Clinical trial NCT03534180
Conditions: Anaplastic Large Cell Lymphoma Recurrent Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
Sponsor: City of Hope Medical Center
Start date: 2018-08-21; Completion date: 2023-07-26
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the side effects and best dose of venetoclax and romidepsin to see how well it works in treating patients with mature T-cell lymphoma that has come back (recurrent) or does not respond to treatment (refractory). Venetoclax and romidepsin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of the combination of venetoclax with romidepsin, including the dose ramp-up, in adults with relapsed or refractory mature T-cell lymphoma. (Safety Lead-in) II. To estimate the efficacy as measured by the overall response rate (ORR) of venetoclax in patients with relapsed or refractory mature T-cell lymphoma. (Phase 2)

SECONDARY OBJECTIVES:

I. To evaluate the complete response rate, duration of response, time to response, overall survival and progression free survival associated with venetoclax and romidepsin in relapsed/refractory mature T-cell lymphoma. (Phase 2) II. To further characterize the safety and toxicities of venetoclax and romidepsin combination in relapsed/refractory mature T-cell lymphoma. (Phase 2)

EXPLORATORY OBJECTIVES:

I. To determine BCL2 protein expression in base line treatment tumor samples and correlatieon with response.

II. To determine changes in Bcl-2 gene expression in pre- and post-treatment tumor samples of mature T- cell lymphoma.

OUTLINE: This is a safety lead-in dose-escalation study, followed by a phase II study.

Patients receive venetoclax orally (PO) once daily (QD) on days 1-28 and romidepsin intravenously (IV) on days 1, 8, and 15. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 24 months.

Arms: arm 1: Patients receive venetoclax PO QD on days 1-28 and romidepsin IV on days 1, 8, and 15. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Romidepsin intervention 3: Venetoclax
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given IV intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
IRB #18119 
 
11/03/2020 
Packet: 05 
CITY OF HOPE MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION 
 
 
TITLE:   A Phase 2 Study of Venetoclax and Romidepsin with Safety Lead-in for Treatment of 
Relapsed/Refractory Mature T-cell Lymphomas 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 18119                     PROTOCOL DATE: 11/03/2020 
 
Initial Review Submission 
 
(Protocol dated 05/10/2018)  
 
 
Version: 00 
COH Amendment 01  
 
(Protocol dated 07/12/2018)  
 
 
Version: 01 
COH Amendment 02  
 
(Protocol dated 03/08/2019)  
 
 
Version: 02 
COH Amendment 03  
 
(Protocol dated 11/21/2019)  
 
 
Version: 03 
COH Amendment 04  
 
(Protocol dated 11/03/2020)  
 
 
 Packet: 04 
COH Amendment 05 at Cont. 
(Protocol dated 11/03/2020)(TP) 
 
 
 Packet: 05 
 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
 
 
DISEASE SITE: 
 
 
T-cell Lymphoma 
 
 
 
  
 
STAGE: 
 
 
 
Relapsed/Refractory  
 
 
 
 
MODALITY:  
 
 
 
  
 
TYPE:  
 
 
 
Phase II 
 
PRINCIPAL INVESTIGATOR: 
Jasmine Zain, M.D. 
 
 
 
 
 
 
CO INVESTIGATOR:  
 
Steven Rosen, M.D. 
 
PARTICIPATING CLINICIANS: 
Elizabeth Budde, M.D., Ph.D.  
  
 
 
 
 
Alex Herrera, M.D.  
  
 
 
 
 
Larry Kwak, M.D., Ph.D.  
  
 
 
 
 
Matthew Mei, M.D.  
  
 
 
 
 
Liana Nikolaenko, M.D.  
  
 
 
 
 
Leslie Popplewell, M.D.  
  
 
 
 
 
Christiane Querfeld, M.D., Ph.D  
  
 
 
 
 
Tanya Siddiqi, M.D.  
 
 
BIOSTATISTICIAN   
 
Lu Chen, Ph.D.  
 
 
PARTICIPATING SITES: 
 
City of Hope Duarte 
 
 
 
 
 
University of Nebraska 


This document is confidential and for research purposes only. Do not copy, redistribute, 
disclose or use except as authorized.  
Office of Clinical Protocol Development 
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
A Phase 2 Study of Venetoclax and Romidepsin with Safety Lead-in for 
Treatment of Relapsed/Refractory Mature T-cell Lymphomas 
 
Version Date: 11/03/20 
Protocol Version: 04 
City of Hope #: 18119 
Agents: Venetoclax 
IND Number: 140127 
Sponsor/ IND Holder: City of Hope 
Funding Support/Industry Partner: AbbVie  
NCT Number: NCT03534180 
Participating Sites: City of Hope, University of Nebraska  
 
 
Principal Investigator 
Jasmine Zain, MD 
City of Hope National Medical Center 
Dept. of Hematology 
T: (626)-256-4673 ext 82405 
Email: jazain@coh.org 
Coordinating Center 
Data Coordinating Center 
City of Hope National Medical Center 
T: (626)-218-7904 
Email: DCC@coh.org 
 


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PROTOCOL TEAM 
Biostatistician 
Lu Chen, PhD 
City of Hope National Medical 
Center 
Dept. Computational and 
Quantitative Medicine  
T: 626-218-6266 
Email: lchen@coh.org  
Protocol Development Scientist 
D. Lynne Smith, PhD 
City of Hope National Medical Center 
Toni Stephenson Lymphoma Center 
T: 626-218-1134 
Email: lysmith@coh.org  
 
o-Co-Investigator 
Steven Rosen, M.D. 
Director, Comprehensive Cancer 
Center and Beckman Research 
Institute 
City of Hope National Medical 
Center 
Dept. of Pathology 
T: (626)-218-9150 
Email: srosen@coh.org  
 
 
 
 
Participating non-COH sites  
Site PI 
Matthew Lunning 
University of Nebraska Medical 
Center 
986840 Nebraska Medical Center 
Omaha, NE 68198-6840 
T: 402-559-8500 
Email: mlunning@unmc.edu 
 
 
 
Site PI 
 
 
 


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EXPERIMENTAL DESIGN SCHEMA 
 
 
 


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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2 Study of Venetoclax and Romidepsin with Safety Lead-in for Treatment of Relapsed/Refractory Mature T-cell 
Lymphomas 
Study Detail 
Population/Indication(s): 
Peripheral T-cell Lymphoma (PTCL) 
Phase: 
Safety Lead-in/ Phase 2 
Sample Size: 
Safety Lead-in: 6 evaluable 
Phase 2: 18 evaluable (Safety Lead-in patients included) 
Estimated Accrual Duration: 
24 months 
Estimated Study Duration 
6 years 
Participant Duration: 
48 months 
Participating Sites: 
 City of Hope Duarte, CA 
 University of Nebraska 
Study Agents: 
Venetoclax, Romidepsin 
Sponsor: 
City of Hope 
Industry Partner:  AbbVie, Celgene   
Industry Partner Protocol #: 
11354 
Rationale for this Study 
Peripheral T cell lymphomas (PTCL) arise from post thymic lymphocytes, representing non-Hodgkin lymphoma (NHL) in the 
western populations. Based on  immunophenotyping, molecular, clinical and pathologic  features, there are about 22 different 
subtypes of PTCL that are broadly classified into nodal, extranodal, leukemic variant and cutaneous T cell lymphomas (CTCL) 
based on the site of origin of the disease. Approximately 5,000 new cases of PTCL are diagnosed annually in the US. Most PTCL 
cases have a dismal prognosis with a 5 year survival of less than 30% with the exception of ALK+ ALCL. 
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway. Bcl-2 over-expression is a major contributor 
to the pathogenesis of some types of lymphoid malignancies and has been extensively studied in B cell lymphomas, including CLL 
and DLBCL. In studies of T-cell lymphoma at City of Hope , Bcl-2 has been found to be expressed in 52-76% of cases of PTCL and 
25% of CTCL. So far there is no published data regarding the use of Bcl-2 inhibitors in the treatment of peripheral T cell lymphomas 
and cutaneous T cell lymphomas. 
Venetoclax (also known as ABT-199) is a novel, orally available, small molecule Bcl-2 family protein inhibitor that binds with high 
affinity to Bcl-2 and with lower affinity to other Bcl-2 family proteins such as Bcl-xL and Bcl-w. There is currently clinical experience 
with venetoclax in CLL/small lymphocytic leukemia and B-cell NHL. In the Phase 1 study of venetoclax in diffuse large B-cell 
lymphoma and follicular lymphoma the overall response rate was 15% and 34%  with a median duration of response of 3.3 months 
and 10 months, respectively. In diffuse large B-cell lymphoma, there is an ongoing trial evaluating the combination of venetoclax 
with rituximab or obinutuzumab plus CHOP (NCT02055820). We hypothesize that interference of BCL2 will lead to antitumor 
activity in mature T-cell lymphomas. 
Experience with the first 6 patients on the venetoclax monotherapy was that only 2 patients were able to complete the 
unacceptable toxicity evaluation period (2 cycles). PTCL are aggressive lymphomas, and during the first version of the protocol 
with a weekly ramp up it became evident that most patients progressed before the completion of C1. Three patients were 
enrolled on the weekly ramp up, two of them had clinical PD/PD after 1 cycle of therapy and terminated treatment without 
unacceptable toxicities; they had to be replaced. The 3rd patient completed 2 cycles with no unacceptable toxicities. The 
protoocl was then modified to accelerate the ramp up to 1 week. This is similar to studies of Venetoclax  that have been conducted 
in aggressive heamtological malignancies including AML[1] where a more rapid ramp up was studied and felt to be safe. Once the 
protocol was modified, 3 additional patients have been accured. Two patients are off-treatment before completing the 1st 
cycle without unacceptble toxicities and had to be replaced, due to disease progression (n=1) or due to neutropenia (n=1, 
several grade 2 and 3 neutropenia events but grade 3 only lasted for a day). The 3rd patient completed 2 cycles without 
unacceptable toxicities. Since it remains a promising strategy to be studied in PTCL, we propose to evaluate venetoclax in 


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combination with another active agent, the histone deacetylase inhibitor (HDACi) romidepsin. Romidepsin has regulatory 
approval for use as a single agent in relapsed CTCL and PTCL, and has been shown in vitro and in primary patient samples to act 
synergistically with venetoclax via effects on Bcl-2 family proteins to increase antineoplastic efficacy. Therefore it is hoped that 
addition of romidepsin will slow disease progression, allow patients to complete the unacceptable toxicity period in the Safety 
Lead-in portion of the trial and then enable accrual and evaluation on the phase 2 portion. 
Objectives 
Primary Objectives 
Safety Lead-in: 
 
To assess the safety and tolerability of the combination of venetoclax with romidepsin, including the dose ramp-up, in 
adults with relapsed or refractory mature T-cell lymphoma.  
Phase 2: 
 
To estimate the efficacy as measured by the overall response rate [ORR]) of venetoclax with romidepsin in patients with 
relapsed or refractory mature T-cell lymphoma. 
Phase 2 Secondary Objectives 
 
To evaluate the complete response rate, duration of response, time to response, overall survival and progression free 
survival associated with venetoclax and romidepsin in relapsed/refractory mature T-cell lymphoma. 
 
To further characterize the safety and toxicities of venetoclax and romidepsin combination in relapsed/refractory 
mature T-cell lymphoma. 
Exploratory Objective 
 
BCL2 protein expression in baseline treatment tumor samples and correlation with response  
 
To determine changes in Bcl-2 gene expression in pre- and post-treatment tumor samples of mature T- cell lymphoma 
 
Study Design 
This is an open-label multi-site Phase 2 study with a Safety Lead-in to test the safety and efficacy of venetoclax with romidepsin 
for the treatment mature T-cell lymphoma.  
During the safety-lead in, 6 evaluable participants will be enrolled using a 3+3 design. A Simon 2-stage optimal design will be 
utilized for the Phase 2 portion of the trial. Participants enrolled during the Safety Lead-in will be included in the Phase 2 portion 
of the study if they are evaluable for response. In the absence of study holds to accrual for toxicity or for futility, accrual will 
continue until 18 evaluable participants are treated. 
PTCL patients will be treated with up to 26 cycles with venetoclax and romidepsin. Treatment cycles will be 28-days.  
Participants will continue with treatment until disease progression, unacceptable toxicity or completion of 26 cycles of protocol 
therapy, whichever comes first.  
Evaluation Criteria and Endpoints 
Safety 
Toxicity will be recorded using the NCI CTCAE v 5.0. During the first 2 cycles, all grades of toxicity will be collected. After cycle 2, 
only the highest grade of any toxicity will be collected for each cycle during protocol treatment and for the period of safety follow-
up after end of treatment. 
Unacceptable toxicity for Safety Lead-in  
Unacceptable toxicity will be defined as one of the following AEs that is at least possibly related to either study drug within the 
first 2 cycles of protocol therapy:  


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 
Hematologic 
− 
Grade 3 or 4 neutropenia lasting > 7 days (despite the use of growth factor support) 
− 
Grade 4 thrombocytopenia associated with bleeding requiring transfusion 
− 
Grade 4 anemia not associated with lymphoma 
 
Non-hematologic 
− 
Clinical TLS (per Howard criteria)  
− 
Grade 4 metabolic laboratory abnormalities that do not resolve within 3 days to ≤ Grade 2 with supportive measures  
− 
Any other ≥ Grade 3 toxicity that does not resolve to ≤ Grade 1 or baseline within 7 days with the exception of: 
− 
Grade 3 asymptomatic laboratory abnormalities, including lipase or amylase, that are not clinically relevant, not requiring 
hospitalization or delay of treatment 
− 
Grade 3 nausea, vomiting, or fatigue controlled with supportive measures 
− 
Vitiligo  
Response 
Lugano Criteria 2014  
Clinical Outcome Endpoints 
Endpoint 
Definition 
Overall response rate 
(ORR) 
Proportion of patients achieving CR or PR 
Complete response 
(CR) rate 
Proportion of patients achieving CR 
Time to response 
Date of initiation of protocol treatment to date when criteria for response (PR or CR) is first 
met 
Duration of response 
(DOR) 
Date when criteria for response (CR or PR) is first met until date criteria for PD or relapse is 
first met 
Progression free 
survival (PFS) 
Date of initiation of protocol treatment to date  criteria for PD is first met or death as a 
result of any cause 
Overall survival (OS) 
Date of initiation of protocol treatment to date of death from any cause 
 
 
Statistical Considerations 
Safety Lead-in 
Up to 6 patients may be enrolled under a “3+3” design at  the proposed dose (maximum dose of 800 mg/day with a 1-week dose 
ramp up schedule). Unacceptable toxicities will be evaluated during the first 2 cycles of therapy. This will ensure monitoring of 
participants during the ramp-up period (Cycle 1, Days 1-8) and while participants are on steady-state dose (Cycle 1 Days 8-28, 
Cycle 2). Initially up to 3 patients can be enrolled and treated. After 3 patients are treated and evaluated for unacceptable 
toxicities, if 0/1 out of 3 patients experience unacceptable toxicities during the first 2 cycles, up to 3 additional patients will be 
enrolled and treated to bring the total number of patients treated to 6. If ≤1/6 patients experience unacceptable toxicities during 
the first 2 cycles, the proposed treatment dose/schedule will be considered tolerable and be used for the subsequent Phase 2 
response evaluation. If ≥2/3 (after the initial 3) or ≥2/6 (after the total 6 in 2 cohorts) patients experience unacceptable toxicities 
during the first 2 cycles, the accrual will be suspended and the study will be amended.  
Phase 2 
The primary endpoint for Phase 2 is ORR after 2 cycles of treatment. The response evaluation will be based on a Simon’s Two-
Stage Optimal design to distinguish a promising 30% response rate (alternative hypothesis) from a disappointing rate (null 
hypothesis) of 10%, at a one-sided type I error of 10% and a power of 80%. In the first stage, 7 evaluable subjects will be accrued. 
If there is 0 response among the 7, the study accrual will be suspended. If there are 1 or more responses among the 7, the study 
will remain open to accrue a total of 18 evaluable patients. Observing 4 or more responses among 18 evaluable patients will 


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reject the null hypothesis and indicate the response rate being promising in this study setting. Observing 3 or fewer responses 
among 18 evaluable patients will fail to reject the null hypothesis and will not establish efficacy of the treatment. 
Stopping rules for Tumor Lysis Syndrome (TLS) 
The study will implement accrual stopping rules for both clinical TLS and laboratory TLS. When a stopping rule is triggered, the 
study PMT will review and assess the safety of the trial and submit a report to the COH DSMC. The COH DSMC will review for 
approval any decision to continue or permanently suspend accrual to the trial. 
 
Clinical TLS Stopping Rule 
− 
Study accrual will be suspended when the first incidence of clinical TLS is reported.   
 
Laboratory TLS Stopping Rule 
The incidence of laboratory TLS will be monitored with 12% being the benchmark based on IB. Operationally, the study 
accrual will be suspended if:  
− 
1 patient experiences laboratory TLS when there have been ≤5 patients treated 
− 
2 patients experience laboratory TLS when there have been ≤14 patients treated 
− 
3 patients experience laboratory TLS regardless of the number of patients treated 
The rule is derived based on a <50% probability of the rule being triggered when the true laboratory TLS incidence is ≤12%. 
Abbreviated Eligibility Criteria 
Main Inclusion Criteria 
 
Adult relapsed/refractory PTCL (WHO criteria 2016) excluding CTCL. Transformed mycosis fungoides is allowed.  
 
ECOG ≤ 2 
 
Failed at least 2 prior systemic therapie 
 
Measurable disease (CT/MRI/PET-CT). At least one measurable lesion (Lugano 2014) 
 
ANC ≥ 1,000/mm3 * (unless documented bone marrow involvement by lymphoma) 
 
Platelets ≥ 30,000/mm3 * (unless documented bone marrow involvement by lymphoma) 
 
Total bilirubin ≤ 1.5 x ULN (except Gilbert’s Syndrome or documented hepatic involvement by lymphoma) 
 
ALT and AST ≤ 3 x ULN (≤ 5 x ULN if hepatic involvement by lymphoma) 
 
Creatinine clearance of ≥ 50 mL/min 
* Platelet transfusions/ growth factor not permitted within 7 days of assessment unless cytopenia is secondary to disease 
involvement 
Main Exclusion Criteria 
 
Bcl2 inhibitors 
 
Any systemic therapy, including monoclonal antibody within 28 days or 5 half-lives (whichever is shorter) of initiating 
protocol therapy 
 
Radiation and/or surgery (except lymph node or other diagnostic biopsies) within 14 days prior to Day 1 of protocol 
therapy 
 
Strong or moderate CYP3A inhibitors within 7 days prior to Day 1 of protocol therapy 
 
Strong or moderate CYP3A inducers within 7 days prior to Day 1 of protocol therapy 
 
P-gp inhibitors within 7 days prior to Day 1 of protocol therapy. 
 
Narrow therapeutic index P-gp substrates within 7 days prior to Day 1 of protocol therapy. 
 
Short course systemic corticosteroids for disease control, improvement of performance status or non-cancer indication 
within 7 days prior to Day 1 of protocol therapy. Stable ongoing corticosteroid use (i.e. at least 30 days) up to an 
equivalent dose of 20 mg of prednisone is permissible. 


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 
Patients with known cardiac abnormalities such as: 
− 
Congenital long QT syndrome 
− 
QTc (Corrected QT interval on ECG) interval >480 milliseconds 
− 
Any cardiac arrhythmia requiring anti-arrhythmic medication. 
 
Patients with a history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or 
cardiac arrest, unless currently addressed with an automatic implantable cardioverter defibrillator (AICD). 
 
 
Investigational Product Dosage and Administration 
 
All participants (safety lead-in and Phase 2) will ramp-up daily over the first week of Cycle 1 to the maximum venetoclax 
dose. From Cycle 1 Days 8-28 and Cycle 2+ Days 1-28, participants will continue at the maximum dose. 
 
Patients will be monitored for TLS on an outpatient basis for the first 8 days of treatment. 
 
