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13.2.2. cycles 2 through 6

The following procedures will be performed on Day 1 of Cycles 2 through 6:
Physical examination  
Update ECOG performance status Vital signs (blood pressure, heart rate, respiratory rate, temperature, and weight) Lymphoma assessment (includes physical examination, a review of the subject's current signs and symptoms, B symptoms, and concomitant medications)
Radiologic assessment (CT/MRI are required at the end of Cycle 2 (± 3 days),
Cycle 4 (± 3 days) and Cycle 6 (± 3 days). If FDG-PET/CT is acquired at baseline, follow-up FDG-PET/CT imaging at Cycle 4 is required)
CBC with differentials Serum chemistries (sodium, potassium, magnesium, phosphate, total protein, chloride, bicarbonate, calcium, BUN, creatinine, uric acid, total bilirubin, alkaline phosphatase, AST, ALT, LDH, albumin, and glucose)
Collect plasma for biomarker sampling Collect plasma for PK sampling on Cycle 4, Day 1 only (2 hours post-dose)
CUDC-907 will be administered in the clinic on PK sampling days.  
Update concomitant medications Collect AEs
CUDC-907 dosing (CUDC-907 is taken PO for 5 days on/2 days off)
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13.2.2.2. cycles 2-6 days 2-5

CUDC-907 dosing (CUDC-907 is taken PO for 5 days on/2 days off)
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13.2.3. cycles 7+

Note: Subjects who continue past Cycle 13 will only be required to have a Day 1 visit at the beginning of every other cycle (14, 16, 18, etc.).  
Pregnancy test (women of childbearing potential)
The following procedures will be performed on Day 1 of Cycles 7+:
Physical examination  
Update ECOG performance status Vital signs (blood pressure, heart rate, respiratory rate, temperature, and weight) Lymphoma assessment (includes physical examination, a review of the subject's current signs and symptoms, B symptoms, and concomitant medications)
Radiologic assessment (CT/MRI [If FDG-PET/CT is acquired at baseline, follow-up FDG-PET/CT imaging at Cycle 10 is required])
CBC with differentials 64 13.2.3.1. **Cycles 7+, Day 1**
Serum chemistries (sodium, potassium, magnesium, phosphate, total protein, chloride, bicarbonate, calcium, BUN, creatinine, uric acid, total bilirubin, alkaline phosphatase, AST, ALT, LDH, albumin, and glucose)
Pregnancy test (women of childbearing potential)
Collect plasma for biomarker sampling Update concomitant medications Collect AEs Collect plasma for PK sampling (2 hours post-dose) every other cycles (i.e., Cycles 6, 8, 10, etc.)
CUDC-907 will be administered in the clinic on PK sampling days.
CUDC-907 dosing (CUDC-907 is taken PO for 5 days on/2 days off)
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13.2.3.2. cycles 7+ days 2-5

CUDC-907 dosing (CUDC-907 is taken PO for 5 days on/2 days off)
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13.2.4. end of therapy visit

The following procedures will be performed at the EOT visit:
Physical examination  
Update ECOG performance status Vital signs (blood pressure, heart rate, respiratory rate, temperature, and weight) ECG
Pregnancy test (women of childbearing potential)
A serum or urine pregnancy test will be performed at the EOT visit, as well as during Screening and at least once per cycle prior to dosing, or more frequently as clinically indicated.  
Lymphoma assessment (includes physical examination, a review of the subject's current signs and symptoms, B symptoms, and concomitant medications)
Done only if not performed within 4 weeks of the EOT visit Radiologic assessment (CT/MRI)
Done only if not performed within 4 weeks of the EOT visit CBC with differentials Serum chemistries (sodium, potassium, magnesium, phosphate, total protein, chloride, bicarbonate, calcium, BUN, creatinine, uric acid, total bilirubin, alkaline phosphatase, AST, ALT, LDH, albumin, and glucose)
Update concomitant medications Collect AEs
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13.3. post-treatment follow-up visits 13.3.1.

Symptom-directed physical examination (performed until time of disease progression, withdrawal of consent, or any other criteria that would make the subject unable to be followed for disease response)
IPI score Lymphoma assessment (includes physical examination, a review of the subject's current signs and symptoms, B symptoms, and concomitant medications)
Radiologic assessment (CT/MRI) Survival status Update concomitant medications (anti-cancer therapies only)
Collect AEs (only treatment-related SAEs will be captured)
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13.3.2. follow-up visits > 6

Symptom-directed physical examination (performed until time of disease progression, withdrawal of consent, or any other criteria that would make the subject unable to be followed for disease response) and updated IPI score Lymphoma assessment (includes physical examination, a review of the subject's current signs and symptoms, B symptoms, and concomitant medications)
Radiologic assessment (CT/MRI)
Survival status Update concomitant medications (anti-cancer therapies only)
Collect AEs (only treatment-related SAEs will be captured)
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14. statistical analyses

