Scan Reimbursement 
The patient and/or his/her health plan/insurance company will need to pay for the costs of the 
PET/CT scans performed at prior to treatment, 3-8 weeks post-Cycle 6, and (if necessary) 2-3 
months after the post-Cycle 6 scan. The costs for as many as two PET/CT scans – a repeat 
baseline PET/CT scan if the original is non-compliant (i.e., not performed per protocol 
specifications), and the PET/CT scan performed at post-Cycle 2 – will be reimbursed by funding 
provided by the Cancer Trials Support Unit, funded by the National Cancer Institute. The 
reimbursement form can be found on the 50303 study page on the Alliance Web site, 
www.allianceforclinicaltrialsinoncology.org. 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
9.1 
Arm A (R-CHOP) Dose Modifications 
9.1.1 Hematologic Toxicity 
9.1.1.1 
Neutropenia 
• 
To begin a cycle, ANC must be ≥ 1500/µL and platelets ≥ 100,000/µL. Delay cycle 
by up to 2 weeks if these values are not met on Day 1 of cycle. If delay is greater 
than two weeks. then contact Study Chair. 
• 
If a patient develops grade 4 neutropenia (ANC < 500/µL) or any febrile 
neutropenia (defined as ANC < 500/µL + fever ≥ 38.5°C (101°F) sustained for 
more than one hour), filgrastim or pegfilgrastim should be administered for all 
subsequent cycles. Administration of colony stimulating factors at time of 
neutropenia is at the discretion of treating physician. 
• 
If febrile neutropenia (defined as ANC < 500/µL + temperature ≥ 38.5°C (101°F) 
sustained for more than one hour) occurs despite filgrastim or pegfilgrastim 
support, reduce doses of cyclophosphamide and doxorubicin by 25% for 
subsequent cycles. If toxicity recurs, cyclophosphamide and doxorubicin doses 
should be reduced by an additional 25% for subsequent cycles. 
• 
If grade 4 neutropenia or febrile neutropenia persists despite two dose reductions, 
remove patient from protocol therapy. 
9.1.1.2 
Thrombocytopenia 
• 
If grade 3 (platelets < 50,000/µL and ≥ 25,000/µL) or 4 thrombocytopenia 
(platelets < 25,000/µL) occurs, reduce doses of cyclophosphamide and 
doxorubicin by 25% for subsequent cycles. If toxicity recurs, cyclophosphamide 
and doxorubicin doses should be reduced by an additional 25% for subsequent 
cycles. 
• 
If grade 3 (platelets < 50,000/µL and ≥ 25,000/µL) or 4 thrombocytopenia 
(platelets < 25,000/µL) recurs despite two dose reductions, remove patient from 
protocol therapy.  
9.1.2 Ileus and Constipation 
Symptomatic ileus/constipation may occur with vincristine. If ileus or constipation require 
hospitalization, the next dose of vincristine should be reduced by 25%. If symptoms do not 
Version Date: 02/15/2018 
49 
Update #18 


CALGB 50303 
recur at the reduced dose, then the vincristine dose may be re-escalated on subsequent 
cycles. 
9.1.3 Neuropathy 
Sensory and motor neuropathy may occur with vincristine. Vincristine doses should only be 
reduced if the patient develops neuropathy that interferes with activities of daily living. Most 
vincristine associated neuropathy resolves after completion of treatment.  
• Sensory neuropathy: If grade 3 toxicity develops, reduce vincristine 25%. If symptoms 
improve, doses may be increased to previous levels. If patient experiences grade 4 
toxicity, discontinue vincristine. 
• Motor neuropathy: If patient experiences grade 2 toxicity, reduce vincristine 25%. If 
patient experiences grade 3 toxicity, reduce vincristine 50%. If symptoms improve, doses 
may be increased to previous levels. If patient experiences grade 4 toxicity, discontinue 
vincristine.  
9.1.4 Hyperbilirubinemia 
• 
Doxorubicin 
No doxorubicin dose modifications will be made for increased bilirubin ≤ 7 mg/dL. 
Doxorubicin should be held for bilirubin > 7 mg/dL, until it returns to ≤ 7 mg/dL. 
Pharmacokinetic data from Dr. Wilson et al. (unpublished data) has shown no 
significant effect of bilirubin on doxorubicin clearance. Specifically, doxorubicin 
pharmacokinetics were measured in 47 patients during multiple cycles of DA-EPOCH 
in which doxorubicin was administered as a continuous infusion. Seven patients 
presented with bilirubin levels above normal. Although doxorubicin clearance was 
delayed in cycle one in these seven patients, the clearance values were within the range 
of those seen in patients with normal bilirubin, and no patients experienced excessive 
toxicity. Significant reductions in doxorubicin clearance were observed primarily in 
patients with bilirubin levels ≥ 2 mg/dL. Bilirubin levels above 2 mg/dL did not 
demonstrate a quantitative relationship with doxorubicin clearance. Clinically, all of 
these patients received full dose doxorubicin, and no patient experienced excessive 
toxicity. Additionally, these patients showed significant increases in doxorubicin 
clearance in cycle 2. 
• 
Vincristine 
Vincristine dose will be decreased for elevated bilirubin only secondary to lymphoma 
as follows: 
Bilirubin (mg/dL) 
Vincristine Dose 
> 1.5 - < 3 
decrease by 25%* 
≥ 3 
decrease by 50%* 
* Vincristine dose will be re-escalated as hyperbilirubinemia improves.
Version Date: 02/15/2018 
50 
Update #18 


CALGB 50303 
 
9.2 
Arm B (DA-EPOCH-R) Dose Modifications 
9.2.1 Hematologic Toxicity 
Delay cycle by up to 2 weeks if ANC < 1000/µL or platelets < 100,000/µL. Filgrastim may 
be used for several days to increase ANC. If no recovery after 2 weeks, contact the Study 
Chair for guidance. 
Doses for doxorubicin, etoposide and cyclophosphamide will be based on measurements of 
the previous cycle ANC or platelet nadir whichever is lower (i.e., twice weekly starting 3-
4 days after completion of chemotherapy). 
If ANC ≥ 500/µL on all measurements: 
↑ one dose level* 
 
If ANC < 500/µL on 1 or 2 measurements 
(3-4 days apart): 
maintain dose level 
If ANC < 500/µL ≥ 3 measurements: 
(3-4 days apart): 
↓ one dose level** 
OR 
If platelet < 25,000/µL on ≥ 1 measurement: 
↓ one dose level  
* 
to a maximum of Dose Level 7. 
** to a minimum of Dose Level –2. Recurrence of a toxicity requiring a dose reduction below Dose 
Level –2 will result in removal of patient from protocol therapy. 
9.2.2 DA-EPOCH Dose Levels 
Dose adjustments for hematologic toxicity apply only to etoposide, doxorubicin and 
cyclophosphamide. Only cyclophosphamide is reduced in Dose Levels –1 through –3. 
 
Dose Levels 
Adjusted Agents 
-3 
-2 
-1 
1 
2 
3 
4 
5 
6 
7 
Doxorubicin (mg/m2/day) 
10 
10 
10 
10 
12 
14.4 
17.3 
20.7 
24.8 
29.8 
Etoposide (mg/m2/day) 
50 
50 
50 
50 
60 
72 
86.4 
103.7 
124.4 
149.3 
Cyclophosphamide (mg/m2) 
384 
480 
600 
750 
900 
1080 
1296 
1555 
1866 
2239 
 
 
 
 
 
 
 
 
 
 
 
Non-Adjusted Agents 
 
 
 
 
 
 
 
 
 
 
Rituximab (mg/m2) 
375 
375 
375 
375 
375 
375 
375 
375 
375 
375 
Vincristine (mg/m2/day) (No cap) 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
Prednisone (mg/m2 BID) 
60 
60 
60 
60 
60 
60 
60 
60 
60 
60 
9.2.3 Non-Hematologic Toxicity 
9.2.3.1 
Ileus and Constipation 
Symptomatic ileus/constipation may occur with vincristine. If ileus or constipation 
requires hospitalization, the next dose of vincristine should be reduced by 25%. If 
symptoms do not recur at the reduced dose, then the vincristine dose may be re-
escalated on subsequent cycles. 
9.2.3.2 
Neuropathy 
Sensory and motor neuropathy may occur with vincristine. Vincristine doses should 
only be reduced if the patient develops neuropathy that interferes with activities of 
Version Date: 02/15/2018 
51 
Update #18 


CALGB 50303 
daily living. Most vincristine associated neuropathy resolves after completion of 
treatment. 
• 
Sensory neuropathy: If grade 3 toxicity develops, reduce vincristine 25%. If 
symptoms improve, doses may be increased to previous levels. If a patient 
experiences grade 4 toxicity, discontinue vincristine. 
• 
Motor neuropathy: If grade 2 toxicity develops, reduce vincristine 25%. If a 
patient experiences grade 3 toxicity, reduce vincristine 50%. If symptoms improve, 
doses may be increased to previous levels. If a patient experiences grade 4 toxicity, 
discontinue vincristine. 
9.2.3.3 
Hyperbilirubinemia 
• 
Doxorubicin 
No doxorubicin dose modifications will be made for increased bilirubin ≤ 7 mg/dL. 
Doxorubicin should be held for bilirubin > 7 mg/dL, until it returns to ≤ 7 mg/dL.. 
Pharmacokinetic data from Dr. Wilson et al. (unpublished data) has shown no 
significant effect of bilirubin on doxorubicin clearance. Specifically, doxorubicin 
pharmacokinetics were measured in 47 patients during multiple cycles of DA-
EPOCH in which doxorubicin was administered as a continuous infusion. Seven 
patients presented with bilirubin levels above normal. Although doxorubicin 
clearance was delayed in cycle one in these seven patients, the clearance values 
were within the range of those seen in patients with normal bilirubin, and no 
patients experienced excessive toxicity. Significant reductions in doxorubicin 
clearance were observed primarily in patients with bilirubin levels ≥ 2 mg/dL. 
Bilirubin levels above 2 mg/dL did not demonstrate a quantitative relationship with 
doxorubicin clearance. Clinically, all of these patients received full dose 
doxorubicin, and no patient experienced excessive toxicity. Additionally, these 
patients showed significant increases in doxorubicin clearance in cycle 2. 
• 
Vincristine 
Vincristine dose will be decreased for elevated bilirubin only secondary to 
lymphoma as follows: 
Bilirubin (mg/dL) 
Vincristine Dose 
> 1.5- < 3 
decrease by 25%* 
≥ 3 
decrease by 50%* 
* Vincristine dose will be re-escalated as hyperbilirubinemia improves. 
9.2.3.4 
Dose Modifications Based on Creatinine Clearance Secondary to Lymphoma 
No etoposide dose modifications will be made for decreased creatinine clearance or 
increase creatinine. It is anticipated that decreased clearance or increased creatinine 
will improve after the first treatment cycle.  
9.3 
Dose Modification for Obese Patients 
All dosing is based on the patient’s BSA as calculated from actual weight. There is no clearly 
documented adverse impact of treatment of obese patients when dosing is performed according 
to actual body weight.  Failure to use actual body weight in the calculation of drug dosages will 
be considered a major protocol deviation. Physicians who are uncomfortable with administering 
chemotherapy dose based on actual body weight should not enroll obese patients on Alliance 
protocols. 
Version Date: 02/15/2018 
52 
Update #18 


CALGB 50303 
10.0 DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
Qualified personnel who are familiar with procedures that minimize undue exposure to themselves 
and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents in a self-contained, protective environment. 
Discard unused portions of injectable chemotherapeutic agents that do not contain a bacteriostatic 
agent or are prepared with unpreserved diluents (i.e., Sterile Water for Injection USP or 0.9% Sodium 
Chloride for Injection USP) within eight hours of vial entry to minimize the risk of bacterial 
contamination. 
The total administered dose of chemotherapy may be rounded up or down within a range of 5% of 
the actual calculated dose. 
The weight at Cycle 1 should be used for dose calculations for all cycles unless there is a ≥10% 
change over a period of one cycle. If a weight change ≥ 10% occurs, then doses should be recalculated 
and the new dose used from that time forward. 
10.1 
Doxorubicin HCL (Adriamycin PFS™, Adriamycin RFS™, Rubex®) 
AVAILABILITY 
Doxorubicin is commercially available as a lyophilized powder for reconstitution in 10, 20, 50, 
and 100 mg vials. Also available are 2 mg/mL solutions for injection in 10, 20, 50, and 200 mg 
vials. Please refer to the FDA-approved package insert for doxorubicin for product information, 
extensive preparation instructions, and a comprehensive list of adverse events. 
STORAGE & STABILITY 
Intact vials of doxorubicin solution should be stored in the refrigerator. Intact vials of powder 
for reconstitution should be stored at room temperature. Reconstituted solutions are stable for 7 
days at room temperature and 15 days under refrigeration when protected from light. 
Commercially available solutions labeled as such are intended to be multidose vials. 
Compatibility and stability studies were conducted by the Pharmaceutical Development Service 
[60], Pharmacy Department, NIH Clinical Center, simulating concentrations of each drug that 
would be applicable to this trial. Admixtures of vincristine, doxorubicin, and etoposide in 0.9% 
Sodium Chloride Injection, in polyolefin-lined IV bags were stable for up to 72 hours at room 
temperature, provided that the concentration of etoposide was < 250 mcg/ml. 
PREPARATION 
Reconstitute the vials of doxorubicin powder with 5, 10, 25, or 50 mL, respectively, of sodium 
chloride for injection, USP, resulting in a concentration of 2 mg/mL. 
In Arm A (CHOP-R), withdraw the desired volume into a syringe for IV injection. 
In Arm B (EPOCH-R), doxorubicin will be admixed in 0.9% sodium chloride, along with 
vincristine IV for infusion over 24, 48 or 72 hours. Etoposide may be mixed with doxorubicin 
and vincristine, or it may be infused separately. See reference 49 for specific compatibility and 
stability information base on concentration of each agent. 
ADMINISTRATION 
In Arm A (CHOP-R), doxorubicin is administered intravenously over 3-5 minutes. Avoid 
extravasation, as severe local tissue necrosis may result. 
In Arm B (EPOCH-R), doxorubicin will be administered as a 96-hour continuous IV infusion, 
along with vincristine and etoposide in the same infusion solution (see “Storage and Stability” 
above). The chemotherapy will be administered with a suitable infusion pump via a central 
venous access device. Temporary PICC lines or permanent lines may be used. Extravasation of 
Version Date: 02/15/2018 
53 
Update #18 