 
Clinical Observations and Tests to be Performed 
 
Medical history and physical exam 
 
Safety assessments (CBCs with differential, comprehensive chemistry panel, EKG and coagulation) 
 
Post-dose TLS monitoring during Cycle 1 
 
CT/ MRI/ PET-CT scans  
 
Correlative tumor tissue  
 
 


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TABLE OF CONTENTS 
SECTION ...........................................................................................................................................          PAGE 
Protocol Team ................................................................................................................................................ 2 
Experimental Design Schema ......................................................................................................................... 3 
Protocol Synopsis............................................................................................................................................ 4 
Table of Contents ........................................................................................................................................... 9 
List of Tables and Figures .............................................................................................................................. 11 
Abbreviations ................................................................................................................................................ 12 
1.0 
Objectives ....................................................................................................................................... 13 
1.1 
Primary Objectives .................................................................................................................................... 13 
1.2 
Phase 2 Secondary Objectives .................................................................................................................. 13 
1.3 
Exploratory Objectives .............................................................................................................................. 13 
2.0 
Background..................................................................................................................................... 14 
2.1 
Introduction/Rationale for Development ................................................................................................. 14 
2.2 
BCL2 and Mature T-Cell Lymphomas ........................................................................................................ 14 
2.3 
Venetoclax ................................................................................................................................................ 15 
2.4 
HDAC inhibition in mature T cell lymphomas ........................................................................................... 17 
2.5 
Romidepsin ............................................................................................................................................... 17 
2.6 
Combination of Bcl-2 inhibitors and HDACi .............................................................................................. 18 
2.7 
Overview and Rationale of Study Design .................................................................................................. 19 
3.0 
Eligibility Criteria ............................................................................................................................ 21 
3.1 
Inclusion Criteria ....................................................................................................................................... 21 
3.2 
Exclusion Criteria ...................................................................................................................................... 22 
4.0 
Participant Enrollment ................................................................................................................... 25 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures ................................................................. 25 
4.2 
Participant Enrollment .............................................................................................................................. 25 
4.3 
Slot verification and reservation ............................................................................................................... 25 
4.4 
Registration Process ................................................................................................................................. 25 
4.5 
Screen Failures and Registered Participants Who Do Not begin Study Treatment .................................. 26 
5.0 
Treatment Program ........................................................................................................................ 26 
5.1 
Treatment Program Overview .................................................................................................................. 26 
5.2 
Treatment Cycle Definition ....................................................................................................................... 26 
5.3 
Treatment Plan ......................................................................................................................................... 27 
5.4 
Agent Administration ................................................................................................................................ 27 
5.5 
Assessments and Special Monitoring ....................................................................................................... 28 
5.6 
Duration of Therapy and Criteria for Removal from Protocol Therapy .................................................... 29 
5.7 
Follow-Up.................................................................................................................................................. 29 
5.8 
Duration of Study Participation ................................................................................................................ 30 
5.9 
Supportive Care, Prohibited Medications and Concomitant Therapy ...................................................... 30 
6.0 
Anticipated Toxicities & Dose Modification/ Delay Guidelines ...................................................... 34 
6.1 
Anticipated Toxicities ................................................................................................................................ 34 
7.0 
Dose Delay/ Modification Guidelines ............................................................................................. 36 
7.1 
General Information ................................................................................................................................. 36 
7.2 
Treatment Modification Guidelines .......................................................................................................... 36 
8.0 
Agent Information .......................................................................................................................... 40 
8.1 
Venetoclax ................................................................................................................................................ 40 
8.2 
Romidepsin ............................................................................................................................................... 41 
9.0 
Correlative/ Special Studies............................................................................................................ 44 
9.1 
Tumor Tissue Studies ................................................................................................................................ 44 
10.0 
Study Calendar ............................................................................................................................... 46 


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11.0 
Endpoint Evaluation Criteria/Measurement of Effect .................................................................... 49 
11.1 
Safety ........................................................................................................................................................ 49 
11.2 
Unacceptable Toxicity During Safety Lead-In ........................................................................................... 49 
11.3 
Efficacy Endpoints ..................................................................................................................................... 49 
12.0 
Statistical Considerations ............................................................................................................... 51 
12.1 
Statistical Design ....................................................................................................................................... 51 
12.2 
Accrual and Expected Duration of Trial .................................................................................................... 52 
12.3 
Evaluable Participants and Participant Replacement ............................................................................... 52 
12.4 
Stopping Rules for Tumor Lysis Syndrome (TLS) ....................................................................................... 53 
12.5 
Statistical Analysis Methods ..................................................................................................................... 53 
13.0 
Data Handling, Data Management, Record Keeping ...................................................................... 55 
13.1 
Source Documents .................................................................................................................................... 55 
13.2 
Data Capture Methods and Management ................................................................................................ 55 
13.3 
Case Report Forms/Data Submission Schedule ........................................................................................ 55 
13.4 
Regulatory Records ................................................................................................................................... 55 
14.0 
Adverse Events and Unanticipated Problems ................................................................................ 56 
14.1 
Definitions................................................................................................................................................. 56 
14.2 
Assessment of Adverse Events ................................................................................................................. 57 
14.3 
Reporting of Adverse Events ..................................................................................................................... 58 
14.4 
Secondary Malignancy .............................................................................................................................. 62 
14.5 
Tumor Lysis Syndrome .............................................................................................................................. 62 
14.6 
Overdose................................................................................................................................................... 62 
14.7 
Pregnancies ............................................................................................................................................... 62 
15.0 
Protocol Deviations and Single Subject Exceptions ........................................................................ 63 
15.1 
Definitions................................................................................................................................................. 63 
15.2 
Reporting of Deviations and SSEs ............................................................................................................. 63 
16.0 
Study Oversight, Quality Assurance, and Data & Safety Monitoring ............................................. 65 
16.1 
All Investigator Responsibilities ................................................................................................................ 65 
16.2 
Study Principal Investigator Responsibilities ............................................................................................ 65 
16.3 
Protocol Management Team (PMT) ......................................................................................................... 65 
16.4 
Monitoring ................................................................................................................................................ 66 
16.5 
Quality Assurance ..................................................................................................................................... 66 
16.6 
City of Hope Data and Safety Monitoring Committee .............................................................................. 66 
17.0 
Ethical and Regulatory Considerations ........................................................................................... 67 
17.1 
Ethical Standard ........................................................................................................................................ 67 
17.2 
Regulatory Compliance ............................................................................................................................. 67 
17.3 
Institutional Review Board ........................................................................................................................ 68 
17.4 
Informed Consent ..................................................................................................................................... 68 
17.5 
Participant Withdrawal ............................................................................................................................. 69 
17.6 
Special and Vulnerable Populations.......................................................................................................... 69 
17.7 
Participant Confidentiality ........................................................................................................................ 70 
17.8 
Use of Unused (Leftover) Specimens Collected for this Trial .................................................................... 70 
17.9 
Conflict of Interest .................................................................................................................................... 71 
17.10 
Financial Obligations, Compensation, and Reimbursement of Participants ............................................. 71 
17.11 
Publication/ Data Sharing ......................................................................................................................... 71 
18.0 
References ...................................................................................................................................... 72 
Appendix A: Performance Status .................................................................................................................. 75 
Appendix B: Tumor Lysis Syndrome Classification ....................................................................................... 76 
Appendix C-1: PTCL-Disease Parameters & Methods of Evaluation and Response ..................................... 77 
Appendix C-2: PTCL Response Criteria .......................................................................................................... 80 
Appendix D: Sample List of Prohibited and Cautionary Agents .................................................................... 84 
Appendix E: NYHA Cardiac Grading Criteria ................................................................................................. 85 


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Appendix F-1: Tissue Shipping Guidelines for External Non-COH Sites ........................................................ 86 
Appendix F-2: correlative Tissue form (for all sites) ..................................................................................... 87 
Appendix G-1: Venetoclax Pill Diary Instructions ......................................................................................... 88 
Appendix G-2: Venetoclax Pill Diary (Cycle 1) .............................................................................................. 89 
Appendix G-3: Venetoclax Pill Diary (Cycle 2+)............................................................................................. 91 
Appendix H-1: DCC Registration Coversheet ................................................................................................ 93 
Appendix H-2: SAE/UP Reporting Coversheet .............................................................................................. 94 
 
LIST OF TABLES AND FIGURES 
Table 2.1.1. Current Therapies for PTCL ................................................................................................................... 14 
Figure 5.3. Dosing Schedule ...................................................................................................................................... 27 
Table 5.10.2. Recommended TLS Prophylaxis Pre-Cycle 1 And Blood Chemistry Monitoring During Cycle 1 .......... 31 
Table 6.2.1. Treatment Modification Guidelines ...................................................................................................... 36 
Table 9.1. Overview of Tumor Tissue Studies ........................................................................................................... 44 
Table 10.0 Study Activity Calendar ........................................................................................................................... 46 
Table 11.3. Clinical Endpoints ................................................................................................................................... 50 
Table 13.3 Data Submission Schedule ...................................................................................................................... 55 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Meaning 
AE 
AESI 
BSA 
BUN 
CBC 
CFR 
COH 
CR 
CRC 
CRF 
CT 
CTCAE 
CTCL 
CTEP 
Diff 
DSMC 
ECP 
FDA 
FDG 
GCP 
HIV 
HDAC 
IB 
IDS 
IND 
INR 
IRB 
IV 
MRI 
NCCN 
NCI 
OIDRA 
ORR 
PD 
PET 
PI 
PLT 
PMT 
PR 
PT 
PTCL 
SAE 
SD 
SOC 
SOP 
TNMB 
Tx 
TBSA 
TLS 
ULN 
 
Adverse Event 
Adverse Event of Special Interest 
Body Surface Area 
Blood Urea Nitrogen 
Complete Blood Count 
Code of Federal Regulations 
City of Hope 
Complete Response 
Clinical Research Coordinator 
Case Report Form 
Computed Tomography 
Common Terminology Criteria for Adverse Events 
Cutaneous T-Cell Lymphoma 
Cancer Therapy Evaluation Program 
Differential 
Data & Safety Monitoring Committee 
Extracorporeal Photopheresis 
Food and Drug Administration 
[18F]fluorodeoxyglucose 
Good Clinical Practice 
Human Immunodeficiency Virus 
Histone deacetylase 
Investigator’s Brochure 
Investigational Drug Services 
Investigational New Drug 
International Normalized Ratio 
Institutional Review Board 
Intravenous 
Magnetic Resonance Imaging 
National Comprehensive Cancer Network 
National Cancer Institute 
Office of IND Development and Regulatory Affairs 
Overall Response Rate 
Progressive Disease 
Positron Emission Tomography 
Principal Investigator 
Platelets 
Protocol Management Team 
Partial Response 
Prothrombin 
Peripheral T-cell Lymphoma 
Serious Adverse Event 
Stable disease 
Standard of Care 
Standard Operating Procedure 
Tumor, Node, Metastasis, Blood 
Protocol Therapy 
Total Body Surface Area 
Tumor Lysis Syndrome 
Upper Limit of Normal 
 


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1.0 OBJECTIVES 
1.1 Primary Objectives  
Safety Lead-in: 
o To assess the safety and tolerability of the combination of venetoclax with romidepsin, 
including the dose ramp-up, in adults with relapsed or refractory mature T-cell lymphoma.  
Phase 2: 
o To estimate efficacy (as measured by the overall response rate [ORR]) of venetoclax with 
romidepsin in patients with relapsed or refractory mature T-cell lymphoma. 
1.2 Phase 2 Secondary Objectives 
o To evaluate the complete response rate, duration of response, time to response, overall 
survival and progression free survival associated with venetoclax and romidepsin in 
relapsed/refractory mature T-cell lymphoma. 
o To further characterize the safety and toxicities of venetoclax and romidepsin combination in 
relapsed/refractory mature T-cell lymphoma. 
1.3 Exploratory Objectives 
o To determine BCL2 protein expression in baseline treatment tumor samples and correlate 
with response  
o To determine changes in Bcl-2 gene expression in pre- and post-treatment tumor samples of 
mature T- cell lymphoma 


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2.0 BACKGROUND 
2.1 Introduction/Rationale for Development 
2.1.1 
Burden of disease  
Peripheral T cell lymphomas (PTCL) arise from post thymic lymphocytes, representing non-Hodgkin 
lymphoma (NHL) in the western populations. Approximately 5,000 new cases of PTCL are diagnosed 
annually in the US [2]. Based on immunophenotyping, molecular, clinical and pathologic  features, there 
are about 22 different subtypes of PTCL that are broadly classified into nodal, extranodal, leukemic variant 
and cutaneous T cell lymphomas (CTCL) based on the site of origin of the disease [3, 4]. In North America, 
the most common subtypes are PTCL-not otherwise specified, anaplastic large cell lymphoma (ALCL) and 
angioimmunoblastic T cell lymphoma (AITL) [5] .  
Most PTCL cases have a dismal prognosis with a 5 year survival of less than 30% with the exception of 
ALK+ ALCL. Anthracycline based combination therapies are the most common initial treatment used for 
PTCL but primary response rate is less than 60% and most patients relapse after initial therapy [5]. There 
are now 4 FDA approved agents (Table 2.1.1) for the treatment of PTCL in the relapsed setting in the US 
but none of them are curative. Other than ALCL most patients with PTCL are in dire need for new and 
improved therapeutic options. Currently there are many agents that are being evaluated for relapsed and 
refractory PTCL.  
Table 2.1.1. Current Therapies for PTCL 
Agent 
% 
Overall Response 
Rate/ Complete 
Response  
Duration of 
Response  
FDA approved in 
the US 
Comments 
Pralatrexate [6] 
29/11 
10.1 months 
Yes 
 
Romidepsin [7] 
25/15 
13.4 months 
Yes 
Also approved for relapsed 
CTCL 
Belinostat [8] 
25.8/10.8 
13.6 months 
Yes 
 
Brentuximab vedotin 
in ALCL[9] 
86/57 
12.6 months 
Yes for ALCL 
 
Chidamide[10] 
28/14 
PFS 2.1 months 
No 
Approved in China 
2.2 BCL2 and Mature T-Cell Lymphomas 
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway. The Bcl-2 oncogene 
was first identified in follicular lymphoma where the t(14;18) chromosomal translocation results in 
significant over-expression of the protein in B-cells. The Bcl-2 family of genes encodes a family of closely 
related proteins that possess either pro-apoptotic or anti-apoptotic activity and share up to four Bcl-2 
Homology (BH) domains [11-14]. Bcl-2 over-expression is a major contributor to the pathogenesis of some 
types of lymphoid malignancies and has been extensively studied in B cell lymphomas, including CLL and 
DLBCL. Bcl-2 is also over-expressed in acute and chronic leukemias.  Chronic lymphocytic leukemia (CLL) 
is a genetic disease where the microRNAs miR15a and miR16-1 that negatively regulate the transcription 
of Bcl-2 are deleted or down-regulated, resulting in uncontrolled expression of Bcl-2 [14]. 
Bcl-2 over-expression has been found to be associated with progression of various B cell lymphoid 
malignancies and is targetable with selective anti- BCL2 therapy including Venetoclax resulting in 
meaningful clinical responses in CLL and other B cell malignancies [15]. Similar studies have demonstrated 
over-expression of Bcl-2 in cases of CTCL [16]. Using immunohistochemical methods on tissue samples 


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and a 10% cut off, Bcl-2 was detected in 46% of cases in PTCL along with other members of the Bcl-2 family 
[17]. The expression pattern of the BCL family of proteins was variable, with a distinct pattern seen in only 
Alk +ALCL and EATCL that were Bcl-2 negative and MCL-1 positive. Further studies conducted using a 
TUNEL assay and proliferation index revealed that the Bcl-2 family protein levels correlated with apoptotic 
rates and proliferation index. It was hypothesized that over-expression of these proteins may explain the 
poor response of the many types of PTCL to chemotherapy. A later study attempted to correlate the 
expression of Bcl-2, Bax and p53 with progression of PTCL using paraffin-embedded specimens from 
patients [18]. These included CTCL. In this study, Bcl-2 over-expression was strongly associated with 
advanced stage and a high IPI index. Within the groups that over-expressed BcL2, p53 over-expression 
was associated with poor survival. The 3 year OS was 82% for Bcl-2+/p53- cases and only 32% for Bcl-
2+/p53+ cases, indicating that Bcl-2 over expression seemed to correlate with progression of PTCL through 
a p53-dependent pathway3. In studies of T-cell lymphoma at City of Hope , Bcl-2 has been found to be 
expressed in 52-76% of cases of PTCL and 25% of CTCL [19, 20]  (unpublished data from Joo Song, City of 
Hope). Hence, there is strong rationale to consider that interference of the Bcl-2 pathway in PTCL and 
CTCL may be a favorable anti lymphoma target. So far there is no published data regarding the use of Bcl-
2 inhibitors in the treatment of peripheral T cell lymphomas and cutaneous T cell lymphomas. We 
hypothesize that interference of BCL2 will lead to antitumor activity in mature T-cell lymphomas. 
2.3 Venetoclax  
Venetoclax (also known as ABT-199) is a novel, orally available, small molecule Bcl-2 family protein 
inhibitor that binds with high affinity (Ki < 0.010 nM) to Bcl-2 and with lower affinity to other Bcl-2 family 
proteins such as Bcl-xL and Bcl-w (> 4,000-fold and > 2,000- to > 20,000-fold lower affinity than to Bcl-2, 
respectively) [21]. Selective inhibition by venetoclax disrupts Bcl-2 signaling and rapidly induces multiple 
hallmarks of apoptotic cell death in Bcl-2-dependent human tumor cell lines [22]. Importantly, venetoclax 
inhibition of Bcl-2 is independent of p53 activity.  
Venetoclax has been FDA approved for patients with chronic lymphocytic leukemia (CLL) with 17p 
deletion, as detected by an FDA approved test, who have received at least one prior therapy.  
2.3.1 
Pre-clinical experience 
Previous agents targeting Bcl-2 were non-specific and had inhibitory effects on BCL-XL  as well as BCL-w 
that resulted in significant clinical thrombocytopenia due to the role of  BCL-XL   in platelet survival [23]. 
This led to the development of Venetoclax or ABT-199 which has specific inhibition of Bcl-2 with platelet 
sparing effects with sub-nanomolar affinity to Bcl-2 (Ki < 0.010nM) and anti- tumor activity a gains NHL, 
CLL and acute leukemia in vitro [21, 24, 25]. Multiple experiments demonstrate that venetoclax acts to 
induce apoptosis. As expected, venetoclax was ineffective against murine embryonic fibroblasts (MEFs) 
lacking Bax and Bak, essential mediators of the intrinsic apoptosis program.  However, in the Bcl-2-
dependent ALL cell line RS 4;11, venetoclax rapidly induced key hallmarks of apoptosis, including 
cytochrome c release, caspase activation, and the externalization of phosphatidylserine.
  
Venetoclax exhibited potent activity against patient-derived tumor cells treated ex vivo killing CLL cells 
with an average EC50 of 6.0 nM (N = 35)
 
and AML cells with a median IC50 of 10 to 20 nM (N = 57).
 
Venetoclax was equally potent against the subset of CLL samples bearing the high-risk 17p del, with an 
average EC50 of 0.008 µM (N = 5), indicating that venetoclax may have a significant utility in treating 
patients with this high-risk lesion.
 
Venetoclax also demonstrated cell killing activity against lymphoma and 
leukemia cell lines including B-cell FLs, MCLs, DLBCLs, AMLs, ALLs, and MMs.
 
Venetoclax was especially 
potent against cell lines expressing high levels of Bcl-2.
 
The majority of sensitive FL and DLBCL cell lines 


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were positive for the t(14;18) chromosome translocation that drives high level expression of Bcl-2 from 
the immunoglobulin heavy chain enhancer.  Bcl-2 levels and the t(14;18) chromosome translocation thus 
represent potential predictive biomarkers for sensitivity to venetoclax. Venetoclax also demonstrated 
potent killing of MM cell lines and primary tumor samples bearing the t(11;14) translocation[26].
 
These 
cells tended to express high levels of Bcl-2 relative to Mcl-1.
 