The safety and preliminary efficacy of CUDC-907 will be evaluated when administered in subjects with RR MYC-altered DLBCL. Patients with RR DLBCL will be tested for MYC-altered disease, defined as MYC translocation by FISH, or MYC expression in ≥ 40% of tumor cells by IHC staining and/or MYC gene copy number gain by FISH based on fresh or archived tumor tissue sample (most recent available). Based on central testing and review, subjects will be classified into one of the following categories: (1) Group A: MYC translocation+ by FISH, (2) Group B: MYC expression in ≥ 40%
of tumor cells by IHC and/or MYC gene copy number gain by FISH, or (3) Group C: MYC translocation¯ by FISH and MYC expression in < 40% of tumor cells and no MYC gene copy number gain by FISH. Subjects in all groups will continue to receive treatment until they meet criteria for treatment discontinuation.
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14.2.2. secondary endpoints

ORR (local determination) PFS, median PFS, and PFS6 (central and local determination)
OS
DCR and DOR (central and local determination)  
To evaluate the incidence and severity of AEs, SAEs, and other safety parameters in subjects receiving CUDC-907.  
To characterize the PK of CUDC-907.
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14.2.3. exploratory endpoints

To explore the effects of CUDC-907 on disease-associated biomarkers.  
To explore the relationship between disease-associated biomarkers in plasma and tumor tissue. Among biomarkers of interest, BCL2 and BCL6 protein expression and translocation status in particular will be tested in tumor tissue, where possible.  
To explore biomarkers of response for patient selection.  
To explore the relationship between additional biomarkers and biomarker profiles that may influence biologic and clinical responses to CUDC-907.  
To explore the ORR according to Lugano classification (Cheson et al, 2014; Barrington et al, 2014).
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14.3. sample size considerations

The sample size for Groups A and B was determined based on the following: With a sample size of 50 subjects in Groups A and B with an ORR of 30.0%, a two-sided 95% confidence interval employing the exact binomial method will extend from 17.9% to 44.6%. This confidence bound (CB) about the observed ORR is thought to adequately characterize the disease response of these populations after receiving CUDC-907. Below are the 95% confidence intervals for various response rates using a sample size of 50 subjects and employing the exact binomial methodology.  
| Sample Size      | ORR              | Lower 95%   | Upper 95%   |
|------------------|------------------|-------------|-------------|
| Confidence Bound | Confidence Bound |             |             |
| 50               | 15 (30%)         | 17.9%       | 44.6%       |
| 50               | 14 (28%)         | 16.2%       | 42.5%       |
| 50               | 13 (26%)         | 14.6%       | 40.4%       |
| 50               | 12 (24%)         | 13.1%       | 38.2%)      |  
Enrollment within a group or overall may also terminate early due to other considerations such as those that may preclude timely completion of the study (e.g., low prevalence of MYC-altered DLBCL).
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14.4. statistical analysis

The statistical analyses will be performed using SAS® version 9.4 or later (SAS Institute Inc., Cary, NC). A comprehensive statistical analysis plan (SAP) will be finalized prior to database lock.
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14.4.1. analysis populations

The Intent-to-Treat (ITT) Population will consist of all subjects in Groups A and B. The primary analyses of efficacy will be conducted based on the ITT Population. The Evaluable Population will consist of all subjects in Groups A and B who receive at least one full cycle of treatment and have at least one post-baseline disease assessment and have not had major protocol deviations that are thought to have materially impacted efficacy outcomes. Major protocol deviations will be identified prior to database lock. Secondary analysis of efficacy will also be conducted based on the Evaluable Population. In addition, the primary efficacy endpoint (ORR) will also be assessed using the Evaluable Population as a secondary analysis. The Safety Population will consist of all subjects who receive any treatment. All safety analyses will be conducted based on this population. Demographic and baseline disease characteristics will be summarized. Data to be tabulated will include demographic features such as sex, age, race, and weight, as well as disease-specific characteristics, such as tumor stage and histology.
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14.4.3. efficacy analyses

The primary analyses of efficacy will be based on the ITT Population. The interim analyses will be performed on the Evaluable Population. The primary efficacy endpoint, ORR, will be based on the proportion of subjects with CR or PR using the central determination of disease response in Groups A and B, separately. The estimate will be accompanied by a two-sided exact binomial 95% CB. Progression-free survival, OS, and DOR will be summarized descriptively for Groups A and B using the Kaplan-Meier method. For such subjects, the progression or censoring date will be determined based on described conventions (Food and Drug Administration, 2007). Progression-free survival, median PFS, and the estimated rate at 6 months (PFS6) based on the Kaplan-Meier analyses will be reported separately for Groups A and B. For OS, the estimated rates at 3, 6, 9, and 12 months based on the Kaplan-Meier analyses will be reported for Groups A and B. For DOR, the estimate of the median based on the Kaplan-Meier analyses for Groups A and B will be reported. Waterfall plots will be used to depict graphically the maximum decrease from baseline in the sum of the product diameters in measurable nodes and nodal masses. Secondary analyses of efficacy will be conducted based on the ITT and Evaluable Populations using response as determined by both the central determination of disease response and investigator site. In these analyses, the primary efficacy endpoint, ORR, will be estimated using the proportion of subjects with CR or PR. The estimate will be accompanied by a two-sided exact binomial 95% lower CB.
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14.4.3.1. interim analyses

