Conditions: Previously Untreated Peripheral T-cell Lymphoma
Keywords: Peripheral T-cell Lymphoma Azacitidine Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
This is a phase II, multi-center study to determine the efficacy and safety of first-line CC-486 plus CHOP in patients with PTCL who have received no prior systemic therapy. The study has a sample size of 20, and follows two-stage minimax design for primary efficacy analysis.

Detailed description:
Study Summary:

This is a phase II, multi-center study to determine the efficacy and safety of first-line CC-486 plus CHOP in patients with Peripheral T-cell Lymphoma (PTCL) who have received no prior systemic therapy. The main objective is to determine the complete response rate (CR) of CC486-CHOP in PTCL. CR rate after cycle 6 will be used for the purpose of interim efficacy analysis.

* The study includes 6 cycles (\~18 weeks) of treatment and 2 years of follow-up. The projected end date is 12/31/2022. Patients achieving complete remission will be evaluated every 6 months for 2 years or until disease progression. Patients who have disease progression will be contacted every 6 months to assess for survival status.
* Standard dose CHOP will be provided on day 1 of each cycle and repeat every 3 weeks for a total of 6 cycles.
* CC486 at 300 mg daily will be administered orally from day -6 to day 0 for cycle 1 priming, and on days 8-21 following cycles 1-5.
* Patients in CR/PR following 6 cycles of treatment have the option to proceed to consolidative autologous stem cell transplant.
* Will continue on treatment as long as they are responding to therapy and not experiencing unacceptable side effects.

Arms:
arm 1: CC486 +CHOP

Interventions: intervention 1: CC-486 Administration intervention 2: CHOP Administration
Intervention descriptions: intervention 1: CC-486 at 300 mg once daily is to be administered Cycle 1, Day -6 to 0 and Cycles 1 to 5, Day 8 to 21. Antiemetic prophylaxis is recommended before dosing. All efforts should be made to administer CC-486 on all scheduled days of the Cycle 1 priming dosing (7 days, Cycle 1 Day -6 to Cycle 1 Day 0) and the Cycle 1-5 dosing (14 days, Day 8-21). A dose missed earlier in a day can be administered later that day as long as it is taken at least 8 hours before the next scheduled dose. Any missed dose should not be taken beyond the last scheduled day of CC-486 administration for the cycle, but should be returned by the subject for CC 486 accountability. If vomiting occurs after a dose of CC-486 is administrated, that dose should not be made up later that day. intervention 2: CHOP is to be administered on Days 1 to 5 of Cycles 1-6. Chemotherapy can be administer within +72h or -24h of Day 1 of each scheduled Cycle. Preparation and infusion rate are according to the package insert and local practice. The doses to be used are:

Cyclophosphamide: 750 mg/m2 IV on day 1 Doxorubicin: 50 mg/m2 IV on day 1 Vincristine: 1.4 mg/m2 IV (not to exceed 2.0 mg total) on day 1 Prednisone: 100 mg PO days 1-5

Protocol document:
Prot_SAP_000.pdf: 
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IRB Protocol # 1711018777 
Version Date: February 25, 2020 
ii 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional 
review boards. The contents of this document shall not be disclosed to others without written 
authorization from WCM. 


IRB Protocol # 1711018777 
Version Date: February 25, 2020 
iii 
List of Abbreviations 
AE 
AESI 
Adverse Event 
Adverse events of special interest  
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTSC 
Clinical Translational Science Center  
DSMB 
Data Safety Monitoring Board 
DSMP 
DDPCR 
Data Safety Monitoring Plan 
Digital Droplet PCR 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HUD 
Humanitarian Use Device  
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption  
IND 
IP 
Investigational New Drug 
Investigational Product 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
UAP 
Unanticipated Problem 
WCM 
Weill Cornell Medicine 


 
 
IRB Protocol # 1711018777 
 
 
Version Date: February 25, 2020 
 
1 
 
Table of Contents 
40TPROTOCOL SUMMARY40T ............................................................................................................. 4 
40TSCHEMA40T ....................................................................................................................................... 7 
40TSTUDY PROCEDURES40T ............................................................................................................... 8 
40T1.40T 
40TSTUDY OBJECTIVES40T ........................................................................................................ 10 
40T1.140T 
40TPrimary Objective40T ........................................................................................................ 10 
40T1.240T 
40TSecondary Objectives40T .................................................................................................. 10 
40T1.340T 
40TExploratory Objectives40T ................................................................................................ 10 
40T2.40T 
40TBACKGROUND40T ................................................................................................................. 10 
40T2.140T 
40TPeripheral T-cell Lymphoma40T ....................................................................................... 10 
40T2.240T 
40TInvestigational Agent40T ................................................................................................... 11 
40T2.2.1 40T 
40TCC-48640T ................................................................................................................. 11 
40T2.2.2 40T 
40TCHOP40T ................................................................................................................... 12 
40T2.340T 
40TRationale40T ...................................................................................................................... 13 
40T2.440T 
40TCorrelative Studies Background40T .................................................................................. 14 
40T3.40T 
40TSUBJECT SELECTION40T ...................................................................................................... 15 
40T3.140T 
40TStudy Population40T .......................................................................................................... 15 
40T3.240T 
40TInclusion Criteria40T ......................................................................................................... 15 
40T3.340T 
40TExclusion Criteria40T ........................................................................................................ 16 
40T4.40T 
40TREGISTRATION PROCEDURES40T ..................................................................................... 17 
40T5.40T 
40TSTUDY PROCEDURES40T ..................................................................................................... 18 
40T5.140T 
40TStudy Design40T ................................................................................................................ 18 
40T5.140T 
40TSchedule of Evaluations40T ............................................................................................... 18 
40T5.1.1 40T 
40TScreening Visit40T ..................................................................................................... 18 
40T5.1.2 40T 
40TTreatment Phase40T ................................................................................................... 19 
40T5.1.2.1 40T 
40TCycle 1, Day -640T ................................................................................................ 19 
40T5.1.2.2 40T 
40TCycle 1-6, Day 140T .............................................................................................. 19 
40T5.1.2.3 40T 
40TCycle 1-5, Day 8 and Cycle 1-2, Day 1540T ......................................................... 19 
40T5.1.3 40T 
40TTreatment Discontinuation40T .................................................................................. 20 
40T5.1.4 40T 
40TFollow-up Phase40T .................................................................................................. 20 
40T5.240T 
40TTreatment Administration40T ............................................................................................ 21 
40T5.2.1 40T 
40TCC-486 Administration40T ........................................................................................ 21 
40T5.2.2 40T 
40TCHOP Administration40T .......................................................................................... 21 
40T5.2.3 40T 
40TGrowth Factors40T .................................................................................................... 21 
40T5.2.4 40T 
40TCNS Prophylaxis40T .................................................................................................. 21 
40T5.2.5 40T 
40TTumor Lysis Management40T ................................................................................... 22 
40T5.340T 
40TGeneral Concomitant Medication and Supportive Care Guidelines40T ............................ 22 
40T5.3.1 40T 
40TRecommended Concomitant Medications/Procedures40T ........................................ 22 
40T5.3.2 40T 
40TProhibited Concomitant Medications/Procedures40T ............................................... 22 


 
 
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40T5.440T 
40TDuration of Therapy and Criteria for Removal from Study40T ........................................ 22 
40T5.540T 
40TDuration of Follow Up40T ................................................................................................. 23 
40T6.40T 
40TDOSING DELAYS/DOSE MODIFICATIONS40T ................................................................. 23 
40T6.140T 
40THematologic Requalification and Dose Adjustment40T ................................................... 23 
40T6.240T 
40TCC-486 Dose Levels40T .................................................................................................... 25 
40T6.340T 
40TCHOP Dose Modification40T ............................................................................................ 26 
40T7.40T 
40TPHARMACEUTICAL INFORMATION40T ............................................................................ 26 
40T7.140T 
40TCC-48640T ......................................................................................................................... 26 
40T7.1.1 40T 
40TDescription40T ........................................................................................................... 26 
40T7.1.2 40T 
40TAvailability40T .......................................................................................................... 27 
40T7.1.3 40T 
40TAgent Ordering40T .................................................................................................... 27 
40T7.1.4 40T 
40TAgent Accountability40T ........................................................................................... 27 
40T7.1.5 40T 
40TSide Effects40T .......................................................................................................... 27 
40T7.2 40T 
40TCyclophosphamide40T ....................................................................................................... 28 
40T7.2.1 40T 
40TDescription and Mode of Action40T ......................................................................... 28 
40T7.2.2 40T 
40TAvailability and Accountability40T ........................................................................... 28 
40T7.2.3 40T 
40TClinical Use40T .......................................................................................................... 28 
40T7.2.4 40T 
40TSide Effects40T .......................................................................................................... 28 
40T7.3  40T 
40TDoxorubicin40T ................................................................................................................. 28 
40T7.3.1 40T 
40TDescription and Mode of Action40T ......................................................................... 28 
40T7.3.2 40T 
40TAvailability and Accountability40T ........................................................................... 28 
40T7.3.3 40T 
40TClinical Use40T .......................................................................................................... 29 
40T7.3.4 40T 
40TSide Effects40T .......................................................................................................... 29 
40T7.440T 
40TVincristine40T .................................................................................................................... 29 
40T7.4.1 40T 
40TDescription and Mode of Action40T ......................................................................... 29 
40T7.4.2 40T 
40TAvailability and Accountability40T ........................................................................... 29 
40T7.4.3 40T 
40TClinical Use40T .......................................................................................................... 29 
40T7.4.4 40T 
40TSide Effects40T .......................................................................................................... 30 
40T7.540T 
40TPrednisone40T .................................................................................................................... 30 
40T7.5.1 40T 
40TDescription and Mode of Action40T ......................................................................... 30 
40T7.5.2 40T 
40TAvailability and Accountability40T ........................................................................... 30 
40T7.5.3 40T 
40TClinical Use40T .......................................................................................................... 30 
40T7.5.4 40T 
40TSide Effects40T .......................................................................................................... 30 
 
 
 
  
 
  
 
40T9.40T 
40TMEASUREMENT OF EFFECT40T ......................................................................................... 32 
40T9.140T 
40TResponse Criteria40T ......................................................................................................... 32 
40T9.240T 
40TDuration of Response40T ................................................................................................... 35 
40T9.340T 
40TProgression-Free Survival (PFS)40T ................................................................................. 35 
40T9.440T 
40TOverall Survival (OS)40T .................................................................................................. 35 


 
 
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40T10. 40T 40TDATA REPORTING / REGULATORY CONSIDERATIONS40T ......................................... 35 
40T10.140T 
40TData Collection40T ............................................................................................................ 35 
40T10.240T 
40TRegulatory Considerations40T ........................................................................................... 36 
40T11.40T 
40TSTATISTICAL CONSIDERATIONS40T ................................................................................ 36 
40T11.140T 
40TStudy Design40T ................................................................................................................ 36 
40T11.240T 
40TSample Size40T .................................................................................................................. 36 
40T11.3 40T 
40TAnalysis Plan for Endpoints40T ........................................................................................ 37 
40T11.3.1 40T 
40TPrimary Endpoints40T ............................................................................................... 37 
40T11.3.2 40T 
40TSecondary Clinical Endpoints40T .............................................................................. 37 
40T11.3.3 40T 
40TLaboratory Correlates40T .......................................................................................... 37 
40T12. ADVERSE EVENT REPORTING REQUIREMENTS40T ........................................................ 37 
40T12.140T 
40TAdverse Event Definition40T ............................................................................................ 37 
40T12.1.1 40T 
40TAdverse Event Characteristics and Related Attribututions40T .................................. 38 
40T12.1.2 40T 
40TRecording of Adverse Events40T .............................................................................. 38 
40T12.1.3 40T 
40TReporting of AE to WCM IRB40T ............................................................................ 39 
40T12.240T 
40TDefinition of SAE40T ........................................................................................................ 39 
40T12.2.1 40T 
40TReporting of SAE to IRB40T ..................................................................................... 40 
40T12.2.2 40T 
40TReporting of SAE to FDA40T ................................................................................... 40 
40T12.2.3 40T 
40TReporting of SAE to Celgene40T .............................................................................. 42 
40T12.340T 
40TIND Annual Reports40T .................................................................................................... 43 
40T12.440T 
40TAE/SAE Follow Up40T ..................................................................................................... 43 
40T13. DATA AND SAFETY MONITORING PLAN (DSMP)40T ...................................................... 43 
40T14. REFERENCES40T ...................................................................................................................... 43 
40TAPPENDIX A:  COCKCROFT-GAULT ESTIMATION OF CRCL40T ......................................... 47 
40TAPPENDIX B:  INTERNATIONAL PROGNOSTIC INDEX (IPI) SCORE40T ............................ 48 
40TAPPENDIX C:  PERFORMANCE STATUS CRITERIA40T .......................................................... 49 
40TAPPENDIX D: NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION FOR 
CONGESTIVE HEART FAILURE40T ............................................................................................. 50 
40TAPPENDIX E: DEAUVILLE CRITERIA FOR PET SCAN INTERPRETATION40T .................. 51 
40TAPPENDIX F: RECOMMENDATIONS FOR MANAGEMENT OF TREATMENT-INDUCED 
DIARRHEA40T ................................................................................................................................. 52 
40TAPPENDIX G: CORRELATIVE STUDIES LABORATORY INSTRUCTIONS40T .................... 53 
 
 
 


 
 
IRB Protocol # 1711018777 
 
 
Version Date: February 25, 2020 
 
4 
 
PROTOCOL SUMMARY 
 
Full Title:  
 
 
 
 
A Multi-center Phase II Study of CC486-CHOP in Patients with Previously Untreated Peripheral 
T-cell Lymphoma   
 
Short Title:  
 
 
CC486-CHOP for Untreated Peripheral T-cell Lymphoma 
 
Clinical Phase: 
 
 
 
Phase II 
 
Principal Investigator:  
Jia Ruan, M.D., Ph.D. 
 