Mouse xenograft studies showed activity 
against aggressive Myc positive lymphoma as well as acute leukemia [27, 28]. 
2.3.2 
Clinical experience 
As of version 11 of the venetoclax Investigator's Brochure [29] a total of 2939 subjects received at least 
1 dose of venetoclax in AbbVie studies and had data available as of 28 November 2018. Among these 2939 
subjects, 1313 subjects had CLL/small lymphocytic leukemia (SLL), 570 subjects had non-Hodgkin's 
lymphoma (NHL), 218 subjects had multiple myeloma (MM), 361 had acute myeloid leukemia (AML), 59 
subjects had myelodysplastic syndrome (MDS), 20 subjects had acute lymphocytic leukemia (ALL) and 
219 were healthy volunteers. A total of 1137 received the drug as monotherapy, and 1406 received the 
drug in combination with other therapies. Doses administered in venetoclax clinical studies have ranged 
from 20 mg to 1200 mg. 
The most common adverse events (incidence > 20%) reported for all subjects in monotherapy studies 
were nausea, diarrhea, neutropenia, anemia, thrombocytopenia and lymphopenia. Infections, including 
serious infections, although also common with the underlying malignancies, have been reported with 
venetoclax treatment and their incidence is higher with combination treatments. The most common 
adverse events that were grade 3 and above were neutropenia (31.0%) and anemia (13.8%). The most 
common serious adverse events were febrile neutropenia and malignant neoplasm progression (5.7% 
each). The most common treatment emergent adverse event that led to death was malignant neoplasm 
progression (2.1%). 
Tumor lysis syndrome (TLS) is an important risk of Bcl-2 inhibitors, and is highest in CLL and MCL. As a 
result of on-target effects, the potential for TLS with venetoclax was identified early in the program when 
the initial 3 subjects with CLL/SLL received starting doses of 100 mg or 200 mg and experienced TLS, which 
was reported as an adverse event for each. Subsequently, 2 fatal events in the setting of TLS and another 
event of clinical TLS in subjects with CLL/SLL occurred in December 2012. After comprehensive review of 
all safety data available from studies with venetoclax, starting from May 2013, a revised dosing regimen 
with a dose-titration phase of 4 to 5 weeks and enhanced TLS prophylaxis and monitoring measures were 
implemented in all CLL studies. In May 2014, a subsequent analysis of data from subjects with CLL/SLL 
following the implementation of prophylaxis measures, who completed monotherapy, indicated a marked 
reduction in severity and frequency of TLS when compared to the previous analysis. None of the subjects 
experienced any serious (including fatal) or non-serious events of clinical TLS or laboratory TLS or had 
study treatment discontinued because of TLS. Overall, the clinical data strongly support that the risk of 
TLS with venetoclax in CLL/SLL subjects is highest when initiating venetoclax dosing (5 week dose titration 
phase), as well as being greater in subjects with a large tumor burden. Currently, since May 2014, a more 
personalized approach for prophylaxis and monitoring measures, where subjects with low tumor burden 
could receive venetoclax on an out-patient basis, has been implemented with no clinical TLS [30]. 
More specifically, in the Phase 1 study of venetoclax in CLL, the recommended Phase 2 dose (R2PD) of 
venetoclax was 400 mg per day. Given the risk of tumor lysis, dosing was ramped up weekly for 5 weeks 
(20 mg, 50 mg, 100 mg, 200 mg, 400 mg). Among the 116 patients who received venetoclax on this study, 
the overall response rate was 79%, and complete remissions occurred in 20% of patients. The 15 month 
estimate for progression-free survival for those dosed at 400 mg was 69% [31]. Clinical tumor lysis 


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syndrome did not occur in any of the 60 patients treated in the expansion cohort of this study but did 
occur in 3 of the 56 patients treated in the Phase 1 portion of the study. There was one death due to 
tumor lysis in the dose escalation portion of the study. 
In the Phase 1 study of venetoclax in diffuse large B-cell lymphoma and follicular lymphoma, the RP2D 
dose was 1200 mg. In this study, there were two events of laboratory tumor lysis syndrome, but no 
patients had clinical tumor lysis. Therefore, in the expansion cohort portion for this study, dosing was 
ramped up weekly over 3 weeks (400 mg, 800 mg, 1200 mg). Of the 41 patients with diffuse large B-cell 
lymphoma, the overall response rate was 15% with a median duration of response of 3.3 months. Among 
the 29 patients with follicular lymphoma, the overall response rate was 34%, and the median duration of 
response was 10 months. The most common adverse events were diarrhea (44%), fatigue (44%), nausea 
(33%), and vomiting (23%). Serious adverse events included hyponatremia (4%), dehydration (3%), 
diarrhea (3%), and febrile neutropenia (3%) [15, 32]. In diffuse large B-cell lymphoma, there is an ongoing 
trial evaluating the combination of venetoclax with rituximab or obinutuzumab plus CHOP 
(NCT02055820). 
2.4 HDAC inhibition in mature T cell lymphomas 
Histone deacetylases (HDAC) are enzymes that catalyze the removal or acetyl groups from the lysine 
residues of various proteins, including histones and transcription factors. The transcription of genes is 
partially regulated by acetylation of nucleosomal histones. The core nucleosomal histones are the most 
widely studied of the proteins that become acetylated following inhibition of HDAC activity.[33] In some 
cancer cells there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic 
transcription factors causing hypoacetylation of core nucleosomal histones. Hypoacetylation of histone is 
associated with a condensed chromatin structure and repression of gene transcription. 
Inhibition of HDAC activity allows for the accumulation of acetyl groups on the histone lysine residues 
resulting in an open chromatin structure and transcription activation. HDAC inhibitors can induce tumor 
cell growth arrest, differentiation, or apoptosis in vitro and inhibit tumor growth in animals.[34, 35] HDAC 
inhibitors as a class appear to have significant activity in T-cell lymphomas for reasons that are not clearly 
understood. HDAC inhibitors work through several different mechanisms including alteration in the 
expression of genes that regulate cell cycle, acetylation of non-histone proteins that may impair their 
function to influence cell growth and survival, and by direct activation of apoptotic pathways.[36] 
Attempts at understanding the mechanisms of HDAC inhibitors have involved gene expression profiling 
on paired tissue samples both pre- and post-treatment that have shown only 5-10% of the genome can 
be affected. As many genes are unregulated as are down regulated following treatment with most HDAC 
inhibitors. The genes that were consistently affected included genes that alter cell cycle (CCND1, IGF1), 
apoptosis (septin10, TEF, SORBBS2), angiogenesis (GUCY1A1, ANGPT1), and immune modulation (LAIR1). 
[37] QT-PCR was used to confirm that the findings on the gene array analysis were indeed biologically 
accurate, with a strong correlation between gene array and the PCR data. Tumor tissue specimens treated 
with various HDAC inhibitors have shown an increase in histone acetylation, decreased vascularity, and 
translocation of nuclear proteins like STAT-s which is associated with inactivation. [38] 
2.5 Romidepsin 
Romidepsin (also known as Istodax®, FK228) is a HDAC inhibitor commercially available from Celgene. It 
is a unique HDAC inhibitor as it is a prodrug. Upon entering cells romidepsin is reduced to an active 
compound, capable of preferentially interacting with zinc in the active site of HDAC1, HDAC2 and HDAC3 
(Class I). [39] Romidepsin currently has FDA approval for patients with cutaneous T-cell lymphomas (CTCL) 


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that have received at least one prior therapy (as well as for relapsed/refractory PTCL). It is currently being 
assessed for the treatment of a variety of malignant and inflammatory diseases. 
2.5.1 
Clinical Experience 
The clinical experience with romidepsin from multiple clinical trials has shown a well-tolerated toxicity 
profile. Phase 1 trials have provided the safety profile and dosing schedule. [40, 41] Romidepsin doses 
ranging from 1.0 to 24.9 mg/m2 administered intravenously over 4 hours have been investigated in 
treatment of advanced cancers.[42] A more standardized regimen has been defined as 14 mg/m2 
intravenously over a 4 hour period on days 1, 8, and 15 of a 28-day cycle. [7] The major hematologic 
toxicity includes anemia, leukopenia, lymphopenia, and thrombocytopenia. Other common adverse 
events include gastrointestinal symptoms, constitutional symptoms, and dysgeusia. In addition, it was 
found that romidepsin may cause QTc prolongation/ECG changes, however, this may be the result of a 
drug:drug interaction with select antiemetics. Based on on-clinical findings, male and female fertility may 
be compromised by treatment with romidepsin. 
The use of romidepsin is best established in CTCL. A phase 2 trial with romidepsin in relapsed CTCL showed 
single agent activity in patients that previously had been heavily pretreated with a median of 4 prior 
therapies. [43] A total of 71 patients were treated with an overall response rate (ORR) of 34% including 4 
patients with complete response. The median duration of response (DOR) was 13.7 months. This trial and 
a registration directed trial by Gloucester Pharmaceuticals, previous owners of romidepsin, led to full 
regulatory approval by the FDA for the treatment of relapsed CTCL. A phase 2 trial of romidepsin in 
patients with heavily treated relapsed/refractory PTCL demonstrated an ORR of 25% with median DOR 
lasting a somewhat remarkable 17 months. [7] The treatment regimen was romidepsin administered as a 
4-hour infusion on days 1, 8, and 15 of a 28-day cycle with a dose of 14 mg/m2. Based on this trial, 
romidepsin gained FDA approval in 2011 for used in relapsed/refractory PTCL.  
2.6 Combination of Bcl-2 inhibitors and HDACi 
There is a growing body of work suggesting that Bcl-2 inhibition and HDAC inhibition are synergistic and 
therefore hold promise as combination therapy in lymphoma, where Bcl-2 prosurvival proteins are 
commonly overexpressed. In the Eμ-myc lymphoma cell model the HDACi vorinostat and romidepsin both 
mediated apoptosis via the intrinsic apoptotic pathway, mediated by the BH3-only proteins Bim and 
Bid.[44] These proteins show tumor-suppressor function in certain contexts and inactivating mutations or 
loss of expression in human cancer samples have been reported. Transcriptional activation of the 
proapoptotic Bcl-2 family BH3-only genes BIM, BMF, and NOXA is the apparent mechanism of HDACi-
induced apoptosis. Selective knockdown of the three corresponding proteins rescued cells from 
vorinostat-induced apoptosis. Combined inhibition of BcL2 members and HDACis has shown synergistic 
effects in CTCL and other malignancies, including mantle cell lymphoma and glioblastoma: vorinostat 
enhanced the activity of the BH3-mimetic ABT-263 (navitoclax) in MCL cells, leading to synergistic 
apoptosis induction.[45] Notably, overexpression of the prosurvival protein Bcl-2, which inhibits activation 
of the intrinsic apoptotic pathway, completely suppressed the apoptotic and therapeutic activities of 
vorinostat. [46, 47] Another mechanism of pan HDACis panobinostat and vorinostat to rapidly inhibit 
HDAC7 and induce the expression and translocation of the proapoptotic nuclear orphan receptor Nur 77 
to the mitochondria where it binds to Bcl-2 and promotes apoptosis. Cotreatment with the Bcl-2/ Bcl xL 
antagonist ABT-737 decreased resistance and was synergistic with panobinostat in inducing apoptosis.[47] 
Higher sensitivity to venetoclax that correlates with higher levels of BcL-2 expression and mRNA has been 
seen in CTCL patient samples in vitro,[48] similar to observations in CLL. In addition, when these patient 


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samples were exposed to a combination of venetoclax with either vorinostat or romidepsin a synergistic 
cell death was seen that involved caspase 3/7 activation.  
2.7 Overview and Rationale of Study Design 
This is an open-label multi-site Phase 2 study with a Safety Lead-in to test the safety and efficacy of 
venetoclax with romidepsin for the treatment of relapsed/refractory mature T-cell lymphoma. 
Eligibility 
Eligible patients will be adults with histologically confirmed peripheral T-cell lymphoma as defined per the 
WHO criteria 2016 [49]. Eligible patients must be naïve to prior Bcl-2 therapies and must have failed at 
least one prior systemic therapy. 
Treatment program 
Participants will receive venetoclax once daily orally, and romidepsin once a week for the first three weeks 
of each 28-days treatment cycle. Prior data suggest that B-cell NHL patients can tolerate up to 1200 
mg/day venetoclax [15, 32]. However, due to biologic differences in T cell and B cell lymphomas and 
aggressive nature of T-cell disease, a maximum dose of 800 mg/day will be tested in this study. 
Romidepsin dosing will be according to the label. 
On-target effect of either romidepsin or venetoclax could lead to rapid cell death and pose a risk of TLS. 
Based on prior clinical experience with the agent, a ramp up dosing schedule will be implemented during 
Cycle 1. The venetoclax dose will be ramped up over 7 days, in line with current practice for AML [30]. 
Once the safety and tolerability of the proposed dose combination and schedule is established after the 
safety lead-in, additional patients will be enrolled and treated for the Phase 2 response evaluation using 
the same dose combination and schedule (which includes the ramp-up in Cycle 1). 
Participants will continue with treatment until disease progression, unacceptable toxicity or completion 
of 26 cycles (~24 months) of therapy, whichever comes first. If a patient is still benefiting from treatment 
at the completion of 26 cycles of therapy, we will consider amending the study to extend the duration of 
therapy for that particular patient. 
Dose and Schedule: 
During Cycle 1, participants will take venetoclax 20 mg/day on Day 1, 50 mg/day on Day 2, 100 mg/day on 
Day 3, 200 mg/day on Day 4, 400 mg/day on Day 5, and 800 mg/day on Days 6-7 in the ramp-up phase 
and 800 mg/day on Days 8-28. Romidepsin 14 mg/m2 will be administered on Days 1, 8, and 15 of the 28-
day cycle.  
During Cycle 2+, participants will take 800 mg/day venetoclax. Romidepsin 14 mg/m2 will be administered 
on Days 1, 8, and 15 of each 28-day cycle.  
Safety Lead-in 
During the safety-lead in, up to 6 evaluable participants will be enrolled using a 3+3 design.  
In the event the proposed combination of venetoclax (20-800 mg/day) with romidepsin is not tolerable 
(2+ patients with unacceptable toxicity in ≤ 6 evaluable participants), the accrual will be suspended and 
the study will be amended.  
Unacceptable toxicities will be evaluated during the first 2 cycles of therapy. This will ensure monitoring 
of participants during the ramp-up period (Cycle 1) and while participants are on steady-state dose (Cycle 


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2). Unacceptable toxicities will focus on commonly observed toxicities for venetoclax such as neutropenia, 
thrombocytopenia, blood chemistries and tumor lysis syndrome. 
Phase 2 
Once the Safety Lead-in is completed and the proposed dose combination and schedule (including ramp-
up) is confirmed safe and tolerable, additional patients will be enrolled and treated for the Phase 2 
response evaluation. The Phase 2 portion will utilize a Simon’s two-stage optimal design. Patients enrolled 
during the Safety Lead-in will be included in the Phase 2 portion of the study if they are evaluable for 
response. In the absence of study holds to accrual for toxicity or for futility, accrual will continue until 18 
evaluable participants are treated at the tolerated dose and schedule. 
An early stopping rule for futility will be based on the response rate in the first 7 patients. Accrual may 
need to be temporarily held at 7 patients pending response evaluation.  
TLS Prophylaxis and Monitoring 
To mitigate the risk for TLS, all participants will initiate TLS prophylaxis and undergo pre-dose and real-
time post-dose monitoring during the ramp-up stage (see Section 5.10.2). Patients will be monitored for 
TLS on an outpatient basis for the first 8 days of treatment. 
Response  
PTCL specific response assessment criteria per Lugano Classification will be used for this study [50]; these 
criteria incorporate PET for response assessment. PTCL is considered [18F] fluorodeoxyglucose (FDG) avid 
[51, 52] and PET-CT is recommended for staging of routinely FDG-avid histologies [50]. CT is preferred for 
low or variable FDG avidity.  
Radiographic imaging will occur every 2 cycles. Ending treatment due to disease progression will occur 
after completing at least two cycles of treatment. This is to ensure that participants have had enough time 
to be exposed to the steady-state venetoclax dose.  
Correlative studies 
Baseline and optional tumor tissue samples during Cycle 1 or 2 treatment will be collected. Correlative 
studies will characterize the gene expression profile in patient samples and explore relevance to the Bcl-
2 pathway. Additionally, these studies will explore response to therapy and toxicity based on the patient’s 
BCL-2 status. 


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3.0 ELIGIBILITY CRITERIA 
Patient MRN  
Patient Initials (F, M, L): 
Participants must meet all of the following criteria on screening examination to be eligible to participate 
in the study:  
3.1 Inclusion Criteria 
Informed Consent and Willingness to Participate 
__1. Documented informed consent of the participant and/or the legally authorized representative 
__2. Be willing to provide tissue (See Section 9.1)  
Age and Performance Criteria 
__3. Age ≥ 18 years 
__4. ECOG ≤ 2 
Nature of Illness and Treatment History 
__5. Resolution of all acute toxic effects of prior therapy or surgical procedures to CTCAE Grade ≤ 1 
(except alopecia). 
__6. Failed at least 2 prior systemic therapies. For ALCL histologies this must include failure or 
intolerable side effects of brentuximab vedotin 
__7. Histologically confirmed PTCL as defined by the WHO criteria 2016, excluding CTCL. 
Transformed mycosis fungoides is allowed. 
__8. Measurable disease defined as: 
 
CT/MRI/ or PET scan, with at least one nodal site of disease which is 1.5 cm in longest 
dimension, and/or spleen > 13 cm in vertical length, and/or diffuse enlargement of liver 
with or without focal nodules (Lugano 2014). Extra nodal sites with biopsy proven 
abnormal lesions are allowed including skin. 
 
Patients with only bone marrow involvement will be acceptable.  
__9. Prior stem cell transplant allowed 
 
If allogeneic HCT must have recovered from acute toxicity 
 
Cannot have active acute or chronic GvHD and must be off immunosuppressive therapies  
Clinical Laboratory Criteria (To be performed within 14 days prior to Day 1 of protocol therapy) 
__10. ANC ≥ 1,000/mm3  
NOTE: Growth factor is not permitted within 7 days of ANC 
assessment unless cytopenia is secondary to disease involvement. 
Exception: Unless documented bone marrow involvement by 
lymphoma 
ANC: 
Date: 
__11. Platelets ≥ 30,000/mm3  
NOTE: Platelet transfusions are not permitted within 7 days of 
platelet assessment unless cytopenia is secondary to disease 
involvement. 
Exception: Unless documented bone marrow involvement by 
lymphoma 
Plts: 
 
Date: 


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__12. Total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN for Gilbert’s Syndrome or 
documented hepatic involvement by lymphoma) 
ULN: 
Bil: 
Date: 
__13. AST ≤ 3 x ULN 
If hepatic involvement by lymphoma: AST ≤ 5 x ULN 
ULN: 
AST: 
Date: 
__14. ALT ≤ 3 x ULN 
If hepatic involvement by lymphoma: ALT ≤ 5 x ULN 
ULN: 
ALT: 
Date: 
__15. Creatinine clearance of ≥ 50 mL/min per 24 hour urine or the 
Cockcroft-Gault formula 
 
Serum Cr: 
 
Cr Clearance: 
Date: 
__16. Women of childbearing potential (WOCBP): negative urine or 
serum pregnancy test  
If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required 
Urine: 
Serum: 
 
Date: 
Contraception 
__17. Agreement by WOCBP and males of childbearing potential* to use an adequate method of 
birth control (hormonal contraception is inadequate) or abstain from heterosexual activity for the 
course of the study through 90 days after the last dose of protocol therapy.  
*Childbearing potential defined as not being surgically sterilized (men and women) or have not 
been free from menses for > 1 year (women only). 
3.2 Exclusion Criteria 
Previous therapies 
__1.  Bcl2 inhibitors 
__2.  Any systemic anti-lymphoma therapy, including monoclonal antibody within 28 
days or 5 half-lives (whichever is shorter) of initiating protocol therapy 
__3.  Radiation and/or surgery (except lymph node or other diagnostic biopsies) within 
14 days prior to Day 1 of protocol therapy. 
__4.  Short course systemic corticosteroids for disease control, improvement of 
performance status or non-cancer indication within 7 days prior to Day 1 of protocol 
therapy. Stable ongoing corticosteroid use (i.e. at least 30 days) up to an equivalent dose 
of 20 mg of prednisone is permissible. 
__5.  Strong or moderate CYP3A inhibitors within 7 days prior to Day 1 of protocol 
therapy. 
__6.  Strong or moderate CYP3A inducers within 7 days prior to Day 1 of protocol 
therapy. 
__7.  P-gp inhibitors within 7 days prior to Day 1 of protocol therapy. 


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__8.  Narrow therapeutic index P-gp substrates within 7 days prior to Day 1 of protocol 
therapy. 
__9.  Any other investigational agent or used an investigational device within 21 days 
prior to Day 1 of protocol therapy. 
Other illnesses or conditions 
__10.  Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., 
gastric bypass surgery, gastrectomy) 
__11.  Active human immunodeficiency virus (HIV) or hepatitis C virus (HCV) or hepatitis 
B virus (HBV). Subjects who have an undetectable HIV viral load with CD4 > 200 and are 
on HAART medication are allowed. Subjects who are positive for hepatitis B core 
antibody or hepatitis B surface antigen must have a negative polymerase chain reaction 
(PCR) result before enrollment. Those who are PCR positive will be excluded.  Patients 
who have had Hepatitis C but have finished treatment and are PCR negative will be 
allowed. (Testing to be done only in patients suspected of having infections or 
exposures). 
__12.  Concurrent malignancy requiring active therapy. 
__13.  Known central nervous system or meningeal involvement (in the absence of 
symptoms, investigation into central nervous system involvement is not required). 
__14.  Congestive heart failure (CHF) that meets New York Heart Association (NYHA) 
Class II to IV definitions (See Appendix E). 
__15.  Patients with known cardiac abnormalities such as: 
 
Congenital long QT syndrome 
 
QTc (Corrected QT interval on ECG) interval >480 milliseconds 
 
Any cardiac arrhythmia requiring anti-arrhythmic medication. 
__16.  Patients with a history of sustained ventricular tachycardia (VT), ventricular 
fibrillation (VF), Torsade de Pointes, or cardiac arrest, unless currently addressed with an 
automatic implantable cardioverter defibrillator (AICD). 
__17.  Active infection requiring systemic therapy. 
__18.  Unable to swallow capsules, has a partial or small bowel obstruction, or has a 
gastrointestinal condition resulting in a malabsorptive syndrome (e.g. small bowel 
resection with malabsorption). 
__19.  WOCBP: Pregnant or breastfeeding. 
__20.  Any other condition that would, in the Investigator’s judgment, contraindicate the 
patient’s participation in the clinical study due to safety concerns with clinical study 
procedures. 
Noncompliance 
__21.  Prospective participants who, in the opinion of the investigator, may not be able 
to comply with all study procedures (including compliance issues related to 
feasibility/logistics). 