69 14.4.2. **Baseline Characteristics** Interim analyses of efficacy using the Evaluable Population will be performed after ORR has been determined in 25 evaluable subjects for both Groups A and B, separately. In both Groups A and B, the ORR using the local determination of disease response will be obtained. If the lower bound of a single-sided 95% confidence interval using the exact binomial method is less than 10% (i.e., 5 responses or less out of 25 patients) in either group, enrollment in that group will not continue. Below are the 95% single-sided lower confidence intervals for various response rates using a sample size of 25 patients and employing the exact binomial methodology.  
70  
Sample Size ORR Lower 95%  
Single-Sided Confidence Bound  
| Sample Size                                                        | ORR     | Lower 95%   |
|--------------------------------------------------------------------|---------|-------------|
| Single-Sided Confidence Bound                                      |         |             |
| 25                                                                 | 7 (28%) | 14.0%       |
| 25                                                                 | 6 (24%) | 11.0%       |
| 25                                                                 | 5 (20%) | 8.2%1       |
| 25                                                                 | 4 (16%) | 5.7%1       |
| 1 Would result in stopping enrollment in that particular group(s). |         |             |
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14.4.4. safety analysis

The analyses of safety will be conducted based on the Safety Population. Analyses will be stratified by treatment. Safety will be assessed based on AEs, SAEs, laboratory values, vital signs, and ECG results. Summary tables will be produced for all reported treatment-emergent AEs (TEAEs), defined as AEs that start or worsen on or after the first administration of study treatment. The reported AE term will be assigned a standardized preferred term using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). TEAEs will be summarized based on the number and percentage of subjects experiencing the event by MedDRA system organ class and preferred term. The causal relationship between the occurrence of an AE and study treatment will be judged by the Investigator. In the event a subject experiences repeat episodes of the same AE, then the event with the highest severity grade and the event with the strongest causal relationship to study drug will be used for purposes of incidence tabulations. Tabular summaries will be provided for:
All TEAEs  
TEAEs by relationship to study treatment TEAEs by severity TEAEs occasioning treatment modification Serious TEAEs
All deaths that occur on study (defined as during treatment or within 30 days of treatment discontinuation) will be reported in a subject listing, which will include the primary cause of death and the number of days between the date of the last dose of study treatment and death. For subjects on combination treatment, the listing will show the date of last dose of each component. Hematology and serum chemistries will be summarized using conventional summary statistics (mean, standard deviation, median, and range) for the following: baseline value, minimum and maximum post-baseline values, average post-baseline value, and last post-baseline value. Standard shift tables will also be prepared presenting worst post-baseline toxicity grade vs baseline. Vital signs and ECG results will be summarized in a descriptive manner by calculating Prior and concomitant medications will be coded to the generic term using the current version of the World Health Organization Drug Dictionary and will be tabulated by group and listed by subject.
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14.4.5. pharmacokinetic analysis

71 the mean, standard deviation, median, and range by time point in the same manner described for laboratory values. Population PK analysis will be conducted to further understand the PK profile of CUDC-907 in patients with RR MYC-altered DLBCL. Linear mixed-effect modeling and/or a nonlinear mixed-effect modeling approach will be used in the study to better understand the PK profile of CUDC-907 in general Preliminary PK information has been collected during Phase 1, and the basic PK models of the drug have been established. In this study, blood samples will be obtained at 2 hours post-dose on Cycle 1 Day 1, Cycle 4 Day 1, and on Day 1 of every other cycle thereafter (i.e., Day 1 of Cycles 6, 8, 10, etc.). In addition, for the first 50 subjects enrolled on amendment 4, blood samples will also be obtained 2 hours post-dose on Days 8 and 15 of Cycle 1.
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14.4.8. missing data

Unless otherwise stated, there will be no imputation of missing data, but dates for AEs and concomitant medications may be imputed conservatively if partial. Regulatory authorities, the IRB/Independent Ethics Committee (IEC), and/or the Sponsor's clinical quality assurance group, or its designee, may request access to all source documents, eCRFs, and other study documentation for on-site audit or inspection. Direct access to these documents must be guaranteed by the Investigator, who must provide support at all times for these activities.
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15.1. case report forms and

For each subject, an eCRF and corresponding source records will be maintained at each clinical site. The eCRFs should be completed in a timely manner, and every effort should be made to have electronic forms completed and up-to-date in anticipation of a visit by the Sponsor's monitor. The Investigator must prepare and maintain adequate and accurate records of all observations and other data pertaining to the clinical study for each study participant. All aspects of the study will be carefully monitored with respect to GCP and standard operating procedures for compliance with applicable government regulations. The study monitor will be an authorized individual designated by the Sponsor. The study monitor will have access to all records necessary to ensure integrity of the data and will periodically review the progress of the study with the PI. An electronic data capture system to manage data collection will be utilized during this trial. The electronic data capture system is a software tool designed to ensure quality assurance and facilitate data capture during clinical trials. The system is fully compliant with Code of Federal Regulations 21 Part 11. The Investigator will ensure the accuracy, completeness, and timeliness of the data reported to the Sponsor. Data collection processes and procedures will be reviewed and validated to ensure completeness, accuracy, reliability, and consistency.  
A complete audit trail will be maintained of all data changes. The Investigator (or designee) will cooperate with the Sponsor (or its representative[s]) for the periodic review of study documents to ensure the accuracy and completeness of the data capture system at each scheduled monitoring visit.
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15. study administration