CALGB 50303 
these diluted agents has not caused local tissue damage due to their low concentrations in the 
solution. 
TOXICITIES 
Hematologic: Leukopenia (dose-limiting), thrombocytopenia, anemia. Nadir in 10-14 days with 
recovery usually in 21 days. 
Dermatologic: alopecia (usually complete; reversible) radiation recall reactions; increased 
sensitivity to sunlight. 
Gastrointestinal: nausea and vomiting (doxorubicin is generally considered moderately to highly 
emetogenic), anorexia, diarrhea, mucositis (stomatitis, esophagitis). 
Cardiovascular: cardiomyopathy may occur and is related to total cumulative lifetime dose. The 
risk for cardiomyopathy increases with total doses > 450 mg/m2. ECG changes and less often, 
arrhythmias, are seen. Rarely, sudden death has occurred. 
Other: Red discoloration of urine for 24-48 hours after drug administration. Doxorubicin is a 
vesicant and can cause tissue necrosis if extravasated, especially at the concentration usually 
employed for bolus injections (i.e., 2 mg/mL). 
10.2 
Etoposide (VePesid®, Epidophyllotoxin, VP-16) 
AVAILABILITY 
Etoposide is commercially available as a solution for injection in 5 mL, 7.5 mL, 25 mL, and 50 
mL vials containing 20 mg/mL. Please refer to the FDA-approved package insert for etoposide 
for product information, extensive preparation instructions, and a comprehensive list of adverse 
events. 
STORAGE & STABILITY 
Intact vials of etoposide for injection should be stored at room temperature and protected from 
light. 
Compatibility and stability studies were conducted by the Pharmaceutical Development Service 
[60], Pharmacy Department, NIH Clinical Center, simulating concentrations of each drug that 
would be applicable to this trial. Admixtures of vincristine, doxorubicin, and etoposide in 0.9% 
Sodium Chloride Injection, in polyolefin-lined IV bags were stable for up to 72 hours at room 
temperature, provided that the concentration of etoposide was < 250 mcg/ml. 
PREPARATION 
Etoposide will be admixed in 0.9% sodium chloride for IV infusion over 24, 48 or 72 hours. 
Etoposide may be mixed with doxorubicin and vincristine or it may be infused separately. See 
reference 49 for specific compatibility and stability information based on concentration of each 
agent. Infusion solutions should be changed every 24 hours. The volume of the infusion solution 
will be determined by the 24 hour etoposide dose. If etoposide ≤ 150 mg per 24 hours, then 
dilute drugs in 500 mL 0.9% sodium chloride; if etoposide > 150 mg per 24 hours, then dilute 
drugs in 1000 mL 0.9% sodium chloride. 
ADMINISTRATION 
Etoposide is administered in Arm B only. Etoposide will be administered as a 96-hour 
continuous IV infusion, along with vincristine and doxorubicin (see “Storage & Stability” 
above). The chemotherapy will be administered with a suitable infusion pump via a central 
venous access device. Temporary PICC lines or permanent lines may be used. Extravasation of 
these diluted agents has not caused local tissue damage due to their low concentrations in the 
solution. 
 
Version Date: 02/15/2018 
54 
Update #18 


CALGB 50303 
TOXICITY 
Myelosuppression, predominantly neutropenia and thrombocytopenia, is the most common 
toxicity associated with etoposide. Nausea and vomiting range from mild to severe in severity, 
depending on the dose. At the dose used in this study, etoposide is moderately highly 
emetogenic. Mucositis is also more common at the dose used in this study. Alopecia is likely. 
Hypotension is associated with too rapid administration of etoposide. This would be unlikely to 
occur in this trial. 
10.3 
Vincristine sulfate (VCR, Leurocristine sulfate, Oncovin®, Vincasar PFS) 
AVAILABILITY 
Vincristine is commercially available in 1 mL, 2 mL, and 5 mL vials in a concentration of 1 
mg/mL. Please refer to the FDA-approved package insert for vincristine sulfate for product 
information, extensive preparation instructions, and a comprehensive list of adverse events. 
STORAGE & STABILITY 
Unopened vials should be stored under refrigeration and proteced from light. Commercially 
available solutions labeled as such are intended to be multidose vials. 
Compatibility and stability studies were conducted by the Pharmaceutical Development Service 
[49], Pharmacy Department, NIH Clinical Center, simulating concentrations of each drug that 
would be applicable to this trial. Admixtures of vincristine, doxorubicin, and etoposide in 0.9% 
Sodium Chloride Injection, in polyolefin-lined IV bags were stable for up to 72 hours at room 
temperature, provided that the concentration of etoposide was < 250 mcg/ml. 
PREPARATION 
In Arm A (CHOP-R), withdraw the desired volume into a syringe for IV injection. 
In Arm B (EPOCH-R), vincristine will be admixed in 0.9% sodium chloride for IV infusion 
over 24, 48 or 72 hours. Etoposide may be mixed with doxorubicin and vincristine or it may be 
infused separately. See reference 49 for specific compatibility and stability information based 
on concentration of each agent. Infusion solutions should be changed every 24 hours. The 
volume of the infusion solution will be determined by the 24 hour etoposide dose. If etoposide 
≤ 150 mg per 24 hours, then dilute drugs in 500 mL 0.9% sodium chloride; if etoposide > 150 
mg per 24 hours, then dilute drugs in 1000 mL 0.9% sodium chloride. Infusion solutions should 
be protected from light. 
ADMINISTRATION 
In Arm A (CHOP-R), administer without further dilution by slow IV push. Precaution: 
Maximum single dose is 2 mg. 
In Arm B (EPOCH-R), vincristine will be administered as a 96-hour continuous IV infusion, 
along with etoposide and doxorubicin (see “Storage & Stability” above). The chemotherapy will 
then be administered with a suitable infusion pump via a central venous access device. 
Temporary PICC lines or permanent lines may be used. Extravasation of these diluted agents 
has not caused local tissue damage due to their low concentrations in the solution. 
TOXICITY 
The most common toxicity associated with vincristine is neurotoxicity. Peripheral 
manifestations of neurotoxicity include: numbness of extremities, paresthesias, loss of deep 
tendon reflexes, neuropathic pain and muscle weakness. GI manifestations of neurotoxicity 
include constipation, and adynamic ileus. Cranial nerve manifestations include: diplopia, 
hoarseness, tinnitus, jaw pain (the latter usually occurring with the first dose of vincristine). 
Orthostatic hypotension & SIADH may also be seen. Vincristine is a vesicant and may cause 
Version Date: 02/15/2018 
55 
Update #18 


CALGB 50303 
tissue necrosis upon extravasation. This is more likely with bolus injections as opposed to dilute 
infusions. 
10.4 
Cyclophosphamide (Cytoxan®; Neosar®) 
AVAILABILITY 
Commercially available as a powder for reconstitution in 100 mg, 200 mg, 500 mg, 1 gram, and 
2 gram vials. Please refer to the FDA-approved package insert for cyclophosphamide for product 
information, extensive preparation instructions, and a comprehensive list of adverse events. 
PREPARATION 
Reconstitute 100 mg, 200 mg, 500 mg, 1 gram and 2 gram vials with 5, 10, 25, 50, or 100 mL 
of sterile water for injection or normal saline to give a final concentration of 20 mg/mL. 
Vigorous shaking and/or gentle warming may be necessary for non–lyophilized preparations. 
Bacteriostatic water for injection (paraben preserved only) may be used; benzyl alcohol 
derivatives may NOT be used. 
STORAGE & STABILITY 
Intact vials should be stored at room temperature. Reconstituted and diluted solutions are stable 
for 24 hours at room temperature and 6 days if refrigerated. 
ADMINISTRATION 
The total dose of cyclophosphamide will be administered by IV. 
All patients should receive hydration with normal saline at the following volumes (based on 
cyclophosphamide dose levels) and rates with half administered before and half administered 
after cyclophosphamide. 
R-CHOP and DA-EPOCH-R Levels 1-2 (see § 9.2.2): 
1 liter NS @ 300-500 cc/hr 
DA-EPOCH-R Levels 3-5 (see § 9.2.2): 
2 liter NS @ 300-500 cc/hr 
DA-EPOCH-R Level ≥ 6 (see § 9.2.2): 
2.5 liter NS @ 300-500 cc/hr 
TOXICITY 
Myelosuppression, hemorrhagic cystitis (patients must be well-hydrated before, during, and 
after treatment and have adequate renal function). Syndrome of inappropriate antidiuretic 
hormone (SIADH), fatigue, alopecia, anorexia, nausea, vomiting, hyperuricemia, azospermia, 
amenorrhea, cardiotoxicity (myocardial necrosis) usually at doses higher than those used in this 
study. 
DRUG INTERACTIONS 
Cyclophosphamide undergoes metabolic activation via cytochrome P450 3A4 in the liver and 
may potentially interact with any drug affecting the same isoenzyme. Inhibitors of 3A4 (e.g., 
itraconazole) could theoretically inhibit activation and inducers of 3A4 (e.g., phenytoin) could 
theoretically enhance activation of cyclophosphamide to active alkylating species. For the most 
part, such interactions have not yet been documented clinically. 
10.5 
Prednisone (Deltasone, miscellaneous) 
AVAILABILITY 
Commercially available in 1, 2.5, 5, 10, 20, 25, and 50 mg tablets, or as an oral solution or syrup 
- 5 mg/5 ml (in 5% alcohol); solution concentrate - 5 mg/ml (with 30% alcohol). Please refer to 
the FDA-approved package insert for prednisone for product information, and a comprehensive 
list of adverse events. 
STORAGE & STABILITY 
Version Date: 02/15/2018 
56 
Update #18 


CALGB 50303 
Store tablets, solutions and syrup in tightly closed containers at room temperature. 
ADMINISTRATION 
Oral. 
TOXICITY 
Side effects likely to be encountered with intermittent high doses include: GI (dyspepsia, 
ulceration), insomnia, and hyperglycemia. Occasionally a “withdrawal syndrome” after short-
term high doses, such as in this study, manifest muscle aches and pains. Immunosuppression 
with risk of infection is also seen. 
10.6 
Rituximab 
AVAILABILITY 
Rituximab is commercially available in 10 mL and 50 mL single-use vials containing 100 mg 
or 500 mg rituximab solution, respectively, at a concentration of 10 mg/mL. Please refer to the 
FDA-approved package insert for rituximab for product information, extensive preparation 
instructions, and a comprehensive list of adverse events. 
STORAGE & STABILITY 
Intact vials should be stored under refrigeration. Dilute solutions for infusion (1-4 mg/mL) are 
stable for 24 hours under refrigeration, and for an additional 24 hours at room temperature. 
PREPARATION 
The desired dose of rituximab should be diluted in 0.9% NaCl or D5W to a final concentration 
of 1-4 mg/mL. The solution should be mixed by gently inverting the bag. 
ADMINISTRATION 
Oral pre-medication 650 mg of acetaminophen and 50-100 mg diphenhydramine hydrochloride 
will be administered 30 to 60 minutes prior to starting each infusion of rituximab. Rituximab 
will be administered as an intravenous infusion at 375 mg/m2 on day 1 of each cycle of R-CHOP 
or DA-EPOCH-R, immediately prior to the start of chemotherapy. The first rituximab infusion 
should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a 
maximum rate of 400 mg/hr. If this rate of escalation is well tolerated the second and subsequent 
infusions can begin at a rate of 100 mg/hr and increase in 100 mg/hr increments every 30 minutes 
to a maximum of 400 mg/hr. CAUTION: DO NOT ADMINISTER AS AN INTRAVENOUS 
PUSH OR BOLUS. 
TOXICITY 
The most severe serious adverse events associated with rituximab include severe infusion 
reactions, tumor lysis syndrome, and severe mucocutaneous reactions. Severe infusion reactions 
consisting of hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation or cardiogenic shock may be fatal. Most reported fatal 
reactions occurred within 24 hours of the first dose of rituximab. 
Tumor lysis syndrome resulting in renal failure has been described, and occasional fatalities 
noted. Tumor lysis syndrome is more likely in patients with high numbers of circulating 
malignant cells (≥ 25,000/µL). 
Severe mucocutaneous reactions associated with rituximab include Stevens-Johnson syndrome 
and toxic epidermal necrolysis. The onset of these reactions has been from 1-3 weeks. 
Less severe infusion reactions are common with rituximab. These include fever, chills, and 
dyspnea. The mechanism of rituximab infusion reactions is thought to be secondary to release 
of cytokines. If a reaction occurs, then the infusion should be stopped until the symptoms 
resolve, and then restarted at a 50% slower rate. 
Version Date: 02/15/2018 
57 
Update #18 


CALGB 50303 
Recent reports describe hepatitis B reactivation with fulminant hepatitis, hepatic failure and 
death in some patients with hematologic malignancies treated with rituximab. The majority of 
these patients received rituximab in combination with chemotherapy. The median time to 
diagnosis of hepatitis was approximately 4 months after starting rituximab and approximately 1 
month after the last dose. 
Exacerbation or reactivation of other viral infections has also been reported with rituximab. 
Recent reports describe JC virus reactivation leading to progressive multifocal 
leukoencephalopathy (PML) in patients who were receiving rituximab. Patients presenting with 
new neurologic findings (e.g., major changes in vision, unusual eye movements, loss of balance 
or coordination, confusion) should be evaluated for PML. 
10.7 
Filgrastim (G-CSF; r-met HuG-CSF; Granulocyte Colony Stimulating Factor; 
Neupogen®) 
AVAILABILITY  
Commercial filgrastim is available in 1 mL and 1.6 mL vials containing 300 mcg and 480 mcg 
filgrastim, and in prefilled syringes containing 300 mcg/0.5 mL or 480mcg/0.8 mL. Please refer 
to the FDA-approved package insert for filgrastim for product information, extensive 
preparation instructions, and a comprehensive list of adverse events. 
STORAGE & STABILITY 
Intact vials and prefilled syringes should be stored in the refrigerator at 2-8° Centigrade (36-46° 
Fahrenheit). Do not freeze.  
ADMINISTRATION 
Filgrastim will be administered as a subcutaneous injection. In both arms, the daily dose will be 
480 mcg. 
In Arm A (CHOP-R), filgrastim (or pegfilgrastim) will be administered after subsequent cycles 
following the occurrence of grade 4 neutropenia or febrile neutropenia. Filgrastim will be given 
daily from Day 2 until ANC > 5000 after the nadir (nadir usually between Days 10-12) or for 
10 days (Days 2-11) if the ANC is not being monitored. 
In Arm B (EPOCH-R), filgrastim will be given daily from Day 6 until ANC > 5000 after the 
nadir (nadir usually between Days 10-12) or for 10 days (Days 6-15) if the ANC is not being 
monitored, in all cycles. 
TOXICITY 
The most common side effect associated with filgrastim is medullary bone pain. Bone pain is 
usually reported as mild or moderate and, if necessary, may be treated with non-opioid or opioid 
analgesics. 
10.8 
Pegfilgrastim (Neulasta®) 
AVAILABILITY 
Pegfilgrastim is commercially available prefilled single-dose syringes containing 6 mg/0.6 mL 
of pegfilgrastim (10 mg/mL). Please refer to the FDA-approved package insert for pegfilgrastim 
for product information, extensive preparation instructions, and a comprehensive list of adverse 
events. 
STORAGE & STABILITY 
Intact syringes should be stored under refrigeration and protected from light. Pegfilgrastim 
syringes are reportedly stable at room temperature for up to 48 hours prior to injection, if 
protected from light. Syringes that are frozen unintentionally may be allowed to thaw in the 
refrigerator. Pegfilgrastim syringes that have been frozen a second time should be discarded. 
Version Date: 02/15/2018 
58 
Update #18 