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Eligibility Confirmed* by 
(Choose as applicable): 
Print Name 
Signature 
Date 
 Site PI 
 
 
 
 Authorized study MD 
 
 
 
 Study Nurse 
 
 
 
 Study CRA/ CRC 
 
 
 
Other:______________ 
 
 
 
*Eligibility should be confirmed per institutional policies. 


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4.0 PARTICIPANT ENROLLMENT  
NOTE: Sites must meet activation requirements prior to enrolling participants. 
4.1 Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only after 
obtaining written informed consent.  Studies or procedures that are performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values and/or to determine pre-
eligibility, even if the studies were done before informed consent was obtained. The informed consent 
process is to be fully documented (see Section 16.4), and the prospective participant must receive a copy 
of the signed informed consent document.  Screening procedures are listed in Section 10.0. 
4.2 Participant Enrollment 
Eligible participants will be registered on the study centrally by the DCC at City of Hope.  DCC staff are 
available between the hours of 8:00 a.m. and 5:00 p.m. PST, Monday through Friday (except holidays).   
DCC contact information is as follows: 
o Phone: (626) 218-7904 
o E-mail: DCC@coh.org 
4.3 Slot verification and reservation 
Once the Safety Lead-in is completed and the proposed dose and schedule is shown to be tolerable, 
participants will enroll at the tolerable dose and schedule (which includes the ramp-up stage) (Section 
5.3). 
Issues that would cause treatment delays should be discussed with the Principal Investigator. 
Designated study staff should call the DCC to verify current slot availability, and to reserve a slot for a 
specific prospective subject.  Slots can only be held for a limited time.   
The DCC should be notified of cancellations of prospective participants holding slots as soon as possible. 
4.4 Registration Process 
To register a participant, the subsequent procedure is to be followed. 
1. The participating site’s data manager/coordinator/research nurse should contact the DCC via 
telephone or email to provide notification regarding the pending registration and communicate 
desired timeline of the registration, especially if it must be completed promptly to meet the 
registration window. 
2. The data manager/coordinator/research nurse should then e-mail copies to DCC@coh.org of the 
following documents to the DCC:  
 Registration Cover Sheet (Appendix H-1) 
 Completed Eligibility Criteria List (printed from Section 3.0 of the protocol) 
 Source documentation to support eligibility criteria**  
 Signed informed consent document 
 Signed HIPAA authorization form (if separate from the informed consent document) 
 Signed subject’s Bill of Rights (COH only)  


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**For COH participants, provide copies of source documentation only if not readily available 
as a finalized record in a COH Electronic Medical Record (EMR).  
3. After having received all transferred documentation, the DCC will complete the review the documents 
to verify eligibility, working with the participating site as needed to resolve any missing required 
source elements. A participant failing to meet all protocol eligibility requirements will not be 
registered.  
4. Once eligibility has been confirmed, DCC staff will register the participant by: assigning a subject 
accession number, register the subject on study centrally into COH clinical trials management system 
for non-COH participants, and enter the participant into the eCRF system, Medidata RAVE. 
5. Once registration has been completed, DCC staff will send a Confirmation of Registration Form within 
24 hours, including the participant study number to:  
 The study team: Site Lead Investigator, treating physician, protocol nurse, CRC and pharmacy 
 The COH sponsor team designees 
4.5 Screen Failures and Registered Participants Who Do Not begin Study Treatment 
The DCC is to be notified of all participants who sign consent but do not meet eligibility criteria or do not 
initiate protocol therapy.  For non-COH sites, the reason for screen failure will be documented in 
registration coversheet (see Appendix H-1) and submitted to the DCC. 
5.0 TREATMENT PROGRAM 
5.1 Treatment Program Overview 
This is a multi-center, open-label, single-arm Phase 2 trial of venetoclax with romidepsin for patients with 
relapsed/refractory mature T-cell lymphoma. 
The study consists of a Safety Lead-in stage to evaluate safety/tolerability and a Phase 2 stage to evaluate 
anti-tumor activity in the study population (Section 5.3). Participants will receive up to 26 cycles of therapy 
and each cycle will be 28 days.  
Protocol treatment will continue until disease progression, unacceptable toxicities, completing 26 cycles 
of therapy, or meeting other Section 5.7 criteria, whichever comes first. If a patient is still benefiting from 
treatment at the completion of 26 cycles of therapy, we will consider amending the study to extend the 
duration of therapy for that particular patient. 
During Cycle 1, all participants will be monitored closely for tumor lysis syndrome (TLS, Section 5.9.2). 
Participants who discontinue protocol therapy will undergo follow-up (see Section 5.8). Windows for all 
assessments and treatments are detailed in Section 10.0. 
5.2 Treatment Cycle Definition 
The treatment cycle will be a fixed 28 days (Note: exceptions due to unusual operational considerations 
may be permitted as described in Section 6.2).  
The cycle day count and cycle count will continue despite a hold in venetoclax or romidepsin 
administration due to toxicities (See Section 6.2) - i.e. a cycle may initiate even if either drug is being held.  
Cycle 1 Day 1 is defined as the first day of venetoclax and romidepsin administration. 


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5.3 Treatment Plan 
Participants will ramp-up daily over the first week of Cycle 1 to the maximum venetoclax dose. From Cycle 
1 Days 8-28 and Cycle 2+ Days 1-28, participants will continue at the maximum dose (Figure 5.3) of 
venetoclax. Romidepsin 14 mg/m2 will be administered on days 1, 8, and 15 of each cycle.  
Figure 5.3. Dosing Schedule 
 
5.3.1 
Safety Lead-in 
During the safety-lead in, 6 evaluable participants will be enrolled using a 3+3 design. Unacceptable 
toxicities are defined in Section 11.2 and will be evaluated during the first 2 cycles of therapy. 
In the event the proposed dose (20-800 mg/day) of venetoclax plus romidepsin is not tolerable (2+ 
participants with unacceptable toxicity in ≤ 6 evaluable participants), the accrual will be suspended and 
the study will be amended. 
5.3.2 
Phase 2 
Once the Safety Lead-in is completed and the proposed dose is shown to be tolerable, additional patients 
will be enrolled and treated for the Phase 2 response evaluation. A Simon 2-stage optimal design will be 
utilized. Patients enrolled during the Safety Lead-in will be included in the Phase 2 portion of the study if 
they are evaluable for response. In the absence of study holds to accrual for toxicity or for futility, accrual 
will continue until 18 evaluable participants are treated. 
 See Section 12.0 for details. 
5.4 Agent Administration 
5.4.1 
Venetoclax 
Participants must initiate TLS prophylaxis prior to initiating venetoclax (refer to Table 5.9.1). Delay 
initiating Cycle 1 Day 1 dose if the participant is experiencing laboratory TLS (see Appendix B).  
Venetoclax tablets should be taken orally once daily with a meal with water. The tablets should be 
swallowed whole.  


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If a participant misses a dose and > 8 hours have passed since the scheduled dose time, the missed dose 
will be skipped and will not be made up.   
Doses that are vomited will not be made up. Doses that are withheld due to toxicity will not be made up. 
Participants will be given a Pill Diary to document each dose of venetoclax that is taken or missed 
(Appendix G). 
Management and dose reductions/delays associated with protocol-therapy related AEs, including TLS are 
outlined in Section 6.2. 
5.4.2 
Romidepsin 
Romidepsin should be handled in a manner consistent with recommended safe procedures for handling 
cytotoxic drugs.  
Romidepsin must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium 
Chloride Injection, USP before intravenous infusion.  
Each 10 mg single-use vial of romidepsin must be reconstituted with 2mL of the supplied diluent. With a 
suitable syringe, aseptically withdraw 2 mL from the supplied Diluent vial, and slowly inject it into the 
romidepsin for injection vial. Swirl the contents of the vial until there are no visible particles in the 
resulting solution. The reconstituted solution will contain romidepsin 5 mg/mL. The reconstituted 
romidepsin solution is chemically stable for at least 8 hours at room temperature. However, whenever 
possible, drug should be prepared within 4 hours of dose administration. 
Extract the appropriate amount of romidepsin from the vials to deliver the desired dose, using proper 
aseptic technique. Before intravenous infusion, further dilute the romidepsin in 500mL 0.9% Sodium 
Chloride Injection, USP.  
Infuse over 4 hours. Patients will receive romidepsin (at a dose of either 14 or 12 mg/m2 – see Section 7.2 
for details) IV on days 1, 8, and 15 of each cycle. On these days it does not matter whether venetoclax is 
given before or after the romidepsin infusion. 
The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), 
polyethylene (PE) infusion bags as well as glass bottles. Romidepsin is stable for 24 hours at room 
temperature after reconstitution per package insert.  
Parenteral drug products should be inspected visually for particulate matter and discoloration before 
administration, whenever solution and container permit. 
5.5 Assessments and Special Monitoring 
Section 10.0 summarizes the trial procedures to be performed. It may be necessary to perform study 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Note the following: 
o Review of safety assessments must be performed within 72 hours prior to the first 
venetoclax administration (Cycle 1 Day 1). 
o Cycle 1 Day 1-6 (venetoclax ramp-up stage): The 24 hours post-dose laboratory values must 
be reviewed prior to the next venetoclax administration. 


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Tumor Lysis Syndrome (TLS) 
 There is a potential risk with both venetoclax and romidepsin for TLS in participants with 
PTCL, especially in those with renal dysfunction and dehydration. In addition, on-target 
effect of venetoclax could lead to rapid cell death and pose a risk of TLS.  
 Patients will be closely monitored for the first 8 days of treatment (Cycle 1, Days 1-8) for 
signs and symptoms of TLS, laboratory evaluation, and appropriate intervention. 
− 
Examples of TLS symptoms: fever, chills, tachycardia, nausea, vomiting, diarrhea, 
diaphoresis, hypotension, muscle aches, weakness, paresthesias, mental status 
changes, confusion and seizures.   
 If any clinical features are observed (see Appendix B), recheck potassium, phosphorus, 
uric acid, calcium and creatinine within 1 hour. 
 A rapidly rising serum potassium is a medical emergency. 
 TLS monitoring during Cycle 1 and prophylaxis are described in Table 5.9.1. 
5.6 Duration of Therapy and Criteria for Removal from Protocol Therapy 
Participants will receive protocol therapy until one of the below criteria are met: 
o Disease progression 
o Completed 26 cycles (~24 months) of protocol therapy 
o Participant is deemed intolerant to protocol therapy because of toxicity, despite dose 
modification/ delay  
o General or specific changes in the patient's condition which render the patient unacceptable 
for further treatment in the judgment of the investigator 
o Withdrawal of consent for further protocol therapy (see Section 16.5) 
Once participants meet criteria for removal from protocol therapy, the participant should then proceed 
to End of Treatment assessments. If a patient is still benefiting from treatment at the completion of 26 
cycles of therapy, we will consider amending the study to extend the duration of therapy for that 
particular patient. 
Documentation of the reason for discontinuing protocol therapy and the date effective should be made 
in the source documentation and appropriate eCRF. The COH DCC should be promptly notified of the 
change in participant status. 
5.7 Follow-Up 
Following completion of protocol therapy, all participants will enter follow-up for up to 24 months after 
ending protocol treatment.  This is comprised of: 
o Follow-up for safety- All participants will be followed until resolution or stabilization of 
reportable AEs occurring during protocol therapy or starting within 30-days post last dose of 
protocol therapy. Refer to Section 7.7 for reporting details. 
o Follow-up for response for those who have yet to have disease progression. 
o Follow-up for survival - for those who initiated an anti-cancer therapy or have disease 
progression. 
Assessment time points and windows are detailed in Section 10.0. 


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5.8 Duration of Study Participation 
Study participation may conclude when any of the following occur:  
o Completion of study activities (treatment and follow-up) 
o Participant withdrawal (see Section 16.5). 
o Participant is lost to follow-up. All attempts to contact the participant must be documented. 
o At the discretion of the investigator for safety, behavioral or administrative reasons 
Documentation of the reason for discontinuing study participation and the date effective should be made 
in the medical record and appropriate eCRF. The COH DCC should be promptly notified of the change in 
participant status.   
5.9 Supportive Care, Prohibited Medications and Concomitant Therapy  
Participants must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator.  
Participants should not consume grapefruit, grapefruit products, Seville oranges (including marmalades 
containing Seville oranges), or star fruits while receiving protocol therapy.  
With the exception of prohibited therapies listed in Section 5.9.1, participants should receive appropriate 
supportive care measures as deemed necessary by the treating investigator per institutional standards. 
TLS prophylaxis guidelines are detailed in Section 5.9.3. Examples of prohibited and cautionary 
medications are listed in Appendix D. 
5.9.1 
Prohibited and Cautionary Agents 
Prohibited Agents 
The following are prohibited until from Day 1 of protocol therapy to 30 days post last dose. 
o Live virus vaccines 
o Other anticancer agents 
o Other investigational therapy/agent 
o Herbal medications 
Prohibited Agents During Cycle 1 and Cautionary Thereafter with Venetoclax Dose Reductions 
o Strong CYP3A inhibitors 
 Prohibited during Cycle 1 and consider alternative medications. If subject requires use of these 
medications after Cycle 1, use with caution and reduce the venetoclax dose by at least 4-fold 
during co-administration.   
o Moderate CYP3A inhibitors or P-gp inhibitors 
 Prohibited during Cycle 1 and consider alternative medications. If subject requires use of these 
medications after Cycle 1, use with caution and reduce the venetoclax dose by 2-fold during 
co-administration.   
 
After discontinuation of CYP3A inhibitor, wait for 2 to 3 days before venetoclax dose is increased 
back to the initial maintenance/target dose.  Examples of moderate and strong CYP3A inhibitors are 
found in Appendix D 
 


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o Strong and moderate CYP3A inducers 
 Prohibited during Cycle 1.  Consider alternative medications. If subject requires use of these 
medications after Cycle 1, use with caution as they may reduce venetoclax exposure and 
efficacy.   
 
Cautionary Agents 
o Warfarin and coumarin derivatives 
P-gp substrates 
BCRP substrates 
OATP1B1/1B3 substrates 
BCRP inhibitors 
5.9.2 
Supportive Therapy for Romidepsin Infusions 
o 30 min prior: 5-HT3 receptor antagonist 
 The recommended agent/dose is Zofran 16 mg IVPB or equivalent 
o Dexamethasone 10 mg IVPB 
5.9.3 
Tumor Lysis Syndrome (TLS) Prophylaxis Guidelines 
To mitigate the risk for TLS all participants will initiate TLS prophylaxis and undergo monitoring (see Table 
5.9.1). Consider all participant co-morbidities before final determination of prophylaxis. 
Table 5.9.1. Recommended TLS Prophylaxis Pre-Cycle 1 and Blood Chemistry Monitoring During Cycle 
1 
Recommended TLS Prophylaxis 
Blood Chemistry Monitoringc and Frequency 
Hydrationa  
Anti-hyperuricemicsb 
Oral (1.5-2 L) and 
intravenous (150-200 
mL/hr as tolerated) 
Allopurinol; consider 
rasburicase if baseline uric 
acid is elevated 
 
Cycle 1-Day 1-8: Pre venetoclax dosed, and post-dose at 6-
8, 24 (±2) hours for each dose level increase. Next dose 
should not be administered until 24 h blood chemistry 
values are evaluated. 
****NOTE: Cycle 1 post-dose Day 1-8 blood chemistry must 
be reviewed in real-time unless stated otherwise.**** 
a Administer intravenous hydration for any patient who cannot tolerate oral hydration. IV hydration must be initiated 
the night before dosing and continued for 24 hours after dose. 
b Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of venetoclax. 
c Evaluate blood chemistries (potassium, uric acid, inorganic phosphorus, calcium, and creatinine) 
d Pre-dose blood collection is to be performed within 4 hours from venetoclax administration. 
 
The management recommendations below focus on the minimum initial responses required.  Any 
abnormal chemistry tests should be corrected promptly. 
If a diagnosis of TLS is established, ongoing intensive monitoring and multi-disciplinary management will 
be per institutional practice. Refer to Table 7.2.1. 
 
5.9.3.1 Hyperkalemia (including rapidly rising potassium) 


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 For potassium increase ≥0.5 mmol/L from baseline, or any value >5.0 mmol/L, recheck 
potassium, phosphorus, uric acid, calcium and creatinine and follow first guideline. 
If Potassium ≥ 0.5 mmol/L increase from prior value (even if potassium within normal limits 
[WNL]) 
 Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour.   
− 
If further ≥ 0.2 mmol/L increase in potassium, but still < upper limit of normal (ULN), 
manage as per potassium ≥ ULN (see below).   
− 
Otherwise recheck in 1 hour. 
 Resume per protocol testing if change in potassium is < 0.2 mmol/L, and potassium < ULN, 
and no other evidence of tumor lysis.   
 Per investigator discretion recheck prior to hospitalization.   
− 
If stable or decreased, and still WNL, hospitalization is at the discretion of the 
investigator.   
− 
Potassium, phosphorus, uric acid, calcium and creatinine must be rechecked within 
24 hours. 
If Potassium ≥ ULN 
 Perform EKG and commence telemetry. 
 Consult Nephrology (or other acute dialysis service). 
 Administer Kayexalate 60 g (or Resonium A 60 g). 
 Administer furosemide 20 mg IV × 1. 
 Administer calcium gluconate 100 to 200 mg/kg IV slowly if there is EKG/telemetry 
evidence of life threatening arrhythmias. 
 Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour. 
− 
If potassium < ULN 1 hour later, repeat potassium, phosphorus, uric acid, calcium and 
creatinine 1, 2 and 4 hours, if no other evidence of tumor lysis. 
If Potassium > 6.0 mmol/L(6.0 mEq/L) and/or symptomatic (e.g. muscle cramps, weakness, 
paresthesias, nausea, vomiting, diarrhea) 
 Perform EKG and commence telemetry. 
 Nephrology (or other acute dialysis service) assessment with consideration of initiating 
dialysis. 
 Administer Kayexalate 60 g (or Resonium A 60 g). 
 Administer furosemide 20 mg IV × 1. 
 Administer sodium bicarbonate 1 to 2 mEq/kg IV push. 
− 
If sodium bicarbonate is used, rasburicase should not be used as this may exacerbate 
calcium phosphate precipitation. 
 Administer calcium gluconate 100 to 200 mg/kg IV slowly if there is 
 EKG/telemetry evidence of life threatening arrhythmias.  Do not administer in same IV 
line as sodium bicarbonate. 
 Recheck potassium, phosphorus, uric acid, calcium and creatinine. 
5.9.3.2 Hyperuricemia 
If Uric acid ≥ 8.0 mg/dL (476 μmol/L) 
 Consider rasburicase (dose based on institutional guidelines). 


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− 
If rasburicase is used, sodium bicarbonate should not be used as this may exacerbate 
calcium phosphate precipitation. 
 Recheck potassium, phosphorus, uric acid, calcium and creatinine. 
If Uric acid ≥ 10 mg/dL (595 μmol/L)  
OR  
Uric acid ≥ 8.0 mg/dL(476 μmol/L) with 25% increase and creatinine increase ≥ 0.3 mg/dL (≥ 
0.027 mmol/L) from pre dose level 
 Administer rasburicase (dose based on local guidelines and/or institutional standards). 
− 
When rasburicase is used, sodium bicarbonate should not be used as this may 
exacerbate calcium phosphate precipitation. 
 Notify nephrology (or other acute dialysis service). 
 Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour. 
 If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hours later, if no other evidence of tumor lysis. 
5.9.3.3 Hypocalcemia 
If Calcium ≤ 7.0 mg/dL (1.75 mmol/L) AND Patient symptomatic (e.g. muscle cramps, 
hypotension, tetany, cardiac arrhythmias) 
 Administer calcium gluconate 50 to 100 mg/kg IV slowly with EKG monitoring. 
 Telemetry. 
 Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour. 
 If calcium normalized 1 hour later, repeat potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hours later, if no other evidence of tumor lysis. 
 Calculate corrected calcium and check ionized calcium if albumin low. 
5.9.3.4 Hyperphosphatemia 
If Phosphorus increase of >0.5 mg/dL AND >4.5 mg/dL 
 Administer phosphate binder and recheck potassium, phosphorus, uric acid, calcium and 
creatinine. 
If Phosphorus ≥ 5.0 mg/dL (1.615 mmol/L) with≥ 0.5 mg/dL (0.16 mmol/L) increase 
 Administer a phosphate binder (eg, aluminum hydroxide, calcium carbonate, sevelamer 
hydroxide, or lanthanum carbonate). 
 Nephrology (or other acute dialysis service) notification (dialysis required for phosphorus 
≥ 10 mg/dL). 
 Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour. 
 If phosphorus < 5.0 mg/dL 1 hour later, repeat potassium, phosphorus, uric acid, calcium 
and creatinine 2 and 4 hours later, if no other evidence of tumor lysis. 
5.9.3.5 Creatinine  
Increase ≥ 25% from baseline 
 Start or increase rate of IV fluids.  
 Recheck potassium, phosphorus, uric acid, calcium and creatinine. 
 