Study staff will maintain appropriate medical and research records for this study, in compliance with International Conference on Harmonisation (ICH) E6, Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of subjects. Study staff will permit authorized representatives of regulatory agencies to examine (and when required by applicable law, to copy) research records for the purposes of quality assurance reviews, audits, and evaluation of the study safety, progress and data validity. The Investigator will provide the Sponsor with a fully executed FDA Form 1572 including the Investigator's curriculum vitae. The Investigator will indicate on Form 1572 the name and
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15.3. record retention

The Investigator will retain a copy of all study records in a secure location for a period of 2 years after the last approval of a marketing application and until there are no pending or contemplated marketing applications OR until at least 3 years have elapsed since the formal discontinuation of clinical development of the investigational product.
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15.4. protocol deviations and amendment

The Investigator is not permitted to alter or deviate from the protocol without written agreement from the Sponsor. Any such agreement should be reported by the Investigator to their IRB/IEC. An immediate and unapproved deviation is permitted if immediate health care concerns mandate it. All protocol revisions (amendments) must originate with and be documented by the Sponsor. The Investigator must submit the amendment to his/her IRB/IEC for review and approval prior to implementation. Documentation of approval signed by the chairperson or designee must be sent to the Sponsor.
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15.5. institutional review board/independent ethics

The protocol, ICF(s), recruitment materials, and all patient materials will be submitted to the IRB/IEC for review and approval. Approval of both the protocol and the consent form must be obtained before any patient is enrolled at any given investigative center, and a copy of the approval letter supplied to the Sponsor or Sponsor's designee. Any amendment to the protocol will require review and approval by the IRB/IEC before the changes are implemented in the study. 73 location of the clinical laboratory which will be used for subject evaluation. The laboratory's certification, certification number, and date of certification and the laboratory normal values will be provided. Any changes in the clinical laboratory or laboratory values will be provided promptly to the Sponsor who will report the changes to the FDA as required.  
During the course of the study, the Investigator shall make timely and accurate reports to the IRB/IEC on study progress at intervals not exceeding one year, as well as satisfying any other local IRB/IEC reporting regulations. Copies of all reports to, and correspondence with, the IRB/IEC must be provided to the Sponsor or Sponsor's designee. Further, within three months of the completion or early termination of the study, a final report should be made to the IRB/IEC and Sponsor by the Investigator. It is the Investigator's obligation to maintain an IRB/IEC correspondence file and to make this available for review to Sponsor representatives as part of the routine study monitoring process.
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15.6. study committees

A Safety Review Committee (SRC) comprised of the Medical Monitor, PI, and Sponsor representatives will be convened to review safety information for ongoing safety surveillance.
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15.7. sponsor monitoring

Monitoring and auditing procedures approved by the Sponsor will be followed in order to comply with GCP guidelines. After satisfactory receipt of all necessary regulatory paperwork, the Sponsor's monitor will arrange that all study material be delivered to the study site at a mutually convenient time. An initiation visit by the Sponsor and its monitoring personnel will be made. At this meeting, all personnel expected to be involved in the conduct of the study will undergo an orientation to include review of study protocol, instruction for eCRF completion and overall responsibilities, including those for drug accountability and study file maintenance. 74 The SRC is tasked with making a recommendation to continue or stop the trial based on their assessment of available efficacy and safety information (see Section 9.3.2 for SRC stopping criteria). Throughout the course of the study, the Sponsor's monitor will make frequent contact with the Investigator. This will include telephone and/or on-site visits. On-site checking of the eCRFs for completeness and clarity, cross-checking with source documents, and clarification of administrative matters will be performed. As part of the data audit, it is expected that source documents (e.g., hospital records, office records) will be made available for review by the monitor. The monitor also will perform drug accountability checks, and may periodically request review of the Investigator's study file to assure completeness of documentation in all respects of study conduct. Upon study completion, the monitor will arrange for a final review of the study files, after which the file should be secured by storage for the appropriate period as specified in Section 15.3. The Investigator or appointed delegate will receive the Sponsor's representative during these on-site visits and will cooperate in providing the documents for inspection and responding to inquiries that may arise as part of this review. The Investigator will also permit inspection of the study files by authorized representatives of the FDA and regulatory authorities of other countries.
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15.8. publication/data sharing policy

Publication by the sites of any data from this study must be in accordance with the clinical trial agreement.
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16.1. ethical conduct of the