Sample Size: 
 
 
N=20 
 
Accrual Ceiling: 
 
 
The study will screen up to 25 patients to account for screening failure and early drop out. 
  
Study Population: 
 
 
Key inclusion criteria include: 
• Histologically confirmed diagnosis of PTCL of the following subtypes: 
o Nodal T-cell lymphoma with T-follicular helper (TFH) phenotype* 
a. Angioimmunoblastic T-cell lymphoma  
b. Follicular T-cell lymphoma  
c. PTCL/NOS, T-follicular helper (TFH) variant 
o PTCL-NOS 
o Anaplastic large cell lymphoma, ALK negative 
o Anaplastic large cell lymphoma, ALK positive with IPI > 2 
o Adult T-cell leukemia / lymphoma 
*: Nodal TCL with TFH phenotype will represent at least 2/3 of the total enrollment.  
• No prior systemic therapy for lymphoma  
• Measurable disease defined by a tumor mass ≥ 1.5 cm in one dimension and measurable in 
two dimensions  
• Age 18-80 years  
• ECOG performance status ≤ 2 
• Required initial laboratory parameters:  
          Absolute neutrophil count (ANC) ≥ 1500 cells/mmP3
P (1000 if BM involvement) 
          Platelet count ≥ 75,000 cells/mmP3
P (50,000 if BM involvement) 
          Calculated creatinine clearance ≥ 30 ml/min by Cockcroft-Gault formula 
          Total bilirubin ≤ 2.0 x ULN  
          AST/SGOT or ALT/SGPT ≤ 3.0 x ULN 


 
 
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Version Date: February 25, 2020 
 
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• LVEF ≥ 50% 
 
Key exclusion criteria include: 
• Known central nervous system (CNS) involvement by lymphoma  
• Known HIV disease  
• Known seropositivity for or active viral infection with hepatitis B virus (HBV) or hepatitis 
C virus (HCV).  Seropositive HBV patients are eligible if they are negative for HBV DNA 
by PCR and receive concomitant antiviral therapy.  
• Prior history of malignancies other than PTCL unless the patient has been disease free for 
≥ 5 years.  Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin; 
carcinoma in situ of cervix; carcinoma in situ of breast, or localized prostate cancer   
• Pregnant or breastfeeding females 
• Patients with active uncontrolled infections 
• Patient is receiving other systemic anti-neoplastic or investigational drugs  
• Known GI disorders interfering with absorption and metabolism of oral CC-486 
• Patients with bulky disease who require immediate cyto-reductive chemotherapy 
 
Accrual Period: 
 
 
1/2018 – 1/2020 
  
Study Design: 
 
 
This is a phase II, multi-center study to determine the efficacy and safety of first-line CC-486 plus 
CHOP in patients with PTCL who have received no prior systemic therapy.  The study has a sample 
size of 20, and follows two-stage minimax design for primary efficacy analysis.  
 
Study Duration: 
 
The study includes 6 cycles (~18 weeks) of treatment and 2 years of follow-up. The projected end 
date is 12/31/2022. Patients achieving complete remission will be evaluated every 6 months for 2 
years or until disease progression.  Patients who have disease progression will be contacted every 
6 months to assess for survival status. 
 
Study Agent/ Intervention Description: 
 
• Standard dose CHOP will be provided on day 1 of each cycle and repeat every 3 weeks for 
a total of 6 cycles.  
• CC486 at 300 mg daily will be administered orally from day -6 to day 0 for cycle 1 priming, 
and on days 8-21 following cycles 1-5.   
• Patients in CR/PR following 6 cycles of treatment have the option to proceed to 
consolidative autologous stem cell transplant.  
 
Primary Objective:  
 
To determine the complete response rate (CR) of CC486-CHOP in PTCL by 2014 International 
Working Group (IWG) criteria, and the Deauville Criteria for scan interpretation.  CR rate after 
cycle 6 will be used for the purpose of interim efficacy analysis. 
 


 
 
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Secondary Objectives: 
To determine overall response rate (ORR), safety, survival (progression-free survival and overall 
survival), and time to next treatment. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Endpoints: 
 
 
• The primary end point is to determine CR rate.  CR rate after cycle 6 of treatment will be 
used for interim and final efficacy analysis. 
• The secondary endpoints include progression-free survival (PFS), overall survival (OS), 
and time to next treatment. 
 
 
 


 
 
IRB Protocol # 1711018777 
 
 
Version Date: February 25, 2020 
 
7 
 
SCHEMA 
 
 
 
Eligibility 
Diagnosed with one of the following PTCL histologic subtypes: 
• 
Nodal T-cell lymphoma with T-follicular helper (TFH) phenotype (tumor cells 
must express 2 or 3 TFH-related antigens, including PD1, CD10, BCL6, 
CXCL13, ICOS, SAP and CCR5) * 
a. Angioimmunoblastic T-cell lymphoma  
b. Follicular T-cell lymphoma  
c. PTCL/NOS, T-follicular helper (TFH) variant 
• 
PTCL-NOS 
• 
Anaplastic large cell lymphoma, ALK negative 
• 
Anaplastic large cell lymphoma, ALK positive with IPI >2 
• 
Adult T-cell leukemia / lymphoma 
*: Nodal TCL with TFH phenotype will represent at least 2/3 of the total enrollment.  
Must have measurable disease and no prior systemic treatment 
Response Assessment 
• 
Response assessed with imaging (either NM PET/CT or diagnostic CT with contrast) 
after cycles 3 and 6 and then every 6 months thereafter if in CR for 2 years. 
• 
Patients in CR/PR following 6 cycles of treatment have the option to proceed to 
consolidative stem cell transplant.  
Treatment 
1              8          15         21
1              8          15         21
1              8          15         21
-6
CHOP
CC-486
CC-486
C1
C2 to C5
C6
CC-486: cycle 1, days -6 to 0; cycles 1-5, days 8-21
Cyclophosphamide, doxorubicin, vincristine: day 1
Prednisone: days 1-5
Growth factor e.g. pegfilgrastim: 
CHOP
CHOP
CC-486


 
 
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Version Date: February 25, 2020 
 
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STUDY PROCEDURES 
Table 1 Schedule of Study ProceduresP1 
 
Procedures 
Screening 
Treatment Phase 
 
End of Treatment 
Follow-up Phase 
 
 
Cycle 1, 
Day -6 
Cycle 1-6, 
Day 1 
Cycle 1-5, 
Day 8, 
Cycle 1-2, 
Day 15 
28 days from last 
dose 
Q6m for 2 years if 
CR, or until PODP6 
Informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical exam with vital signs 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
 
 
X 
X 
IPI score 
X 
 
 
 
 
 
 
LVEF assessmentP2 
X 
 
 
 
 
X 
 
12-lead ECGP3 
X 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
 
AE assessment 
 
Continuous from C1D-6 until 28 days after last dose 
 
Staging 
 
 
 
 
 
 
 
Lymph node biopsyP4 
X 
 
 
 
 
 
 
Bone marrow studyP5  
X 
 
 
 
 
X 
 
Diagnostic CT (MRI)P6 
X 
 
Cycle 3, between days 15 and 21 
X 
XP6 
PETP6 
X 
 
 
 
 
X 
 
Laboratory studies 
 
 
 
 
 
 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
CMP including LFT 
X 
X 
X 
X 
X 
X 
X 
LDH, uric acid, phosphate 
X 
X 
X 
X 
X 
X 
X 
PT, aPTT 
X 
 
 
 
 
 
 
Creatinine clearanceP7 
X 
 
 
 
 
 
 
Pregnancy testP8 
X 
X 
X 
 
 
X 
 
HIV Ab 
X 
 
 
 
 
 
 
HTLV-1 Ab 
X 
 
 
 
 
 
 
EBV viral DNAP9 
X 
 
XP9 
 
 
XP9 
 
HBsAg, HBsAb, HBcAb 
X 
 
 
 
 
 
 
HBV viral DNAP10 
X 
 
XP10 
 
 
XP10 
 
HCV Ab 
X 
 
 
 
 
 
 
Exploratory biomarkers 
 
 
 
 
 
 
 


 
 
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FFPE LN/tumor 
biopsy/Archival tissueP4 
X 
 
 
 
 
 
 
Fresh LN/tumor biopsy 
(optional)P11 
 
X 
X 
 
 
 
 
Blood sampleP12 
 
X 
X 
XP12 
XP12 
 
 
 
P1
P Unless otherwise specified, all screening requirements are within 28 days, all other assessments and procedures are +/- 3 days. 
P2
P Left ventricular ejection fraction will be performed by standard methods (either by multi-gated acquisition [MUGA] scan or echocardiogram) at 
Screening and End of Treatment to evaluate doxorubicin toxicity.  Screening assessment may be acceptable within 3 months prior to starting study 
treatment. 
P3
P 12-lead ECG is performed at screening/baseline and as clinically indicated. 
P4
P All subject must have pre-treatment diagnostic unstained FFPE biopsy slides available demonstrating PTCL (archival tissue has no time limit); 
additionally, one-time buccal swab collection for germline control should occur at screening, on treatment or off treatment.P  
P5
P Screening bone marrow biopsy may be acceptable within 3 months prior to starting study treatment.  During the study bone marrow biopsy is 
required only if the patient has otherwise fulfilled the criteria for CR. 
P6
P Tumor assessment will be by means of PET/CT (CT with diagnostic quality) at Screening (within 6 weeks of starting study treatment) and End 
of Treatment after completion of therapy.  CT scan with contrast or MRI will be performed between Days 15 and 21 of Cycle 3 during treatment, 
and during Follow-up Phase every 6 months for 2 years assuming patient has achieved CR. Additional PET/CT imaging every 3 months during 
Follow-up Phase for patients in PR is recommended at discretion of treating investigator.  
P7
P Creatinine clearance (CrCl) is estimated using the Cockcroft-Gault formula where CrCl (mL/min) = (140 – age)(weight [kg]) / 72 (serum 
creatinine [mg/dL]; for females, the formula is multiplied by 0.85 (Cockcroft, 1976). Creatinine clearance should be calculated using actual body 
weight. 
P8 
PPregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months).  Serum pregnancy test with sensitivity of at least 25 mIU/mL is to be obtained in 
females of childbearing potential (FCBP) at Screening and Cycle 1 Day -6; remaining pregnancy tests may be serum or urine at the Investigator’s 
discretion. A serum pregnancy test must be done within 72 hours prior to Cycle 1 Day -6 of starting study therapy and either serum or urine 
pregnancy test on Day 1 of every cycle in Treatment Period (except Cycle 1) and at Treatment Discontinuation. 
P9
P If a subject has EBV viremia at Screening, EBV viral DNA will be measured on day 1 of each cycle and End of Treatment. 
P10
P All patients must be screened for hepatitis B before starting treatment. Carriers of hepatitis B should be closely monitored, including HBV DNA 
testing at Screening, day 1 of each cycle and End of Treatment. For patients with evidence of prior HBV infection, HBV suppressive therapy is 
strongly recommended. 
P11
P Fresh core lymph node/tumor biopsies are collected before and after the CC-486 Cycle 1 priming course.  The pre CC-486 biopsy on Cycle 1 
Day -6 can be replaced by a Screening biopsy if the frozen sample is collected according to the Laboratory Manual (see Section 8). The post CC-
486 priming biopsy is collected on Cycle 1 Day 1 prior to the administration of CHOP. 
P12
P Correlative study blood samples will be collected at on cycle 1 day -6, and days 1, 8, 15 of cycles 1 and 2. 