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6.0 ANTICIPATED TOXICITIES & DOSE MODIFICATION/ DELAY GUIDELINES 
6.1 Anticipated Toxicities 
6.1.1 
Venetoclax 
Per the IB version 11 dated Jun 2019 the expected toxicities for venetoclax are as follows: 
System Organ Class 
Adverse Reactions 
Blood and lymphatic (including hematological labs) 
Very Common 
Common 
Anemia, neutropenia, febrile neutropenia, thrombocytopenia 
lymphopenia 
Gastrointestinal 
Very Common 
Constipation, diarrhea, nausea, vomiting, abdominal pain, mucositis 
General disorders and administration site conditions 
Very Common 
Fatigue, edema 
Infections and infestations 
Very Common 
Common 
Pneumonia, upper respiratory tract infection 
Sepsis, urinary tract infection 
Investigations 
Common 
 
Uncommon 
Blood creatinine increased, blood phosphorus increased, lymphocyte count 
decreased, neutrophil count decreased, serum albumin decreased 
Blood calcium decreased, blood potassium increased, hemoglobin decreased 
Metabolism and Nutrition Disorders 
Common 
Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, 
hyponatremia, tumor lysis syndrome 
Musculoskeletal and connective tissue disorders 
Very Common 
Musculoskeletal pain, arthralgia 
Nervous system disorders 
Common 
Headache, dizziness 
Respiratory, thoracic and mediastinal disorders 
Common 
Dyspnea, cough 
Skin and subcutaneous tissue disorders 
Very Common 
rash 
Vascular disorders 
Common 
Hypertension 
Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to 
<1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data). 
6.1.2 
Romidepsin 
Per the package insert dated March 2020 the expected toxicities for romidepsin are as follows: 
System Organ 
Class 
 
Adverse Reactions 
Blood and lymphatic (including hematological labs) 
Very Common 
Common 
thrombocytopenia, neutropenia, anemia, leukopenia 
febrile neutropenia 
 
Gastrointestinal 


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System Organ 
Class 
 
Adverse Reactions 
Very Common 
nausea, vomiting, diarrhea, constipation, abdominal pain, stomatitis 
General disorders and administration site conditions 
Very Common 
Fatigue, edema, pyrexia, chills, peripheral edema 
Infections and infestations 
Very Common 
Common 
infections 
pneumonia, sepsis, cellulitis, HBV reactivation 
Investigations 
Very Common 
 
Common 
weight decreased, aspartate aminotransferase increased, alanine aminotransferase 
increased 
ECG T-wave changes, blood bilirubin increased 
Metabolism and Nutrition Disorders 
Very Common 
Common 
anorexia, hypokalemia 
dehydration, hypocalcemia, tumor lysis syndrome 
Musculoskeletal and connective tissue disorders 
Very Common 
Musculoskeletal pain, arthralgia 
Nervous system disorders 
Very Common 
disguesia, headache 
Respiratory, thoracic and mediastinal disorders 
Very Common 
Common 
dyspnea, cough 
hypoxia 
Cardiac disorders 
Very Common 
Common 
tachycardia 
ventricular arrhythmia 
Vascular Disorders 
Very Common 
Common 
hypotension 
deep vein thrombosis 
Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to 
<1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data). 
 


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7.0 DOSE DELAY/ MODIFICATION GUIDELINES 
7.1 General Information 
o Baseline values are from screening evaluations.  
o For supportive care guidelines see Section 5.9. 
o Venetoclax doses missed for toxicity will not be made up. 
o Romidepsin doses missed for toxicity will not be made up. 
o Permanently discontinue protocol therapy if:  
 Participant requires a dose reduction and is already on 100 mg/day of venetoclax 
 Participant requires a dose reduction and is already on 10 mg/m2 romidepsin  
 Unable to resume treatment within 14 days after last dose of venetoclax 
o If the venetoclax dose was reduced during Cycle 1, intra-patient daily re-escalation to steady-
state venetoclax dose may be permitted in the absence of a recurrence of the toxicity that 
led to the reduction following consultation with the Study PI. 
o The initiation of a new cycle may be delayed for up to 7 days with written approval from the 
Study PI in circumstances where the participant is unable to come to the clinic as planned to 
initiate the new cycle (e.g. planned vacation by participant, lack of transportation etc.).* 
*If prior approval from the Study PI is obtained, then these modifications will not be 
considered a protocol deviation. The Study PI will document assessment of the impact of 
these determinations on the study design, objectives and endpoints or risk to participants. If 
any modifications to the treatment plan might affect the study design, objectives, and 
endpoints, or impact the risk of participants, a single subject exception will be sought by the 
IRB.  If the treating investigator is the Study PI, the determination and the rationale for the 
determination will clearly be documented in the source document(s). 
 
7.2 Treatment Modification Guidelines 
Toxicity  
Treatment Modification 
Metabolic and nutrition 
Romidepsin 
Venetoclax 
Hyperuricemia, 
hyperphosphatemia, hyperkalemia, 
hypocalcemia and creatinine 
changes with no evidence of clinical 
TLS (See Appendix B). 
 
Potassium > 6.0 mmol/L 
 
Potassium ≥ 0.5 mmol/L increase 
from prior value (even if potassium 
within normal limits [WNL]) 
 
Potassium > upper limit of normal 
Phosphorus > 4.5 mg/dL (1.5 mmol/L) 
 
Uric acid > 8.0 mg/dL (475.8 μmol/L) 
 
 
Hold the dose until resolution  
 
Refer to Section 5.10.3 for 
recommended supportive care. 
 
1st occurrence 
− 
If resolved within 3 days 
to resume at the same 
dose 
− 
If toxicity resolves > 3 days 
resume at a 50% dose 
reduction  
 
2nd occurrence 
− 
If resolves within 3 days to 
≤ Grade 1 or baseline, 


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Toxicity  
Treatment Modification 
Metabolic and nutrition 
Romidepsin 
Venetoclax 
 
Corrected calcium <7.0 mg/dL 
  
Creatinine increase ≥ 25% from 
baseline 
 
resume at a 50% dose 
reduction 
− 
If toxicity lasts > 3 days 
permanently discontinue 
protocol therapy 
Symptoms suggestive of clinical TLS 
(e.g. acute renal failure, cardiac 
arrythmia, seizures) See Appendix 
B. 
 
 
 
Hold venetoclax dose until TLS 
is resolved 
 
If toxicity resolves within 24-48 
hours resume venetoclax at 
current dose 
 
If toxicity takes longer than 48 
hours to resolve, resume at the 
previous dose in the ramp 
sequence.2nd occurrence, 
consider permanently 
discontinuing protocol therapy  
 
Other Grade 4 metabolic laboratory 
abnormalities  
  
 
Hold the dose until resolution 
to ≤ Grade 2 or baseline 
 
1st occurrence 
− 
If resolved within 3 days 
to resume at the same 
dose 
 
If toxicity resolves > 3 days 
resume at a 50% dose 
reduction 
 
2nd occurrence 
− 
If resolves within 3 days to 
≤ Grade 2 or baseline, 
resume at a 50% dose 
reduction 
− 
If  toxicity lasts > 3 days 
permanently discontinue 
protocol therapy 
Hematologic 
Romidepsin 
Venetoclax 
Grade 3 neutropenia 
<1000 - 500/mm3 
 
1st occurrence 
− 
Hold until ANC ≥1.5 x 
109/L 
− 
Restart at prior dose 
 
2nd occurrence 
− 
Hold until ANC ≥1.5 x 
109/L 
− 
Dose reduce to 12 mg/m2 
 
Hold the dose until ANC ≤ 
Grade 2 or baseline  
 
Consider using G-CSF 
 
Resume at pre-hold dose 


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Toxicity  
Treatment Modification 
Metabolic and nutrition 
Romidepsin 
Venetoclax 
 
3rd occurrence 
 
Remove from trial 
Grade 4 neutropenia 
<500/mm3 
 
1st occurrence 
− 
Hold until ANC ≥1.5 x 
109/L 
− 
Restart at prior dose 
 
2nd occurrence 
− 
Hold until ANC ≥1.5 x 
109/L 
− 
Dose reduce to 12 mg/m2 
 
3rd occurrence 
− 
Remove from trial  
 
Hold the dose until ANC ≤ 
Grade 2 or baseline  
 
Consider using G-CSF 
 
Consider a 50% dose reduction 
per investigator discretion 
Grade 3 febrile neutropena  
 
G3: < ANC <1000/mm3 with a single 
temperature of > 38.3 degrees 
C (101 degrees F) or a sustained 
temperature of ≥ 38 degrees C (100.4 
degrees F) for more than one hour. 
 
 
 
Hold the dose until ANC ≤ 
Grade 2 or baseline  
 
Consider using G-CSF 
 
Consider a 50% dose reduction 
per investigator discretion 
Grade 4 febrile neutropena 
 
G4: life threatening consequences 
 
1st occurrence 
− 
Hold until cytopenia 
returns to Grade 1 or 
baseline 
− 
Restart at prior dose 
 
2nd occurrence 
− 
Hold until ANC ≥1.5 x 
109/L 
− 
Dose reduce to 12 mg/m2 
 
3rd occurrence 
− 
Remove from trial 
 
Hold the dose until ANC ≤ 
Grade 2 or baseline  
 
Consider using G-CSF 
 
Consider a 50% dose reduction 
per investigator discretion 
Grade 3-4 thrombocytopenia, 
and/or anemia, and/or 
thrombocytopenia requiring 
transfusion 
 
1st occurrence 
− 
Hold until platelet count 
≥75 x 109/L or baseline 
− 
Restart at prior dose 
 
2nd occurrence 
− 
Hold until platelet count 
≥75 x 109/L or baseline 
− 
Dose reduce to 12 mg/m2 
 
3rd occurrence 
 
Remove from trial 
 Grade 4 other unspecified 
hematologic toxicities (except 
lymphopenia) 
 For Grade 4 thrombocytopenia 
− 
Hold the dose until 
platelets ≤ Grade 2 or 
baseline  
 
1st occurrence,  
− 
resume at same dose if 
toxicity resolves within 7 
days 
 
consider a 50% dose reduction 
if toxicity lasts > 7 days 2nd 


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Toxicity  
Treatment Modification 
Metabolic and nutrition 
Romidepsin 
Venetoclax 
occurrence and subsequent 
occurrence,  
− 
consider a 50% dose 
reduction if toxicity 
resolves within 7 days 
if toxicity lasts > 7 days, 
consider permanently 
discontinuing protocol therapy 
Other unspecified Non-
hematologic- RELATED 
Romidepsin 
Venetoclax 
≥ Grade 3 
 
1st occurrence 
− 
Hold until resolved to ≤ 
Grade 1 
− 
then reduce to 12 mg/m2 
 2nd or 3rd occurrence Grade 3 
− 
Hold until resolved to ≤ 
Grade 1 
− 
Dose reduce to 10 mg/m2 
 Any recurrence of Grade 4 
 
Remove from trial therapy  
 
Hold the dose until ≤ Grade 1 
or baseline  
 
1st occurrence,  
− 
resume at same dose if 
toxicity resolves within 7 
days 
 
consider a 50% dose reduction 
if toxicity lasts > 7 days 2nd 
occurrence and subsequent 
occurrence,  
− 
consider a 50% dose 
reduction if toxicity 
resolves within 7 days 
− 
if toxicity lasts > 7 days, 
consider permanently 
discontinuing protocol 
therapy 
Other unspecified Non-
hematologic- UNRELATED 
Romidepsin 
Venetoclax 
Any Grade 
 1st occurrence 
− 
Maintain protocol therapy 
for Grades 0-2 
− 
Hold until resolved from 
Grade 3-4 to ≤ Grade 1 
− 
Dose reduce to 12 mg/m2 
 2nd or 3rd occurrence Grade 3 
− 
Hold until resolved to ≤ 
Grade 1 
− 
Dose reduce to 10 mg/m2 
 Any recurrence of Grade 4 
− 
Remove from trial therapy 
 
Maintain protocol therapy 
 
Interruption of protocol 
therapy is permitted if the 
investigator consults the Study 
PI to determine that this is in 
the best interest of the 
participant. 


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8.0 AGENT INFORMATION 
8.1 Venetoclax 
Venetoclax has been FDA approved for patients with chronic lymphocytic leukemia (CLL) with 17p 
deletion, as detected by an FDA approved test, who have received at least one prior therapy.  
For additional information refer to the IB. 
8.1.1 
Other Names 
VENCLEXTATM, ABT-199, A-1195425.0, GDC-0199, RO5537382 
8.1.2 
Description  
Structural Formula: 
Molecular Formula: 
C45H50ClN7O7S 
Molecular Weight:  868.44 kDa 
8.1.3 
Mechanism of Action 
Venetoclax is a novel, orally available small molecule Bcl-2 family protein inhibitor that binds with > 500-
fold higher affinity to Bcl-2 and with lower affinity to other Bcl-2 family proteins Bcl-XL and Bcl-w. 
Overexpression of anti-apoptotic Bcl-2 family proteins is associated with increased resistance to 
chemotherapy, and antagonism of the action of these proteins might enhance response to such therapy 
and overcome resistance.  Anti-apoptotic Bcl-2 family members are associated with tumor initiation, 
disease progression, and drug resistance, making them compelling targets for antitumor therapy.  
8.1.4 
Pharmacokinetics 
Half-life: 
~26 hrs 
Distribution: 
Highly bound to plasma protein 
Metabolism:  Predominantly by CYP3A4/5; M27 is a major metabolite 
Excretion: 
>99.9% feces, < 0.1% urine 
8.1.5 
Human Toxicity 
See Section 6.1. 
8.1.6 
Formulation  
Venetoclax tablets will be used for this study.   
8.1.7 
Storage  
Store at 15o to 25 oC. 


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8.1.8 
Handling and Dispensing 
The investigator should ensure that investigational agent venetoclax is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as per product information and the 
Investigator Brochure and per local regulations.  
The investigational product must be dispensed only from official study sites by authorized personnel 
according to local regulations.  
If concerns regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact AbbVie immediately. 
8.1.9 
Administration 
See Section 5.4.1 
8.1.10 Supplier 
The investigational venetoclax will be supplied free of charge by AbbVie. 
8.1.11 Ordering 
Sites will place orders for venetoclax via the AbbVie drug portal.  The timing for initial and resupply will 
be the same.  
Sites should place orders a week in advance of the shipment. 
8.1.12 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent (investigational or free of charge) using a drug accountability 
log. 
It is the responsibility of the investigator to ensure that investigational product is only dispensed to study 
participants.  
8.1.13 Destruction and Return 
The investigator is responsible for keeping accurate records of the clinical supplies received from AbbVie 
or designee, the amount dispensed to participants, and the amount remaining at the conclusion of the 
trial.  
Any unused agent at the end of the study, expired agent, and damaged agent will be destroyed according 
to applicable federal, state, local and institutional guidelines and procedures. Prior to the destruction of 
venetoclax, the DCC should be notified and an acknowledgement to proceed from the DCC should be 
received.   
Destruction will be documented in a drug accountability log. 
8.2 Romidepsin 
8.2.1 
Other names 
Istodax®, Romidepsin for injection, FK228, depsipeptide 


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8.2.2 
Description 
Structural Formula: 
Molecular Formula: 
C24H36N4O6S2•CH4O 
Molecular Weight:  572.74 kDa 
8.2.3 
Mechanism of Action 
Romidepsin is a unique bicyclic depsipeptide originally isolated from Chromobacterium violaceum strain 
968. Romidepsin is an antineoplastic agent that has been identified as a novel HDAC inhibitor. Romidepsin 
has been shown to induce hyperacetylation of histones and other nonhistone protein species resulting in 
a variety of phenotypic changes, induction of the upregulation of gene transcription, G1 and G2/M arrest 
of the cell cycle, morphological reversion of transformed cells, cell growth inhibition, apoptotic cell death, 
and inhibition of angiogenesis. In vitro, romidepsin causes the accumulation of acetylated histones, and 
induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. 
The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has 
not been fully characterized. 
8.2.4 
Pharmacokinetics 
Half-life: 
~3 hrs 
Distribution: 
Highly bound to plasma protein 
Metabolism:  Predominantly by CYP3A4/5 
Excretion: 
accumulates in bile and excreted in feces 
8.2.5 
Human Toxicity 
See Section 6.2 
8.2.6 
Formulation 
Romidepsin Injection is a sterile, clear colorless to pale yellow solution and is supplied in single-dose vials. 
Each mL contains romidepsin 5 mg, povidone 10 mg, DL-apha-tocopherol 0.05 mg, dehydrated alcohol 
157.8 mg (20.1% v/v) and propylene glycol 828.8 mg. 
8.2.7 
Storage 
20° to 25° C, excursions permitted between 15° to 30° C. (See USP Controlled Room Temperature.) 
8.2.8 
Handling and dispensing 
Romidepsin should be handled in a manner consistent with recommended safe procedures for handling 
cytotoxic drugs.  


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Romidepsin must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium 
Chloride Injection, USP before intravenous infusion. 
8.2.9 
Administration 
See Section 5.4.2. 
8.2.10 Supplier 
Romidepsin will be available through commercial supply. 


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9.0 CORRELATIVE/ SPECIAL STUDIES 
9.1  Tumor Tissue Studies 
An overview of collection, processing, and analysis details are shown in Table 9.1. 
Table 9.1. Overview of Tumor Tissue Studies 
Tissue Type 
Timepoint of collection 
Planned Future Analaysis 
Formalin fixed 
archived biopsy  
Baseline 
 BCL2 expression status and correlation with response 
 Changes in gene expression 
Fresh tissue 
 Baseline  
 Optional: During Cycle 1 or Cycle 2  
9.1.1 
Timepoints of Collection 
o Baseline tissue:  
 Fresh tissue (after informed consent): If a standard of care fresh core or excisional biopsy of 
the tumor lesion is to be performed, attempts should be made to take extra tissue for research.  
 Formalin-fixed tissue: Archived biopsy tumor tissue should be submitted. 
o During Cycle 1 or Cycle 2 (optional): Submit fresh core or excisional biopsy of the tumor lesion 
for research if the participant is willing. 
9.1.2 
Guidelines for archival specimens  
Using the formalin-fixed paraffin embedded (FFPE) tissue block, the following samples will be processed 
for correlative studies:  
o If tissue block is available submit: 
 
6 paraffin scrolls measuring 10 µm thick placed into a Nunc tube and frozen at -80° C AND 
 
10 x 5 µm unstained slides 
o If tissue block is unavailable submit 20 x 5 µm unstained slides 
9.1.3 
Guidelines for fresh tumor tissue processing  
9.1.3.1 Non-COH sites 
Tumor lesion core or excisional biopsies should be flash frozen and kept at -80oC until batch shipment. 
9.1.3.2 COH only 
Tumor lesion core or excisional biopsies will be collected in saline.  
9.1.4 
Labeling of samples 
Samples will labeled with the study number, institution (for non-COH sites), subject ID, date, timepoint of 
collection (i.e. baseline or progression) and if applicable patient initials.  


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9.1.5 
Sample shipment and receiving lab 
Tissue specimens collected at the above indicated timepoints will either be taken to (COH only) or batch-
shipped (non-COH sites) to COH Pathology Core. For all sites, please include the Correlative Tissue form 
(Appendix F-2) with your shipment. 
Please note that samples should only be batch shipped from non-COH sites on Monday-Wednesday for 
receipt Tuesday-Friday. Refer to Appendix F-1 for shipment details.  
 