CALGB 50303 
ADMINISTRATION 
The dosage of pegfilgrastim is a single subcutaneous injection of 6 mg administered between 24 
and 36 hours after the completion of the cyclophosphamide infusion. Pegfilgrastim will be 
administered as a subcutaneous injection. In Arm A, pegfilgrastim (or filgrastim) will be 
administered after subsequent cycles following the occurrence  of grade 4 neutropenia or febrile 
neutropenia. Pegfilgrastim will be administered at a dose of 6 mg one time per cycle. If 
pegfilgrastim is given, the patient should not receive additional filgrastim.  
Note: DA-EPOCH-R dosing has only been validated using filgrastim. Pegfilgrastim has 
different kinetics of neutrophil recovery and its use may adversely affect dosing and reduce 
disease cure rates. Use of pegfilgrastim must be approved by the Study Chair and will only be 
approved if the patient cannot receive filgrastim. 
TOXICITY 
The most common side effect associated with pegfilgrastim is bone pain. Bone pain is usually 
reported as mild or moderate, and, if necessary, may be treated with non-opioid or opioid 
analgesics. 
Other reported side effects include reversible elevations in LDH, alkaline phosphatase, and uric 
acid. These laboratory abnormalities are not usually of clinical significance and do not require 
any intervention. 
10.9 
Methotrexate (MTX, Folex) 
AVAILABILITY 
Methotrexate is commercially available in 2 mL (25 mg/mL) vials or 20 mg, 25, mg, 50 mg, or 
100 mg vials for reconstitution. Read the manufacturer’s package labeling carefully for solution 
concentrations. Please refer to the agent’s package insert for additional information. 
STORAGE & STABILITY 
Unopened vials of methotrexate should be stored at room temperature, and protected from light. 
PREPARATION 
For intrathecal injection: reconstitute to a concentration of 1-5 mg/mL with an appropriate 
sterile, preservative free medium such as Sodium Chloride Injection, USP. 
ADMINISTRATION 
In this study, methotrexate will be administered as an intrathecal injection of 12 mg. 
Methotrexate will be given to select patients in Arm A and Arm B, as described in Section 7.1.3 
and 7.2.3. 
TOXICITY 
Toxicities associated with intrathecal administration: arachnoiditis, ataxia, coma, confusion, 
dementia, encephalopathy, headache, paresis, seizures. 
DRUG INTERACTIONS 
The use of NSAIDs, probenecid, salicylates, sulfonamides may prolong methotrexate levels and 
enhance toxicity. 
11.0 ANCILLARY THERAPY 
11.1 
Supportive Care 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc., when appropriate. The reason(s) for treatment, dosage, and the 
dates of treatment should be recorded on CALGB Form C-260 (Remarks Addenda). 
Version Date: 02/15/2018 
59 
Update #18 


CALGB 50303 
11.2 
Hormones and Other Chemotherapeutic Agents 
Treatment with hormones or other chemotherapeutic agents may not be administered except for 
steroids given for adrenal failure or hormones administered for non-disease-related conditions 
(e.g., insulin for diabetes) Use of dexamethasone and other steroidal anti-emetics is prohibited 
in this protocol. 
11.3 
Epoetin 
The use of epoetin is allowed at the discretion of the investigator. It is recommended that epoetin 
not be used in this protocol unless hemoglobin is ≤ 10 g/dL, and that it be held or the dose 
modified for hemoglobin > 12 g/dL. 
12.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE 
R-CHOP patients will be re-evaluated after Cycles 4 and 6. DA-EPOCH-R patients will be re-
evaluated after Cycles 4 and 6. 
12.1 
Definitions of Response [61] 
12.1.1 Complete Response (CR) 
• 
Complete disappearance of all detectable clinical and radiographic evidence of target 
lesions and disappearance of all disease-related symptoms if present prior to therapy, as 
well as normalization of those biochemical abnormalities (e.g., LDH, etc.) definitely 
assignable to DLBCL. 
• 
All lymph nodes and nodal masses must have regressed to normal size (≤ 1.5 cm in their 
greatest transverse diameter for nodes > 1.5 cm prior to therapy). Previously involved 
nodes that were 1.1 to 1.5 cm in their greatest transverse diameter prior to treatment 
must have decreased to ≤ 1 cm in their greatest transverse diameter after treatment, or 
by more than 75% in the sum of the products of their greatest transverse diameters 
(SPD). 
• 
The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must 
have regressed in size and must not be palpable on physical examination. (No normal 
size can be specified, however, because of the difficulties in evaluating splenic and 
hepatic size.) Any macroscopic nodules in any organs detectable on imaging studies 
should no longer be present. Similarly, other organs considered to be enlarged prior to 
therapy due to involvement of lymphoma (i.e., kidneys, liver, etc.) must have decreased 
in size. 
• 
If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must be 
cleared on repeat bone marrow aspirate and biopsy of same site. 
12.1.2 Complete Response Unconfirmed (CRu) 
Complete response/unconfirmed will include those patients who have met the criteria in 
Section 12.1.1 bullet points 1 and 3, but with one or more of the following: 
• A residual node > 1.5 cm in greatest transverse diameter that has regressed more than 
75% in the product of its diameters. Individual nodes that were previously confluent must 
have regressed more than 75% in the product of their diameters compared with the size 
of the original mass. PET is recommended at the end of treatment in patients with 
CRu. If positive, follow with repeat PET or biopsy. 
• Indeterminate bone marrow (increased number or size of aggregates without cytologic 
or architectural atypia). 
Version Date: 02/15/2018 
60 
Update #18 


CALGB 50303 
12.1.3 Partial Response (PR) 
• 
A decrease of ≥ 50% in the SPD of the six largest dominant nodes or nodal masses. 
These nodes or masses should be selected according to the following features: a) they 
should be clearly measurable in at least two perpendicular measurements; b) they should 
be from as disparate regions of the body as possible; and c) they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are involved. PET 
is recommended at the end of treatment in patients with PR. If positive, follow with 
repeat PET or biopsy.   
• 
No increase in the size of other nodes, liver, or spleen. 
• 
Splenic and hepatic nodules must regress by at least 50% in SPD. 
• 
With the exception of splenic and hepatic nodules, involvement of other organs is 
considered assessable and not measurable disease. 
• 
Bone marrow assessment is irrelevant for determination of a PR because it is assessable 
and not measurable disease; however, if positive the cell type should be specified in the 
report, e.g., large-cell lymphoma. 
• 
No new sites of disease. 
12.1.4 Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking 
as reference the smallest SPD since the treatment started. 
12.1.5 Progression (PD) or Relapse 
• 
≥ 50% increase from nadir in the SPD of any previously identified abnormal node for 
PRs or nonresponders. 
• 
Appearance of any new lesion during or after completion of therapy. 
• 
PET+ is not a criterion for progressive disease. Patients only with PET+ findings must 
have evidence of progression on CT or biopsy proven. 
12.2 
Response Assessment Table 
Response 
Category 
Lymph Nodes  
Splenic or Extranodal Sites 
Bone Marrow 
CR 
Normal size 
Negative 
Negative for tumor 
CRu 
> 75% decrease and PET 
negative. If PET equivocal, 
observe or biopsy. PET + is 
not a criterion for treatment 
failure.    
Measurable sites > 75% decrease 
and PET negative. If PET equivocal, 
observe or biopsy. PET + is not a 
criterion for treatment failure. Non-
measurable (e.g. bone), MRI and CT 
improved and PET negative. 
Negative for tumor 
PR   
50-75% decrease or CRu 
with PET positive or biopsy 
positive.  
Measurable sites 50-75% decrease 
or CRu with PET positive or biopsy 
positive. 
If positive for tumor, must 
have PR in measurable 
disease sites.  
SD  
No Change (Section 12.1.4) 
No change (Section 12.1.4) 
No change (Section 12.1.4) 
PD/Relapse  ≥ 50% increase from nadir 
or new site. PET + alone is 
not a criterion for treatment 
failure. 
Measurable sites ≥ 50% increase 
from nadir or new site. Non-
measurable (e.g. bone), evidence of 
progressive worsening on MRI/CT 
and PET positive. Strongly suggest 
biopsy.   
Newly positive for tumor.  
Version Date: 02/15/2018 
61 
Update #18 


CALGB 50303 
12.3 
Criteria for FDG-PET Response 
12.3.1 Primary Endpoint: IWG Criteria + FDG-PET Response 
The primary FDG-PET response endpoint is defined by visual reading of FDG uptake after 
Cycle 
6 
of 
chemotherapy. 
For 
responders, 
tumor 
FDG 
uptake 
is 
≤ ABP FDG uptake in all tumors, and no new avid lesions are seen. 
In a recent study, 54 patients with aggressive NHL underwent CT and PET exams 1-16 
weeks after completing four to eight cycles of CHOP therapy. Each patient was assessed for 
one of the following using the standard IWG criteria or the IWG criteria with PET: a 
complete response (CR), an unconfirmed complete response (CRu), a partial response (PR), 
stable disease (SD), and progressive disease (PD). Progression-free survival was also 
compared between IWG criteria and IWG criteria + PET [70]. 
The study found that with IWG alone, 17 patients had a CR, seven had a CRu, 19 had a PR, 
nine had SD, and two had PD. By comparison, IWG + PET produced a significantly higher 
response rate: 35 patients had a CR, 12 had a PR, six had SD, one had PD, and zero had 
CRu. Additionally, extensive analysis revealed that when the response rates were measured 
by IWG criteria alone and compared to IWG criteria + PET, the IWG + PET assessments 
provided a more accurate response classification in patients with aggressive NHL. 
For this imaging companion study, the FDG-PET endpoint will be combined with IWG 
criteria to further assess and refine the improved response classification seen in the 54-
patient study. 
12.3.2 Secondary Endpoints 
As secondary endpoints, metabolic response after Cycles 6 and 2 is defined by decreases in 
tumor SUV in the index tumors. In responders after Cycle 6, the ratio of tumor SUVmax to 
ABP SUVmean is ≤ 1.25 in all index tumors, and no FDG-PET uptake greater than 
background is seen in any other lesion. In responders after Cycle 2, tumor SUVmax is 
decreased ≥ 85% from baseline for index tumors, or the ratio of tumor SUVmax to ABP 
SUVmean is ≤ 1.75 in all index tumors, and no new avid lesions are seen. 
Because of uncertainty regarding the optimal values of tumor SUVmax decrement and 
tumor SUVmax to ABP SUVmean ratio, ROC curves will be calculated to determine the 
best values of these measurements as correlates of PFS and other measurements of clinical 
outcome. 
13.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
13.1 
Duration of Treatment 
13.1.1 CR/CRu & PR: Complete all required treatment cycles.  
13.1.2 Disease Progression 
Remove from protocol therapy any patient with rapid disease progression during treatment. 
PET positivity is not a criterion for treatment failure. Document details, including tumor 
measurements, on CALGB Form C-260 (Remarks Addenda). Patients with isolated disease 
progression in the CNS without evidence of systemic progression will remain on study and 
receive CNS directed treatment. 
13.2 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient’s health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Notify the Study Chair. 
Version Date: 02/15/2018 
62 
Update #18 


CALGB 50303 
• 
Document the reason(s) for discontinuation of therapy on CALGB Form C-260 (Remarks 
Addenda). 
• 
Continue to follow the patient for response, progression, toxicity, survival and secondary 
malignancy, as indicated in Section 5.2. 
14.0 STATISTICAL CONSIDERATIONS 
14.1 
Clinical Endpoints 
14.1.1 Sample Size and Power Estimates 
The primary clinical endpoint will be event-free survival (EFS) measured from 
randomization until documented progression or death from any cause. Sample size is 
determined based on this endpoint. Patients will be randomized with equal probability to 
treatment with R-CHOP or DA-EPOCH-R. Patients will be stratified according to the 
International Prognostic Index. 
Fifty-five percent (55%) of patients treated with R-CHOP are expected to be event-free at 
three years. This corresponds under exponential survival to median EFS of 3.5 years. With 
430 patients (96 patients enrolled over 4.5 years and followed for 3 years) a hazard ratio 
(HR) of 1.53 for R-CHOP versus DA-EPOCH-R is detectable with 90% power (2-sided 
logrank test, α=0.05). Two hundred forty-two (242) events are expected at the time of the 
final analysis. The targeted sample size will be inflated to 478 patients to allow for a 10% 
pathologic ineligibility rate. Accrual is expected to be approximately 106 patients per year 
(approximately 96 eligible). Analysis will be “intent-to-treat” as randomized for eligible 
patients (i.e., with an histologic diagnosis of diffuse large B cell lymphoma). 
As of protocol update #14, the following change has been made: 
Sample Size Increase: Given the fewer than predicted PET scans and biopsies on 50303, 
accrual will be extended to 45 additional patients, for a total of 523 (=478+45) patients. 
Extended accrual will be limited to institutions and patients participating the required 
imaging companion study CALGB 580603. 
As of protocol update #17, the following change has been made: 
Revised final analysis timing due to low event rate: At the protocol specified interim 
analysis at the time of the May 2015 Alliance DSMB meeting, the pooled event rate was 
much lower than that specified by the study design. The observed number of events at this 
time was 158 (based on protocol assumptions this would have been the time for final 
analysis with 242 events). In order to provide a timely final analysis, the final analysis plan 
was revised to reduce the study power from 90% to 80%. With 178 events, we have 80% 
power if the hazard ratio between the two arms is 1.53 as specified by the original design. 
Based on the estimated pooled event rates, the final data analysis is now expected in May 
2016. By the current Kaplan-Meier estimate, there are no events after 6 years, so that we do 
not expect more events after 6 years of additional follow-up. So, the maximum number of 
events expected based on the current survival estimate is 194, which will occur about May 
2019 (i.e. after 6 years of additional follow-up). 
14.1.2 Secondary Analysis 
Secondary endpoints will be response rate, overall survival (OS), and toxicity. Overall 
survival will be measured from randomization until death from any cause. 
Different treatment effects are expected in different biological subgroups. In a secondary 
analysis, the two arms will be compared adjusting for the subgroups, ABC and GCB. The 
interactions between treatment and the subgroups will be tested using a Cox regression 
model. We will also conduct the log-rank test for the treatment effect within each subset. 
Version Date: 02/15/2018 
63 
Update #18 