 
 
IRB Protocol # 1711018777 
 
 
Version Date: February 25, 2020 
 
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1. 
STUDY OBJECTIVES 
 
1.1 Primary Objective 
To determine the complete response rate (CR) of CC486-CHOP in PTCL by 2014 International 
Working Group (IWG) criteria, and the Deauville Criteria for scan interpretation.  CR rate after 
cycle 6 will be used for the purpose of interim efficacy analysis. 
 
1.2 Secondary Objectives 
To determine overall response rate (ORR), safety, survival (progression-free survival and overall 
survival), and time to next treatment. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
2. 
BACKGROUND 
 
2.1 Peripheral T-cell Lymphoma 
Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin lymphomas 
(NHL), encompassing 5-10% NHL in western countries with a higher incidence of 15-20% in Asia 
and South America 
P1,2
P.  The most prevalent nodal T-cell lymphomas include PTCL-NOS, 
angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL).  
Despite divergent cells of origin and mechanisms of lymphomagenesis, PTCL therapy has 
historically followed the treatment framework for aggressive B-cell NHL, in part due to lack of 
dedicated prospective studies.  CHOP is the most commonly prescribed initial treatment for 
systemic PTCL.  With the exception of ALK-positive ALCL, CHOP generally provides ORR of 
60-80%, CR of 30-40%, and long-term survival measured by 5-yr OS in the range of 20-30% 3-5.  
While autologous stem cell transplant may extend PFS for some patients (3- and 5-yr PFS 40-
50%), relapse remains common 4,6.  There are tremendous unmet needs in developing novel 
frontline therapy for PTCL to improve response quality and duration, ultimately better survival.  
Emerging genetic studies with gene expression profiling (GEP) and next generation sequencing 
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(TET2), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3A (DNMT3A), 
and Ras homolog gene family, member A (RHOA), which contribute to lymphomagenesis and may 
represent the target of tailored therapies such as epigenetic modifiers 2. Aberrant DNA methylation 
patterns have been characterized in PTCL subtypes, providing insight into potential targets for 
clinical application of demethylation agents.  Nodal Peripheral T-cell lymphoma with T-follicular 
helper (TFH) phenotype, which includes AITL and a subset of PTCL/NOS variant with follicular 
helper T-cell (TFH), have recurrent mutations affecting RHOA, TET2, DNMT3A, and IDH2.  
Integrative analysis of gene expression and promoter methylation revealed recurrently 
hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely 
contribute to lymphomagenesis in AITL 7,8, providing a strong rationale for considering the use of 
hypomethylating agents in AITL treatment.  Other PTCL subtypes that have demonstrated 
differential hypermethylation associated with disease and progression include ALCL, ATLL, and 
extranodal NK-T cell lymphoma 9-12.   
In preclinical interventional studies, treatment of ATLL cell lines with azacitidine (AZA) restored 
expression of epigenetically silenced tumor suppressor genes include p14ARF and p16INK4a, and 
induced growth inhibition of lymphoma cells 13.  In ALCL cell lines xenografts, low-dose 
treatment with 5-aza-2’-deoxycytidine led to apoptosis and cell cycle arrest in vitro and in vivo 14.  
5-AZA treatment of ALCL PDTX led to global hypomethylation 9.  Decitabine treatment of NK 
cell lines was associated with re-expression of selected methylated and epigenetically silenced 
genes, which sensitized these cell lines to chemotherapy-induced apoptosis 12.  Combination of 
hypomethylating agents and HDAC inhibitors was shown to be synergistic in cell lines and in vivo 
xenograft models of T-cell lymphoma 15.   
In human PTCL patients, a retrospective French cohort study reported clinical outcome of 19 
patients with R/R PTCL treated with 5-AZA. Treatment consisted of subcutaneous daily injection 
of 75 mg/m² 5-AZA for 7 consecutive days every 28-day cycle, until progression or unacceptable 
toxicity. Ten patients had previous or concomitant diagnosis of myelodysplastic syndrome, mostly 
(9/10) chronic myelomonocytic leukemia (CMML).  Patients received a median number of 3 
cycles of 5-AZA. Overall response rate (ORR) was 53% (10/19), significantly higher in AITL 
patients than in patients with other PTCL entities (9/12, 75% vs. 1/7, 15%, p=0.0198).  Five 
patients with AITL achieved CR, leading to a CR rate of 42% in AITL. Responses in 7 out of 9 
AITL patients appeared to be durable. TET2 was sequenced in 14 patients and was mutated in 8/10 
(80%) AITL and 1/4 (25%) other PTCL; 8/8 AITL patients who responded to 5-AZA treatment 
were TET2 mutated. 16-18. 
2.2 Investigational Agent  
 
2.2.1  CC-486 
Azacitidine, an analog of the pyrimidine nucleoside cytidine, has effects on cell differentiation, 
gene expression, and deoxyribonucleic acid (DNA) synthesis and metabolism.  Azacitidine 
promotes antineoplastic activity via two mechanisms – as an epigenetic modifier of DNA 
methylation by inhibition of DNA methyltransferase at low doses, and as a direct cytotoxic agent 
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can be administered by the intravenous (IV) or subcutaneous (SC) routes, is approved by the US 
Food and Drug Administration (FDA) for myelodysplasia (MDS). Vidaza is also approved by the 
European Commission (EU) for intermediate-2 (INT-2) and high-risk MDS, CMMoL, and AML 
with multilineage dysplasia. An oral formulation of azacitidine (CC-486) has been developed and 
is currently being evaluated in clinical trials, either as a single agent or in combination with other 
drugs, for the treatment of hematological and solid malignancies. CC-486 is not yet approved by 
any regulatory agency worldwide for any indication. For a comprehensive overview of both 
Vidaza® and CC-486, please refer to the IB. 
 
The safety, pharmacokinetics, and pharmacodynamics of oral azacitidine in subjects with MDS, 
chronic myelomonocytic leukemia (CMMoL), or AML was evaluated in a phase 1/2, open-label 
dose escalation trial 19,20. Dose levels of 120, 180, 240, 300, 360, 480, and 600 mg were evaluated 
in Part 1 of the study, while Part 2 further evaluated safety, tolerability and efficacy of 14-day and 
21-day once daily (QD) treatment. A total of 131 subjects were enrolled of which 127 received 
CC-486. Median time to peak plasma levels was 1 hour with maximum effect on global DNA 
methylation at day 15 of each cycle. From Part 2 of the study, the dose of 300 mg QD for 14 or 21 
days was considered safe and tolerable and was carried forward in Phase 3 studies in AML and 
MDS. The most frequently observed non-hematologic TEAEs included GI symptoms of diarrhea, 
nausea, constipation, and vomiting. The dose levels of 200 mg and 300 mg were further supported 
by clinical and pharmacodynamics data from a Phase 1 study (AZA-ST-001), in which CC-486 
was administered for a total of 14 out of 21-days as a priming agent in combination with cytotoxic 
agents of carboplatin or nab-paclitaxel in solid tumor patients 21. In an ongoing phase 1, open-label 
trial of frontline oral azacitidine (36TCC-48636T) plus R-CHOP in subjects with large B-cell 35Tlymphoma35T 
or follicular 35Tlymphoma35T or transformed 35Tlymphoma (35TNCT02343536), the dose level of 300 mg QD 
for 14 days out of 21-day cycle was found to be effective with manageable safety profile for 
administration with R-CHOP regimen in frontline aggressive lymphoma patients 22.   
 
2.2.2  CHOP 
CHOP is the most commonly prescribed initial therapy for PTCL, despite results showing that it 
is largely ineffective and that the majority of PTCL patients have an inferior outcome compared 
with their B-cell counterparts receiving CHOP, with the exception of ALK positive ALCL. In the 
collaborative International T-cell Lymphoma Project which evaluated a cohort of 1,314 previously 
untreated cases of PTCL and NKTCL from 22 centers worldwide diagnosed between 1990 and 
2002, over 85% patients received an anthracycline-containing regimen. The 5-year OS for PTCL-
NOS, AITL, and NKTCLs was 32% compared with 14% for ATLL. ALCL, ALK positive, 
demonstrated 5-year OS of 70%, compared to 49% with ALCL, ALK negative 1. Contemporary 
real world studies appear to confirm the treatment practice and clinical outcome in PTCL.  In the 
Swedish lymphoma registry study which reviewed 755 PTCL patients diagnosed during the 10-
year period between 2000 and 2009, 84% patients receiving chemotherapy were treated with 
CHOP or CHOEP, ORR was 70% among the evaluable patients, and <17% patients were planned 
for autologous stem cell transplant (ASCT) in first remission 23. In the US multicenter cohort study 
including 341 newly diagnosed PTCL patients enrolled from 2000 to 2011 at 9 US academic 
centers, 70% patients received CHOP, ORR was 73%, 3-year PFS and OS were 32% and 52% 
respectively, and 10% patients underwent ASCT in first remission 24.  Adding etoposide to CHOP 
in the form of CHOEP may improve EFS but not OS in younger PTCL patients 23,25. 
 


 
 
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Although CHOP is largely inadequate and anthracycline may not be essential 1, there is a paucity 
of prospective randomized trials comparing alternative chemotherapy combinations with CHOP 
in frontline setting, given disease rarity and heterogeneity.  The majority of information regarding 
the efficacy of alternative regimens is based on retrospective or phase 2 data with historical 
comparisons. Examples of single arm phase 2 studies with intensive or non-anthracycline based 
combination included the CyclOBEAP 26 and PEGS regimens 27.  A randomized phase 3 trial by 
GOELAMS compared VIP-reinforced-ABVD to standard CHOP, demonstrating that VIP-rABVD 
was not superior to CHOP/21 in terms of EFS as first-line treatment of PTCL 5.  To date, standard 
dose CHOP remains the reference regimen in PTCL treatment.  Exception to CHOP backbone 
applies to extranodal NK/T cell lymphoma which requires incorporation of asparaginase and 
radiation, and hepatosplenic T cell lymphoma which responds to intensive chemotherapy such as 
ICE or IVAC and early consolidative stem cell transplant. 
 
To improve efficacy of CHOP, there are a number of phase 1/2 and phase 3 prospective studies 
aiming to incorporate novel agents into chemotherapy backbone.  In CD30+ PTCL, based on phase 
1 data which showed high CR rate (88%) with brentuximab vedotin plus CHP 28, the phase 3 
randomized Echelon-2 study (NCT01777152) assesses survival and response rates in CD30+ 
PTCL patients receiving experimental brentuximab vedotin plus CHP versus standard CHOP.  
High CR rate (51%) was achieved in a phase 1b/II study of CHOP plus romidepsin 29, which forms 
the basis for the ongoing phase 3 LYSARC study (NCT01796002 ) evaluating survival and 
response with Ro-CHOP vs CHOP.  The current study aims to evaluate efficacy and safety of 
incorporating hypomethylating agent CC-486 into CHOP backbone for chemo-sensitization.  
ASCT is permitted in first remission. 
 