The study will be conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH, GCP guidelines, applicable regulatory requirements, and Curis policies. The Investigator will ensure that this study is conducted in full conformity with the principles set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Patients of Research, as drafted by the U.S. National Commission for the Protection of Human Patients of Biomedical and Behavioral Research (18 April 1979) and codified in 45 Code of Federal Regulations (CFR) Part 46 and/or the ICH E6.
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16. ethics/protection of human patients

Informed consent is a process that is initiated prior to the individual agreeing to participate in the study and continues throughout study participation. Extensive discussion of risks and possible benefits of study participation will be provided to patients and their families, if applicable. A consent form describing in detail the study procedures and risks will be given to the patient. Before each patient is enrolled in the clinical study, written informed consent will be obtained from the patient according to the regulatory and legal requirements of the participating country. The patient will receive all information that is required by regulatory authorities and ICH guidelines. The Investigator (or designee) will provide the Sponsor with a copy of the IRB-/ IEC-approved ICF prior to the start of the study. The ICF must be signed and dated; one copy will be given to the patient and the Investigator will retain a copy as part of the clinical study records. The Investigator will not undertake any investigation specifically required for the clinical study until written consent has been obtained. The terms of the consent and when it was obtained must also be documented. Patients will be given the opportunity to discuss the study with their surrogates or think about it prior to agreeing to participate. They may withdraw consent at any time throughout the course of the study. The rights and welfare of the patients will be protected by emphasizing to them that the quality of their clinical care will not be adversely affected if they decline to participate in this study. If a protocol amendment is required, then the ICF may need to be revised to reflect the changes to the protocol. If the ICF is revised, it must be reviewed and approved by the responsible IRB/IEC and signed by all subjects subsequently enrolled in the clinical study as well as those currently enrolled in the clinical study. Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization will be obtained and documented from each patient prior to entry into the study. The consent process will be documented in the eCRF.
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16.3. confidentiality and data protection