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10.0 STUDY CALENDAR 
All procedures may increase in frequency if clinically indicated. 
Table 10.0 Study Activity Calendar  
Protocol Activity dd 
Screening a 
Protocol Therapy b,c 
EOT g 
Post-last Dose Follow-
up (24 months) 
Cycle 1 
Cycle 2 
D1 & 
then 
weekly  
Cycle 3+ 
D1  
Safety 
30-days post h 
Response i 
Survival j 
D 
1d,e 
D 
2-7f 
D 
8 
D 
15 
D 
22 
Informed Consentk 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History l 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility m 
X 
 
 
 
 
 
 
 
 
 
 
 
Registrationn 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam o &  
Vital signs p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG Status (Appx. A) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Con-med review q  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AE Assessment r  
X r 
--------------------------------------------------Xs---------------------------------------------- 
 
 
12-lead EKG 
X u 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy t 
X u 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, plt & Serum 
chemistry v 
X u 
X 
X f 
X  
X  
X 
X 
X 
X 
 
 
 
TLS serum chemistry 
monitoring w 
 
X w 
X w 
X w 
 
 
 
 
 
 
 
 
CT/MRI imaging x 
X 
 
 
 
 
 
 
X y 
X g 
 
X 
 
FDG-PET scan z 
X 
 
 
 
 
 
 
 
X 
 
 
 
Bone marrow  
biopsy/ aspirate  
X aa 
 
 
 
 
 
 
 
 
 
 
 
Response bb 
 
 
 
 
 
 
 
X y 
X 
 
X 
 
TLS prophylaxis 
X cc 
 
 
 
 
 
 
 
 
 
 
 
Venetoclax 
 
Orally, daily e,f 
 
 
 
 
Romidepsin ee 
 
X 
 
X 
X 
 
X ee 
X ee 
 
 
 
 
Pill diary ff 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Tumor tissue  
X gg 
Optional: During Cycle 1 or 2 hh 
 
 
 
 
 
 
Survival status j 
 
 
 
 
 
 
 
 
 
 
 
X 


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a. Screening activities to occur within 28 days prior to start of protocol therapy except for laboratory assessments, 
bone marrow biopsy/aspirate and TLS prophylaxis. 
b. Protocol therapy may last up to 26 cycles (~ 24 months), until unacceptable toxicity or disease progression (see 
Section 5.7 for more comprehensive list). If a patient is still benefiting from treatment at the completion of 26 cycles 
of therapy, we will consider amending the study to extend the duration of therapy for that particular patient. 
c. 
Each treatment cycle lasts 28 days. The cycle duration does not change, even if venetoclax is held (Note: exceptions 
due to unusual operational considerations may be permitted; see Section 6.2). 
d. Cycle 1 Day 1 is defined as the day of venetoclax and romidepsin initiation. Delay the Cycle 1 Day 1 dose if the 
participant is experiencing laboratory TLS as defined in Appendix B. 
e. Assessments must be performed and reviewed within 72 hours prior to the C1D1 venetoclax dose (except tumor 
imaging). 
f. 
Cycle 1 Day 2-7 (± 2 hours) laboratory assessments must be performed and reviewed prior to administration of the 
Cycle 1 Day 2-7 venetoclax doses. 
g. End of protocol therapy (EOT) assessments to be performed no later than 7 days after decision to end treatment 
(except tumor imaging); assessments performed after last dose of study agent and within 7 days of the decision to 
end treatment may serve as EOT assessments. NOTE: Tumor imaging performed after last dose of study agent and 
within 28 days of the decision to end treatment may serve as EOT imaging assessment. 
h. Safety visit to occur 30 (-2/+7) days post-last dose of protocol therapy. Expedited reporting will occur during this 
period (See Section 7.7.2). Safety follow-up may be extended until resolution/ stabilization of reportable AEs. 
i. 
For participants yet to progress, Response Follow-up will occur every 2 months (+/- 7 days) from the day of last 
response evaluation until progression or the initiation of a new therapy. 
j. 
Participants who end Response Follow-up will enter Survival Follow-up. Survival assessment to occur bi-annually or 
as requested by the Study PI via medical record review, review of social security registry, or telephone call. 
k. 
Informed consent process to be fully documented (see Section 16.4). Informed consent must occur prior to any 
research only (non-SOC) screening procedures. 
l. 
Medical history to include a review of treatment history, any ongoing medical conditions and medical history 
pertaining to eligibility on study and involvement during study  
m. Eligibility criteria are detailed in Section 3.0.  
n. Registration into a COH clinical trial management system (CTMS).  
o. Standard physical exam includes weight and skin analysis.  
p. Vital signs: heart rate, blood pressure, respiration rate, and temperature.   
 
q. Concurrent medications and reason for administration to be documented from within 10 days prior to protocol 
therapy up to 30-days-post last dose visit. See Section 5.9 for concomitant medication restrictions and guidelines.  
r. 
Adverse event (AE) will be assessed using CTCAE v.5.0. SAEs related to study procedures will be recorded and 
reported from time of informed consent until Day 1 of protocol therapy.  
s. 
Toxicities AE recording and reporting will continue until the completion of Safety Follow-up period or until resolution 
or stabilization of any reportable AE occurring during Safety Follow-up.  
t. 
Women of child bearing potential: Pregnancy serum or urine test. 
u. Screening laboratory assessments to be performed within 14 days prior to start of protocol therapy. 
v. 
Serum chemistry panel to include: glucose, Blood Urea Nitrogen (BUN), creatinine, uric acid, total protein, albumin, 
magnesium, bicarbonate, calcium, inorganic phosphorous, sodium, potassium, chloride, total CO2, total bilirubin, 
alkaline phosphatase, ALT, AST, and LDH. 
w. TLS serum chemistry monitoring post-Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7 and Day 8 dose to include 
potassium, uric acid, phosphorus, calcium, and creatinine. Monitoring times are: predose, and post dose 6-8 hours 


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and 24 (+/- 2) hours. Next dose should not be administered until 24 h blood chemistry values are evaluated. See 
Table 5.9.1. 
x. 
CT/MRI imaging for PTCL at baseline.  
y. 
Disease and response assessment: Cycle 3 Day 1 (-7 days), then every 2 cycles (-7 days). CT scan may take place 
within 7 days prior to D1 but not after D1 of the cycle in question. 
z. 
FDG-PET scan will be performed at screening. Subsequent PET scans will not be needed until the EOT visit or disease 
progression, whichever comes first. 
aa. Bone marrow biopsy/aspirate that was performed within 120 days prior to Day 1 may serve as Screening 
assessment. 
bb. PTCL response (Lugano criteria). Refer to Section 11.3 for details.  
cc. TLS prophylaxis to be initiated prior to protocol therapy within 72 hours as stated in Table 5.9.1. Participants should 
receive continued TLS prophylaxis as clinically indicated.  
dd. Refer to Section 5.3 for the treatment plan. Refer to Section 6.2 for dose modification/ delay guidelines and Section 
5.9 for supportive care guidelines. 
ee. Romidepsin will be administered intravenously on Days 1, 8, and 15 of each cycle. A window is allowed for 
romidepsin infusion visits (within ±3 days of day 1 and within +3 days of days 8 and 15) 
ff. Pill Diary will be given to the participant and will be reviewed for adherence. See Appendix G. 
gg. Baseline tissue: Archival tissue of a biopsy and if applicable, fresh core or excisional biopsy of a tumor lesion at time 
of standard of care biopsy. 
hh. Optional: Research fresh core or excisional biopsy of the tumor lesion only if the participant is willing. 
 
 
 


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11.0 ENDPOINT EVALUATION CRITERIA/MEASUREMENT OF EFFECT 
11.1 Safety 
Toxicity will be graded according to the NCI-Common Terminology Criteria for Adverse Events version 5.0. 
During the first 2 cycles, all grades of toxicity will be collected. After cycle 2, only the highest grade of any 
toxicity will be collected for each cycle during protocol treatment and for the period of safety follow-up 
after end of treatment.  
11.2 Unacceptable Toxicity During Safety Lead-In 
Unacceptable toxicity will be defined as one of the following AEs that is at least possibly related to either 
venetoclax or romidepsin treatment within the first 2 cycles of protocol therapy:  
Hematologic 
o Grade 3 or 4 neutropenia lasting > 7 days (despite the use of growth factor support) 
o Grade 3 or 4 thrombocytopenia associated with bleeding requiring transfusion 
o Grade 4 anemia not associated with lymphoma 
Non-hematologic 
o Clinical TLS (per Howard criteria)   
o Grade 4 metabolic laboratory abnormalities that do not resolve within 3 days to ≤ Grade 2 
with supportive measures  
o Any other ≥ Grade 3 toxicity that does not resolve to ≤ Grade 1 or baseline within 7 days with 
the exception of: 
 Grade 3 asymptomatic laboratory abnormalities, including lipase or amylase, that are not 
clinically relevant, not requiring hospitalization or delay of treatment 
 Grade 3 nausea, vomiting, or fatigue controlled with supportive measures 
 Vitiligo  
11.3 Efficacy Endpoints 
11.3.1 PTCL Efficacy Endpoints 
Disease parameters and methods for assessing the disease are in Appendix C-1. PTCL response will be 
assessed using Lugano Classification (see Appendix C-2) [50].  Endpoints are describes in Table 11.3.  


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Table 11.3. Clinical Endpoints  
Endpoint 
Patients 
Definition 
Overall response 
rate (ORR) 
Evaluable patients 
Proportion of patients achieving CR or PR 
Complete response 
(CR) rate 
Evaluable patients 
Proportion of patients achieving CR 
Time to response 
Evaluable patients 
Date of initiation of protocol treatment to date when criteria for 
response (PR or CR) is first met 
Duration of 
response (DOR) 
CR and PR only 
Date when criteria for response (CR or PR) is first met until date 
criteria for PD or relapse is first met 
Progression free 
survival (PFS) 
Evaluable patients 
Date of initiation of protocol treatment to date  criteria for PD is 
first met or death as a result of any cause 
Overall survival 
(OS) 
Evaluable patients 
Date of initiation of protocol treatment to date of death from 
any cause 
Note: Evaluable patients are patients evaluable for response, as defined in Section 12.3. 
 


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12.0 STATISTICAL CONSIDERATIONS 
12.1 Statistical Design 
This is a multi-institution, single arm Phase 2 trial to evaluate the anti-tumor activity and safety/tolerability 
of venetoclax with romidepsin in patients with relapsed/refractory mature T-cell lymphoma. Patients will 
take oral venetoclax daily and romidepsin on days 1, 8, and 15 of each cycle for up to 26 cycles (28-day 
cycle) Response will be assessed after every 2 cycles until disease relapse/progression. Patients will be 
followed for 24 months after the end of protocol treatment. The primary endpoint is overall response 
rate. Secondary endpoints include toxicities, CR rate, duration of response, time to response, PFS, and OS. 
The study will accrue up to 18 evaluable patients for the primary response endpoint evaluation. The first 
6 patients enrolled on the study will be part of a Safety Lead-in to evaluate the safety and tolerability of 
the proposed dose of venetoclax with romidepsin as described below in Section 12.1.1. 
12.1.1 Safety Lead-In 
Prior to formally initiating the Phase 2 response evaluation, a patient Safety Lead-in will be conducted to 
ensure the proposed treatment is tolerable. Up to 6 evaluable patients may be enrolled in two cohorts of 
3 patients each at the proposed venetoclax dose (maximum dose of 800 mg/day with a 1-week dose ramp 
up schedule) plus romidepsin as outlined below. Initially up to 3 evaluable patients can be enrolled and 
treated. After 3 patients are treated and evaluated for unacceptable toxicities, if 0/1 out of 3 evaluable 
patients experience unacceptable toxicities during the first 2 cycles, up to 3 additional patients will be 
enrolled and treated to bring the total number of patients treated to 6. If ≤1/6 evaluable patients 
experience unacceptable toxicities during the first 2 cycles, the proposed treatment dose/schedule 
(including ramp-up) will be considered tolerable and be used for the subsequent Phase 2 response 
evaluation. At any time during the Safety Lead-in, if ≥2 patients experience unacceptable toxicities during 
the first 2 cycles, the accrual will be suspended and the study will be amended. The unacceptable toxicities 
are defined in Section 11.2. Unacceptable toxicities will be evaluated during the first 2 cycles of therapy 
to ensure monitoring of participants during the venetoclax ramp-up period (Cycle 1) and while participants 
are on steady-state venetoclax dose (Cycle 2). Patients inevaluable for unacceptable toxicities during the 
Safety Lead-in will be replaced (see below in Section 12.3). 
12.1.2 Phase 2 
The Phase 2 response evaluation will accrue a minimum of 7 evaluable patients and a maximum of 18 
evaluable patients. Patients enrolled during the Safety Lead-in period of the study (n=6) will be included 
in the Phase 2 response evaluation provided that they are evaluable for response (defined in Section 12.3). 
The response evaluation will be based on a Simon’s Two-Stage Optimal design [53], to distinguish a 
promising 30% response rate (alternative hypothesis) from a disappointing rate (null hypothesis) of 10%, 
at a one-sided type I error of 10% and a power of 80%. In the first stage, 7 evaluable subjects will be 
accrued. If there is 0 response among the 7, the study accrual will be suspended. If there are 1 or more 
responses among the 7, the study will remain open to accrue a total of 18 evaluable patients. Observing 
4 or more responses among 18 evaluable patients will reject the null hypothesis and indicate the response 
rate being promising in this study setting.  Observing 3 or fewer responses among 18 evaluable patients 
will fail to reject the null hypothesis and will not establish efficacy of the treatment.  
For the purpose of the 1st stage response evaluation, study accrual may be temporarily suspended until 
all Stage 1 enrollments are assessed for response after at least 4 cycles of treatment or are otherwise off-
treatment. If by that time no responders have been observed, the study accrual will be terminated. On 


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the other hand, if at least one responder has been observed prior to enrolling the 7th patient for Phase II, 
then Phase II accrual will continue directly to Stage 2 without interruption.   
If no toxicity is noted at the proposed dose/schedule and there is no efficacy either, the protocol may be 
amended after discussion with the industry partner to increase the maximum dose of venetoclax up to 
1200 mg/day. 
12.2 Accrual and Expected Duration of Trial 
The expected sample size for the Phase 2 response evaluation is 18 patients evaluable for response 
(assuming the response evaluation passes the first stage). Patients enrolled during the Safety Lead-in of 
the romidepsin/venetoclax combination will be included in the Phase 2 response evaluation if they are 
evaluable for response which requires a response evaluation after 2 cycles. We expect that all patient 
enrolled during safety lead-in will have a response evaluation after 2 cycles. Therefore, the total sample 
size for the study including the Safety Lead-in is expected to be 18 evaluable patients. Assuming 
approximately 10% of the patients need to be replaced for safety lead-in or Phase 2 evaluation, the 
maximum sample size for evaluating the combination of venetoclax and romidepsin is 20 patients.  
The 6 patients enrolled on the previous versions of protocols with single agent venetoclax will be analyzed 
separately and excluded from the main analyses which evaluate the combination of venetoclax and 
romidepsin. Therefore, the maximum sample size of the study will be 26 accounting for these 6 prior 
enrollments.  
City of Hope saw ~160 PTCL patients per year, with ~30 new patients per year (mix of newly diagnosed 
and relapsed or refractory). This will be a multicenter study with 3 total sites. We expect a total accrual of 
1-2 patients per month across all sites. Therefore, accrual is expected to be completed in 24 months.  
Participant duration is planned for 4 years which includes maximum time for treatment (24 months) and 
expected post-treatment follow-up (24 months). The estimated total study duration will be 6 years, with 
2 years of accrual and approximately 4 years of treatment and follow-up for the last patient.  
12.3  Evaluable Participants and Participant Replacement 
o Evaluable for unacceptable toxicity during Safety Lead-in: Patients evaluable for 
unacceptable toxicity (defined in Section 11.2) are: 
1) Those who received at least 75% of the total dose of each drug for the first 2 cycles of 
therapy combined OR  
2) Those who experience any unacceptable toxicity during the first 2 cycles regardless of 
actual dose received.  
During safety lead-in, patients who are not evaluable for unacceptable toxicities will be replaced. 
o Evaluable for response: Patients evaluable for response are those who received at least 2 
cycles of protocol treatment and have a response evaluation after 2 cycles. Subjects who 
terminate treatment prior to 2 cycles due to disease relapse/progression or unacceptable 
toxicity will be considered evaluable for response and be considered non-responders. 
Patients who terminate prior to 2 cycles for other reasons will be inevaluable for response. 
Patients not evaluable for response will be replaced. 


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12.4 Stopping Rules for Tumor Lysis Syndrome (TLS)  
Besides prophylaxis and dose modification for TLS per Section 5.9.3 and Section 7.2, the study will 
implement accrual stopping rules for both clinical TLS and laboratory TLS. When a stopping rule is 
triggered, the study PMT will review and assess the safety of the trial and submit a report to the COH 
DSMC. The COH DSMC will review for approval any decision to continue or permanently suspend accrual 
to the trial. 
12.4.1 Clinical TLS Stopping Rule 
Study accrual will be suspended when the first incidence of clinical TLS is reported.   
12.4.2 Laboratory TLS Stopping Rule 
The incidence of laboratory TLS will be monitored with 12% being the benchmark based on IB. 
Operationally, the study accrual will be suspended if:  
• 
1 patient experiences laboratory TLS when there have been ≤5 patients treated 
• 
2 patients experience laboratory TLS when there have been ≤14 patients treated 
• 
3 patients experience laboratory TLS regardless of the number of patients treated 
The rule is derived based on a <50% probability of the rule being triggered when the true laboratory TLS 
incidence is ≤12%.  
12.5 Statistical Analysis Methods 
Patient demographics and baseline disease characteristics, including age, gender, medical history, and 
prior therapy, will be summarized using descriptive statistics. For continuous variables, descriptive 
statistics such as number, mean, standard deviation, standard error, median (range) etc. will be provided. 
For categorical variables, patient counts and percentages will be provided. 
Rates and 95% Clopper-Pearson binomial confidence interval (CI) will be calculated for overall response 
rate (patients that have confirmed CR or PR), as well as for CR rate. Time to response, duration of response 
(only among subjects achieving CR/PR), overall survival, and progression-free survival will be estimated 
using the product-limit method of Kaplan- Meier with the Greenwood estimator of standard error. Median 
progression-free survival and overall survival and their corresponding 95% CIs will be estimated. Observed 
toxicities will be summarized as summary statistics in terms of type (organ affected or laboratory 
determination), severity, attribution, time of onset, duration, probable association with the study 
treatment, and reversibility of outcome.  
For the exploratory objective on determining the changes in Bcl-2 gene expression in pre- and post-
treatment tumor samples, summary statistics and plots will be used to describe the pre- and post-
treatment gene expression levels and the associated change between the timepoints. Paired t-test or 
Wilcoxon signed rank test will be used to explore the difference in gene expression levels before and after 
treatment. Data transformation such as log transformation will be considered if appropriate. Exploratory 
analyses will be performed to investigate the association of the pre-/post-treatment Bcl-2 gene 
expressions and the change in gene expression with the clinical outcomes. For the exploratory correlation 
of these gene expression level/change with response, analyses comparing groups of participants defined 
by response may be conducted by two-sample t-test or Wilcoxon rank sum test. For the exploratory 
correlation of these endpoints with survival outcomes, survival analysis techniques such as Log rank test 
will be used. Appropriate regression models will also be considered, such as logistic regression model for 


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analyses on response and Cox proportional hazards models for analyses on survival outcomes. All these 
analyses are exploratory in nature and are intended to generate hypotheses that may be validated in 
larger studies; no multiple comparison adjustments will be made in these exploratory analyses.  


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13.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
13.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy dispensing 
records, recorded data from automated instruments, laboratory data) that are relevant to the clinical trial.  
The investigator or their designee will prepare and maintain adequate and accurate source documents.  
These documents are designed to record all observations and other pertinent data for each patient 
enrolled in this clinical trial.  Source documents must be adequate to reconstruct all data transcribed onto 
the case report forms. 
13.2 Data Capture Methods and Management 
Data for this trial will be collected using Medidata Rave.  
13.3 Case Report Forms/Data Submission Schedule 
Study personnel will enter data from source documents corresponding to a participant’s visit into the 
protocol-specific electronic Case Report Form (eCRF) when the information corresponding to that visit is 
available.  
The investigator is responsible for all information collected on participants enrolled in this study.  All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy by 
the investigator. All case report forms must be completed by designated study personnel.  The completed 
case report forms must be reviewed, signed and dated by the Investigator or designee in a timely fashion. 
All data will be collected using electronic data collection, stored as indicated in Section 13.2, and will be 
submitted according to the timelines indicated in Table 13.3. 
Table 13.3 Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 14 calendar days of treatment administration 
Adverse Event Report Forms 
Safety Lead-in Cycle 1 and 2: Within 7 calendar days of the 
assessment/notification 
Safety Lead-in Cycle 3+ and Phase 2: Within 10 calendar days of the 
assessment/notification 
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms  
Within 10 calendar days of the assessment 
Off Treatment/Off Study 
Forms 
Within 10 calendar days of completing treatment or being taken off study 
for any reason 
Follow up/ Survival Forms 
Within 14 calendar days of the protocol defined follow up visit date or call 
13.4 Regulatory Records 
The investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations 


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14.0 ADVERSE EVENTS AND UNANTICIPATED PROBLEMS  
14.1 Definitions 
14.1.1 Adverse Event (AE) 
An adverse event is any untoward medical experience or change of an existing condition that occurs 
during or after treatment, whether or not it is considered to be related to the protocol intervention. 
14.1.2 Serious Adverse Event (SAE) 
A serious adverse event is any expected or unexpected adverse events that result in any of the following 
outcomes: 
• 
Death 
• 
Is life-threatening experience (places the subject at immediate risk of death from the event as it 
occurred) 
• 
Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of existing 
hospitalization 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect 
• 
Secondary malignancy* 
• 
Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias of convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse). 
*Modified from 21 CFR 312.32 
14.1.3 Unanticipated Problems Involving Risks to Subjects or Others 
An unanticipated problem is any incident, experience, or outcome that meets all three of the following 
criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 
protocol, informed consent document or Investigator Brochure (IB); and b) the characteristics of 
the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by the 
drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than previously known or recognized. 
 