2.3 Rationale 
Given the enrichment of mutations in epigenetic modifiers in T-cell lymphoma subtypes which 
leads to an overall hyper-methylated state, chemo-sensitization with azacitidine in combination 
with CHOP appears to be an attractive therapeutic mechanism.    
Oral azacitidine (CC-486) has been studied in subjects with myelodysplastic syndrome/acute 
myelogenous leukemia (MDS/AML) and as monotherapy or in combination with 
chemotherapeutic agents in subjects with solid tumors and lymphoma.  The dose levels of 200 mg 
and 300 mg were selected based on the following available clinical and pharmacodynamic 
evidence: (i) a minimum exposure to CC-486 up to 300 mg daily for 7 days, and ideally 14 days 
or longer 19, resulted in detectable changes in the methylation pattern of the DNA in the peripheral 
blood mononuclear cells of subjects treated with CC-486 given as single agent and in combination 
with cytotoxic agents; and (ii) preliminary data from AZA-ST-001 (Phase 1) combination study 
of CC-486, administered at doses of 200 mg or 300 mg in combination with carboplatin and with 
nab-paclitaxel (on a different schedule than proposed in this study) demonstrated an acceptable 
safety profile for a Phase 2 dose 21.   
The schedule of azacitidine administration relative to the administration of CHOP has been 
evaluated in 2 lymphoma studies.  In a phase 1 study in patients with high risk DLBCL, the 
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R-CHOP was shown to be tolerable and yielded a high rate of complete remission.  Pre- and post-
azacitidine treatment biopsies confirmed genomic demethylation and chemosensitization 30.  
Currently, a phase I trial evaluating the combination of CC486, an oral form of azacitidine, plus 
R-CHOP in patients with previously untreated DLBCL and transformed B-cell NHLs 
(NCT02343536) has reached the recommended dose level of CC-486 of 300 mg for 14 days in 
combination with standard dose R-CHOP for dose expansion phase, demonstrating the safety and 
feasibility of the CC-486 plus CHOP combination in frontline setting 22.  We propose a phase 2 
study to assess the efficacy and safety of CC-486 plus CHOP as initial therapy for PTCL, 
prioritizing enrollment of patients with T-follicular helper (TFH) phenotype and acquired genetic 
predisposition to chemo-sensitization by hypomethylation agent.  Correlative biomarker studies 
are prospectively planned in conjunction with the study treatment to guide future trial design with 
novel epigenetic modifying agents.  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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3. 
SUBJECT SELECTION 
 
3.1 Study Population 
Adults with previously untreated peripheral T-cell lymphoma who meet the inclusion and 
exclusion criteria will be eligible for participation in this study.   
 
3.2 Inclusion Criteria 
• Histologically confirmed diagnosis of PTCL of the following subtypes: 
o Nodal T-cell lymphoma with T-follicular helper (TFH) phenotype (tumor cells 
must express 2 or 3 TFH-related antigens, including PD1, CD10, BCL6, CXCL13, 
ICOS, SAP and CCR5)* 
a. Angioimmunoblastic T-cell lymphoma  
b. Follicular T-cell lymphoma  
c. PTCL/NOS, T-follicular helper (TFH) variant 
o PTCL-NOS 
o Anaplastic large cell lymphoma, ALK negative 
o Anaplastic large cell lymphoma, ALK positive with IPI > 2 
o Adult T-cell leukemia / lymphoma 
*: Nodal TCL with TFH phenotype will represent at least 2/3 of the total enrollment.  
• No prior systemic therapy for lymphoma  
• Measurable disease defined by a tumor mass ≥ 1.5 cm in one dimension and measurable in 
two dimensions  
• Age 18-80 years  
• ECOG performance status ≤ 2 
• Required initial laboratory parameters:  
o Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1000 if secondary to lymphoma 
BM involvement per investigator assessment) 
o Platelet count ≥ 75,000 cells/mm3 (50,000 if secondary to lymphoma BM involvement 
per investigator assessment) 
o Hemoglobin ≥ 8 g/dL 
o Calculated creatinine clearance ≥ 30 ml/min by Cockcroft-Gault formula 
o Total bilirubin ≤ 2.0 x ULN except in cases of Gilberts Syndrome, or documented liver 
of pancreatic involvemebt by lymphoma 
o AST/SGOT or ALT/SGPT ≤ 3.0 x ULN except in subjects with documented liver 
involvement by lymphoma  
o Alkaline phosphatase < 2.5 x ULN 
• LVEF ≥ 50% 


 
 
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• Understand and voluntarily sign an ICF prior to any study related assessments and 
procedures are conducted. 
• Able to adhere to the study visit schedule and other protocol requirements. 
• Negative serum pregnancy test within 72 hours before starting study treatment on Cycle 1 
Day -6 for females of childbearing potential (FCBP). 
A female of child-bearing potential, defined as a sexually mature woman who: 1) has not 
undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy 
(the surgical removal of both ovaries) or, 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time during the preceding 24 
consecutive months), may participate providing they agree to the following conditions: 
o Either commit to complete abstinence from heterosexual contact (which must be 
reviewed on a monthly basis) or agree to the use of a physician-approved 
contraceptive method (oral, injectable, or implantable hormonal contraceptive; 
tubal ligation; intrauterine device; barrier contraceptive with spermicide; or 
vasectomized partner) without interruption, while on CC-486 (including dose 
interruptions); and for 3 months following the last dose of IP; and 
o  A medically supervised serum pregnancy test with sensitivity of at least 25 
mIU/mL is to be obtained in females of childbearing potential (FCBP) at Screening 
and Cycle 1 Day -6; remaining pregnancy tests may be serum or urine at the 
Investigator’s discretion. A serum pregnancy test must be done within 72 hours 
prior to Cycle 1 Day -6 of starting study therapy and either serum or urine 
pregnancy test on Day 1 of every cycle in Treatment Period (except Cycle 1) and 
at Treatment Discontinuation. The subject may not receive IP until the Investigator 
has verified that the result of the pregnancy test is negative. 
• Male subjects with a female partner of childbearing potential must either commit to 
complete abstinence or agree to the use of a physician-approved contraceptive method 
throughout the course of the study and avoid fathering a child during the course of the study 
and for 3 months following the last dose of the IP. 
 
3.3 Exclusion Criteria 
• Known central nervous system (CNS) involvement by lymphoma  
• Active viral infection with HIV or hepatitis type B or C (seropositive HBV patients are 
eligible if they are negative for HBV DNA by PCR and receive concomitant antiviral 
therapy).  
• Prior history of malignancies other than PTCL unless the patient has been disease free for 
≥ 5 years from the signing of the ICF.  Exceptions include basal cell carcinoma or 
squamous cell carcinoma of the skin; carcinoma in situ of cervix; carcinoma in situ of 
breast, or localized prostate cancer   
• Significant active cardiac disease within the previous 6 months including (Appendix D): 
o New York Heart Association (NYHA) class III or IV congestive heart failure 
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o Myocardial infarction 
• Active uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing 
signs/symptoms related to the infection without improvement despite appropriate 
antibiotics, antiviral therapy and/or other treatment) 
• Abnormal coagulation parameters (PT >15 seconds, aPTT>40 seconds, and/or INR >1.5) 
• Known or suspected hypersensitivity to azacitidine or mannitol 
• Contraindication to any drug in the chemotherapy regimen, and specifically 
o LVEF <50% 
o Corrected QT interval >480 msec (using the Fridericia formula) 
o Neuropathy ≥ Grade 2 
• Pregnant or breast feeding females. (Lactating females must agree not to breast feed while 
taking azacitidine) 
• Patient is receiving other systemic anti-neoplastic investigational drugs  
• Known GI disorders interfering with absorption and metabolism of oral CC-486 
• Patients with advanced malignant hepatic tumors 
• Any significant medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from participating in the study 
• Patients with bulky disease who require immediate cyto-reductive chemotherapy 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
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5. 
STUDY PROCEDURES 
 
5.1 Study Design 
39TThis is a single arm phase II study to evaluate the safety and efficacy of CC486 plus CHOP 39Tas 
initial therapy for peripheral T-cell lymphoma, prioritizing enrollment of patients with T-follicular 
helper (TFH) phenotype and acquired genetic predisposition to chemo-sensitization by 
hypomethylation agent. Study treatment will include 6 cycles of CC-486 plus CHOP.   
 
5.1 Schedule of Evaluations 
Screening assessments and all scheduled study visits and assessments are outlined in Table 1.  
 
5.1.1  Screening Visit 
Study screening begins when the subject signs the written informed consent document (ICD). All 
screening assessments and baseline evaluations must be completed within 28 days prior to the start 
of Cycle 1 Day -6 treatment, unless otherwise specified. 
• All patients must have pre-treatment diagnostic unstained FFPE biopsy slides available 
demonstrating PTCL (archival tissue has no time limit) 
• Bone marrow aspirate and core biopsy (within 3 months prior to starting study treatment) 
• Physical examination with history, vital signs including weight, height and performance 
status 
• Concomitant medications 
• 12-lead Electrocardiogram 
• ECHO or MUGA scan to show EF of ≥ 50% (within 3 months prior to starting study 
treatment) 
• PET scan (within 6 weeks prior to starting study treatment) 
• CT scan (or MRI) of neck/chest/abdomen/pelvis (and other areas if indicated to evaluate 
sites of disease involvement) (within 6 weeks prior to starting study treatment)  
• Complete blood count (CBC) with differential  
• Serum chemistries to include CMP, LDH, phosphate and uric acid 
• Coagulation profile with PT and aPTT 
• Creatinine clearance 


 
 
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• Hepatitis B/C screening 
• HIV, HTLV-1, EBV testing 
• Pregnancy test (for female of childbearing potential) 
 
5.1.2  Treatment Phase 
 
5.1.2.1  
Cycle 1, Day -6 
• Physical examination with vital signs and performance status 
• AE assessment 
• Concomitant medications 
• CBC with differential  
• Serum chemistries to include CMP, LDH, phosphate and uric acid 
• Pregnancy test (for female of childbearing potential)  
• Optional fresh lymph node/tumor biopsy (can be replaced by a screening biopsy if the 
frozen sample is collected according to the Laboratory Manual, see Section 8.1.1) 
• Correlative blood samples 
 
5.1.2.2  
Cycle 1-6, Day 1 
• Physical examination with vital signs and performance status 
• AE assessment 
• Concomitant medications 
• CBC with differential  
• Serum chemistries to include CMP, LDH, phosphate and uric acid 
• Pregnancy test (for female of childbearing potential) 
• HBV viral DNA in HBcAb positive, asymptomatic carrier 
• EBV viral DNA in subject with EBV viremia at baseline  
• Optional fresh lymph node/tumor biopsy (Cycle 1 only) 
• Correlative blood samples (Cycles 1 and 2 only) 
 
5.1.2.3  
Cycle 1-5, Day 8 and Cycle 1-2, Day 15 
• Physical examination with vital signs  
• AE assessment 
• Concomitant medications 


 
 
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• CBC with differential 
• Serum chemistries to include CMP, LDH, phosphate and uric acid 
• CT scan (or MRI) of neck/chest/abdomen/pelvis (and other areas if indicated to evaluate 
sites of disease involvement) between days 15 and 21 of cycle 3 
• Correlative blood samples (Cycles 1 and 2 only) 
 
5.1.3  Treatment Discontinuation 
 
At treatment discontinuation, subjects will undergo off study evaluations within 28 days of last 
dose. 
• Physical examination with vital signs and performance status 
• AE assessment 
• Concomitant medications 
• CBC with differential  
• Serum chemistries to include CMP, LDH, phosphate and uric acid 
• HBV viral DNA in HBcAb positive, asymptomatic carrier 
• EBV viral DNA in subject with EBV viremia at baseline  
• Pregnancy test (for female of childbearing potential)  
• ECHO or MUGA scan  
• CT scan (or MRI) of neck/chest/abdomen/pelvis (and other areas if indicated to evaluate 
sites of disease involvement)  
• PET scan for response assessment  
• Bone marrow aspiration and core biopsy (unilateral) only if otherwise in complete 
remission (not repeated once negative) 
 
5.1.4  Follow-up Phase 
Patients will have follow-up evaluations every 6 months for 2 years or until progression of disease, 
whichever occurs first.  At each follow-up evaluation, the patient will have the following:  
• Physical examination with vital signs and performance status 
• CBC with differential  
• Serum chemistries to include CMP, LDH, phosphate and uric acid 
• CT scan (or MRI) of neck/chest/abdomen/pelvis (and other areas if indicated to evaluate 


 
 
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sites of disease involvement)  
• PET scan at shorter interval than 6 months (e.g. 3 months) for patients in PR at discretion 
of investigator 
• Survival and subsequent anti-lymphoma treatment information 
 
5.2 Treatment Administration 
 
5.2.1  CC-486 Administration 
CC-486 at 300 mg once daily is to be administered Cycle 1, Day -6 to 0 and Cycles 1 to 5, Day 8 
to 21.  Antiemetic prophylaxis is recommended before dosing. Subject should take CC-486 with 
approximately 240 mL (8 ounces) of room temperature water. CC-486 may be taken on an empty 
stomach or with food. If CC-486 is taken with food, a light meal (not more than 600 calories) may 
be eaten before or after administration. All efforts should be made to administer CC-486 on all 
scheduled days of the Cycle 1 priming dosing (7 days, Cycle 1 Day -6 to Cycle 1 Day 0) and the 
Cycle 1-5 dosing (14 days, Day 8-21). A dose missed earlier in a day can be administered later 
that day as long as it is taken at least 8 hours before the next scheduled dose. Any missed dose 
should not be taken beyond the last scheduled day of CC-486 administration for the cycle, but 
should be returned by the subject for CC-486 accountability. If vomiting occurs after a dose of 
CC-486 is administrated, that dose should not be made up later that day. The subject should 
continue with the dosing schedule on the next day and inform the Investigator about the vomiting 
event at the next visit. 
 