CALGB 50303 
14.2 
Interim Analysis 
14.2.1 Primary Endpoint 
Ten interim analyses are planned, five during the accrual period and five during the follow-
up period. Interim analyses for the primary endpoint of EFS will be conducted beginning 
when 18% of the expected total number of events (n=242) are observed. This should occur 
at approximately 2.5 years, during the accrual period. After this time, interim analyses will 
be conducted every six months corresponding with scheduled meetings of the Alliance Data 
and Safety Monitoring Board (DSMB). It is estimated that these analyses will occur when 
0.18, 0.25, 0.33, 0.42, 0.52, 0.61, 0.70, 0.78, 0.86, and 0.93 of the expected total number of 
events have been observed. The Lan-DeMets analogue of the O’Brien-Fleming boundaries 
will be used (1-sided α=0.05) truncating at 3.5. These boundaries are as follows: 3.5, 3.5, 
3.5, 3.28, 2.93, 2.70, 2.50, 2.40, 2.26, and 2.18. The final analysis will be conducted at the 
2.10 boundary. 
14.2.2 Futility 
Futility testing will be conducted at the times of interim analyses. The futility statistics 
calculated for HR=1.53 will be compared with the critical values with 1-sided α=0.0025 at 
the first 5 interim analyses and with 1-sided α=0.005 at the following 5 interim analyses. 
This futility rule has about 86% of probability to reject DA-EPOCH-R when the two 
regimens have similar efficacy. If survival on one treatment arm is found to be superior at 
an interim analysis conducted during the accrual period and determination is made to curtail 
enrollment to the inferior treatment arm, enrollment will continue on the superior regimen 
until the targeted sample size of 215 patients is reached. 
14.2.3 Toxicity 
Toxicity data will be provided to the DSMB from the first meeting after patient accrual. If 
there exists significant evidence that one regimen has 10% or higher grade 5 toxicity from 
any cause at two-sided α=0.01 level, the study will be reviewed as grounds for amendment 
or early stopping. Grade 3 or 4 neutropenia/thrombocytopenia themselves should not be 
grounds for stopping the trial as they are goals of EPOCH-R to give the maximum 
deliverable doses of the chemotherapy by escalating with each course. However, if there are 
serious sequelae, such as an increase in hospitalizations due to toxicities, serious/life-
threatening infections (pneumonia, sepsis, or bleeding, in excess of 20% in one regimen 
over the other at two-sided α=0.01 level), then the study will be reviewed for amendment or 
early stopping. 
14.2.4 Accrual Monitoring 
Accrual to this Phase III trial will be monitored according to the NCI guidelines. In addition, 
the proportion of eligible patients with usable biopsies will be monitored. If at any time the 
proportion of patients with usable biopsies falls significantly below the assumed value of 
0.75, consideration will be given to further modifying eligibility requirements or to 
increasing the targeted sample size. 
14.3 
Molecular Characterization Studies 
The Staudt laboratory has recently profiled 197 DLBCLs using Affymetrix U133 A and B 
arrays, and this dataset has enabled us to perform power calculations to estimate the number of 
DLBCL tumors that we would need to analyze in order to achieve the molecular profiling goals 
of the trial. 
An endpoint of the trial is to test whether the gene expression signatures that were previously 
associated with survival following CHOP therapy [62] are associated with survival in either of 
the treatment arms of the prospective trial. The four gene expression signatures that were found 
to be correlated with survival were the germinal center B cell signature, the proliferation 
Version Date: 02/15/2018 
64 
Update #18 


CALGB 50303 
signature, the MHC class II signature and the lymph node signature [44]. These gene expression 
signatures were identified in the Affymetrix data set and their associations with survival are 
shown in Table 1: 
 
 
 
 
 
 
Survival 
# events/arm 
# of patients 
 
 
association 
needed to detect 
required/arm 
Power to detect 
 
relative risk per 2- 
survival association 
assuming75% 
survival assocation 
 
fold change in 
(p<0.05) with 90% 
biopsy rate and 
assuming 215 
Signature 
expression 
power 
30% event rate 
patients/arm 
Germinal Center B 
Cell 
0.36 
27 
119 
0.99 
Proliferation 
0.54 
28 
123 
0.99 
MHC class II 
3.42 
37 
163 
0.96 
Lymph node 
0.53 
43 
189 
0.93 
 
 
 
 
 
GCB vs ABC DLBCL 
1.54 
56 
248 
0.86 
Table 1 shows the number of biopsies that we would need to be profiled in order to detect a 
significant association of these signatures with survival (p<0.05) in a new set of DLBCL patients 
with 90% power. These numbers were used to calculate how many eligible patients would need 
to be enrolled in the trial in order to detect these associations in each treatment arm assuming a 
75% success rate in obtaining biopsies and a 30% event rate. In addition, the survival difference 
between the GCB and ABC DLBCL subgroups in response to CHOP treatment [62,63] was used 
to calculate the number of biopsies that would be needed in order to observe the association with 
survival (p<0.05) with 90% power in the prospective clinical trial. As can be seen from this 
Table, a trial size of 430 eligible patients would allow all of these prognostic features to be 
evaluated in each treatment arm of the prospective trial with at least 86% power. A second goal 
of the trial is to develop new molecular predictors of survival for both of the therapeutic 
regimens being evaluated. Previous gene expression profiling in DLBCL involved patients 
treated with CHOP chemotherapy alone. Both therapeutic regimens being evaluated in the 
proposed prospective trial differ from CHOP chemotherapy in important respects: one regimen 
adds rituximab to CHOP and the other regimen adds etoposide to CHOP and is delivered by 
continuous infusion using a dose escalation scheme. Therefore, the previous predictors of 
survival following CHOP chemotherapy may not necessarily apply to these new regimens. 
The survival data from the proposed trial will be used to discover and validate new molecular 
predictors of survival for each therapeutic regimen. For such an analysis, both arms of the trial 
will be divided into a training set and a validation set of cases, as was done previously [62]. The 
training set will be used to discover associations between gene expression and survival. The 
validation set will be used to test the prognostic models that are generated using the training set 
data. Using this procedure, the danger of over fitting the statistical models of survival to the data 
will be avoided. 
We will not know beforehand which gene expression signatures will be associated with survival 
in each arm. However, we can model the discovery of such signatures and their validation based 
on our experience with molecular profiling in the context of CHOP chemotherapy. Let us assume 
that we wish to discover and validate a new gene expression signature that is associated with 
survival to the same degree as the proliferation signature. To discover an association of this 
magnitude with a statistical significance of p=0.01 and with 90% power, we would need to 
include 113 tumor biopsies in the training set. A p-value cutoff of 0.01 was chosen for the 
discovery phase based on our previous experience in creating a gene expression-based outcome 
Version Date: 02/15/2018 
65 
Update #18 


CALGB 50303 
predictor for DLBCL [62]. At this significance cutoff, all of the gene expression signatures in 
Table 1 were identified as associated with survival, but spurious associations between gene 
expression and survival were largely avoided. In the validation phase, we wish to verify the 
association of a gene expression signature with survival (p<0.05) with 80% power. It is expected 
that multiple gene expression signatures will be discovered in the training set that influence 
survival. Therefore, a power of 80% will insure that most of these univariate predictors of 
survival will be validated within this prospective trial. Using the example of the proliferation 
signature, we would need to include 47 tumor biopsies in the validation set. Based on these 
modeling assumptions, 160 biopsies would need to be profiled in each arm of the clinical trial. 
This translates into a total trial accrual of 426, approximately 430 eligible patients, assuming a 
75% biopsy success rate.  
In summary, an accrual of 349 eligible patients to the prospective trial would be required to test 
the importance of previously identified molecular predictors of outcome in DLBCL. An accrual 
of approximately 430 eligible patients would be required to discover and validate new molecular 
predictors of survival for both treatment regimens in the prospective trial. 
The intent of the genomic characterization is exploratory, aiming to identify somatic DNA 
mutations, copy number alterations, microRNA expression patterns, and DNA methylation 
events that are associated with biological or clinical attributes of the DLBCL tumors.  Recurrent 
genomic abnormalities that are present in at least 5% of patients will be identified and prioritized 
for analysis.  DLBCL cases will be divided into two subgroups based on the presence or absence 
of the abnormality.   
The data will be preprocessed for statistical analysis using the computing software appropriate 
for the used technology platforms. Associations with progression-free and overall survival will 
be assessed using the Kaplan-Meyer method.  A Fisher’s exact test will be used to determine the 
association between these two patient subgroups and components of the International Prognostic 
Index (IPI) as categorical variables (age > 60; ECOG performance status > 1; Ann Arbor stage 
> II; Number of extranodal sites > 1; LDH > 1X normal) as well as the IPI score (low (0-1), 
intermediate (2-3), high (4-5)).  A Fisher’s exact test will also be used to determine the 
association between genomic abnormalities and previously defined molecular subtypes of 
DLBCL (ABC vs. GCB subtypes). 
Joint prediction model will be developed using the gradient lasso method which provides 
variable selection and prediction model fitting [95, 96]. The developed prediction models will 
be validated using a cross-validation method (e.g. 10-fold cross validation). The possible over-
fitting bias in the cross-validation result will be adjusted by using permutation method. Kaplan-
Meier curves will be estimated for the high- and low-risk groups as defined by the fitted 
prediction model and the IPI score groups and the log-rank test will be applied to compare the 
survival distributions among the groups to investigate if the discovered genomic markers are 
independent prognostic factors for PFS and OS. 
14.4 
Study Size Requirements to Achieve Pharmacogenetic Goals 
The primary objective of the pharmacogenetic portion of this study is the assessment of the 
discrepancy in event free survival (EFS), within both treatment arms, between the two genotypic 
groups (Group 1 and Group 2). For notational simplicity, let us denote individuals with ABCB1 
3454 CC genotypes by group 1 and individuals with CT or TT genotypes as group 2. The 
hypotheses of interest can be canonically presented as testing H0: ∆=1 versus H1: ∆>1, where ∆ 
is the hazard ratio between group 1 and group 2 within an arm. 
Assuming that within each arm, the EFS in both groups follow exponential laws, with potentially 
different means, the hazard ratio is given by ∆i=Mi,2/Mi,1 , where Mi,1 and Mi,2 denote median 
EFS for groups 1 and 2 in treatment arm i (1= R-CHOP and 2= DA-EPOCH-R) respectively. 
Version Date: 02/15/2018 
66 
Update #18 


CALGB 50303 
Out of the 430 eligible patients accrued to the study, we expect to have about 344 (roughly 80%), 
which corresponds to n=172 per treatment arm, available for pharmacogenetic sampling. The 
putative prevalence rates for groups 1 and 2 are 0.30 and 0.70 respectively [64]. This 
corresponds to n1=52 and n2=120 patients accrued to groups 1 and 2 in each arm. 
Needless to say, given the small sample size only large discrepancies (as quantified by the hazard 
ratio, will be detectable with large power. The accrual and follow-up periods are 4.5 and 3 years 
respectively. Under the given setup, we will consider the power of two-sided log-rank test, 
assuming exponential survival for both groups, for testing H0: ∆i=1 versus the local alternative 
H1: ∆i=∆, for ∆>1, at a level of significance of α=0.025 (as a crude adjustment for testing the 
hypothesis for each of the two arms, we have used 0.05/2), for various choices of M1,i and ∆. 
Table 2 illustrates, for M1,i ε (2.5,3.0,3.5,4.) years, the smallest hazard ratio ∆ that is detectable 
with at least a power of 0.6 and 0.7: 
Table 2 Power analysis of pharmacogenetic studies 
M1,i 
ß 
M2,i 
Power 
2.5 
1.66 
4.12 
0.60 
2.5 
1.76 
4.40 
0.70 
3.0 
1.70 
5.10 
0.60 
3.0 
1.81 
5.43 
0.70 
3.5 
1.75 
6.13 
0.60 
3.5 
1.87 
6.55 
0.70 
4.0 
1.80 
7.20 
0.60 
4.0 
1.93 
7.72 
0.70 
Secondary Objectives: We will also look at the above questions in the context of other 
genotypes in additional candidate genes of putative importance. The pharmacogenetic analysis 
related to these candidate genes will be conducted as a secondary exploratory analysis of gene-
toxicity, gene-response, and gene-survival relationships. The association between genes 
implicated in metabolism, transporter and clinical phenotype (systemic toxicity, response, and 
survival) will be performed by construction of hazard ratios or other appropriate non-parametric 
techniques. 
14.5 
Overview of FDG-PET/CT Study (CALGB 580603) 
This is a multi-center, prospective study in which 170 patients who consent will undergo 
PET/CT scans at baseline, post-Cycle 2, and post-Cycle 6. Scans will be read without the 
baseline scan, and then again with the baseline scan and knowledge of other relevant clinical 
information. Response (both PET and CT) will be assessed by consensus readings made in the 
context of the baseline scan and knowledge of clinical data. To be classified as a responder, all 
index tumors of the patient must meet the criteria for response and no other evidence of 
lymphoma progression should be present. The accrual goal of 300 patients was changed to 170 
patients because of an unexpectedly low accrual rate to CALGB 580603 among the patients who 
had entered into CALGB 50303 by November 2008. The revised sample size of 170 patients is 
based on the assumption that the FDG-PET study can accrue about 55% of patients that will 
ultimately accrue to CALGB 50303. 
The primary focus of this FDG-PET/CT companion will be a comparison of the ability of PET 
plus IWG criteria after Cycle 6 to predict occurrence of an event or no event within three years 
to that of IWG criteria alone. An event is defined here as progression or death from any cause. 
Secondary endpoints include the predictive ability, sensitivity and specificity of PET after Cycle 
2. Sensitivity and specificity describe the ability to distinguish between those who have and 
Version Date: 02/15/2018 
67 
Update #18 


CALGB 50303 
those who do not have an event within three years. ROC curves will also be constructed as 
secondary endpoints for results that are on a continuous scale. 
14.5.1 FDG-PET/CT Imaging Endpoints and Analyses 
14.5.1.1 Test of Sensitivity and Specificity of PET + IWG Criteria vs IWG Criteria Alone 
Let for a patient, D=1 if the event time is shorter than 3 years and D=0 otherwise, and 
X=1 if the patient is a non-responder by an imaging method (PET + IWG or IWG) and 
X=0 otherwise. Responders are those with a complete response (CR) or complete 
response unconfirmed (CRu). Sensitivity of the imaging is defined as p=(X=1D=1) 
and specificity is defined as q=(X=0D=0). 
Response with PET + IWG criteria evaluated will be defined according to the criteria 
outlined by Juweid et al. [75]. The consensus read will be used as the primary 
assessment of response. 
Only patients who have both PET and IWG criteria evaluated will be used for the 
analyses in this companion study. The study is designed to establish (1) non-inferiority 
of the sensitivity for PET + IWG criteria, and (2) the superiority of the specificity of 
PET + IWG criteria compared to that of IWG criteria alone. 
14.5.1.2 Semi-Quantitative Measurements of FDG Uptake 
The predictive ability and accuracy of SUV-based measurements will be estimated. 
Sensitivity/specificity and responder and non-responder predictive values, 
P(D=0X=0) and P(D=1X=1), respectively, will be estimated, with response defined 
as the ratio of tumor SUVmax to ABP SUVmean for all index tumors ≤ 1.25 (and no 
evidence of lymphoma by visual reading of total scan). ROC curves will be estimated 
using SUVmax decrement and the tumor SUVmax ratio to ABP SUVmean ratio. 
14.5.1.3 Accuracy of Cycle 2 PET Scan 
The predictive ability and accuracy of SUV-based measurements after Cycle 2 will be 
estimated. Here, response is defined as a tumor SUVmax decrease of ≥ 85% from 
baseline or a ratio of tumor SUVmax to ABP SUVmean ≤ 1.75.  
Chi-square test(s) will be conducted to determine if Cycle 2 PET/CT measurements 
can predict clinical response, and EFS and OS using a cutoff of 3 years. The log-rank 
test will be used to compare the raw data of EFS and OS between Cycle 2 PET+ and 
PET- patient groups. 
Response at Cycle 2 will be compared to that at Cycle 6 and patient status at three 
years post-enrollment (i.e., progression free or not progression free at three years). 
ROC curves will also be estimated to compare Cycle 2 PET outcome with Cycle 6 PET 
outcome in terms of EFS at 3 years using the methods of Delong et al. [92] if there is 
no censoring within 3 years or Heagerty et al. [93] in the presence of censoring within 
3 years. The correlation between Cycle 2 PET outcome and Cycle 6 PET outcome will 
be tested by using 2x2 Chi-square test(s) for binary variables and by using regression 
methods for continuous variables. 
14.5.1.4 Evaluating Treatment Effect 
Regression analysis will consider the effect of treatment on the predictive values. This 
will be evaluated with either regression models for predictive values [91] or with a Cox 
model. A multivariate analysis using a Cox regression model will be conducted 
Version Date: 02/15/2018 
68 
Update #18 