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14.1.4 Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities. These events, regardless of seriousness, will be reported. 
14.1.4.1 
Study Specific AESIs 
• 
Tumor lysis syndrome (see Section 7.5) 
• 
Overdose (see Section 7.6) 
14.2 Assessment of Adverse Events 
The site Investigator will be responsible for determining the event name, assessing the severity (i.e. 
grade), expectedness, and attribution of all adverse events.  
14.2.1 Assessment of Adverse Event Name and Grade 
Adverse events will be characterized using the descriptions and grading scales found in the most recent 
version of CTCAE v. 5.0.  A copy of the scale can be found at NCI/ CTEP web site. The determination of 
severity for all other events not listed in the CTCAE v. 5.0 should be made by the investigator based on 
medical judgment and the severity categories of Grade 1 to 5 as defined below: 
• 
Grade 1 (mild) – An event that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living. 
• 
Grade 2 (moderate) – An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject. 
• 
Grade 3 (severe) – An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the clinical status of the subject. 
• 
Grade 4 (life threatening) – An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death or with physical or mental disabilities that affect or limit the ability of the 
subject to perform activities of daily living (eating, ambulation, toileting, etc). 
• 
Grade 5 (fatal) – Death (loss of life) as a result of an event. 
14.2.2 Assessment of Attribution 
The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 
• 
Unrelated – The event is clearly related to other factors such as the participant’s clinical state, 
other therapeutic interventions, or concomitant medications administered to the participant. 
• 
Unlikely – The event is doubtfully related to the investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs. 
• 
Possible – The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s clinical 
state, other therapeutic interventions, or concomitant drugs.  


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• 
Probable – The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot be 
reasonably explained by other factors such as the participant’s clinical state, therapeutic 
interventions, or concomitant drugs.  
• 
Definite – The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions, or 
concomitant drugs, AND occurs immediately following study drug administration, improves 
upon stopping the drug, or reappears on re-exposure.  
14.2.3 Assessment of Expectedness 
The following definitions will be used to determine the expectedness of the event: 
 
• 
Unexpected– An adverse event is unexpected if it is not listed in the investigator’s brochure 
and/or package insert; is not listed at the specificity or severity that has been observed; is not 
consistent with the risk information described in the protocol and/or consent; is not an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk 
factor of the research participant experiencing the adverse event. *Modified from 21 CFR 
312.32 (a) 
• 
Expected – An adverse event is expected if it does not meet the criteria for an unexpected 
event, OR is an expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse event. 
 
14.3 Reporting of Adverse Events 
14.3.1 Routine Reporting of Non-Serious Adverse Events by Site Investigators  
Routine AE recording will occur via data entry into the study eCRF. Recording of adverse events will begin 
once the patient is consented and will continue until 30 days after the last dose of protocol therapy. 
Adverse events will be monitored by the Protocol Management Team (PMT). Adverse events that do not 
meet the criteria of serious OR are not unanticipated problems do not require expedited reporting.  AEs 
reported through expedited processes (i.e. reported to the IRB, DSMC, FDA, etc.) must also be reported 
in routine study data submissions.  
14.3.2 Expedited Reporting Requirements of SAEs and UPs by Site Investigators 
14.3.2.1 
Criteria for Reporting SAEs/UPs to the Coordinating Center 
Serious Adverse Events meeting the criteria specified below will be reported to the Coordinating Center 
within 24 hours of notification that the event occurred.  
 
Adverse events that require expedited reporting include: 
• 
AEs or SAEs that meet the definition of an unanticipated problem 
• 
AEs associated with  
o TLS (Section 14.5) 
o overdose (Section 14.6), suspected abuse/ misuse, 


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o pregnancies (Section 14.7) 
• 
All deaths that occur within 30 days of active treatment 
• 
All deaths that occur after 30 days of active treatment that are unexpected and possibly, 
probably, or definitely related to the study agent or procedure 
• 
All serious adverse events, regardless of relationship to study agent or study procedure, that 
occur within 30 days of the last day of treatment 
• 
All serious adverse events that occurred after 30 days of active treatment/therapy that are 
considered possibly, probably, or definitely related to the study agent or procedure  
 
Note: Follow-up reports must be submitted for all events that require expedited reporting when the status 
of the event changes and until the resolution or stabilization of the event. 
 
Reportable serious adverse events must be followed until the event is resolved, stabilized, or determined 
to be irreversible by the participating investigator; for ongoing reportable adverse events that are 
unrelated to study agent, the follow-up period may end at the 30-days post study-drug assessment. The 
Coordinating Center should be consulted prior to ending the follow-up of events that have stabilized. 
 
14.3.2.2 
Non-COH Sites: Procedure for Reporting SAEs/UPs to the COH Data Coordinating 
Center  
1. Sites are to report to their local IRB per their site’s specific institutional and IRB 
guidelines. As soon as possible, non-COH sites will provide to the COH Data 
Coordinating Center copies of the IRB submission and corresponding IRB 
response.  
2. Document/describe the SAE/UP on each of the following:  
a. MedWatch 3500A   
i. Downloadable form at http://www.fda.gov/medwatch/getforms.htm  
b. UP/SAE Coversheet 
i. SAE Coversheet is found in Appendix H-2.  A modifiable Microsoft Word 
document is also available from the Data Coordinating Center.  An 
electronic signature on the document will be accepted. 
3. Scan and email above documents to DCC@coh.org with the subject title as “IRB 
# SAE”.   
a. All SAE reports received at this account are forwarded immediately to 
study Principal Investigator, and to Coordinating Center personnel.  
b. While not required, if available and applicable, please also include the 
local IRB submission for this event in the submission.  
4. If an email receipt from Coordinating Center personnel is not received within 
one working day, please call 626-218-7904 and/or email DCC@COH.org. 
 


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14.3.2.3 
COH Investigative Sites: Procedure for Reporting SAEs/UPs to the Coordinating 
Center 
1. Email the following information to DCC@coh.org and jazain@coh.org:   
a. Participant ID, date the event met criteria for reporting, whether 
the event meets the definition of serious, whether the event is an 
unanticipated problem, grade of event, attribution of event, 
whether the event is a known expected toxicity to study agent. 
2. Complete the iRIS AE/UP reporting form per COH reporting timeline. 
 
14.3.3 Additional Reporting Requirements of the Study Principal Investigator  
14.3.3.1 
Reporting to COH IRB and DSMC 
The study PI (or designee) will report to COH IRB and DSMC via iRIS all reportable serious adverse events 
that occur at COH and non-COH sites and meet COH IRB and DSMC expedited reporting criteria according 
to City of Hope’s Institutional policy.  The study PI will also submit a Protocol Management Team (PMT) 
report to the COH DSMC at the frequency outlined in Section 3.6. This report will include a review of 
aggregate adverse event data.   
 
14.3.3.2 
Reporting to the FDA  
The study PI (or designee) will be responsible for contacting the Office of IND Development and Regulatory 
Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  OIDRA will assist the PI 
with the preparation of the report and submit the report to the FDA in accordance with the approved City 
of Hope’s Institutional policy. 
 
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety report using the 
MedWatch Form FDA 3500A for Mandatory Reporting. 
 
The criteria that require reporting using the Medwatch 3500A are: 
• 
Any unexpected fatal or life threatening adverse experience associated with use of the drug 
must be reported to the FDA no later than 7 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(2)] 
• 
Any adverse experience associated with use of the drug that is both serious and unexpected 
must be submitted no later than 15 calendar days after initial receipt of the information [21 
CFR 312.32(c)(1)] 
• 
Any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 
 
In addition, the study PI will submit annually within 60 days (via COH OIDRA) of the anniversary date of 
when the IND went into effect, an annual report to the FDA which is to include a narrative summary and 
analysis of the information of all FDA reports within the reporting interval, a summary report of adverse 
drug experiences, and history of actions taken since the last report because of adverse drug experiences. 
 


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14.3.3.3 
Reporting to Participating Investigators 
The study PI (or designee) will report all reportable serious adverse events to participating investigators 
as an IND Safety Report occurring within 30 calendar days of receipt of sponsor (lead site) notification, 
and indicate whether or not a protocol and/or consent form change is required.  A cover letter will 
indicate the protocol title, the IND#, whether the FDA was informed, and, for non-COH sites, a 
statement that the report should be submitted to their local IRB for review as an IND safety report if 
applicable per local IRB policy. 
 
The study PI will also forward to participating sites all IND safety reports received from AbbVie, 
indicating whether a consent form or protocol change is required within 30 days of notification to study 
PI. 
 
14.3.3.4 
Reporting to AbbVie 
All serious adverse events and AESIs (initial and follow-up information) will be reported by the study PI to 
AbbVie within 24 hours per the following guidelines: The initial report will be as complete as possible and 
include an assessment of the causal relationship between the event and the study agent(s).  Information 
not available at the time of the initial report will be documented on a follow-up report and submitted to 
AbbVie. The principal Investigator shall make available to AbbVie promptly such records as may be 
necessary and pertinent to investigate any such event, if specifically requested by AbbVie. In addition, 
report to AbbVie all non-serious adverse events of tumor lysis syndrome (TLS). 
o Copy AbbVie on the submission to the FDA of events meeting the definition of IND safety reports 
at the time of submission to the Agency. 
o Notify AbbVie upon any subjects receiving venetoclax whose pregnancy has resulted in a 
negative outcome or untoward event during the course of pregnancy or upon delivery. 
The AbbVie tracking number (Study # 11354) will be included on expedited reports (or on the fax cover 
letter).  A copy of the fax transmission confirmation of the expedited report to AbbVie will be retained 
with the patient records. 
AbbVie’s contact for reporting serious adverse drug experiences, pregnancy experiences, non-serious 
adverse events of tumor lysis syndrome, and communication of FDA submissions of IND safety reports is: 
E-mail: PPDINDPharmacovigilance@abbvie.com 
o Submit annually within 60 days (via COH OIDRA) of the anniversary date of when the IND went 
into effect, an annual report to the FDA which is to include a narrative summary and analysis of 
the information of all FDA reports within the reporting interval, a summary report adverse drug 
experiences, history of actions taken since the last report because of adverse drug experiences. 
o Report every 3 months to the COH DSMC a Protocol Management Team (PMT) report, to include 
aggregate analysis of safety information and accrual and participant status. 
o Circulate to all participating sites for submission to their IRBs the COH DSMC report and DSMC 
recommendation, in accordance with NIH guidance. 
o Report to AbbVie aggregate safety information every 3 months at time of COH PMT report. 
o Forward to participating sites all reportable AE/UPs as an IND Safety Report occurring within 30 
calendar days of receipt of lead site notification, and indicate whether or not a protocol and/or 
consent form change is required.  A cover letter will indicate the protocol title, the IND#, whether 


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the FDA was informed, and, for non-COH sites, a statement that the report should be submitted 
to their local IRB for review as an IND safety report if applicable per local IRB policy. 
o Forward to participating sites all safety reports received from AbbVie for venetoclax that have not 
occurred directly on this protocol, indicating whether a consent form or protocol change is 
required within 30 days of notification to Study PI. 
Product Complaints:  In addition to compliance with all FDA requirements pursuant to 21 CFR 211 and 21 
CFR 820, Principal Investigator will report to AbbVie within 24 hours any suspected quality defect in an 
AbbVie Product or its AbbVie-provided packaging, labeling, or medical device component (collectively, 
“Product Complaint”). Principal Investigator will report Product Complaints that involve an AbbVie 
Product, whether AbbVie has supplied the AbbVie Product used in the Study or not.  AbbVie’s contact for 
reporting Product Complaints is: 
RD_PQC_QS@abbvie.com 
14.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered 
a metastasis of the initial neoplasm. 
The investigator must immediately notify the Study PI/ DCC via an expedited report (see Section 7.3.2). 
14.5 Tumor Lysis Syndrome  
The investigator must immediately notify the Study PI/ DCC via an expedited report any serious or non-
serious adverse events of TLS (see Section 7.3.2).  
14.6 Overdose 
The maximum allowed daily dose of venetoclax in this study is 800 mg, with the intention that participants 
move incrementally to this dose as described in the protocol. 
Any dose of study drug in excess of that specified in this protocol is considered to be an overdose.  Signs 
and symptoms of an overdose that meet any Serious Adverse Event criterion must be reported as a Serious 
Adverse Event in the appropriate time frame and documented as clinical sequelae to an overdose.   
There is no specific antidote for venetoclax. In the event of an overdose, subjects should be closely 
monitored and given appropriate supportive treatment.    
14.7 Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease 
state) of a female participant occurring after the participant receives the first dose of protocol therapy 
through up to 90 days post-last dose of venetoclax are considered immediately reportable events.  
Protocol therapy is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to the Study PI/ DCC immediately within 24 hours of awareness (see 
Section 7.3.2). The female subject may be referred to an obstetrician-gynecologist (preferably one with 
reproductive toxicity experience) or another appropriate healthcare professional for further evaluation. 
The Investigator should make every effort to follow the female participant until completion of the 
pregnancy per institutional policies, and should notify the Study PI/ DCC.  
Abnormal pregnancy outcomes and neonatal deaths that occur within 28 days of birth should be reported 
as an SAE per expedited reporting guidelines (see Section 7.3.2). 


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Any infant death after 28 days that the Investigator suspects is related to the in utero exposure to protocol 
therapy should also be reported as an SAE per expedited reporting guidelines (see Section 7.3.2) 
14.7.1 Male participants 
If a female partner of a male participant becomes pregnant within 90 days post-last dose, the male 
participant should notify the Investigator, and the pregnant female partner should be advised to call their 
healthcare provider immediately.  
The Investigator should make every effort to follow the outcome of the pregnancy per institutional 
policies, and should notify the Study PI/ DCC.  
15.0 PROTOCOL DEVIATIONS AND SINGLE SUBJECT EXCEPTIONS 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. Brief interruptions and delays may occasionally 
be required because of travel delays, airport closures, inclement weather, family responsibilities, 
security alerts, government holidays, and so forth. Delays can also extend to complications of disease or 
unrelated medical illnesses not related to disease progression. The PI has the discretion to deviate from 
the protocol when necessary so long as such a deviation does not threaten patient safety or protocol 
scientific integrity. As a result of deviations, corrective actions are to be developed by the study staff 
and implemented promptly. 
15.1 Definitions 
15.1.1 Deviation 
A deviation is a divergence from a specific element of a protocol. Deviations from the protocol should be 
avoided, except when necessary to eliminate immediate hazard(s) for the protection, safety, and well-
being of a research participant. All protocol deviations and planned protocol deviations will be reported 
in accordance with the Clinical Research Protocol Deviation Policy. Protocol deviations may be on the 
part of the subject, the investigator, or the study staff. 
15.1.2 Planned Deviations (Single Subject Exceptions) 
A planned deviation involves circumstances that could increase patient risk or alter protocol integrity, 
and require prior IRB approval of a single subject exception (SSE) request.  In addition, if contractually 
obligated, the sponsor must also approve the deviation.  An IRB pre-approved SSE protocol modification 
is considered an amendment to the protocol and not a deviation.   
15.2 Reporting of Deviations and SSEs 
15.2.1 Reporting Deviations 
For any deviation, the Investigator will notify the COH DSMC and IRB within 5 calendar days of its 
occurrence via iRIS in accordance with the Clinical Research Protocol Deviation policy.  
A list of deviations from all participating sites will be submitted along with the Protocol Management 
Team (PMT) progress report to the COH DSMC. 
 
For non-COH sites:  
o The local IRB and/or DSMC must be notified according to local institutional policies.  


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o The study Principal Investigator must be notified as soon as practical (within 24 hours of 
notification of the event) via email to jazain@coh.org and dcc@coh.org.  This email 
should provide input on the following: 
 
Description of the event 
 
Impact on participant safety or the safety to others 
 
Impact on the study design 
 
A corrective and preventative action plan 
15.2.2 Reporting Single Subject Exceptions 
The SSE must be submitted as a “Single Subject Exception Amendment Request” via iRIS in accordance 
with IRB guidelines and the Clinical Research Protocol Deviation policy.  An IRB approved SSE does not 
need to be submitted as a deviation to the DSMC. 
All non-emergency planned deviations from the protocol must have prior approval by the Study Principal 
Investigator, the Site Principal Investigator, COH IRB, and when applicable, the local IRB.  In addition, if 
contractually obligated, the sponsor must also approve the deviation.  


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16.0 STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & SAFETY MONITORING 
16.1 All Investigator Responsibilities 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of subjects under the investigator's care; and for the control of drugs under 
investigation.  
 
All Investigators agree to: 
• 
Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when necessary to protect the safety, rights or welfare of 
subjects. 
• 
Personally conduct or supervise the study (or investigation).  
• 
Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.  
• 
Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance 
with §21 CFR 312.64.  
• 
Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments.  
• 
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those 
records available for inspection with the Sponsor (or designee).  
• 
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible 
for initial and continuing review and approval of the clinical study.  
• 
Promptly report to the IRB and the Sponsor all changes in the research activity and all 
unanticipated problems involving risks to subjects or others (to include amendments and IND 
safety reports).  
• 
Seek IRB and Sponsor approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects.  
• 
Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
 
16.2 Study Principal Investigator Responsibilities 
The Study Principal Investigator is responsible for the conduct of the clinical trial, including overseeing 
that sponsor responsibilities as defined in § 21 CFR 312. Subpart D are executed in accordance with federal 
regulations.  
 
16.3 Protocol Management Team (PMT) 
The Protocol Management Team (PMT), minimally consisting of the study PI, site investigators, 
collaborating investigators, research nurse, clinical research associate/coordinator, and the study 


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biostatistician, is responsible for ongoing monitoring of the data and safety of this study, including 
implementation of the stopping rules for safety/toxicity. 
 
The PMT is recommended to meet (in person or via teleconference) at least monthly to review study 
status. This review will include, but not be limited to, reportable AEs and UPs, and an update of the 
ongoing study summary that describes study progress in terms of the study schema. The meeting will be 
a forum to discuss study related issues including accrual, SAE/AEs experienced, study response, 
deviations/violations and study management issues. The appropriateness of further subject enrollment 
and the specific intervention for subsequent subject enrollment are addressed. It is recommended that 
minutes of these discussions be taken to document the date of these meetings, attendees and the issues 
that were discussed (in a general format).   
 
16.4 Monitoring  
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, that the 
study is implemented in accordance with the protocol and regulatory requirements, and that the quality 
and integrity of study data and data collection methods are maintained.  Monitoring for this study will be 
performed by the City of Hope Office of Clinical Trials Auditing and Monitoring (OCTAM).  
 
The site Investigator/Institution will permit the study monitors and appropriate regulatory authorities 
direct access to the study data and to the corresponding source data and documents to verify the accuracy 
of this data. The Investigator will allocate adequate time for such monitoring activities.  The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given access to all 
the above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.), and has adequate space to conduct the monitoring visit. 
 
Details of clinical site monitoring are documented in the OCTAM SOP that is provided as a supplement to 
this document. This document specifies the frequency of monitoring, monitoring procedures, the level of 
clinical site monitoring activities (e.g., the percentage of subject data to be reviewed), and the distribution 
of monitoring reports.  Staff from OCTAM will conduct monitoring activities and provide reports of the 
findings and associated action items in accordance with the details described in the CMP.  Documentation 
of monitoring activities and findings will be provided to the site study team, the site PI, study PI, and the 
COH DSMC.  
 
16.5 Quality Assurance  
The City of Hope Clinical Research Information Support will provide support for this multi-center trial as 
detailed in the COH DCC Operations Plan provided as a supplement to this document.  
 
16.6 City of Hope Data and Safety Monitoring Committee 
This is a risk level 4 study as defined in the City of Hope Institutional Data and Safety Monitoring Plan. This 
determination was made because the study involves a COH held IND. 
 