5.2.2  CHOP Administration 
CHOP is to be administered on Days 1 to 5 of Cycles 1-6.  Chemotherapy can be administer within 
+72h or -24h of Day 1 of each scheduled Cycle.  Preparation and infusion rate are according to the 
package insert and local practice. The doses to be used are: 
Cyclophosphamide: 750 mg/m2 IV on day 1 
Doxorubicin: 50 mg/m2 IV on day 1 
Vincristine: 1.4 mg/m2 IV (not to exceed 2.0 mg total) on day 1 
Prednisone: 100 mg PO days 1-5 
 
5.2.3  Growth Factors 
Growth factors are mandatory per standard of care. Either pegfilgrastim, lenograstim or 
filgrastim can be used. Pegfilgrastim must be administered a minimum of 24 hours after Day 1 of 
CHOP and 5 days before the start of CC-486. Filgrastim or lenograstim should be started a 
minimum of 24 hours after Day 1 and stopped 24 hours before start of CC-486. 
 
5.2.4  CNS Prophylaxis 
Decisions regarding CNS staging and prophylaxis will be at the discretion of the treating 
investigator. If CNS prophylaxis is deemed appropriate it will be with intrathecal methotrexate, 
cytarabine, or liposomal cytarabine, at the discretion of the treating investigator.  
 


 
 
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5.2.5  Tumor Lysis Management 
All patients should receive prophylaxis for TLS before the initiation of the first dose of CC-486.  
Prophylaxis will include appropriate hydration, administration of an agent to reduce uric acid, such 
as allopurinol (or rasburicase IV for high risk patients with elevated uric acid levels before 
treatment). Laboratory results including electrolyte values will be assessed on a weekly basis 
during cycle 1 of treatment.   
 
5.3 General Concomitant Medication and Supportive Care Guidelines 
 
5.3.1  Recommended Concomitant Medications/Procedures 
Subjects should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, analgesics, and antiemetics when appropriate during treatment phase.  
• It is strongly recommended that all subjects receive a dose of a prophylactic antiemetic, 
preferably a 5-HT3 antagonist, 30 minutes prior to each dose of CC-486. 
• Growth factor prophylaxis is required for all subjects and will be provided and 
administered by the investigative site a minimum of 24 hours after chemotherapy (Day 2 
of CHOP) and at least 5 days before any dose of CC-486 for pegfilgrastim, and stopped 
one day before CC-486 for lenograstim or filgrastim. 
• Prophylaxis against pneumocystis jiroveci is required but choice and dose of agent will be 
selected by the Investigator according to local practice and provided by the investigative 
site.  
• Asymptomatic carriers of Hepatitis B with negative HBV DNA should receive lamivudine, 
tenofovir, or entecavir during therapy and until at least 6 months beyond completion of 
therapy.   
• Other anti-infection prophylaxis (eg, acyclovir, levofloxacin, and other premedications) 
will be selected by the Investigator according to local practice and provided by the 
investigative site.  
• Treatment with antidiarrheal medications should be prescribed for non-infectious diarrhea. 
Pre-medication with antidiarrheal medication for subsequent doses of CC-486 may be 
appropriate at the investigator’s discretion (See Appendix F). 
 
5.3.2  Prohibited Concomitant Medications/Procedures 
Any anti-cancer therapy is prohibited 28 days prior to Day 1 dosing and during the entire Treatment 
Period of the study. An exception applies for subjects with bulky disease and/or rapidly 
progressing systemic symptoms, whereby treatment with 1 mg/kg/day prednisone, or equivalent, 
is permitted at the discretion of the Investigator.  No other anthracycline may be substituted for 
doxorubicin. 
 
5.4 Duration of Therapy and Criteria for Removal from Study 
Study treatment will include 6 cycles of CC-486 plus CHOP.  Subjects who meet the following 
criteria should be discontinued from the study: 
• Withdraw of consent 
• Inability of subject to comply with study requirements 
• Determination by the investigator that it is no longer safe for the subject to continue therapy 
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• Pregnancy or a positive pregnancy test 
Subjects who complete less than 1 cycle of treatment and discontinue treatment for reasons other 
than toxicity will be replaced. 
 
5.5 Duration of Follow Up 
The Follow-up Period for each subject begins upon study treatment discontinuation.  This includes 
subjects who complete the full course of treatment, who discontinue treatment due to progression, 
toxicity, as well as those who withdraw consent from study treatment.  Subjects will be followed 
for response, progression, subsequent anti-lymphoma therapies, and survival according to the 
schedule described in Table 1, until disease progression or 2 years from end of treatment, 
whichever occurs first. 
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 Hematologic Requalification and Dose Adjustment 
In order to ensure adequate administration of the CHOP regimen while limiting toxicity, 
hematologic requalification and dose adjustment rules will be followed as detailed in Table 2. 
 
Table 2: Hematologic Requalification and Dose Adjustments. 
Date 
of 
Assessment 
If Any of the Following Are Present: 
Then, Take the Following Action 
Day -6  
Cycle 1 
CC-486 
ANC < 1,500 cells/mm3 (1.5 x 109/L) 
ANC < 1,000 cells/mm3 (1.0 x 109/L) due to 
lymphoma bone marrow involvement.  
Platelet Count  < 75,000/mm3 (100 x 109/L) 
Platelet Count  < 50,000/mm3 (100 x 109/L) due 
to lymphoma bone marrow involvement 
Hb < 8 g/dL  
Cannot initiate CC-486 study 
treatment as per Exclusion Criteria.  
 
Any other exclusion criteria 
Day 1 
Cycles 1-6 
CHOP 
and 
growth factors 
Hematologic 
Requalification/Dose 
Delay 
Criteria  
ANC < 1,000 cells/mm³ (1.0 x 109/L)  (≥ Grade 
3) unless due to lymphoma in marrow 
Platelet count < 50,000 cells/mm³ (60 x 109/L) 
unless due to lymphoma in marrow. 
 
Hold CHOP.  
Reassess a maximum one week 
later, 
and 
resume 
CHOP 
if 
recovered 
Other AEs 
 


 
 
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Date 
of 
Assessment 
If Any of the Following Are Present: 
Then, Take the Following Action 
IP, CC-486 related diarrhea or vomiting Grade 
2 
or 
worse 
despite 
adequate 
medical 
intervention  
Any other unacceptable CHOP related AE 
except for vincristine-related. 
For Cycles 2 to 6, any IP related non-
hematologic Grade 3 or more toxicity not 
resolved to Grade 2 or less 
For 
non-hematologic 
AEs 
considered to be related to CC486, 
CHOP can be started when AE 
resolved to grade 2 or less. 
For non-hematologic AE related to 
CHOP, delay or discontinue CHOP 
at investigator discretion. 
Day 8 to 14 
Cycles 1-5 
CC-486 
Hematologic 
Requalification/Dose 
Delay 
Criteria  
Grade 3 neutropenia (ANC < 1000 cells/mm3 
(1.0 x 109/L) with fever (temperature > 38.5oC) 
Hold CC-486.  
1. Monitor CBC at least every 
7 days until requalification 
criteria is met.  CC-486 can 
be restarted at the time 
requalification is met on the 
dosing day. 
2. If 
by 
Day 
15 
the 
requalification criteria is 
met, a subject can complete 
the remainder of the CC-
486 dosing Day 15 to Day 
21 
(7 
days). 
 
If 
requalification criteria is 
NOT met on Day 15, 
suspend CC-486 for the 
remainder of the current 
cycle, and reduce by one 
dose level at next cycle. 
If delay 7-14 days in start of CHOP in current 
cycle: 
Restart CC-486 on Day 8 of this 
cycle at next reduced dose level. 
 
 
If delay > 14 days in start of CHOP in current 
cycle:       
Hold CC-486 during entire cycle 
and reduce by one dose level at 
next cycle. 
 
 
If delay > 21 days in start of CHOP in current 
cycle, or >2 occurrences of >14 days delay in 
start of CHOP 
Discontinue CC486 permanently 
 
Other AEs 
For non-hematologic Grade ≥3 
AEs considered to be related to 
CC-486, if held, can be restarted at 


 
 
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Date 
of 
Assessment 
If Any of the Following Are Present: 
Then, Take the Following Action 
the next lower dose when AE is 
resolved to Grade 2 or less.   
Day 15 - 21 
Cycle 1-5 
CC-486 
Hematologic 
Requalification/Dose 
Delay 
Criteria 
ANC < 750 cells/mm³ (0.75 x 109/L) and day 8 
Platelet count < 50,000 cells/mm³ (50 x 109/L) 
unless due to lymphoma bone marrow 
involvement per investigator assessment 
 
 
 
Hold CC-486 until next cycle. 
1. First occurrence: Restart 
CC-486 at same dose level 
at next cycle. 
2. Second occurrence: Reduce 
CC-486 by one dose level 
at next cycle.  
3. Third occurrence: 
Discontinue CC-486 
4. Dose 
delays 
occurring 
during both days 8-14 and 
days 15-21 of the same 
cycle: Hold CC-486 for the 
remainder of the current 
cycle, and reduce by one 
dose level at next cycle. 
If >14 day delay in start of CHOP in current 
cycle: 
 
Hold CC-486 for entire cycle and 
reduce by one dose level at next 
cycle. 
 
If > 21 day delay in start of CHOP in current 
cycle, or >2 occurrences of >14 day delay in 
start of CHOP 
Discontinue CC486 permanently 
 
Other AEs 
For grade ≥ 3 non-hematologic 
AEs considered to be related to 
CC-486, if held, can be restarted at 
the next lower dose when AE is 
resolved to Grade 2 or less. 
 
6.2 CC-486 Dose Levels 
Dose reductions for CC-486 are described in Table 311T. 
Table 3: CC-486 Dose Level Reductions 


 
 
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Dose Level 
Current Dose 
One Level Dose Reduction 
0 
300 mg QD 
200 mg QD 
-1 
200 mg QD 
150 mg QD 
-2 
150 mg QD 
100 mg QD 
-3 
100 mg QD 
None 
QD = once daily; QOD = every other day. 
 
 
6.3 CHOP Dose Modification 
With the exception of vincristine, the dose level for cyclophosphamide, doxorubicin, and 
prednisone may not be modified. For cytopenia, the CC-486 dose adjustments or cycle delay rules 
for CHOP should be implemented as per Table 2.  
The vincristine dose may be modified according to Table 4 and Table 5.  Dose delay for peripheral 
neuropathy due to vincristine per Table 4 does not prevent continuing treatment with the other 
drugs on schedule. If the subject cannot tolerate the lowest level of vincristine, it is acceptable to 
continue on study with chemotherapy plus CC-486 without vincristine. 
Table 4: Dose Modification Rules - Vincristine 
CTCAE Toxicity Grade 
Action Required 
Peripheral neuropathy 
Newly developed ≥ Grade 3 (applies only to 
those neuropathies which begin or worsen while 
on study) 
Hold (interrupt dose) 
When the toxicity resolves to ≤ Grade 2 or to 
baseline, restart at the next lower dose level 
CTCAE= Common Terminology Criteria for Adverse Events. 
 