C A L G B 5 0 3 0 3  
i ncl u di n g P E T + I W G criteria, I W G criteria, treat me nt, a n d ot her pre dict ors t o see if 
a n y of t he i ma gi n g criteria are i n de pe n de nt pre dict ors.  
1 4. 5. 1. 5  E v al u ati n g I nter- I nstit uti o n al Re pr o d uci bilit y of P E T/ C T Me as ure me nts 
C o nc or da nce rate will be esti mate d bet wee n t he rea di n g fr o m eac h i nstit uti o n a n d t hat 
fr o m t he C ore La b.  T he varia nce of t he esti mate d c o nc or da nce rate will be a djuste d 
f or p ossi ble cl usteri n g effect a m o n g differe nt i nstit uti o ns (e. g., J u n g a n d A h n) [ 9 4]. 
1 4. 5. 2 S a m ple Size C o nsi der ati o ns  
A  t otal  of  m = 1 7 0  patie nts  will  be  accr ue d  t o  t his  F D G -P E T/ C T  c o m pa ni o n  st u d y.  T he 
a d diti o n of P E T t o I W G is e x pecte d t o i m pr o ve t he s pecificit y, b ut n ot t he se nsiti vit y. S o, 
t he p o wer a nal yses bel o w are base d o n t he paire d t w o-sa m ple tests f or ( 1) t he n o n-i nferi orit y 
of P E T + I W G i n se nsiti vit y, H 0: p1= p 2-0 vers us H 1: p1> p 2-0, a n d ( 2) t he s u peri orit y of 
P E T + I W G i n s pecificit y, H 0: q1= q 2 vers us H 1: q1> q 2. Here, p1 a n d p 2 ( q1 a n d q 2) are t he 
se nsiti vities  (s pecificities)  of  P E T  +  I W G  a n d  I W G,  res pecti vel y.  We  ass u me  t hat  a 
differe nce of 
0= 0. 1 or s maller i n  se nsiti vit y is c o nsi dere d t o be wit hi n t he n o n-i nferi orit y 
li mit.  
Pair e d t w o-sa m ple tests are use d f or t he s u peri orit y a n d n o n-i nferi orit y tests. F or e xa m ple, 
f or t he patie nt i( = 1, …, m) w h ose e ve nt ti me is s h orter t ha n 3 years ( Di= 1), t he n o n -i nferi orit y 
test rej ects H0: p1= p 2-0 if m1/ 2( P1- P2)/ S is lar ger t ha n z1- α , w here Pk is t he sa m ple esti mate 
of p k a n d S 2 is t he mea n s u m of s q uares of X1i- X2i+
0. T he p o wer of t hese tests de pe n ds o n 
t he c orrelati o n c oefficie nt bet wee n X1i a n d X 2i. Preli mi nar y data are base d o n J u wei d et al. 
[ 7 5]. T he rele va nt ta bles are pr o vi de d bel o w: 
T hree -ye ar E F S t a bles  
Pr o gressi o n or deat h b y year 3 ( D = 1): 
 
I W G Criteri a 
N o n -res p o n der 
Res p o n der  
P E T + I W G 
Criteri a  
N o n -res p o n der 
1 3  
1 
Res p o n der  
2 
4 
 
N o pr o gressi o n ( or deat h) b y year 3 ( D = 0): 
 
I W G Criteri a 
N o n -res p o n der 
Res p o n der  
P E T + I W G 
Criteri a  
N o n -res p o n der 
4 
1 
Res p o n der  
1 1  
1 8  
T he  esti mate d  se nsiti vities  are  P 1= 0. 7  a n d  P 2= 0. 7 5  fr o m  t he  first  ta ble  ( D = 1),  a n d  t he 
esti mate d s pecificities are Q 1= 0. 8 5 a n d Q 2= 0. 5 6 fr o m t he sec o n d ta ble ( D = 0). Fr o m b ot h 
ta bles, t he c orrelati o n c oefficie nt bet wee n X1i a n d X 2i is a b o ut 0. 3. Ass u mi n g 5 5 % are e ve nt 
free at 3 years, a b o ut 7 7 of N = 1 7 0 patie nts will be i n t he D = 1 gr o u p a n d a b o ut 9 3 will be i n 
t he D = 0 gr o u p. I n t he f oll o wi n g p o wer calc ulati o ns, we ass u me one-si de d α = 0. 0 5 a n d a 
c orrelati o n c oefficie nt of 0. 3. Wit h 7 6 patie nts i n t he D = 1 gr o u p, t he n o n -i nferi orit y test of 
P E T  +  I W G  i n  se nsiti vit y  has  5 5 %  p o wer  t o  detect  a n  alter nati ve  h y p ot hesis  of 
H 1: p1= p 2= 0. 7 5, a n d 8 4 % p o wer t o detect H 1: p1= 0. 8, p 2= 0. 7 5. N o te t hat, beca use of t he s mall 
Versi o n Date: 0 2 /1 5/ 2 0 1 8  
6 9  
U p date # 1 8 


CALGB 50303 
sample size, the non-inferiority test will not have enough power unless PET + IWG has a 
larger sensitivity than IWG (i.e. p1>p2). 
With 93 patients in the D=0 group, the superiority test of PET + IWG in specificity has 82% 
power to detect an alternative hypothesis of H1:q1=0.7, q2=0.55, and 93% power to detect 
H1:q1=0.75, q2=0.55. 
15.0 ADVERSE EVENT REPORTING (AER) 
Investigators are required by Federal Regulations to report serious adverse events as defined in the 
table below.  CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be utilized for AE reporting 
beginning April 1, 2018. All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
 
All 
reactions 
determined to be “reportable" in an expedited manner must be reported using the CTEP Adverse 
Event Reporting System (CTEP-AERS). Reporting of cases of secondary AML/MDS should be done 
using CTEP-AERS. New primary malignancies should be reported using Study Form C-1001. 
The Alliance requires investigators to route all adverse event reports (AERs) through the 
Central Office for Alliance-coordinated studies. 
CALGB 50303 Adverse Event Reporting Requirements 
Phase 2 and 3 Trials: CTEP-AERS Expedited Reporting Requirements for Adverse Events 
That Occur Within 30 Days1 of the Last Dose of Treatment 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected Expected 
With  
hospitali-
zation 
Without 
hospitali- 
zation 
With  
hospitali
-zation 
Without 
hospitali
-zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hrs; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 5 expected events 
 
2 Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
March 2005 
Note: All deaths on study require both routine and expedited reporting regardless of causality. 
Attribution to treatment or other cause should be provided. 
• 
Expedited AE reporting timelines defined: 
Version Date: 02/15/2018 
70 
Update #18 


CALGB 50303 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 5 calendar days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
within 10 calendar days of the investigator learning of the event. 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting Requirements 
for Phase 2 and 3 Trials: 
• 
Grade 3 or 4 myelosuppression and hospitalization resulting from grade 3 or 4 
myelosuppression do not require CTEP-AERS, but should be submitted as part of study 
results. 
• 
Grade 3 constipation and hospitalization resulting from such do not require CTEP-AERS, 
but should be submitted as part of study results. 
• 
Grade 3 sensory or motor neuropathy and hospitalization resulting from such do not require 
CTEP-AERS, but should be submitted as part of study results. 
• 
Grade 3 nausea or vomiting and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. 
• 
A list of specific expected adverse events can be found in Section 10.0 (Drug Formulation, 
Availability, and Preparation). 
• 
For the purposes of expedited adverse event reporting, the CAEPR for rituximab may be 
found in Section 15.1 below. 
• 
Exacerbation or reactivation of serious viral infections (e.g., hepatitis, JC) as described in 
Section 10.10 should be reported via CTEP-AERS within 10 calendar days of the 
investigator learning of the event. 
• 
CTEP-AERS 
reports 
are 
to 
be 
submitted 
electronically 
 
• 
The reporting of adverse events described in the table above is in addition to and does not 
supplant the reporting of adverse events as part of the report of the results of the clinical 
trial, e.g., study summary forms or cooperative group data reporting forms (see Section 5.2 
for required CALGB forms). 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB.
Version Date: 02/15/2018 
71 
Update #18 


CALGB 50303 
15.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Rituximab (NSC 
687451) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the Agent 
Specific Adverse Event List (ASAEL), appears in a separate column and is identified with bold 
and italicized text. This subset of AEs (ASAEL) contains events that are considered 'expected' 
for expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting 
Requirements' 
 for 
further clarification. Frequency is provided based on 986 patients. Below is the CAEPR for 
Rituximab. 
 
Version 2.1, March 19, 20101 
 
 Adverse Events with Possible  
 Relationship to Rituximab 
 (CTCAE 4.0 Term) 
[n= 986] 
 
 
 
 EXPECTED AEs FOR 
CTEP-AERS REPORTING  
Agent Specific Adverse Event 
List 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Expected 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia 
 
Blood and lymphatic system 
disorders - Other (Hyperviscosity: 
Waldenstrom’s) 
 
 Blood and lymphatic system 
disorders 
- 
Other 
(Hyperviscosity: 
Waldenstrom’s) 
 
Febrile neutropenia 
 
 Febrile neutropenia 
CARDIAC DISORDERS  
  
 
Myocardial infarction 
 
 Myocardial infarction 
 
Sinus tachycardia 
 
 Sinus tachycardia 
 
Supraventricular tachycardia 
 
 Supraventricular tachycardia 
GASTROINTESTINAL DISORDERS  
  
 
Abdominal pain 
 
 Abdominal pain 
 
Diarrhea 
 
 Diarrhea 
 
Nausea 
 
 Nausea 
 
Vomiting 
 
 Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Chills 
 
 
 Chills 
 
Edema limbs 
 
  
 
Fatigue 
 
 Fatigue 
Fever 
 
 
 Fever 
Infusion related reaction 
 
 
 Infusion related reaction 
 
Pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction 
 
 
Anaphylaxis 
  
 
Serum sickness 
 
 Serum sickness 
INFECTIONS AND INFESTATIONS 
  
Version Date: 02/15/2018 
72 
Update #18 


CALGB 50303 
 
Infection2 
 
 
 
 
 Infection2 
 
Infections and infestations - Other 
(Activation of Hepatitis B, C, 
CMV, parvovirus B19, JC virus, 
varicella zoster, herpes simplex, 
West Nile virus) 
 
 Infections and infestations - 
Other (Activation of Hepatitis 
B, C, CMV, parvovirus B19, JC 
virus, varicella zoster, herpes 
simplex, West Nile virus) 
 
Infections and infestations - Other 
(Infection 
in 
HIV 
Positive 
Patients) 
 
  
INVESTIGATIONS 
  
Lymphocyte 
count 
decreased 
 
 
 Lymphocyte count decreased 
 
Neutrophil count decreased 
 
 Neutrophil count decreased 
 
Platelet count decreased 
 
 Platelet count decreased 
 
White blood cell decreased 
 
 White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS  
  
 
Hyperglycemia 
 
  
 
Hypocalcemia 
 
 Hypocalcemia 
 
Hypokalemia 
 
  
 
 
Tumor lysis syndrome 
 Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia 
 
Back pain 
 
  
 
Myalgia 
 
 Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
Tumor pain 
 
 Tumor pain 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness 
 
Headache 
 
 Headache 
 
Lethargy 
 
  
 
 
Nervous system disorders - 
Other (progressive multifocal 
leukoencephalopathy) 
  
 
Seizure 
 
 Seizure 
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Adult 
respiratory 
distress 
syndrome 
  
 
Allergic rhinitis 
 
  
 
Bronchospasm 
 
 Bronchospasm 
 
Cough 
 
 Cough 
 
Dyspnea 
 
 Dyspnea 
 
Hypoxia 
 
 Hypoxia 
 
Pneumonitis 
 
 Pneumonitis 
 
Sore throat 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Version Date: 02/15/2018 
73 
Update #18 


CALGB 50303 
 
 
Erythema multiforme 
 Erythema multiforme 
 
Hyperhidrosis 
 
 Hyperhidrosis 
 
Pruritus 
 
 Pruritus 
 
Rash maculo-papular 
 
 Rash maculo-papular 
 
Skin and subcutaneous tissue 
disorders - Other (angioedema) 
 
  
 
 
Stevens-Johnson syndrome 
 Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis 
 Toxic epidermal necrolysis 
 
Urticaria 
 
 Urticaria 
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing 
 
Hypertension 
 
 Hypertension 
 
Hypotension 
 
 Hypotension 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
3Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal 
obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small intestinal obstruction under the 
GASTROINTESTINAL DISORDERS SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC. 
 