All clinical study findings and documents will be regarded as confidential. Study documents (protocols, Investigator's Brochures, and other material) will be stored appropriately to ensure 76 their confidentiality. Patient data will be made available upon request to monitors from the Sponsor, the FDA, the Institutional Review Board, and to other government agencies that have responsibility for clinical research activities. The anonymity of participating subjects must be maintained. Data that are released by the Investigator to the Sponsor, the FDA, or IRB/IEC will not be directly traceable to the patient. Documents that identify the patient (e.g., the signed informed consent document) must be maintained in confidence by the Investigator. In the event that a publication of this research incorporates a patient's medical data, that data will not identify the patient. Akyurek N, Uner A, Benekli M, Barista I. Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. Cancer. 2012 Sep 1;118(17):4173-83. Asano T, Yao Y, Zhu J, Li D, Abbruzzese JL, Reddy SA. The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells. Oncogene. 2004 Nov;23(53):8571-80. Barrans S, Crouch S, Smith A, Turner K, Owen R, Patmore R, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010 Jul 10;28(20):3360-5. Barrington SF, Mikhaeel NG, Kostakoglu L, Meignan M, Hutchings M, Müeller SP, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014 Sep 20;32(27):3048-58. Bechard M, Dalton S. Subcellular localization of glycogen synthase kinase 3beta controls embryonic stem cell self-renewal. Mol Cell Biol. 2009 Apr;29(8):2092-104. Bray F, Ren JS, Masuyer E, Ferlay J. Estimates of global cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer. 2013 Mar 1;132(5):1133-45. Carbone PP, Kaplan H, Musshoff K, Smithers D, Tubiana M. Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res. 1971;Nov 31(11):1860-1861. Carbone A, Gloghini A, Kwong YL, Younes A. Diffuse large B cell lymphoma: using pathologic and molecular biomarkers to define subgroups for novel therapy. Ann Hematol. 2014 Aug;93(8):1263-77. Chambers AE, Banerjee S, Chaplin T, Dunne J, Debernardi S, Joel SP, et al. Histone acetylation-mediated regulation of genes in leukaemic cells. Eur J Cancer. 2003 May;39(8):1165-75. Cheah CY, Oki Y, Westin JR, Turturro F. A clinician's guide to double hit lymphomas. Br J Haematol. 2015 Mar;168(6):784-95. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. 77 17. **LIST OF REFERENCES**
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and Colosia A, Njue A, Trask PC, Olivares R, Khan S, Abbe A, et al. Clinical efficacy and safety in relapsed/refractory diffuse large B-cell lymphoma: a systematic literature review. Clin Lymphoma Myeloma Leuk. 2014 Oct;14(5):343-355.e6. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995 Dec 21-28;378(6559):785-9. Cuccuini W, Briere J, Mounier N, Voelker HU, Rosenwald A, Sundstrom C, et al. MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation. Blood. 2012 May 17;119(20):4619-24. Duan H, Heckman CA, Boxer LM. Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol Cell Biol. 2005 Mar;25(5):1608-19. Food and Drug Administration/Center for Drug Evaluation and Research [Internet]. Guidance for industry. Clinical trial endpoints for the approval of cancer drugs and biologics. [Updated 2007; cited 2015 Oct 26]. Available from: http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071590.pdf Friedberg JW, Fisher RI. Diffuse large B-cell lymphoma. Hematol Oncol Clin North Am. 2008 Oct;22(5):941-52. Gandhi S. Diffuse large cell lymphoma. Medscape Drugs & Diseases [Internet]. 2014 Jan 6 [cited 2015 October 28]. Available from: http://emedicine.medscape.com/article/202969overview\#aw2aab6b2b5 Gisselbrecht G, Glass B, Laurent G, Gill DS, Linch MD, Trneny M, et al. Maintenance with rituximab after autologous stem cell transplantation in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL): CORAL final analysis. J Clin Oncol. 2011 May 20 Supplement;29(15):8004. 78 response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012 Oct 1;30(28):3460-7. Gui CY, Ngo L, Xu WS, Richon VM, Marks PA. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1241-6. Gupta M, Maurer MJ, Wellik LE, Law ME, Han JJ, Ozsan N, et al. Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP. Blood. 2012 Nov 22;120(22):4400-6.  
Horn H, Ziepert M, Becher C, Barth TF, Bernd HW, Feller AC, et al; German High-Grade NonHodgkin Lymphoma Study Group. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood. 2013 Mar 21;121(12):2253-63. Hu S, Xu-Monette ZY, Tzankov A, Green T, Wu L, Balasubramanyam A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013 May 16; 121(20):4021-31. Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012 Oct 1;30(28):3452–3. Kenney AM, Widlund HR, Rowitch DH. Hedgehog and PI-3 kinase signaling converge on Nmyc1 to promote cell cycle progression in cerebellar neuronal precursors. Development. 2004 Jan;131(1):217-28. 79 Howlader N, Noone AM, Krapcho M, Garshell J, Neyman N, Altekruse SF, et al (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER web site, April 2014. Klapper W, Stoecklein H, Zeynalova S, Ott G, Kosari F, Rosenwald A, et al; German High-Grade Non-Hodgkin's Lymphoma Study Group. Structural aberrations affecting the MYC locus indicate a poor prognosis independent of clinical risk factors in diffuse large B-cell lymphomas treated within randomized trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). Leukemia. 2008 Dec;22(12):2226-9. Kluk MJ, Chapuy B, Sinha P, Roy A, Dal Cin P, Neuberg DS, et al. Immunohistochemical detection of MYC-driven diffuse large B-cell lymphomas. PLoS One. 2012;7(4):e33813. Kumar A, Marqués M, Carrera AC. Phosphoinositide 3-kinase activation in late G1 is required for c-Myc stabilization and S phase entry. Mol Cell Biol. 2006 Dec;26(23):9116-25. Kurland JF, Tansey WP. Myc-mediated transcriptional repression by recruitment of histone deacetylase. Cancer Res. 2008 May 15;68(10):3624-9. Li S, Weiss VL, Wang XJ, Desai PA, Hu S, Yin CC, et al. High-grade B-cell Lymphoma With MYC Rearrangement and Without BCL2 and BCL6 Rearrangements Is Associated With High P53 Expression and a Poor Prognosis. Am J Surg Pathol. 2016 Feb;40(2):253-61. Liu T, Tee AE, Porro A, Dwarte T, Liu PY, Iraci N, et al. Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis. Proc Natl Acad Sci USA. 2007 Nov 20; 104(47):18682-7. Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol. 1989 Nov 1;7(11):1630-6. Macpherson N, Lesack D, Klasa R, Horsman D, Connors JM, Barnett M, et al. Small noncleaved, non-Burkitt's (Burkit-Like) lymphoma: cytogenetics predict outcome and reflect clinical presentation. J Clin Oncol. 1999 May;17(5):1558-67. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-655. Oki Y, Noorani M, Lin P, Davis RE, Neelapu SS, Ma L, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol. 2014 Sep;166(6):891-901. Perry AM, Alvarado-Bernal Y, Laurini JA, Smith LM, Slack GW, Tan KL, et al. MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab. Br J Haematol. 2014 May;165(3):382-91. Petrich AM, Gandhi M, Jovanovic B, Castillo JJ, Rajguru S, Yang DT, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood. 2014 Oct 9;124(15):2354-61. Pfeifer M, Grau M, Lenze D, Wenzel SS, Wolf A, Wollert-Wulf B, et al. PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12420-5. Polack A, Eick D, Koch E, Bornkamm GW. Truncation does not abrogate transcriptional downregulation of the c-myc gene by sodium butyrate in Burkitt's lymphoma cells. EMBO J. 1987 Oct;6(10):2959-64. Qian C, Lai CJ, Bao R, Wang DG, Wang J, Xu GX, et al. Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin Cancer Res. 2012 Aug 1;18(15):4104-13. Savage KJ, Johnson NA, Ben-Neriah S, Connors JM, Sehn LH, Farinha P, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009 Oct 22;114(17):3533-7. 80 Miura K, Takahashi H, Nakagawa M, Izu A, Sugitani M, Kurita D, et al. Clinical significance of co-expression of MYC and BCL2 protein in aggressive B-cell lymphomas treated with a second line immunochemotherapy. Leuk Lymphoma. 2015 Oct 22:1-7. Scott DW, Mottok A, Ennishi D, Wright GW, Farinha P, Ben-Neriah S, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2015 Sep 10;33(26):2848-56. Sehn LH. Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program. 2012;2012:402-9. Swerdlow SH, Campo E, Harris NL, et al, eds.WHO classification of tumours of haematopoieticand lymphoid tissues. In: Bosman FT, Jaffe ES,Lakhani SR, Ohgaki H, eds. World Health Organization Classification of Tumours. Lyon,France: I ARC; 2008. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May 19;127(20):2375-90 Thieblemont C, Briere J, Mounier N, Voelker HU, Cuccuini W, Hirchaud E, et al. The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy Tzankov A, Xu-Monette ZY, Gerhard M, Visco C, Dirnhofer S, Gisin N, et al. Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP. Mod Pathol. 2014 Jul;27(7):958-71. 81 in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study. J Clin Oncol. 2011 Nov 1;29(31):4079-87. Valera A, López-Guillermo A, Cardesa-Salzmann T, Climent F, González-Barca E, Mercadal S, et al; Grup per l'Estudi dels Limfomes de Catalunya i Balears (GELCAB). MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Haematologica. 2013 Oct;98(10):1554-62. Visco C, Tzankov A, Xu-Monette ZY, Miranda RN, Tai YC, Li Y, et al. Patients with diffuse large B-cell lymphoma of germinal center origin with BCL2 translocations have poor outcome, irrespective of MYC status: a report from an International DLBCL rituximab-CHOP Consortium Program Study. Haematologica. 2013 Feb;98(2):255-63. Zhang X, Zhao X, Fiskus W, Lin J, Lwin T, Rao R, et al. Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell. 2012;22(4):506-23. Zhou K, Xu D, Cao Y, Wang J, Yang Y, Huang M. C-MYC aberrations as prognostic factors in diffuse large B-cell lymphoma: a meta-analysis of epidemiological studies. PLoS One. 2014 Apr 16;9(4):e95020.  
82  
APPENDIX A. EASTERN COOPERATIVE ONCOLOGY GROUP  
(ECOG) PERFORMANCE STATUS SCALE  
| ECOG Performance Status   |                                                                                                                                                            |
|---------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                     | Description                                                                                                                                                |
| 0                         | Fully active, able to carry on all predisease performance without restriction                                                                              |
| 1                         | Restricted in physically strenuous activity but ambulatory and able to carry out work of a light  or sedentary nature, e.g., light house work, office work |
| 2                         | Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and  about more than 50% of waking hours                            |
| 3                         | Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours                                                                   |
| 4                         | Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair                                                                        |
| 5                         | Dead                                                                                                                                                       |
| Source: Oken et al, 1982  |                                                                                                                                                            |  
1. Stage According to Sites Involved by Lymphoma
table of contents list of
stage features