Table 5: Dose Reduction Levels-Vincristine 
Starting Dose 
1.4 mg/m2 (maximum of 2.0 mg total) 
Level -1 Dose 
1.0 mg max 
 
 
7. 
PHARMACEUTICAL INFORMATION 
 
7.1 CC-486 
 
7.1.1  Description 
CC-486 contains AZA, which is a pyrimidine nucleoside analog of cytidine. It differs from 
cytidine in having nitrogen in the 5-position of the heterocyclic ring.   It has the following chemical 
structure: 
 
Chemical Structure of Azacitidine 


 
 
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Azacitidine is (4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one).   
The empirical formula is CR8
RHR12
RNR4
ROR5
R. The molecular weight is 244 amu. 
 
7.1.2  Availability 
Different formulations of oral azacitidine (CC-486) have been developed and are being used in 
clinical studies. The oral azacitidine formulations may use any of the following excipients:  
mannitol USP, silicified microcrystalline cellulose NF, crospovidone NF, magnesium stearate NF, 
croscarmellose sodium, vitamin E TPGS NF, methacrylic acid copolymer (enteric coating) NF, 
Opadry coating, triethyl citrate NF, talc USP, hydroxypropyl cellulose NF, and hard gelatin 
capsule.  Azacitidine capsules contain 100 mg of the active ingredient only.   
 
7.1.3  Agent Ordering 
CC-486 will be supplied by Celgene in appropriate strengths for oral administration. 
Investigational product will be supplied as labeled blister cards.  Store the CC-486 oral formulation 
as directed on the label.  Procedures for proper handling and disposal should be applied according 
to standards established at each facility for cytotoxic drugs.  
 
7.1.4  Agent Accountability 
CC-486 Inventory Records – The investigator, or a responsible party designated by the 
investigator, will maintain a careful record of the inventory and disposition of all agents received 
from Celgene on a Drug Accountability Record Form (DARF). 
 
7.1.5  Side Effects 
The most common AEs reported during the azacitidine clinical trials reflect the underlying nature 
of the disease and the cytotoxic properties of azacitidine. The most commonly reported adverse 
reactions with azacitidine treatment were hematological reactions including anemia, 
thrombocytopenia, neutropenia, febrile neutropenia, and leukopenia, gastrointestinal events 
including nausea, vomiting, abdominal pain, constipation, and diarrhea. For the most frequently 
reported TEAEs (≥ 10% of subjects), the highest incidence of first occurrence was observed within 
Cycles 1-2. In general, no clinically relevant differences were seen when the safety data were 
analyzed for age, gender, or disease subtypes. The most common adverse reactions can be 
managed through delays or dose decrease of azacitidine and/or supportive measures. The overall 
safety profile of azacitidine from the ongoing clinical studies is consistent with that described in 
the IB; however, diarrhea may be more frequent and/or more severe in patients receiving orally-


 
 
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administered azacitidine. 
 
7.2  
Cyclophosphamide 
 
7.2.1  Description and Mode of Action 
Cyclophosphamide is an alkylating agent that prevents cell division primarily by cross-linking 
DNA strands.  Cyclophosphamide is considered cell cycle phase non-specific. Cyclophosphamide 
is bio-transformed principally in the liver to active alkylating metabolites that cross-link to tumor-
cell DNA.  Please refer to the FDA-approved package insert for product information, extensive 
preparation instructions, and a comprehensive list of adverse events.  
 
7.2.2  Availability and Accountability 
Cyclophosphamide is commercially available as 100 mg, 200 mg, 500 mg, 1 gm, or 2 gm vials in 
5, 10, 25, 50, and 100 ml of water respectively, resulting in a solution of 20 mg/ml.  Shake vials 
and warm slightly in lukewarm water to facilitate dissolution.  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.  Procedures for proper handling and disposal should be applied according to 
standards established at each facility for cytotoxic drugs. 
 
7.2.3  Clinical Use 
The desired dose is diluted into 100-500 ml of 5% dextrose or 0.9% normal saline for IV 
administration usually over 15-45 minutes. 
7.2.4  Side Effects 
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  
 
7.3   
Doxorubicin 
 
7.3.1  Description and Mode of Action 
Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces 
peucetius var. caesius.  Doxorubicin binds to nucleic acids, presumably by specific intercalation 
of the planar anthracycline nucleus with the DNA double helix, which inhibits nucleotide 
replication and action of DNA and RNA polymerases. Doxorubicin also inhibits topoisomerase II. 
Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu (II) and 
Fe (III) reduction at the cellular level. Doxorubicin does not cross the blood brain barrier. Please 
refer to the FDA-approved package insert for doxorubicin for product information, extensive 
preparation instructions, and a comprehensive list of adverse events. 
 
7.3.2  Availability and Accountability 
Doxorubicin is commercially available in 10, 20, 50, an 100 mg vials as a red-orange lyophilized 
powder which has a storage stability of at least two years – see expiration date on vial.  After 
adding the diluent, the vial should be shaken and the contents allowed to dissolve.  The 
reconstituted solution is stable for 7 days at room temperature and 15 days under refrigeration (2 


 
 
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to 8° C) when protected from light.  It should be protected from exposure to sunlight.  Discard any 
of the unused solution from single dose vials.  Unused solutions of the multiple dose vial remaining 
beyond the recommended storage times should be discarded. 
 
7.3.3  Clinical Use 
The vials should be reconstituted with sodium chloride injection, USP (0.9%) to give a final 
concentration of 2 mg/ml.  Doxorubicin should be slowly administered into the tubing of a freely 
running intravenous infusion of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.  
The tubing should be attached to a Butterfly needle inserted preferably into a large vein. Push of 
bolus administration should be done over 5 – 10 minutes through the side arm of a free flowing IV 
line.  Care must be taken not to infiltrate doxorubicin, as it is a tissue vesicant.  If extravasation 
occurs: stop the infusion; aspirate blood solution from the injection site; disconnect the syringe/IV 
bag from the catheter; inject 0.5 ml of hydrocortisone phosphate mixed in 2 mL NS into the 
catheter; remove the catheter/needle; apply ice packs 30’QID to the area for one day.  Doxorubicin 
is not compatible with heparin so it should not be administered through a heparin-lock. 
 
7.3.4  Side Effects 
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). 
 
7.4 
Vincristine 
 
7.4.1  Description and Mode of Action 
Vincristine sulfate, USP is a vincaleukoblastine, 22-oxo-, sulfate (1:1) salt of an alkaloid obtained 
from a common flowering herb, the periwinkle plant (Vinca rosea Linn).  The mechanism of action 
of Oncovin has been related to the inhibition of microtubule formation in the mitotic spindle, 
resulting in an arrest of dividing cells at the metaphase stage.  Please refer to the FDA-approved 
package insert for vincristine sulfate for product information, extensive preparation instructions, 
and a comprehensive list of adverse events. 
 
7.4.2  Availability and Accountability 
Vincristine is commercially available in 1, 2, and 5 mg vials (1 mg/mL).  Vials should be 
refrigerated and protected from light. 
 
7.4.3  Clinical Use 
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rapid IV bolus or continuous infusion through a central venous catheter.  Care must be taken not 
to infiltrate vincristine, as it is a tissue vesicant.  If extravasation occurs: stop the infusion; aspirate 
blood solution from the injection site; disconnect the syringe/IV bag from the catheter; inject 1 mL 
of hyaluronidase (150 units/ml) into the catheter; remove the catheter/needle; apply dry heat 
30’QID to the area for one day.   
 
7.4.4  Side Effects 
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 tissue necrosis upon extravasation. This 
is more likely with bolus injections as opposed to dilute infusions 
 
7.5 
Prednisone 
 
7.5.1  Description and Mode of Action 
Prednisone is a potent synthetic glucocorticoid that affects almost every body system. It has anti-
inflammatory, immunosuppressant, and minimal mineralocorticoid activity, and antineoplastic 
properties. As an antineoplastic agent, prednisone may bind to specific proteins (receptors) within 
the cell forming a steroid-receptor complex. Binding of the receptor-steroid complex with nuclear 
chromatin alters mRNA and protein synthesis within the cell.  Please refer to the FDA-approved 
package insert for prednisone for product information and a comprehensive list of adverse events. 
 
7.5.2  Availability and Accountability 
Prednisone is commercially available in 5, 10, 20, and 50 mg scored tablets and in an oral solution 
containing 1 mg of prednisone/ml. All forms are stable at room temperature. 
 
7.5.3  Clinical Use 
Administer orally with meals to minimize indigestion or GI irritation. 
 
7.5.4  Side Effects 
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. 
 
 
 
 
 
 
 
 


 
 
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9. 
MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the Lugano criteria for lymphoma 
response.33 The response assessment time points are: once between Days 15 and 21 of Cycle 3 and 
at the end of cycle 6 (or at treatment discontinuation). Subjects entering the Follow-up Period will 
have CT scans every 6 months for up to 2 years or until disease progression. If an additional CT 
scan is performed earlier than the specified time points due to changes in the subject’s clinical 
status, please also perform an additional response assessment at that time.  Once a subject has 
progressed, no further response assessments are required. 
 
PET-CT. PET-CT is the preferred imaging modality. At present, the low dose or attenuation 
correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for 
response assessment.  However, if the site can document that the CT performed as part of a PET-
CT is of sufficient quality to allow for measurement of target lesions, then the CT portion of the 
PET-CT can be used for response assessment.   
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness greater than 
5 mm, the minimum size of a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations. 
 
9.1 Response Criteria 
Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all of 
the following) 
Lymph nodes and 
extralymphatic 
sites 
Score 1, 2, or 340T*0T40T 0Twith or without a residual 
mass on 5PS40T†40T 
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi 
It is recognized that in Waldeyer's ring or 
extranodal sites with high physiologic uptake 
or with activation within spleen or marrow (eg, 
with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater 
than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response 
may be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake 
No extralymphatic sites of disease 
Nonmeasured 
Not applicable 
Absent 
 
 
 
 
 


 
 
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Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
lesion 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if 
indeterminate, IHC negative 
Partial 
Partial metabolic response 
Partial remission (all of the 
following) 
Lymph nodes and 
extralymphatic 
sites 
Score 4 or 540T†0T40T 0Twith reduced uptake compared 
with baseline and residual mass(es) of any size 
≥ 50% decrease in SPD of up to 6 
target measurable nodes and 
extranodal sites 
 
At interim, these findings suggest responding 
disease 
When a lesion is too small to 
measure on CT, assign 5 mm × 5 
mm as the default value 
 
At end of treatment, these findings indicate 
residual disease 
When no longer visible, 0 × 0 mm 
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by > 
50% in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive 
changes from chemotherapy allowed). If there 
are persistent focal changes in the marrow in 
the context of a nodal response, consideration 
should be given to further evaluation with MRI 
or biopsy or an interval scan 
Not applicable 
No response or 
stable disease 
No metabolic response 
Stable disease 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or end of 
treatment 
< 50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and extranodal 
sites; no criteria for progressive 
disease are met 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with 
progression 
Organ 
enlargement 
Not applicable 
No increase consistent with 
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Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive 
disease 
Progressive metabolic disease 
Progressive disease requires at least 
1 of the following 
Individual target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
PPD progression: 
Extranodal 
lesions 
New FDG-avid foci consistent with lymphoma 
at interim or end-of-treatment assessment 
An individual node/lesion must be 
abnormal with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir 
and 
An increase in LDi or SDi from 
nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 
50% of the extent of its prior 
increase beyond baseline (eg, a 15-
cm spleen must increase to > 16 
cm). If no prior splenomegaly, must 
increase by at least 2 cm from 
baseline 
New or recurrent splenomegaly 
Nonmeasured 
lesions 
None 
New or clear progression of 
preexisting nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma 
rather than another etiology (eg, infection, 
inflammation). If uncertain regarding etiology 
of new lesions, biopsy or interval scan may be 
considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
• 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance 
imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular 
diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the 
perpendicular diameters for multiple lesions. 
• 
28T*0T28T 0TA score of 3 in many patients indicates a good prognosis with standard treatment, especially 
if at the time of an interim scan. However, in trials involving PET where de-escalation is 
investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid 


 
 
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undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal 
masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes 
should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, 
spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. 
Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal 
masses, and extranodal sites not selected as dominant or measurable or that do not meet the 
requirements for measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In 
Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be 
greater than in the mediastinum with complete metabolic response, but should be no higher 
than surrounding normal physiologic uptake (eg, with marrow activation as a result of 
chemotherapy or myeloid growth factors). 
• 
28T†0T28T 0TPET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > 
mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver 
and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
 
9.2 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
Duration of CR: The duration of CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started.  
 