Also reported on rituximab trials but with the relationship to rituximab still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other (cyanosis); Left ventricular 
systolic dysfunction; Sinus bradycardia; Ventricular fibrillation 
EYE DISORDERS - Conjunctivitis; Eye disorders - Other (ocular edema); Uveitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia; Dysphagia; Gastrointestinal obstruction3; 
Gastrointestinal perforation4; Mucositis oral 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac 
chest pain 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (Opportunistic infection associated with 
>=Grade 2 Lymphopenia) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin 
increased; Cardiac troponin I increased; Cardiac troponin T increased; Creatinine increased; Investigations - Other 
(hyperphosphatemia); Investigations - Other (LDH increased); Weight loss 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Hypercalcemia; Hyperkalemia; Hypermagnesemia; 
Hypernatremia; Hyperuricemia; Hypoglycemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis 
NERVOUS SYSTEM DISORDERS - Nervous system disorders - Other (Cranial Neuropathy NOS); Peripheral 
motor 
neuropathy; 
Peripheral 
sensory 
neuropathy; 
Pyramidal 
tract 
syndrome; 
Reversible 
posterior 
leukoencephalopathy syndrome; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Depression; Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Epistaxis; Pharyngolaryngeal pain; Pleural 
effusion; Pulmonary edema; Respiratory, thoracic and mediastinal disorders - Other (bronchiolitis obliterans) 
Version Date: 02/15/2018 
74 
Update #18 


CALGB 50303 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Skin and subcutaneous tissue disorders - Other 
(paraneoplastic pemphigus) 
VASCULAR DISORDERS - Phlebitis; Thromboembolic event; Vasculitis 
 
Note: Rituximab in combination with other agents could cause an exacerbation of any adverse event currently known 
to be caused by the other agent, or the combination may result in events never previously associated with either agent. 
Version Date: 02/15/2018 
75 
Update #18 


CALGB 50303 
16.0 REFERENCES 
1. 
Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA, 
Jr., Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy 
regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993;328:1002-1006. 
2.  
Martelli M, Gherlinzoni F, De Renzo A, Zinzani PL, De Vivo A, Cantonetti M, Falini B, Storti 
S, Meloni G, Rizzo M, Molinari AL, Lauria F, Moretti L, Lauta VM, Mazza P, Guardigni L, 
Pescarmona E, Pileri SA, Mandelli F, Tura S. Early autologous stem-cell transplantation versus 
conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's 
lymphoma: an Italian multicenter randomized trial. J Clin Oncol. 2003;21:1255-1262. 
3. 
Kaiser U, Uebelacker I, Abel U, Birkmann J, Trumper L, Schmalenberg H, Karakas T, Metzner 
B, Hossfeld DK, Bischoff HG, Franke A, Reiser M, Muller P, Mantovani L, Grundeis M, 
Rothmann F, von Seydewitz CU, Mesters RM, Steinhauer EU, Krahl D, Schumacher K, Kneba 
M, Baudis M, Schmitz N, Pfab R, Koppler H, Parwaresch R, Pfreundschuh M, Havemann K. 
Randomized study to evaluate the use of high-dose therapy as part of primary treatment for 
"aggressive" lymphoma. J Clin Oncol. 2002;20:4413-4419. 
4. 
Tilly H, Lepage E, Coiffier B, Blanc M, Herbrecht R, Bosly A, Attal M, Fillet G, Guettier C, 
Molina TJ, Gisselbrecht C, Reyes F. Intensive conventional chemotherapy (ACVBP regimen) 
compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood. 
2003;102:4284-4289. 
5. 
Pfreundschuh M TL, Kloess M et al. 2-weekly vs. 3-weekly CHOP with and without etoposide 
in for patients >60 years of age with aggressive non-Hodgkin's lymphoma (NHL): Results of 
the completed NHL-B-2 trial of the DSHNHL. Blood. 2002;99:Abstract 3060. 
6. 
Pfreundschuh M TL, Schmits R, et al. 2-weekly vs. 3-weekly CHOP with and without 
etoposide in young patients with low-risk (low LDH) aggressive non-Hodgkin's lymphoma: 
Results of the completed NHL-B-1 trial of the DSHNHL. Blood. 2002;99:Abstract # 340. 
7. 
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste 
E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus 
rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. 
N Engl J Med. 2002;346:235-242. 
8. 
Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-Lopez A, Gilman P, Lowe A, Kunkel 
LA, Fisher RI. Phase II study of rituximab in combination with chop chemotherapy in patients 
with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2001;19:389-
397. 
9. 
Habermann TM WE, Morrison VA, Cassileth PA, Cohn JB, Dakhil SR, Gascoyne RD, Woda 
B, Fisher RI, Peterson BA, Horning SJ. Phase III Trial of Rituximab-CHOP (R-CHOP) vs. 
CHOP with a Second Randomization to Maintenance Rituximab (MR) or Observation in 
Patients 60 Years of Age and Older with Diffuse Large B-cell Lymphoma (DLBCL). 
Proceedings American Society of Hematology. 2003;102:Abstract 8. 
10. 
Mounier N, Briere J, Gisselbrecht C, Emile JF, Lederlin P, Sebban C, Berger F, Bosly A, Morel 
P, Tilly H, Bouabdallah R, Reyes F, Gaulard P, Coiffier B. Rituximab plus CHOP (R-CHOP) 
overcomes bcl-2--associated resistance to chemotherapy in elderly patients with diffuse large 
B-cell lymphoma (DLBCL). Blood. 2003;101:4279-4284. 
11. 
Lai GM, Chen YN, Mickley LA, Fojo AT, Bates SE. P-glycoprotein expression and schedule 
dependence of adriamycin cytotoxicity in human colon carcinoma cell lines. Int J Cancer. 
1991;49:696-703. 
Version Date: 02/15/2018 
76 
Update #18 


CALGB 50303 
12. 
Gutierrez M, Chabner BA, Pearson D, Steinberg SM, Jaffe ES, Cheson BD, Fojo A, Wilson 
WH. Role of a doxorubicin-containing regimen in relapsed and resistant lymphomas: an 8-year 
follow-up study of EPOCH. J Clin Oncol. 2000;18:3633-3642. 
13. 
Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N, Steinberg SM, Little 
RF, Janik J, Gutierrez M, Raffeld M, Staudt L, Cheson BD, Longo DL, Harris N, Jaffe ES, 
Chabner BA, Wittes R, Balis F. Dose-adjusted EPOCH chemotherapy for untreated large B-
cell lymphomas: a pharmacodynamic approach with high efficacy. Blood. 2002;99:2685-2693. 
14. 
Wilson WH PS, Gutierrez M, et al. Dose-Adjusted EPOCH-Rituximab in Untreated Diffuse 
Large B-cell Lymphoma: Benefit of Rituximab Appears Restricted to Tumors Harboring Anti-
apoptotic Mechanisms. Proceedings American Society of Hematology. 2003;102. 
15. 
Wilson WH, Teruya-Feldstein J, Fest T, Harris C, Steinberg SM, Jaffe ES, Raffeld M. 
Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin's 
lymphomas. Blood. 1997;89:601-609. 
16. 
Hermine O, Haioun C, Lepage E, d'Agay MF, Briere J, Lavignac C, Fillet G, Salles G, 
Marolleau JP, Diebold J, Reyas F, Gaulard P. Prognostic significance of bcl-2 protein 
expression in aggressive non- Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de 
l'Adulte (GELA). Blood. 1996;87:265-272. 
17. 
Miller TP, Grogan TM, Dahlberg S, Spier CM, Braziel RM, Banks PM, Foucar K, Kjeldsberg 
CR, Levy N, Nathwani BN, et al. Prognostic significance of the Ki-67-associated proliferative 
antigen in aggressive non-Hodgkin's lymphomas: a prospective Southwest Oncology Group 
trial. Blood. 1994;83:1460-1466. 
18. 
Ichikawa A, Kinoshita T, Watanabe T, Kato H, Nagai H, Tsushita K, Saito H, Hotta T. 
Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma. N Engl J Med. 
1997;337:529-534. 
19. 
Loni L, Del Tacca M, Danesi R. Pharmacogenetics of anticancer drugs in non-Hodgkin 
lymphomas. Br J Cancer. 2001;85:1425-1431. 
20. 
Wilson WH, Gutierrez M, O'Connor P, Frankel S, Jaffe E, Chabner BA, Grossbard ML. The 
role of rituximab and chemotherapy in aggressive B-cell lymphoma: a preliminary report of 
dose-adjusted EPOCH-R. Semin Oncol. 2002;29:41-47. 
21. 
Jaffe ES, Harris NL, Stein H, Vardiman JW eds. Tumours of Haematopoietic and Lymphoid 
Tissues. In: P. K, L.H. S eds. World Health Organization Classification of Tumours (ed First). 
Lyon: IARC Press; 2001. 
22. 
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, 
Falini B, Gatter KC. A revised European-American classification of lymphoid neoplasms: a 
proposal from the International Lymphoma Study Group. Blood. 1994;84:1361-1392. 
23. 
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, 
Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J, Jr., Lu L, Lewis DB, 
Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, 
Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM. Distinct types of 
diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503-
511. 
24. 
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-
Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, 
Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger 
DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, Lopez-Guillermo 
Version Date: 02/15/2018 
77 
Update #18 


CALGB 50303 
A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke 
T, Staudt LM. The use of molecular profiling to predict survival after chemotherapy for diffuse 
large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. 
25. 
Miller TP LM, Spier C, et al. CHOP alone compared to CHOP plus radiotherapy for early stage 
aggressive non-Hodgkin's lymphomas: Update of the Southwest Oncology Group (SWOG) 
randomized trial. Proceedings American Society of Hematology. 2001;98:Abstract # 3024. 
26. 
Horning SJ GJ, Kim K et al. Final report of E1484: CHOP v CHOP + Radiotherapy (RT) for 
limited stage diffuse aggressive lymphoma. Proceedings American Society of Hematology. 
2001;98:Abstract # 3023. 
27. 
Reyes F LE, Munck, JN, Morel P, Coiffier B, Lederlin P, Simon D, Bosly A, Fabiani B, 
Bordessoule D, Ganem G, Tilly H. Superiority of Chemotherapy Aone with the ACVBP 
Regimen over Treatment with Three cycles of CHOP plus Radiation in Low Risk Localized 
Aggressive Lymphoma: The LNH93-1 GELA Study. Proceedings American Society of 
Hematology. 2002;100:Abstract 343. 
28. 
Zinzani PL, Martelli M, Magagnoli M, Pescarmona E, Scaramucci L, Palombi F, Bendandi M, 
Martelli MP, Ascani S, Orcioni GF, Pileri SA, Mandelli F, Tura S. Treatment and clinical 
management of primary mediastinal large B-cell lymphoma with sclerosis: MACOP-B 
regimen and mediastinal radiotherapy monitored by (67)Gallium scan in 50 patients. Blood. 
1999;94:3289-3293. 
29. 
Raz I, Siegal T, Polliack A. CNS involvement by non-Hodgkin's lymphoma. Response to a 
standard therapeutic protocol. Arch Neurol. 1984;41:1167-1171. 
30. 
Bishop PC, Wilson WH, Pearson D, Janik J, Jaffe ES, Elwood PC. CNS involvement in 
primary mediastinal large B-cell lymphoma. J Clin Oncol. 1999;17:2479-2485. 
31. 
van Besien K, Ha CS, Murphy S, McLaughlin P, Rodriguez A, Amin K, Forman A, Romaguera 
J, Hagemeister F, Younes A, Bachier C, Sarris A, Sobocinski KS, Cox JD, Cabanillas F. Risk 
factors, treatment, and outcome of central nervous system recurrence in adults with 
intermediate-grade and immunoblastic lymphoma. Blood. 1998;91:1178-1184. 
32. 
Haioun C, Besson C, Lepage E, Thieblemont C, Simon D, Rose C, Tilly H, Sonet A, Lederlin 
P, Attal M, Briere J, Reyes F. Incidence and risk factors of central nervous system relapse in 
histologically aggressive non-Hodgkin's lymphoma uniformly treated and receiving intrathecal 
central nervous system prophylaxis: a GELA study on 974 patients. Groupe d'Etudes des 
Lymphomes de l'Adulte. Ann Oncol. 2000;11:685-690. 
33. 
Evans WE, McLeod HL. Pharmacogenomics--drug disposition, drug targets, and side effects. 
N Engl J Med. 2003;348:538-549. 
34. 
Watters JW, McLeod HL. Cancer pharmacogenomics: current and future applications. Biochim 
Biophys Acta. 2003;1603: 99-111. 
35. 
Dresser 
MJ. 
The 
MDR1 
C3435T 
polymorphism: 
Effects 
on 
P-glycoprotein 
expression/function and clinical significance. AAPS PharmSci. 2001; 3:3. 
36. 
Sparreboom A, Danesi R, Ando Y, Chan J, Figg WD. Pharmacogenomics of ABC transporters 
and its role in cancer chemotherapy. Drug Resist Updat. 2003;6: 71-84. 
37. 
Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Lamba J, Bowman P, Burckart GJ. The 
MDR1 polymorphisms at exons 21 and 26 predict steroid weaning in pediatric heart transplant 
patients. Hum Immunol. 2002;63: 765-770. 
Version Date: 02/15/2018 
78 
Update #18 


CALGB 50303 
38. 
Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne, A Cascorbi I, Gerloff 
T, Roots I, Eichelbaum M, Brinkmann U. Functional polymorphisms of the human multidrug-
resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein 
expression and activity in vivo. Proc Natl Acad Sci USA. 2000;97: 3473-3478. 
39. 
Fellay J, Marzolini C, Meaden ER, Back DJ, Buclin T, Chave JP, Decosterd LA, Furrer H, 
Opravil M, Pantaleo G, Retelska D, Ruiz L, Schinkel AH, Vernazza P, Eap CB, Telenti A. The 
Swiss HIVCS, Response to antiretroviral treatment in HIV-1-infected individuals with allelic 
variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet. 2002;359: 
30-36. 
40. 
Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, Wood NW, Sisodiya 
SM. Association of multidrug resistance in epilepsy with a polymorphism in the drug-
transporter gene ABCB1. N Engl J Med. 2003;348: 1442-1448. 
41. 
Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S, Freund D, Schakel U, 
Ehninger G, Schaich M. MDR1 gene polymorphisms affect therapy outcome in acute myeloid 
leukemia patients. Cancer Res. 2002 62: 4955-4962. 
42. 
Lenz G, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 
2008; 319: 1676-1679. 
43. 
Davis RE, et al. Chronic active B-cell receptor signalling in diffuse large B-cell lymphoma. 
Nature. 2010; 463: 88-92. 
44. 
Ngo VN, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011. 
470; 115-119.  
45. 
Yap DB, et al. Somatic mutations of EZH2 Y641 act dominantly through a mechanism of 
selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2010. 
46. 
Sneeringer CJ, et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-
associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell 
lymphomas. Proc Natl Acad Sci USA. 2010; 107:20980-20985. 
47. 
Morin RD, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-
cell lymphomas of germinal-center origin. Nat Genet. 2010; 42: 181-185. 
48. 
Lenz G, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic 
pathways. Proc Natl Acad Sci USA. 2008; 105: 13520-13525. 
49. 
Alizadeh AA, et al. Distinct types of diffuse large B-cell lymphoma identified by gene 
expression profiling. Nature. 2000; 403: 503-511. 
50. 
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-
Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, 
Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger 
DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, Lopez-Guillermo 
A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke 
T, Staudt LM. The use of molecular profiling to predict survival after chemotherapy for diffuse 
large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. 
51. 
Lenz G, et al. Stromal gene signatures in large B-cell lymphomas. N Engl J Med. 2008; 359: 
2313-2323. 
52. 
Jima DD, et al. Deep sequencing of the small RNA transcriptome of normal and malignant 
human B cells identifies hundreds of novel microRNAs. Blood. 2010; 166:e118-127. 
Version Date: 02/15/2018 
79 
Update #18 