I Involvement of a single lymph node region* or lymphoid structure II Involvement of two or more lymph node regions,* or localized involvement of one extranodal site and one or lymph node regions, all on the same side of the diaphragm III Involvement of lymph node regions* or structures on both sides of the diaphragm 83
table of contents list of
appendix b. ann arbor classification

IV Diffuse or disseminated involvement of one or more extralymphatic organs, OR isolated extralymphatic organ involvement without adjacent regional lymph node involvement, but with disease in distant site(s), OR any involvement of the liver, bone marrow, pleura or CSF
* Lymph node regions include: right cervical (including cervical, supraclavicular, occipital, and preauricular lymph nodes), left cervical, right axillary, left axillary, right infraclavicular, left infraclavicular, mediastinal, hilar, periaortic, mesentery, right pelvic, left pelvic, right inguinal femoral, and left inguinal femoral
table of contents list of
2. relevant suffixes suffix meaning

A Absence of constitutional symptoms B Constitutional symptoms: fever (> 38°C), drenching sweats, weight loss (10% body weight over 6 months)
E Involvement of a single, extranodal site contiguous or proximal to a known nodal site
(stages I to III only; additional extranodal involvement is stage IV)
S Splenic involvement X Bulky disease, defined as one or more site of disease of > 10 cm diameter, or mediastinal widening to > 1/3 of the chest width on chest X-ray Other designations may include involved extranodal site(s): M = marrow, L = lung, H = liver, P = pleura, O = bone, D = skin and subcutaneous tissue; and the number of disease sites (e.g. II2, II4)
Source: Adapted from Carbone et al, 1971 and Lister et al, 1989
appendix c. recommendations for initial
lugano classification