9.3 Progression-Free Survival (PFS) 
PFS is defined as the duration of time from start of treatment to time of documentation of progression or 
death from any cause. 
 
9.4 Overall Survival (OS) 
OS is defined as the duration of time from start of treatment to death from any cause. 
 
10.  
DATA REPORTING / REGULATORY CONSIDERATIONS 
 
10.1 
Data Collection 
REDCap will be used to capture all treatment, toxicity, efficacy, and adverse event data for all 
enrolled patients. 
 


 
 
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REDCap (Research Electronic Data Capture) is a free data management software system that is 
fully supported by the Weill-Cornell Medical Center CTSC. It is a tool for the creation of 
customized, secure data management systems that include Web-based data-entry forms, reporting 
tools, and a full array of security features including user and group based privileges, authentication 
using institution LDAP system, with a full audit trail of data manipulation and export procedures. 
REDCap is maintained on CTSC-owned servers that are backed up nightly and support encrypted 
(SSL-based) connections. Nationally, the software is developed, enhanced and supported through 
a multi-institutional consortium led by the Vanderbilt University CTSA. 
 
10.2 
Regulatory Considerations 
All protocol amendments and consent form modifications will be made by the Principal 
Investigator. Celgene will have the opportunity to review and approve the changes prior to 
submission of these changes to the local IRB and distribution to participating sites. 
 
11. 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design 
39TThis is an exploratory phase II study to study the safety and efficacy of CC486 + CHOP in patients 
with mature peripheral T-cell lymphoma39T. If the data from this trial provide evidence of efficacy 
in this patient population, the treatment will be considered for further investigation. A total of 20 
patients (17 eligible and evaluable patients) will be enrolled on this trial, with at least 2/3 of the 
subjects having T-cell lymphoma with T-follicular helper (TFH) phenotype. 
 
11.2 
Sample Size 
The primary endpoint for this study will be the complete response rate (CR).  Sample size 
recommendations for the phase II design are determined according to Simon’s two-stage Minimax 
design 34.  We project a complete response proportion of 35%, below which the response will be 
unacceptable, and a complete response proportion of 60%, above which the combination regimen 
will be considered worthy of further exploration.  The null hypothesis that the complete response 
proportion is less than or equal to 35% will be tested against the alternative hypothesis that the 
complete response proportion is greater than or equal to 60%. 
 
The sample size computations were performed assuming 10% level of significance and 80% 
power.  In the first stage, 13 patients (at least 2/3 of subjects with T-cell lymphoma with T-
follicular helper (TFH) phenotype) will enter the study.  If 4 or fewer achieve CR, the study will 
be terminated early and declared to have a negative result.  If 5 or more patients achieve CR, 
enrollment will be extended to 17 patients.  At Stage 2, the treatment will be declared effective 
and worthy of further testing if 9 or more patients achieve CR among the 17 patients (at least 2/3 
of subjects with T-cell lymphoma with T-follicular helper (TFH) phenotype) entered.  This two-
stage design yields a ≥ 0.80 probability of a positive result if the true percentage of complete 
responders is ≥ 60%.  It yields a ≥ 0.90 probability of a negative result if the true percentage of 
complete responders is ≤ 35%.  Assuming 15% are unevaluable/ineligible, we anticipate that a 
total of 20 patients will be enrolled in study (assuming we proceed to the second stage). 
 
Table 1.  Numbers of complete responders required to accept or reject HR0 
Rat each stage.  Under 


 
 
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this design, HR0
R will not be rejected at Stage 1. 
 
N 
Accept HR0 
Reject HR0 
Stage 1 
13 
≤ 4 
--- 
Stage 2 
17 
≤ 8 
≥ 9 
 
 
Table 2.  Summary of 90% confidence intervals for potential complete response rates.  To allow 
for a 15% ineligibility rate, we will accrue 20 patients to this study. 
No. responses in 17 
eligible patients 
Complete 
response rate 
90% CI 
8 
0.470 
0.306, 0.639 
9 
0.529 
0.360, 0.693 
10 
0.588 
0.416, 0.745 
11 
0.647 
0.474, 0.795 
 
11.3  
Analysis Plan for Endpoints 
 
11.3.1  Primary Endpoints 
The primary endpoint of complete response rate will be estimated and a 95% confidence interval 
will be estimated via Clopper-Pearson exact binomial method.  
 
11.3.2  Secondary Clinical Endpoints 
With adequate follow-up time, secondary endpoints of progression-free survival (PFS), overall 
survival (OS), and time to next treatment will be assessed by Kaplan-Meier survival analysis and 
95% confidence intervals will be calculated using Greenwood’s formula.  PFS will be defined as 
the time from first treatment day until objective or symptomatic progression or death.  OS will be 
defined as the time from first treatment day until death.   
 
The frequency of subjects experiencing toxicities will be tabulated.  Toxicities will be assessed 
and graded according to CTCAE v. 4.0 terminology.  Exact 95% confidence intervals around the 
toxicity proportions will be calculated to assess the precision of the obtained estimates. 
 
 
 
 
 
 
 
12. ADVERSE EVENT REPORTING REQUIREMENTS 
 
12.1 
Adverse Event Definition 
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other protocol-imposed 


 
 
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intervention, regardless of attribution. 
 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with NHL that were not present 
prior to the AE reporting period 
• 
Complications that occur as a result of protocol-mandated interventions 
• 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period 
 
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters: the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures. 
 
All AEs will be recorded by the Investigator from the time the subject initiates study treatment 
until 28 days after the last dose of investigational product and those SAEs made known to the 
Investigator at any time thereafter that are suspected of being related to study treatment. AEs and 
serious adverse events (SAEs) will be recorded on the AE page of the CRF and in the subject’s 
source documents.  All SAEs must be reported to Celgene Drug Safety within 24 hours of the 
Investigator’s knowledge of the event by facsimile, or other appropriate method, using the SAE 
Report Form, or approved equivalent form. 
 
12.1.1  Adverse Event Characteristics and Related Attribututions 
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will 
be utilized for AE reporting.  A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site (40Thttp://ctep.cancer.gov40T) 
• 
Attribution of the AE: 
o Definite – The AE is clearly related to the study treatment. 
o Probable – The AE is likely related to the study treatment. 
o Possible – The AE may be related to the study treatment. 
o Unlikely – The AE is doubtfully related to the study treatment. 
o Unrelated – The AE is clearly NOT related to the study treatment. 
 
12.1.2  Recording of Adverse Events 
All adverse events will be recorded on a patient specific adverse event log.  The AE log will be 
maintained by the research staff and kept in the patient’s research chart. 
 


 
 
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12.1.3  Reporting of AE to WCM IRB 
The participating investigator will report all adverse events and serious adverse events to the 
Principal Investigator and to the IRB according to the local IRB’s policies and procedures in 
reporting adverse events.  In the event of a multi-center study, the Principal Investigator will report 
adverse events and serious adverse events from all participating sites to the WCM IRB according 
to the IRB’s policies and procedures in reporting adverse events. 
 
12.2 
Definition of SAE 
A serious adverse event (SAE) is any AE occurring at any dose that: 
• Results in death; 
• Is life-threatening (i.e., in the opinion of the Investigator, the subject is at immediate risk 
of death from the AE); 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay); 
• Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions); 
• Is a congenital anomaly/birth defect; 
• Constitutes an important medical event 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. Medical 
and scientific judgment should be exercised in deciding whether such an AE should be considered 
serious.  
Events not considered to be SAEs are hospitalizations for: 
• A standard procedure for protocol therapy administration. However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be reported as 
an SAE. 
• Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. The administration of blood or platelet transfusion as routine 
treatment of studied Indication. However, hospitalization or prolonged hospitalization for 
a complication of such transfusion remains a reportable SAE. 
• A procedure for protocol/disease-related investigations (e.g., surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling). However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable SAE. 
• Hospitalization or prolongation of hospitalization for technical, practical, or social reasons, 
in absence of an AE. 


 
 
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• A procedure that is planned (i.e., planned prior to starting of treatment on study); must be 
documented in the source document and the CRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE. 
• An elective treatment of or an elective procedure for a pre-existing condition unrelated to 
the studied indication. 
• Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. If an AE is considered serious, both the AE 
page/screen of the CRF and the SAE Report Form must be completed.  
The following event will NOT be considered SAE: 
• Leukopenia and lymphopenia of any grade as these are expected pharmacodynamic 
outcomes of study treatment.  
• Grade 3 or 4 neutropenia that is not accompanied by fever ≥ 100.4°F [38°C]) and improves 
to Grade ≤ 2 by Day 1 of the next cycle 
• Grade 3 thrombocytopenia that does not result in bleeding and improves to Grade ≤ 2 by 
Day 1 of the next cycle  
• Grade 3 or 4 anemia 
• Grade 3 nausea or vomiting ≤ 7 days (in the absence of premedication or that can be 
managed with oral or IV anti-emetics) 
 
12.2.1  Reporting of SAE to IRB 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy.  The 
IRB requires immediate reporting of all unexpected and study-related (definite or probable) 
adverse events.  The following procedure will be followed for reporting SAE to the IRB: 
• Complete the SAE Cover Sheet (See Appendix B) 
• If the event is unexpected AND definitely or probably related to the study, complete the 
IRB Unexpected, Study-related Adverse Events, Incidents, and Information Reporting 
Form.  This form should be submitted within 24 hours of investigator notification of the 
event. 
• If the event is expected OR possibly or unrelated to the study, only the SAE Cover Sheet 
must be completed.  These events will be reported to the IRB at the time of continuing 
renewal on the Adverse Event & IND Safety Reporting Cumulative Table. 
 
 
 
12.2.2  Reporting of SAE to FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly associated to 
the drug, and that have not previously been reported in the Investigators brochure, or reference 
safety information document should be reported promptly to the Food and Drug Administration 


 
 
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(FDA) by telephone or by fax.  Fatal or life threatening SAEs that meet the criteria for reporting 
to the FDA must be reported to the FDA within 7 calendar days after awareness of the event.  All 
other SAEs that meet the criteria for reporting to the FDA must be reported to the FDA within 15 
calendar days after awareness of the event.  A clear description of the suspected reaction should 
be provided along with an assessment as to whether the event is drug or disease related. For 
multicenter trial, all participating study sites should NOT report SAEs to the FDA.  Rather, 
participating sites should report SAEs to Celgene and the primary study site, and the primary site 
will be responsible for reporting to FDA. 
 
If an SAE occurs on this study, the event will be filed on a MedWatch 3500A form with the FDA.  
MedWatch 
3500A 
(Mandatory 
Reporting) 
form 
is 
available 
at 
40Thttp://www.fda.gov/medwatch/getforms.html40T 
 
 
 
 
 
  
  
 
 
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be reported 
in an expedited manner in accordance with 21 CFR 312.32. 
 
Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following information: 
• Any AE suspected of being related to with the use of drug in this study or in other studies 
that is both serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected AE(s) 
or significant risks to subjects. The investigator must keep copies of all pertinent safety information 
on file, including correspondence with Celgene and the IRB/EC. All pregnancies or suspected 
pregnancies occurring in either a female subject or partner of a male subject are immediately 
reportable events. 
 
Pregnancies 
Pregnancies and suspected pregnancies (including elevated βhCG or positive pregnancy test in a 
female subject of reproductive potential, regardless of disease state) occurring while the subject 
is on IP, or within 28 days of the subject’s last dose of IP, are considered immediately reportable 
events. IP is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by email, phone or 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form. The female subject should be referred to an obstetrician-gynecologist, 


 
 
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(preferably one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation. 
 