CALGB 50303 
53. 
Zhang J, et al. Patterns of microRNA expression characterize stages of human B-cell 
differentiation. Blood. 2009; 113: 4586-4594. 
54. 
Figueroa ME, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation 
phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 
2010; 18: 553-567. 
55. 
Figeuroa ME, et al. DNA methylation signatures identify biologically distinct subtypes in acute 
myeloid leukemia. Cancer Cell. 2010; 17: 13-27. 
56. 
Martin-Subero, et al. New insights into the biology and origin of mature aggressive B-cell 
lymphomas by combined epigenomic, genomic, and transcriptional profiling. Blood. 2009; 
113: 2488-2497. 
57. 
Li H & Durvin R. Fast and accurate short read alignment with Burros-Wheeler transform. 
Bioinformatics. 2009; 25: 1754-1760. 
58. 
Trapnell C, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated 
transcripts and isoform switching during cell differentiation. Nature Biotechnology. 2010; 28: 
511-515. 
59. 
Jacinto FV, Ballestar E, Esteller M. Methyl-DNA immunoprecipitation (MeDIP): hunting 
down the DNA methylome. Biotechniques. 2008; 44: 35, 37, 39 passim. 
60. 
Wolfe JL, Thoma LA, Du C, Goldspiel BR, Gallelli JF, Grimes GJ, Potti GK. Compatibility 
and stability of vincristine sulfate, doxorubicin hydrochloride, and etoposide in 0.9% sodium 
chloride injection. Am J Health Syst Pharm. 1999;56:985-989. 
61. 
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, 
Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, 
Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an international 
workshop to standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol. 
1999;17:1244. 
62. 
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-
Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, 
Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger 
DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, Lopez-Guillermo 
A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke 
T, Staudt LM. The use of molecular profiling to predict survival after chemotherapy for diffuse 
large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. 
63. 
Wright G, Tan B, Rosenwald A, Hurt EH, Wiestner A, Staudt LM. A gene expression-based 
method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl 
Acad Sci U S A. 2003;in press. 
64. 
McLeod HL, Sargent DS, Marsh S, Fuchs C, Ramanathan RK, Williamson S, Findlay B, 
Thibodeau SG, Petersen R. Pharmacogenetic analysis of systemic toxicity and response after 
5-Fluorouracil (5-FU)/CPT-11, 5FU/Oxaliplatin (oxal), or CPT-11/oxal therapy for advanced 
colorectal cancer (CRC: Results from an intergroup trial. Am Soc Clin Oncol. 2003;22: 1013. 
65. 
Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the 
treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe 
d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23:4117-4126. 
66. 
Pfreundschuh M, Kloess M, Schmits R, et al. Six, not eight cycles of bi-weekly CHOP with 
rituximab (R-CHOP) is the preferred treatment for elderly patients with diffuse large B-cell 
Version Date: 02/15/2018 
80 
Update #18 


CALGB 50303 
lymphoma (DLBCL): Results of the RICOVER-60 trial of the German High-Grade Non-
Hodgkin Lymphoma Study Group (DSHNHL). ASH Annual Meeting Abstracts. 2005;106:13. 
67. 
Wilson WH, Dunleavy K, Pittaluga S, et al. Dose-adjusted EPOCH-rituximab is highly 
effective in the GCB and ABC subtypes of untreated diffuse large B-cell lymphoma. ASH 
Annual Meeting Abstracts. 2004;104:159. 
68. 
Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize 
response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. 
J Clin Oncol. 1999;17:1244. 
69. 
Kelloff GJ, Hoffman JM, Johnson B, et al. Progress and promise of FDG-PET imaging for 
cancer patient management and oncologic drug development. Clin Cancer Res. 2005;11:2785-
2808. 
70. 
Haioun C, Itti E, Rahmouni A, et al. [18F]Fluoro-2-deoxy-D-glucose positron emission 
tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting 
patient outcome. Blood. 2005;106:1376-1381. 
71. 
Meignan M, Haioun C, Itti E, Rahmouni A, Reyes F. Value of [18F]fluorodeoxyglucose-
positron emission tomography in managing patients with aggressive non-Hodgkin’s lymphoma 
Clin Lymphoma Myeloma. 2006;6:306-313. 
72. 
Hutchings M, Loft A, Hansen M, et al. FDG-PET after two cycles of chemotherapy predicts 
treatment failure and progression-free survival in Hodgkin lymphoma. Blood. 2006;107:52-59. 
73. 
Spaepen K, Stroobants S, Dupont P, et al. Prognostic value of positron emission tomography 
(PET) with fluorine-18 fluorodeoxyglucose ([18F]FDG) after first-line chemotherapy in non-
Hodgkin’s lymphoma: is [18F]FDG-PET a valid alternative to conventional diagnostic 
methods? J Cin Oncol. 2001;19:414-419. 
74. 
Juweid ME, Cheson BD. Role of positron emission tomography in lymphoma. J Clin Oncol. 
2005;23:4577-4580. 
75. 
Juweid ME, Chson BD. Positron-emission tomography and assessment of cancer therapy. N 
Engl J Med. 2006;254:496-507. 
76. 
Juweid ME, Wiseman GA, Vose JM, et al. Response assessment of aggressive non-Hodgkin’s 
lymphoma by integrated International Workshop Criteria and fluorine-18-fluorodeoxyglucose 
positron emission tomography. J Clin Oncol. 2005;23:4652-4661. 
77. 
Shankar LK, Hoffman JM, Bacharach S, et al. Consensus Recommendations for the Use of 
18F-FDG PET as an Indicator of Therapeutic Response in Patients in National Cancer Institute 
Trials. J Nucl Med. 2006;47:1059-1066. 
78. 
Spaepen K, Stroobants S, Dupont P, et al. Can positron emission tomography with [(18)F]-
fluorodeoxyglucose after first-line treatment distinguish Hodgkin’s disease patients who need 
additional therapy from others in whom additional therapy would mean avoidable toxicity? Br 
J Haematol. 2001;115:272-278. 
79. 
Spaepen K, Stroobants S, Dupont P, et al. Prognostic value of pretransplantation positron 
emission tomography using fluorine 18-fluorodeoxyglucose in patients with aggressive 
lymphoma treated with high-dose chemotherapy and stem cell transplantation. Blood. 
2003;102:53-59. 
80. 
Jerusalem G, Beguin Y, Fassotte MF, et al. Persistent tumor 18F-FDG uptake after a few cycles 
of polychemotherapy is predictive of treatment failure in non-Hodgkin’s lymphoma. 
Haematologica. 2000;85:613-618. 
Version Date: 02/15/2018 
81 
Update #18 


CALGB 50303 
81. 
Cremerius U, Fabry U, Neuerburg J, et al. Prognostic significance of positron emission 
tomography using fluorine-18-fluorodeoxyglucose in patients treated for malignant lymphoma. 
Nuklearmedizin. 2001;40:23-30. 
82. 
Cremerius U, Fabry U, Wildberger JE, et al. Pre-transplant positron emission tomography 
(PET) using fluorine-18-fluoro-deoxyglucose (FDG) predicts outcome in patients treated with 
high-dose chemotherapy and autologous stem cell transplantation for non-Hodgkin’s 
lymphoma. Bone Marrow Transplant. 2002;30:103-111. 
83. 
Naumann R, Vaic A, Beuthien-Baumann B, et al. Prognostic value of positron emission 
tomography in the evaluation of post-treatment residual mass in patients with Hodgkin’s 
disease and non-Hodgkin’s lymphoma. Br J Haematol. 2001;115:793-800. 
84. 
de Wit M, Baumann D, Beyer W, Herbst K, Clausen M, Hossfeld DK. Whole-body positron 
emission tomography (PET) for diagnosis of residual mass in patients with lymphoma. Ann 
Oncol. 1997;8 Suppl 1:57-60. 
85. 
Reske SN. PET and restaging of malignant lymphoma including residual masses and relapse. 
Eur J Nucl Med Mol Imaging. 2003;30 Suppl 1:S89-96. 
86. 
Kostakoglu L, Coleman M, Leonard JP, Kuji I, Zoe H, Goldsmith SJ. PET predicts prognosis 
after 1 cycle of chemotherapy in aggressive lymphoma and Hodgkin’s disease. J Nucl Med. 
2002;43:1018-1027. 
87. 
Talbot JN, Haioun C, Rain JD, et al. [18F]-FDG positron imaging in clinical management of 
lymphoma patients. Crit Rev Oncol Hematol. 2001;38:193-221. 
88. 
Kostakoglu L, Goldsmith SJ. Fluorine-18 fluorodeoxyglucose positron emission tomography 
in the staging and follow-up of lymphoma: is it time to shift gears? Eur J Nucl Med. 
2000;27:1564-1578. 
89. 
Foo SS, Mitchell PL, Berlangieri SU, Smith CL, Scott AM. Positron emission tomography 
scanning in the assessment of patients with lymphoma. Intern Med J. 2004;34:388-397. 
90. 
Lang O, Bihl H, Hultenschmidt B, Sautter-Bihl ML. Clinical relevance of positron emission 
tomography (PET) in treatment control and relapse of Hodgkin’s disease. Strahlenther Onkol. 
2001;177:138-144. 
91. 
Leisenring W, Alonzo T, Pepe MS. Comparisons of predictive values of binary medical 
diagnostic tests for paired designs. Biometrics. 2000;56:345-351. 
92. 
DeLong ER, DeLong DM, Clarke-Pearson DL.  Comparing the areas under two or more 
correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 
1988;44(3):837-845. 
93. 
Heagerty PJ, Lumley T, Pepe MS.  Time-dependent ROC curves for censored survival data 
and a diagnostic marker. Biometrics. 2000;56(2):337-344. 
94. 
Jung SH, Ahn C.  Estimation of response probability in correlated binary data: A new approach. 
Drug Information Journal.  2000;34:599-604. 
95. 
Kim J, Kim Y, Kim Y. A gradient-based optimization algorithm for LASSO. J Comput Graph 
Stat. 2008; 17: 994-1009. 
96. 
Sohn I, Kim J, Jung SH, Park C. Gradient lasso for Cox proportional hazards model. 
Bioinformatics. 2009; 25: 1775-1781. 
 
 
 
Version Date: 02/15/2018 
82 
Update #18 


CALGB 50303 
APPENDIX I 
CANCER TRIALS SUPPORT UNIT (CTSU) PARTICIPATION PROCEDURES 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION: 
To submit site registration documents: 
For patient enrollments: 
 
 
 
 
Hours: 9:00AM – 5:30PM Eastern Time, Monday–Friday 
(excluding holidays) 
[Registrations received after 5:00PM ET will be handled the next 
business day. For CTSU patient enrollments that must be 
completed within approximately one hour, or other extenuating 
circumstances, call 
 between 9:00AM and 
5:30PM.] 
Submit study data directly to the Lead Cooperative Group unless otherwise specified in the protocol: 
 
 
 
Sites should submit Teleforms via Fax or Mail. See section 5.2 Data Submission Section for details on forms 
submission. 
Do not submit study data or forms to CTSU Data Operations. Do not copy the CTSU on data submissions. 
For patient eligibility or treatment related questions: Contact the CALGB Study Chair. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help Desk by 
phone or e-mail:  
CTSU General Information Line: 
 All calls and correspondence 
will be triaged to the appropriate CTSU representative. 
The CTSU Web site is located at: 
 
Registration/Randomization 
Prior to the recruitment of a patient for this study, investigators must be registered members of the CTSU. Each 
investigator must have an NCI investigator number and must maintain an “active” investigator registration status 
through the annual submission of a complete investigator registration packet (FDA Form 1572 with original signature, 
current CV, Supplemental Investigator Data Form with signature, and Financial Disclosure Form with original 
signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI. These forms are available on the CTSU 
registered member Web site or by calling the PMB at 
 Monday through Friday between 8:30AM and 
4:30PM Eastern time. 
Each CTSU investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and 
submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can enroll patients. 
Study centers can check the status of their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member Web site at 
. 
All forms and documents associated with this study can be downloaded from the CALGB 50303 Web page on the 
CTSU registered member Web site 
 Patients can be registered only after pre-treatment 
evaluation is complete, all eligibility criteria have been met, and the study site is listed as “approved” in the CTSU 
RSS. 
Version Date: 02/15/2018 
83 
Update #18 


CALGB 50303 
Requirements for CALGB 50303 site registration: 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
Pre-study requirements for patient enrollment on CALGB 50303: 
• 
Patient must meet all inclusion criteria, and no exclusion criteria should apply. 
• 
Patient has signed and dated all applicable consents and authorization forms. 
• 
All baseline laboratory tests and pre-study evaluations performed within the time period specified in the protocol 
and fresh (frozen) tumor biopsy must be available or attempted. 
• 
As of protocol update #14, and starting August 1, 2012, registration to the companion study CALGB 580603 is 
required to register to the treatment study CALGB 50303, and will be performed at the same time as registration 
to the treatment study. Registration to CALGB 580603 must be done at time of patient enrollment. Sites must 
submit the institutional approval letter provided by the Imaging Core Laboratory to the CTSU with each patient 
enrollment for CALGB 50303 and 580603. 
• 
As of protocol update #14, and starting August 1, 2012, all sites that enroll patients must be approved (or have 
previously been approved) by the Alliance Imaging Core Laboratory at the Ohio State University Medical Center. 
See the “Special Materials and Substudies” section below for further information on procedures.  
CTSU PROCEDURES FOR PATIENT ENROLLMENT 
1. Contact the CTSU Patient Registration Office by calling 
 between 9:00AM and 5:30PM Eastern 
Time, Monday-Friday. Leave a voicemail to alert the CTSU Patient Registrar that an enrollment is forthcoming. 
For immediate registration needs, e.g., within one hour, call the registrar cell phone at 
 
2. Complete the following forms: 
• 
CTSU Patient Enrollment Transmittal Form 
• 
CALGB 50303 Eligibility Checklist 
• 
CALGB Registration Worksheet (indicate participation on companion studies CALGB 60405 and CALGB 
580603) 
• 
Copy of approval letter from the Alliance Imaging Core Laboratory for the FDG-PET/CT Imaging 
Companion  
3. Fax these forms to the CTSU Patient Registrar at 
 between the hours of 9:00AM and 5:30PM, 
Mon-Fri, Eastern Time (excluding holidays); however, please be aware that registrations received after 5:00PM 
will be processed the next day. Registration is limited to the operating hours of the CALGB Registration Office 
(9:00AM – 5:00PM ET). The CTSU registrar will check the investigator and site information provided to ensure 
that all regulatory requirements have been met. The registrar will also check that forms are complete and follow-
up with the site to resolve any discrepancies. 
4. Once investigator eligibility is confirmed and enrollment documents are reviewed for compliance, the CTSU 
registrar will contact the CALGB, within the confines of CALGB’s registration hours. The CTSU registrar will 
access the CALGB’s on-line registration system, to obtain assignment of treatment arm and assignment of a 
unique patient ID (to be used on all future forms and correspondence). The CTSU registrar will confirm 
registration by fax. 
• 
Protocol treatment must begin within 7 days of randomization. 
Registration to Companion Study (CALGB 60405) 
• 
Sites must offer participation in the companion studies to all patients. 
• 
Registration to the companion study CALGB 60405 for those patients who have agreed to participate, will be 
performed at the same time as registration to the treatment study. Although it is preferable that patients be 
registered to CALGB 60405 at the same time they are registered to CALGB 50303, registration to CALGB 60405 
may occur up to 60 days following registration to the treatment trial.  
Version Date: 02/15/2018 
84 
Update #18 


CALGB 50303 
Procedures for late enrollment on CALGB 60405 (pharmacogenomics companion): 
- 
Submit CTSU Patient Enrollment transmittal form (with note indicating delayed registration to CALGB 60405 
companion study). 
- 
Submit revised CALGB 50303 Registration Worksheet (indicating patient consent for CALGB 60405). 
Note: Although it is preferable that patients are registered to 60405 at the same time they are registered to CALGB 
50303, registration to CALGB 60405 may occur up to 60 days following registration to the treatment trial. 
DATA SUBMISSION AND RECONCILIATION 
1. All case report forms (CRFs) and transmittals associated with this study must be downloaded from the C50303 
Web page located on the CTSU registered member Web site 
. Sites must use the current 
form versions and adhere to the instructions and submission schedule outlined in the protocol. 
2. Submit all completed CRFs (with the exception of patient enrollment forms), clinical reports, and transmittals 
directly to the Alliance Statistics and Data Center (see contact table and Section 5.2 of protocol), unless an 
alternate location is specified in the protocol. Do not send study data to the CTSU. A completed CTSU-CALGB 
coversheet should accompany all data submissions. 
3. The Alliance Statistics and Data Center will send (generally via e-mail but may be sent via postal mail or fax) 
query notices and delinquency reports directly to the site for reconciliation. Please send query responses and 
delinquent data to the Alliance Statistics and Data Center (via postal mail or fax) and do not copy the CTSU Data 
Operations. Each site should have a designated CTSU Administrator and Data Administrator and must keep their 
CTEP AMS account contact information current. This will ensure timely communication between the clinical 
site and the Alliance Statistics and Data Center. 
SPECIAL MATERIALS OR SUBSTUDIES 
1. Mandatory Histologic Review (Protocol Section 5.3) 
 
• 
Fresh (frozen) tumor biopsy sample is mandatory. 
 