| Table 3. Revised Criteria for Response Assessment             |                                                              |                                                           |
|---------------------------------------------------------------|--------------------------------------------------------------|-----------------------------------------------------------|
| Response and Site                                             | PET-CT-Based Response                                        | CT-Based Response                                         |
| Complete                                                      | Complete metabolic response                                  | Complete rediologic response (all of the following)       |
| Lymph nodes and                                               | Score 1, 2, or 3" with or without a residual mass on 5PSt    | Target nodes/nodal masses must regress to ~ 1.5 cm in LDi |
| extralymphatic sites                                          | It is recognized that in Waldeyer's ring or extranodal sites | No extralymphatic sites of disease                        |
| 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         |                                                              |                                                           |
| utake                                                         |                                                              |                                                           |
| Nonmeasured lesion                                            | Not applicable                                               | Absont                                                    |
| Organ enlargement                                             | Not applicable                                               | Regress to normal                                         |
| New lesions                                                   | None                                                         | None                                                      |
| No evidence of FDG-avid disease in marrow                     |                                                              |                                                           |
| Bone marrow                                                   | Normal by morphology; if indeterminate, IHC negative         |                                                           |
| Partial                                                       | Partial metabolic response                                   | Partial remission (all of the following)                  |
| Score 4 or 5t with reduced uptake compared with baseline      | ≥ 50% decrease in SPD of up to 6 target measurable nodes     |                                                           |
| Lymph nodes and                                               |                                                              |                                                           |
| extralymphatic sites                                          | and residual mass(es) of any size                            | 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      | Not applicable                                            |
| 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                                           |                                                              |                                                           |
| No response or stable disease                                 | No metabolic response                                        | Stable disease                                            |
| Score 4 or 5 with no significant change in FDG uptake from    | < 50% decrease from baseline in SPD of up to 6 dominant,     |                                                           |
| Target nodes/nodal masses,                                    |                                                              |                                                           |
| oxtranodal losions                                            | baseline at interim or end of treatment                      | maasurable nodes and extranedal 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 progression                   |
| New lesions                                                   | None                                                         | None                                                      |
| Bone marrow                                                   | No change from baseline                                      | Not applicable                                            |
| Progressive disease requires at least 1 of the following      |                                                              |                                                           |
| Progressive disease                                           | Progressive metabolic disease                                |                                                           |
| Individual target nodes/nodal                                 | Score 4 or 5 with an increase in intensity of uptake from    | PD progression:                                           |
| masses                                                        | baseline and/or                                              |                                                           |
| Extranodal lesions                                            | New FDG-avid foci consistent with lymphorna at interim or    | An individual node/lesion must be abnormal with:          |
| end-of-treatment assessment                                   | 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                                                       |                                                              |                                                           |
| (continued on following page)                                 |                                                              |                                                           |  
CUDC-907 Protocol CUDC-907-201 Amendment 4 30 August 2016  
| Table 3. Revised Criteria for Response Assessment (continued)                                                                                                  |                                                            |                                         |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|-----------------------------------------|
| Response and Site                                                                                                                                              | PET-CT–Based Response                                      | CT-Based Response                       |
| Now losions                                                                                                                                                    | New FDG-avid foci consistent with lymphoma rather than     | Regrowth of previously resolved lesions |
| another etiology (eg, infection, inflammation). If                                                                                                             | A new node > 1.5 cm in any axis                            |                                         |
| uncertain regarding etiology of new lesions, biopsy or                                                                                                         | A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in |                                         |
| interval scan may be considered                                                                                                                                | any axis, its presence must be unequivocal and must be     |                                         |
| attributable to lymphoma                                                                                                                                       |                                                            |                                         |
| Assessable disease of any size unequivocally attributable to                                                                                                   |                                                            |                                         |
| lymphorna                                                                                                                                                      |                                                            |                                         |
| Bone marrow                                                                                                                                                    | New or recurrent FDG-avid foci                             | New or recurrent involvement            |
| Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunchistochemistry; 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.                                                                       |                                                            |                                         |
| * A 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 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        |                                                            |                                         |
| proportional and the proportion of the body and should include, where applicable, modiastinal and retroportioneal 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 regurements 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             |                                                            |                                         |  
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).  
†PET 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.  
Source: Cheson et al, 2014 86 APPENDIX D. **ROLE OF IMAGING IN THE STAGING AND RESPONSE**
ASSESSMENT OF LYMPHOMA: CONSENSUS OF THE
INTERNATIONAL CONFERENCE ON MALIGNANT
LYMPHOMAS IMAGING WORKING GROUP; 5-PS SCORE
The 5-PS scores the most intense uptake in a site of initial disease, if present, as follows:
1. No uptake above background  
2. Uptake <mediastinum 3. Uptake >mediastinum but <liver 4. Uptake moderately higher than liver 5. Uptake markedly higher than liver and/or new lesions X. New areas of uptake unlikely to be related to lymphoma
Source: Barrington et al, 2014
appendix c. recommendations for initial
87 appendix e. international prognostic

One point is assigned for each of the following risk factors:
Age greater than 60 years Stage III or IV disease Elevated serum LDH
ECOG/Zubrod performance status of 2, 3, or 4 More than 1 extranodal site Source: The International Non-Hodgkin's Lymphoma Prognostic Factors Project, 1993