The Investigator will follow the female subject until completion of the pregnancy outcome and 
up to 1 year to monitor the baby, and must notify Celgene Drug Safety immediately about the 
outcome of the pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up 
Report Form and Infant Follow-Up Form, or approved equivalent form.   
 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion, 
STILLBIRTH, NEONATAL DEATH, OR CONGENITAL ANOMALY), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form, or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form. 
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator immediately, and the pregnant female partner 
should be advised to call their healthcare provider immediately.  Male patients treated with 
azacitidine and CC-486 are advised to continue complete abstinence or condom use during 
treatment and 28 days after stopping treatment.  
 
12.2.3  Reporting of SAE to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in writing 
using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of being 
aware of the event.  The written report must be completed and supplied to Celgene by facsimile 
within 24 hours/1 business day.  The initial report must be as complete as possible, including an 
assessment of the causal relationship between the event and the investigational product(s), if 
available.  Information not available at the time of the initial report (e.g., an end date for the adverse 
event or laboratory values received after the report) must be documented on a follow-up report.  A 
final report to document resolution of the SAE is required. 
 
  A copy of the fax transmission confirmation of the SAE 
report to Celgene should be attached to the SAE and retained with the patient records. 
All participating study sites must report SAEs to Celgene as described and within 24 hours of 
awareness.  Participating sites should also report SAEs to the primary study site. 
 
 


 
 
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12.3 
IND Annual Reports 
 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual report 
is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 312.33 provides the 
data elements that are to be submitted in the report.  The Annual Report should be filed in the 
study's Regulatory Binder, and a copy provided to Celgene Corporation as a supporter of this study 
as follows. 
 
 
 
 
 
 
 
 
 
 
 
 
12.4 
AE/SAE Follow Up 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. This 
requirement indicates that follow-up may be required for some events after the patient discontinues 
participation from the study. 
 
13. DATA AND SAFETY MONITORING PLAN (DSMP) 
This is a multi-institution study. The data and safety monitoring for this study will be overseen by 
the Weill Cornell IRB as well as the principal investigators from each site. The study will be 
reviewed by the Weill Cornell Medical College Data and Safety Monitoring Board (DSMB) as an 
independent means of data and safety monitoring. Enrollment information, adverse event and 
safety information, protocol changes, and other interim data will be evaluated by the DSMB on a 
semi-annual basis. After each evaluation, the Board will provide the principal investigator with 
recommendations for protocol modification, continuation, or termination. 
 
14. REFERENCES 
 
 
1. 
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Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical 
Outcomes. Journal of Clinical Oncology 26:4124-4130, 2008 


 
 
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2. 
Swerdlow SH, Campo E, Pileri SA, et al: The 2016 revision of the World Health 
Organization classification of lymphoid neoplasms. Blood 127:2375-2390, 2016 
 
3. 
Mourad N, Mounier N, Brière J, et al: Clinical, biologic, and pathologic features in 
157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d'Etude des 
Lymphomes de l'Adulte (GELA) trials. Blood 111:4463-4470, 2008 
 
4. 
Reimer P, Rüdiger T, Geissinger E, et al: Autologous Stem-Cell Transplantation 
As First-Line Therapy in Peripheral T-Cell Lymphomas: Results of a Prospective Multicenter 
Study. Journal of Clinical Oncology 27:106-113, 2009 
 
5. 
Simon A, Peoch M, Casassus P, et al: Upfront VIP-reinforced-ABVD (VIP-
rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of 
the randomized phase III trial GOELAMS-LTP95. British Journal of Haematology 151:159-166, 
2010 
 
6. 
d'Amore F, Relander T, Lauritzsen GF, et al: Up-Front Autologous Stem-Cell 
Transplantation in Peripheral T-Cell Lymphoma: NLG-T-01. Journal of Clinical Oncology 
30:3093-3099, 2012 
 
7. 
Odejide O, Weigert O, Lane AA, et al: A targeted mutational landscape of 
angioimmunoblastic T-cell lymphoma. Blood 123:1293-1296, 2014 
 
8. 
Wang C, McKeithan TW, Gong Q, et al: IDH2/R172 mutations define a unique 
subgroup of patients with angioimmunoblastic T-cell lymphoma. Blood 126:1741-1752, 2015 
 
9. 
Pan H, Gaudiano M, Tabbo F, et al: A pharmacologically reversible epigenomic 
signature of relapse and chemotherapy resistance in anaplastic large cell lymphoma. Blood 
128:3932, 2016 
 
10. 
Kataoka K, Nagata Y, Kitanaka A, et al: Integrated molecular analysis of adult T 
cell leukemia/lymphoma. Nat Genet 47:1304-1315, 2015 
 
11. 
Chen Y-W, Guo T, Shen L, et al: Receptor-type tyrosine-protein phosphatase κ 
directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma. Blood 
125:1589-1600, 2015 
 
12. 
Küçük C, Hu X, Jiang B, et al: Global Promoter Methylation Analysis Reveals 
Novel Candidate Tumor Suppressor Genes in Natural Killer Cell Lymphoma. Clinical Cancer 
Research 21:1699-1711, 2015 
 
13. 
Uenogawa K, Hatta Y, Arima N, et al: Azacitacine induces demethylation of 
p16INK4a and inhibits growth in adult T-cell leukemia/lymphoma. International Journal of 
Molecular Medicine 28:835-9, 2011 
 
14. 
Hassler MR, Klisaroska A, Kollmann K, et al: Antineoplastic activity of the DNA 
methyltransferase inhibitor 5-aza-2′-deoxycytidine in anaplastic large cell lymphoma. Biochimie 
94:2297-2307, 2012 
 
15. 
Marchi E, Zullo KM, Amengual JE, et al: The combination of hypomethylating 
agents and histone deacetylase inhibitors produce marked synergy in preclinical models of T-cell 
lymphoma. British Journal of Haematology 171:215-226, 2015 
 
16. 
Delarue R, Dupuis J, Sujobert P, et al: Blood 128:4164, 2016 
 
17. 
Cheminant M, Bruneau J, Kosmider O, et al: Efficacy of 5-Azacytidine in a TET2 
mutated angioimmunoblastic T cell lymphoma. British Journal of Haematology 168:913-916, 
2015 
 
18. 
Saillard C, Guermouche H, Derrieux C, et al: Response to 5-azacytidine in a patient 
with TET2-mutated angioimmunoblastic T-cell lymphoma and chronic myelomonocytic 
leukaemia preceded by an EBV-positive large B-cell lymphoma. Hematological Oncology:n/a-


 
 
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n/a, 2016 
 
19. 
Garcia-Manero G, Gore SD, Cogle C, et al: Phase I Study of Oral Azacitidine in 
Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia. 
Journal of Clinical Oncology 29:2521-2527, 2011 
 
20. 
Garcia-Manero G, Gore SD, Kambhampati S, et al: Efficacy and safety of extended 
dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic 
syndromes. Leukemia 30:889-896, 2016 
 
21. 
LoRusso P, Rasco D, Bendell J, et al: A phase 1b study of CC-486 (oral azacitidine) 
as a priming agent for carboplatin or NAB-paclitaxel in subjects with relapsed and refractory solid 
tumors. Mol Cancer Ther 12:A120, 2013 
 
22. 
Martin  P, et al: A phase I, open-label, multicenter trial of oral azacitidine (CC-486) 
plus R-CHOP in patients with high-risk, previously untreated diffuse large B-cell lymphoma, 
grade 3B follicular lymphoma, or transformed lymphoma. Blood 130:192, 2017 
 
23. 
Ellin F, Landström J, Jerkeman M, et al: Real-world data on prognostic factors and 
treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry. Blood 
124:1570-1577, 2014 
 
24. 
Abramson JS, Feldman T, Kroll-Desrosiers AR, et al: Peripheral T-cell lymphomas 
in a large US multicenter cohort: prognostication in the modern era including impact of frontline 
therapy. Annals of Oncology 25:2211-2217, 2014 
 
25. 
Schmitz N, Trümper L, Ziepert M, et al: Treatment and prognosis of mature T-cell 
and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the 
German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 116:3418-3425, 2010 
 
26. 
Niitsu N, Hayama M, Yoshino T, et al: Multicentre phase II study of the 
CyclOBEAP regimen for patients with peripheral T-cell lymphoma with analysis of biomarkers. 
British Journal of Haematology 153:582-588, 2011 
 
27. 
Mahadevan D, Unger JM, Spier CM, et al: Phase 2 trial of combined cisplatin, 
etoposide, gemcitabine, and methylprednisolone (PEGS) in peripheral T-cell non-Hodgkin 
lymphoma. Cancer 119:371-379, 2013 
 
28. 
Fanale MA, Horwitz SM, Forero-Torres A, et al: Brentuximab Vedotin in the Front-
Line Treatment of Patients With CD30+ Peripheral T-Cell Lymphomas: Results of a Phase I Study. 
Journal of Clinical Oncology 32:3137-3143, 2014 
 
29. 
Dupuis J, Morschhauser F, Ghesquières H, et al: Combination of romidepsin with 
cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with 
peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study. The Lancet Haematology 
2:e160-e165 
 
30. 
Clozel T, Yang S, Elstrom RL, et al: Mechanism-Based Epigenetic 
Chemosensitization Therapy of Diffuse Large B-Cell Lymphoma. Cancer Discovery 3:1002-1019, 
2013 
 
31. 
Martinez-Delgado B, Fernandez-Piqueras J, Garcia M, et al: Hypermethylation of 
a 5' CpG island of p16 is a frequent event in non-Hodgkin lymphoma. Leukemia 11:425-8, 1997 
 
32. 
Pinyol M, Cobo F, Bea S, et al: p16<sup>INK4a</sup> Gene Inactivation by 
Deletions, Mutations, and Hypermethylation Is Associated With Transformed and Aggressive 
Variants of Non-Hodgkin's Lymphomas. Blood 91:2977-2984, 1998 
 
33. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The 
Lugano Classification. J Clin Oncol, 2014 


 
 
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34. 
Simon R: Optimal two-stage designs for phase II clinical trials. Controlled Clinical 
Trials 10:1-10, 1989 
 
 
 


 
 
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Appendix A:  Cockcroft-Gault estimation of CrCl 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl): 
(Cockcroft, 1976; Luke 1990) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)__ 
(Males) 
 
72 x (serum creatinine, mg/dL) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)_    x 0.85 
(Females) 
 
72 x (serum creatinine, mg/dL) 
 
 
 
 
 


 
 
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Appendix B:  International Prognostic Index (IPI) Score 
 
 
One point is assigned for each of the following risk factors: 
• 
Age greater than 60 years 
• 
Stage III or IV disease 
• 
Elevated serum LDH 
• 
Eastern Cooperative Oncology Group performance status of 2, 3, or 4 
• 
More than 1 extranodal site 
 
IPI Score 
Risk Group 
0 - 1 
Low risk 
2 
Low-intermediate risk 
3 
High-intermediate risk 
4 - 5 
High risk 
 
 
 
42TSource: A Predictive Model for Aggressive Non-Hodgkin’s Lymphoma. The International Non-
Hodgkin’s Lymphoma Prognostic Factor Project.  New England Journal of Medicine42T 
1993;329:987-94 
 
 
 
 


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


 
 
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Appendix D: New York Heart Association (NYHA) Classification for 
Congestive Heart Failure 
 
Functional Capacity 
Objective Assessment 
Class I. Patients with cardiac disease but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
A. No objective evidence of 
cardiovascular disease. 
Class II. Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
B. Objective evidence of 
minimal cardiovascular 
disease. 
Class III. Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
C. Objective evidence of 
moderately severe 
cardiovascular disease. 
Class IV. Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical activity 
is undertaken, discomfort is increased. 
D. Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of the New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & 
Co; 1994:253-256.  
 


 
 
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Appendix E: Deauville Criteria for PET Scan Interpretation 
 
Interpretation 
• A visual analysis using the 5-point scale should be applied 
• The preferable reference scale should be the mediastinum and the liver 
 
Scoring per the five point scale 
1. No uptake 
2. Uptake ≤ mediastinum 
3. Uptake > mediastinum but ≤ liver 
4. Uptake moderately increased compared to the liver at any site. 
5. Uptake markedly increased compared to the liver at any site and/or new sites of disease. 
 
 


 
 
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Appendix F: Recommendations for Management of Treatment-Induced 
Diarrhea 
The following published guidelines were modified in order to be consistent with the clinical study 
protocol. 
 
Source: Benson, AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA Jr, et al: Recommended 
guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol Jul 15;22(14):2918-26, 2004. 


 
 
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