• 
Failure to submit a pathology block within 60 days of patient registration will be considered a major protocol 
violation. 
 
• 
Collect, prepare, and submit specimens as outlined in the protocol. 
 
• 
Do not send specimens, supporting clinical reports, or transmittals to the CTSU. 
2. Specimen Collection for Correlatives (Protocol Section 5.4) 
 
• 
Pharmacogenomic Substudy, CALGB 60405, requires patient consent and separate registration. 
 
• 
Collect, prepare, and submit specimens as outlined in the protocol. 
 
• 
Do not send specimens, supporting clinical reports, or transmittals to the CTSU. 
3. FDG-PET/CT Imaging (Protocol Section 8.0) 
 
• 
Imaging Substudy, CALGB 580603, requires separate registration  
 
• 
See instructions outlined in Protocol Section 8.0. regarding participation on this study. Sites must submit 
required documentation to the Imaging Core Laboratory and receive institutional approval. 
 
• 
Submit institutional approval letter for imaging substudy participation to the CTSU with each patient 
enrollment on CALGB 580603. 
 
• 
Do not send images to the CTSU. 
Version Date: 02/15/2018 
85 
Update #18 


CALGB 50303 
SERIOUS ADVERSE EVENT (AE) REPORTING (SECTION 15.0) 
1. CTSU sites must comply with the expectations of their local Institutional Review Board (IRB) regarding 
documentation and submission of adverse events. Local IRBs must be informed of all reportable serious adverse 
reactions. 
2. CTSU sites will assess and report adverse events according to the guidelines and timelines specified in the 
protocol. You may navigate to the CTEP Adverse Event Expedited Report System (CTEP-AERS) from either the 
Adverse Events tab of the CTSU member home page (https://www.ctsu.org) or by selecting Adverse Event 
Reporting Forms from the document center drop down list on the protocol number Web page. 
3. Do not send adverse event reports to the CTSU. 
4. Secondary AML/MDS/ALL reporting: Report occurrence of secondary AAML, MDS, or ALL via the NCI/CTEP 
AML-MDS Report Form in lieu of CTEP-AERS. Submit the completed form and supporting documentation as 
outlined in the protocol. 
DRUG PROCUREMENT (SECTION 10.0) 
Commercial Agents: Doxorubicin, Etoposide, Vincristine, Cyclophosphamide, Prednisone, Rituximab, Filgrastim, 
Pegfilgrastim, Methotrexate 
1. Information on drug formulation, procurement, storage and accountability, administration, and potential toxicities 
are outlined in Section 10.0 of the protocol. 
2. You may navigate to the drug forms by selecting Pharmacy Forms from the document center drop down list on 
the CALGB 50303 Web page. 
REGULATORY AND MONITORING 
Study Audit 
To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 312, 314, and HHS 45 CFR 46] 
and National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) Clinical Trials Monitoring Branch 
(CTMB) guidelines for the conduct of clinical trials and study data validity, all protocols approved by NCI/CTEP that 
have patient enrollment through the CTSU are subject to audit. 
Responsibility for assignment of the audit will be determined by the site’s primary affiliation with a Cooperative 
Group or CTSU. For Group-aligned sites, the audit of a patient registered through CTSU will become the responsibility 
of the Group receiving credit for the enrollment. For CTSU Independent Clinical Research Sites (CICRS), the CTSU 
will coordinate the entire audit process. 
For patients enrolled through the CTSU, you may request the accrual be credited to any Group for which you have an 
affiliation provided that Group has an active clinical trials program for the primary disease type being addressed by 
the protocol. Per capita reimbursement will be issued by the credited Group provided they have endorsed the trial, or 
by the CTSU if the Group has not endorsed the trial. 
Details on audit evaluation components, site selection, patient case selection, materials to be reviewed, site 
preparation, on-site procedures for review and assessment, and results reporting and follow-up are available for 
download from the CTSU Operations Manual located on the CTSU Member Web site. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
The HIPAA Privacy Rule establishes the conditions under which protected health information may be used or 
disclosed by covered entities for research purposes. Research is defined in the Privacy Rule referenced in HHS 45 
CFR 164.501. Templated language addressing NCI-U.S. HIPAA guidelines are provided in the HIPAA Authorization 
Form located on the CTSU Web site. 
The HIPAA Privacy Rule does not affect participants from outside the United States. Authorization to release 
Protected Health Information is NOT required from patients enrolled in clinical trials at non-U.S. sites. 
Version Date: 02/15/2018 
86 
Update #18 


CALGB 50303 
Clinical Data System (CDS) Monitoring 
This study will be monitored by the Clinical Data System (CDS-web). Cumulative CDS data will be submitted 
quarterly to CTEP by electronic means. The sponsoring Group fulfills this reporting obligation by electronically 
transmitting to CTEP the CDS data collected from the study-specific case report forms. 
 
Version Date: 02/15/2018 
87 
Update #18 


CALGB 50303 
APPENDIX II 
CALGB 580603 PET/CT INSTRUMENT TECHNICAL SPECIFICATIONS FORM 
(From ACRIN Credentialing Application, 2005) 
Page 1 of 5 
 
 
Institution: 
 
 
 
 
 
 
Date: 
 
Institution Address: 
 
 
 
Institution Contact Name and Telephone Number: 
 
E-mail:  
 
 
 
 
 
Fax: 
 
 
 
PET Center Name: 
 
 
 
 
 
Date: 
 
PET Center Address: 
 
 
 
PET Center Contact Name and Telephone Number: 
 
E-mail:  
 
 
 
 
 
Fax: 
 
 
 
Type of Scanner: 
(e.g., GE Discovery ST, Siemens Biograph, Philips Gemini, GE Advance, Siemens/CTI ECAT, etc.) 
 
 
Transmission Source: 
(e.g., 68GE-rods, 137Cs-point, CT) 
 
 
Method of Attenuation Correction: 
(e.g., segmentation, subtraction of emission contribution to transmission scan, CTAC) 
 
 
 
Routine QC Testing Performed 
 
Daily: 
 
Monthly: 
 
Quarterly: 
 
Yearly: 
 
Other: 
 
Version Date: 02/15/2018 
88 
Update #18 


CALGB 50303 
APPENDIX II 
CALGB 580603 PET/CT INSTRUMENT TECHNICAL SPECIFICATIONS FORM 
(From ACRIN Credentialing Application, 2005) 
Page 2 of 5 
UNIFORM PHANTOM SCAN INFORMATION 
 
Phantom Length: 
 
 
 
Phantom Diameter: 
 
Phantom Volume: 
 
Radionuclide: 
 
Scan Date: 
 
 
Scan Time: 
 
 
 
Scan Duration: 
 
 
For Water-Fillable Phantoms, Provide the Following Data: 
 
Assayed Activity in Syringe before injection: 
mCi 
 
Time: 
 
Assayed Activity in Syringe after injection: 
mCi 
 
Time: 
 
 
 
For Ge-68/Ga-68 Calibration Phantoms, Provide the Following Data: 
 
Calibration Date: 
 
 
 
Time: 
 
Calibration Activity: 
mCi  
Time: 
 
 
 
 
 
 
 
 
 
 
 
 
Std Dev of SUV 
Number of Pixels in 
Slice # 
Average SUV in ROI1 
 
  (if available) 
ROI: 
 
 
1 
 
 
________ 
 
     ________ 
 
 
2 
 
 
________ 
 
     ________ 
 
 
3 
 
 
________ 
 
     ________ 
 
 
4 
 
 
________ 
 
     ________ 
 
 
5 
 
 
________ 
 
     ________ 
 
 
6 
 
 
________ 
 
     ________ 
 
 
7 
 
 
________ 
 
     ________ 
 
 
8 
 
 
________ 
 
     ________ 
Report info for EVERY 
9 
 
 
________ 
 
     ________ 
slice of the phantom 
10 
 
 
________ 
 
     ________ 
 
 
11 
 
 
________ 
 
     ________ 
 
 
12 
 
 
________ 
 
     ________ 
 
 
13 
 
 
________ 
 
     ________ 
 
 
14 
 
 
________ 
 
     ________ 
 
 
15 
 
 
________ 
 
     ________ 
 
 
16 
 
 
________ 
 
     ________ 
 
 
17 
 
 
________ 
 
     ________ 
 
 
18 
 
 
________ 
 
     ________ 
 
 
19 
 
 
________ 
 
     ________ 
 
 
20 
 
 
________ 
 
     ________ 
 
1 A circular or elliptical region of interest (ROI) covering most of the interior of the phantom. 
Version Date: 02/15/2018 
89 
Update #18 


CALGB 50303 
APPENDIX II 
 
CALGB 580603 PET/CT INSTRUMENT TECHNICAL SPECIFICATIONS FORM 
(From ACRIN Credentialing Application, 2005) 
 
Page 3 of 5 
 
 
FOR CALGB IMAGING CORE LABORTORY USE ONLY: 
 
Phantom Images Review: 
 
Date: 
Comments: 
 
 
 
 
 
 
        Approved 
 
        Disapproved 
 
 
_________________________________________        ___________________ 
 Signature                                                            Date 
 
 
 
 
Version Date: 02/15/2018 
90 
Update #18 


CALGB 50303 
APPENDIX II 
CALGB 580603 PET/CT INSTRUMENT TECHNICAL SPECIFICATIONS FORM 
(From ACRIN Credentialing Application, 2005) 
Page 4 of 5 
 
WHOLE BODY FDG-PET TEST PATIENT #1: 
 
 
File Name: 
 
 
 
Patient Height:  
Patient Weight: 
 
FDG Dose (mCi): 
 
 
Dose Assay Time: 
 
Blood glucose prior to FDG administration (mg/dL): 
 
Injection Time:  
 
Start Time of Emission Scan: 
 
ACQUISITION No. of Bed Positions: 
 
 
EMISSION TIME (MIN/BED):  
TRANSMISSION TIME (MIN/BED): 
 
 
RECONSTRUCTION ALGORITHM: 
(e.g., 2D FBP, 2D OSEM, 3D FORE/OSEM, 3D 
RAMLA) 
PIXEL SIZE (mm) 
X-Y: 
 
Z: 
 
 
Scatter Correction Applied: 
 
  Yes 
 
No 
 
(Include algorithm type, e.g., model-based, tail-fit, Bergstrom): 
 
 
Randoms Correction Applied: 
  Online Smoothed Randoms (offline) 
  None 
 
 
FOR CALGB IMAGING CORE LABORTORY USE ONLY: 
 
Test Patient #1 Review: 
 
Date: 
Comments: 
 
 
 
        Approved 
 
        Disapproved 
 
 
_________________________________________        ___________________ 
 Signature                                                            Date 
 
 
Version Date: 02/15/2018 
91 
Update #18 


CALGB 50303 
APPENDIX II 
CALGB 580603 PET/CT INSTRUMENT TECHNICAL SPECIFICATIONS FORM 
(From ACRIN Credentialing Application, 2005) 
Page 5 of 5 
 
 
WHOLE BODY FDG-PET TEST PATIENT #2: 
 
 
File Name: 
 
 
 
Patient Height:  
Patient Weight: 
 
FDG Dose (mCi): 
 
 
Dose Assay Time: 
 
Blood glucose prior to FDG administration (mg/dL): 
 
Injection Time:  
 
Start Time of Emission Scan: 
 
ACQUISITION No. of Bed Positions: 
 
 
EMISSION TIME (MIN/BED):  
TRANSMISSION TIME (MIN/BED): 
 
 
RECONSTRUCTION ALGORITHM: 
(e.g., 2D FBP, 2D OSEM, 3D FORE/OSEM, 3D 
RAMLA) 
PIXEL SIZE (mm) 
X-Y: 
 
Z: 
 
 
Scatter Correction Applied: 
 
  Yes 
 
No 
 
(Include algorithm type, e.g., model-based, tail-fit, Bergstrom): 
 
 
Randoms Correction Applied: 
  Online Smoothed Randoms (offline) 
  None 
 
 
FOR CALGB IMAGING CORE LABORTORY USE ONLY: 
 
Test Patient #2 Review: 
 
Date: 
Comments: 
 
 
 
        Approved 
 
        Disapproved 
 
 
_________________________________________        ___________________ 
 Signature                                                            Date 
 
Version Date: 02/15/2018 
92 
Update #18 


CALGB 50303 
APPENDIX III CALGB 580603 IMAGING SITE PERSONNEL FORM 
 
Responsible CRA Contact 
Complete Address 
E-mail 
Phone Number 
Fax Number 
Radiology Department Contact 
Complete Address 
E-mail 
Phone Number 
Fax Number 
 
 
 
 
Please provide the information requested above. Provide the middle initial for 
individuals who commonly use them. Also, please add or correct the degree/title as 
necessary. This information will be retained by the Alliance Imaging Core Lab at 
IROC Ohio. 
 
Once completed, you may send this form to: 
 
  
 
  
  
 
  
  
 
  
  
 
 
Call the Imaging Core Laboratory at 
 with any questions. Thank you 
for your assistance. 
Version Date: 02/15/2018 
93 
Update #18