The DSMC is a multidisciplinary committee charged with overseeing the monitoring of safety of 
participants in clinical trials, and the conduct, progress, validity, and integrity of the data for all clinical 


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trials that are sponsored by City of Hope. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. The committee reviews the 
progress and safety of all active research protocols that are not monitored by another safety and data 
monitoring committee or board.  
 
The Study Principal Investigator is required to submit periodic status reports (the PMT report) according 
to the guidelines outlined in the City of Hope Institutional Data and Safety Monitoring Plan.  The PMT 
report will be submitted to the COH DSMC every 3 months from the date of activation.   
 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data 
from this trial. The DSMC will review up-to-date participant accrual; summary of all adverse events 
captured via routine and expedited reporting; a summary of deviations; any response information; 
monitoring reports, and summary comments provided by the study team. Other information (e.g. scans, 
laboratory values) will be provided upon request. For Phase I studies, a Phase I Tracking Log will be utilized 
and reviewed by the DSMC to monitor data and safety for dose escalation.  A review of outcome results 
(response, toxicity and adverse events) and factors external to the study (such as scientific or therapeutic 
developments) is discussed, and the Committee votes on the status of each study. Information that raises 
any questions about participant safety will be addressed with the Principal Investigator, statistician and 
study team. The PMT report and DSMC recommendations will be circulated to all participating sites for 
submission to their IRBs, in accordance with NIH guidance. 
 
17.0 ETHICAL AND REGULATORY CONSIDERATIONS 
17.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
17.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the following 
considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 
Title 21 Part 11 – Electronic Records; Electronic Signatures  
 
Title 21 Part 50 – Protection of Human Subjects  
 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 
Title 21 Part 56 – Institutional Review Boards  
 
Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
 
Title 21 Part 312 – Investigational New Drug Application  
 
Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 
Health Insurance Portability and Accountability Act of 1996  
 
Section 801 of the Food and Drug Administration Amendments Act   
o Applicable state and local laws. For research occurring in California, this includes but is not 
limited to State of California Health and Safety Code, Title 17 


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o Applicable institutional research policies and procedures 
17.3 Institutional Review Board 
Each participating institution must provide for the review and approval of this protocol and the associated 
informed consent documents by an appropriate IRB holding a current US Federal wide Assurance issued 
by and registered with the Office for Human Research Protections (OHRP).  
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the IRB.  The 
IRB’s written unconditional approval of the study protocol and the informed consent document will be in 
the possession of the Investigator, and, for sites external to COH, the possession of the coordinating 
center, before the study is initiated. The Investigator will obtain assurance of IRB/IEC compliance with 
regulations. 
The IRB will be informed of revisions to other documents originally submitted for review; serious 
unexpected or unanticipated adverse experiences occurring during the study, and any additional adverse 
experiences in accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; an annual 
update and/or request for re-approval; and when the study has been completed. 
Any amendment to the protocol document and accompanying informed consent document/template, as 
developed and provided by the Study PI, will require review and approval by the IRB before the changes 
are implemented in the study.  The protocol and consent will be reviewed and approved by the COH IRB 
before submission to a participating site IRB. 
17.4 Informed Consent 
For a multi-site study, each participating institution will be provided with a model informed consent form. 
Each institution may revise or add information to comply with local and/or institutional requirements, but 
may not remove procedural or risk content from the model consent form. Furthermore, prior to 
submission to the IRB (initial submission and amendments), the consent and accompanying HIPAA form, 
if separate to the consent, must be reviewed and approved by the DCC. 
After the study has been fully explained, written informed consent will be obtained from either the patient 
or his/her guardian or legal representative before study participation.  The method of obtaining and 
documenting the informed consent and the contents of the consent must comply with the ICH-GCP and 
all applicable regulatory requirements. 
Before implementing any study procedure, informed consent shall be documented by the use of a written 
consent form approved by the IRB/IEC and signed and dated by the patient or the patient’s legally 
authorized representative at the time of consent.  A copy of the signed informed consent will be given to 
the patient or patient’s legally authorized representative.  The original signed consent must be maintained 
by the Site Investigator and available for inspection sponsor designated representatives, or regulatory 
authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. 


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17.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies. The COH DCC should be promptly notified of 
the change in participant status.   
Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, but agreement to continue with active study procedures and 
chart review and survival follow-up. 
o Withdrawal from study treatment and all active procedures, but agreement for chart review and 
survival follow-up. 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
Participants who agreed to the collection of research blood samples may withdraw consent to use their 
specimens, if they are not yet processed as detailed in the consent form.  Once the PI and site PI is notified 
of this withdrawal of informed consent, the research specimens will not be used in any research. At that 
time, any of the existing specimens will be destroyed. 
17.6 Special and Vulnerable Populations 
17.6.1 Inclusion of Women and Minorities 
The study is open anyone regardless of gender, race or ethnicity.  Efforts will be made to extend the 
accrual to a representative population. If differences in outcome that correlate to gender, racial, or ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to investigate those 
differences more fully.   
Pregnant women are excluded because the effect of Bcl-2 inhibition on pregnancy has not been fully 
characterized. 
17.6.2 Exclusion of Pediatric Population 
Pediatric participants (< 18 years old of age) are excluded from this study since safety and effectiveness 
of protocol therapy has not been defined for PTCL. Additional studies may be performed in the pediatric 
population once safety and effectiveness of protocol therapy is defined in the adult PTCL population. 
The incidence of PTCL is rare in the pediatric population. 
17.6.3 Inclusion of HIV Positive Individuals 
Patients with active human immunodeficiency virus (HIV) are excluded. Subjects who have an 
undetectable HIV viral load with CD4 > 200 and are on HAART medication are allowed. 
17.6.4 Vulnerable Populations 
45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, 
mentally incapacitated persons, or economically or educationally disadvantaged persons as vulnerable 
populations.  
Adults lacking capacity to consent are not excluded from participation. This study does not pose additional 
risks for adults lacking capacity than for the general population.  In such instances, informed consent will 
be sought and documented from the prospective participant’s legally authorized representative in 
agreement with institutional policies and local IRB approval. 


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17.7 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents. This confidentiality is extended to cover testing of biological samples in addition to any study 
information relating to participants.  
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  HIPAA regulations require a signed subject authorization informing 
the subject of the nature of the PHI to be collected, who will have access to that information and why, 
who will use or disclose that information, ant the rights of a research participant to revoke their 
authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, 
the investigator, by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be carried out in 
accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used.  
Medical records of subjects will be securely maintained in the strictest confidence, according to current 
legal requirements.  Data will be entered, analyzed and stored in encrypted, password protected, secure 
computers that meet all HIPAA requirements. All data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number. Source 
documents provided to coordinating center for the purpose of auditing or monitoring will be de-identified 
and labeled with the study number, subject ID, and if applicable patient initials. 
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist of trial-
related monitoring, including remote monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority 
inspections. The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
Participant specimens will be de-identified (coded) prior to submission to research laboratories. The 
specimens will be labeled with the study number, subject ID, date and timepoint of collection. The key to 
the code will be maintained in the COH clinical trials management system which is a secure environment.  
17.8 Use of Unused (Leftover) Specimens Collected for this Trial  
Unused samples in existence at study completion (i.e. completion of all research activities under this 
study) will either be: (a) placed in a COH IRB approved biorepository with some clinical information and 
potentially PHI attached or (b) discarded.   
With regard to which option will apply, each site IRB may choose to either: (a) leave the determination 
to the participant via a question in the informed consent document, which would be communicated to 
the study registrar (DCC) at the time of participant registration, OR b) may choose to make a single 
determination on behalf of their respective participants, and communicate that determination to their 
respective participants via the informed consent. 


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17.9 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study.  All City of Hope investigators will follow the City of Hope conflict of interest policy. 
17.10 Financial Obligations, Compensation, and Reimbursement of Participants 
Venetoclax will be provided free of charge to participants. 
Neither the research participant nor the insurance carrier will be responsible for the research procedures 
related to this study. 
Standard of care drugs or procedures provided during the course of study participation will be the 
responsibility of the research participant and/or the insurance carrier. The participant will be responsible 
for all copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth by 
the insurance carrier.  The participant and/or the insurance carrier will be billed for the costs of treatment 
and diagnostic procedures in the same way as if the participant were not in a research study.   
In the event of physical injury to a participant resulting from research procedures, appropriate medical 
treatment will be available at City of Hope or at the non-COH site to the injured participant. There are no 
plans for City of Hope to provide financial compensation in the event of physical injury to a participant.  
The research participant will not receive reimbursement or payment for taking part in this study. 
17.11 Publication/ Data Sharing 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of the Study PI. Any investigator involved with 
this study is obligated to provide City of Hope with complete test results and all data derived from the 
study. 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement between City of Hope and AbbVie. 
The publication or presentation of any study results shall comply with all applicable privacy laws, including, 
but not limited to, the Health Insurance Portability and Accountability Act of 1996.  
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov and results will be 
reported on ClinicalTrials.gov within 12 months of the estimated or actual completion date of the trial, 
whichever date is earlier. 


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18.0 REFERENCES 
1. 
DiNardo, C.D., et al., Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients 
with acute myeloid leukemia. Blood, 2019. 133(1): p. 7-17. 
2. 
Abouyabis, A.N., et al., Incidence and outcomes of the peripheral T-cell lymphoma subtypes in the United 
States. Leuk Lymphoma, 2008. 49(11): p. 2099-107. 
3. 
Jaffe, E.S., et al., Classification of lymphoid neoplasms: the microscope as a tool for disease discovery. Blood, 
2008. 112(12): p. 4384-99. 
4. 
Savage, K.J., Peripheral T-cell lymphomas. Blood Rev, 2007. 21(4): p. 201-16. 
5. 
Weisenburger, D.D., et al., Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from 
the International Peripheral T-cell Lymphoma Project. Blood, 2011. 117(12): p. 3402-8. 
6. 
O'Connor, O.A., et al., Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: 
results from the pivotal PROPEL study. J Clin Oncol, 2011. 29(9): p. 1182-9. 
7. 
Coiffier, B., et al., Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory 
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APPENDIX A: PERFORMANCE STATUS 
ECOG Performance Scale [54] 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-
disease performance without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited self-
care, confined to bed or chair more than 50% of waking 
hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on 
any self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 


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APPENDIX B: TUMOR LYSIS SYNDROME CLASSIFICATION 
Based on Howard et al., 2011 [55]. 
Metabolic Abnormality 
Criteria for Classification of Laboratory 
Tumor Lysis Syndrome* 
Criteria for Classification of Clinical 
Tumor Lysis Syndrome** 
Hyperuricemia 
Uric acid > 8.0 mg/dl (475.8 µmol/L) 
 
Hyperphosphatemia 
Phosphorus > 4.5 mg/dl (1.5 mmol/L)  
 
Hyperkalemia 
Potassium > 6.0 mmol/L 
Cardiac dysrhythmia or sudden death 
probably or definitely caused by 
hyperkalemia 
Hypocalcemia 
Corrected calcium < 7.0 mg/dL (1.75 
mmol/L( or ionized calcium < 1.12 (0.3 
mmol/L)† 
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(tetany, paresthesias, muscle 
twitching, carpopedal spasm, 
Trousseau's sign, Chvostek's sign, 
laryngospasm, or bronchospasm), 
hypotension, or heart failure 
probably or definitely caused by 
hypocalcemia 
Acute kidney injury‡  
If no institutional ULN is 
specified, age/sex ULN 
creatinine may be defined 
as follows: > 1 to < 12 
years of age, both male 
and female, 61.6 μmol/L; ≥ 
12 to < 16 years, both 
male and female, 88 
μmol/L; ≥ 16 years, female 
105.6 μmol/L, male 114.4 
μmol/L. 
N/A 
Increase in the serum creatinine level of 
0.3 mg/dL (26.5 μmol/liter) or the 
presence of oliguria (average urine 
output of < 0.5 mL/kg/hr over a 6-hour 
period) 
* In laboratory tumor lysis syndrome ≥ 2 metabolic abnormalities must be present during the same 24-hour 
period within 3 days before the start of therapy or up to 7 afterwards. 
** Clinical TLS requires the presence of laboratory TLS plus an increased creatinine level, seizures, cardiac 
dysrhythmia, or death. 
†  Corrected calcium = measured calcium level in mg/dL + 0.8 x (4-albumin in g/dL). 
‡  Acute kidney injury, unless attributable to another cause, represents clinical TLS even if criteria for laboratory 
TLS are not satisfied. 
 
 
 
 


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APPENDIX C-1: PTCL-DISEASE PARAMETERS & METHODS OF EVALUATION AND RESPONSE 
Response will be assessed per Lugano Classification [50] 
Disease Parameters 
o Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥15 mm (≥ 1.5 cm) by chest x-ray, CT scan, MRI, 
or calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable 
 
o Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm (≥1.5 
cm) in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm [0.5 cm]). At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
o Non-measurable disease 
Pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] short axis), are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
o Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement in which circumstance the 
next largest lesion which can be measured reproducibly should be selected. A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 


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o Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation 
by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam. 
o Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using calipers (e.g., skin 
nodules). In the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
 
o Conventional CT and MRI 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm (0.5 cm) or less. If CT scans have slice thickness greater than 5 mm (0.5 
cm), the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of disease. Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline and the lesions 
should be measured/assessed on the same pulse sequence. It is beyond the scope of the Lugano 
Classification [5] to prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases. For this trial, MRI will not be used as standard imaging study for disease assessment. 
 
o PET-CT at present, the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with Lugano Classification [5]. However, if the site 
can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
measurements and can be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data 
which may bias an investigator if it is not routinely or serially performed.  
 


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o FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can 
be identified according to the following algorithm: 
 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
 
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-
up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are 
needed to determine if there is truly progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice 
that of the surrounding tissue on the attenuation corrected image. 
 
 


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APPENDIX C-2: PTCL RESPONSE CRITERIA 
Response 
Site 
CT-Based Response 
PET-CT Based Response 
Complete 
Response 
 
Complete radiologic response 
(all of the following) 
Complete metabolic response (even 
with a persistent mass) 
Lymph nodes and 
extralymphatic 
sites 
Target nodes/nodal masses 
must regress to ≤1.5 cm in 
longest diameter.  
No extralymphatic sites of 
disease. 
Score ≤ 3* with or without a residual 
mass on 5-point scale†. 
It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with 
activation within spleen or 
marrow (e.g., 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. 
Nonmeasured 
lesion 
Absent 
Not applicable 
Organ enlargement 
Regress to normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Normal by morphology; if 
determinate, IHC negative 
No evidence of FDG-avid disease in 
marrow 
Partial 
Response 
 
Partial remission (all of the 
following) 
Partial metabolic response 
Lymph nodes and 
extralymphatic 
sites 
≥ 50% decrease in SPD of up to 
6 target measurable nodes 
and extranodal sites 
When a lesion is too small to 
measure on CT, assign 5 
mm X 5 mm as the default 
value 
When no longer visible, 0 X 0 
mm 
For a node > 5 mm X 5 mm, but 
smaller than normal, use 
actual measurement for 
calculation 
Score 4 or 5† with reduced uptake 
compared with baseline and 
residual mass(es) of any size 
At interim, these findings suggest 
responding disease 
At end of treatment, these findings 
indicate residual disease 


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Response 
Site 
CT-Based Response 
PET-CT Based Response 
Nonmeasured 
lesion 
Absent/normal, regressed, but 
no increase 
Not applicable 
Organ enlargement 
Spleen must have regressed by 
> 50% in length beyond 
normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
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 
No response 
or stable 
disease 
 
Stable disease 
No metabolic response 
Target nodes/nodal 
masses, 
extranodal 
lesions 
< 50% decrease from baseline 
in SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria 
for progressive disease are 
met 
Score 4 or 5† with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment 
Nonmeasured 
lesion 
No increase consistent with 
progression 
Not applicable 
Organ enlargement 
No increase consistent with 
progression 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
No change from baseline 
Progressive 
disease 
 
Progressive disease requires at 
least 1 of the following 
Progressive metabolic disease 
Individual target 
nodes/nodal 
masses 
PPD progression: 
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or 
Extranodal lesions 
An individual node/lesion must 
be abnormal with: 
Longest diameter (LDi) > 1.5 cm 
and 
Increase by ≥ 50% from PPD 
nadir and 
New FDG-avid foci consistent with 
lymphoma at interim OR 
 End-of-treatment assessment 


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Response 
Site 
CT-Based Response 
PET-CT Based Response 
An increase in LDi or smallest 
diameter (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 (e.g., 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 
lesion 
New or clear progression of 
preexisting nonmeasured 
lesions 
None 
New lesions 
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 
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. 
Bone marrow 
New or recurrent involvement 
New or recurrent FDG-avid foci 
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 (e.g., 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 (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete 


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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). 
 
*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).  
 
†PET 5-point score:  
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. 
Abbreviations:   
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. 
 
 


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APPENDIX D: SAMPLE LIST OF PROHIBITED AND CAUTIONARY AGENTS 
Prohibited during Cycle 1 and Cautionary Thereafter:  
Strong CYP3A inducers - avasimibe, carbamazepine, enzalutamine, mitotane, phenytoin, rifampin, St. John's wort 
Moderate CYP3A inducers - bosentan, efavirenz, etravirine, modafinil, nafcillin, 
Strong CYP3A inhibitors† - boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, elvitegravir/ritonavir, 
idelalisib,* indinavir, itraconazole, ketoconazole, mibefradil, lopinavir/ritonavir, nefazodone, nelfinavir, ritonavir, 
paritaprevir/ritonavir combinations, posaconazole, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, voriconazole 
Moderate CYP3A inhibitors‡ - amprenavir, aprepitant, atazanavir, cimetidine, ciprofloxacin, clotrimazole, crizotinib*, 
cyclosporine*, darunavir/ritonavir, diltiazem1, erythromycin, fluconazole, fosamprenavir, imatinib*, isavuconazole,  
tofisopam,  verapamil 
P-gp inhibitors 
Amiodarone, azithromycin, captopril, carvedilol, dronedarone, felodipine, quercetin, quinidine, ronalzine, ticagrelor 
 
Cautionary 
Warfarin and coumarin derivatives** 
P-gp substrates 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus*, fexofenadine, lapatinib*, loperamide, 
maraviroc, nilotinib*, ranolazine, saxagliptin, sirolimus*, sitagliptin, talinolol, tolvaptan, topotecan* 
BCRP substrates 
Methotrexate*, mitoxantrone*, irrinotecan*, lapatinib*, rosuvastatin, sulfasalazine, topotecan* 
OATP1B1/1B3 substrates 
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, rosuvastatin, simvastatin acid, pitavastatin, pravastatin, 
repaglinide, telmisartan, valsartan, olmesartan 
BCRP inhibitors 
Geftinib* 
Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm  
In addition to the medications listed in this table, subjects receiving venetoclax should not consume grapefruit, grapefruit 
products, Seville oranges (including marmalade containing Seville oranges) or starfruit. 
* These are anticancer agents; consult contact AbbVie medical monitor before use. 
** Closely monitor the international normalized ratio (INR). 
1 Moderate CYP3A inhibitor per venetoclax FDA USPI. 
†Reduce the venetoclax dose by at least 4-fold during co-administration 
‡Reduce the venetoclax dose by 2-fold during co-administration 
 
 


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APPENDIX E: NYHA CARDIAC GRADING CRITERIA 
 
Modified from Dolgin et al., 1994 [56] 
 
New York Heart Association Classification of Heart Failure 
Class I 
No symptoms. Ordinary physical activity such as walking and climbing stairs does not cause fatigue 
or dyspnea. 
Class II 
Symptoms with ordinary physical activity. Walking or climbing stairs rapidly, walking uphill, walking 
or stair climbing after meals, in cold weather, in wind or when under emotional stress causes undue 
fatigue or dyspnea. 
Class III 
Symptoms with less than ordinary physical activity. Walking one to two blocks on the level and 
climbing more than one flight of stairs in normal conditions causes undue fatigue or dyspnea. 
Class IV 
Symptoms at rest. Inability to carry on any physical activity without fatigue or dyspnea. 
 


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APPENDIX F-1: TISSUE SHIPPING GUIDELINES FOR EXTERNAL NON-COH SITES  
These guidelines apply to non-COH sites only. 
All biological material must be shipped according to applicable government and International Air 
Transport Association (IATA) regulations. 
Shipping guidelines can also be found on the FedEx website. 
1. Aim to ship samples on a Monday through Wednesday. If this is not feasible, advance 
arrangements should be made with City of Hope Pathology Core (DL-PATHCORE-
BiospecimenSupport@COH.org). 
2. Notify City of Hope Pathology Core (DL-PATHCORE-BiospecimenSupport@COH.org) of impending 
shipment. To request a FedEx shipping label, email DCC@coh.org and indicate the planned 
shipment date. 
3. Slides/Blocks: Batch ship at room temperature via FedEx. During extreme heat, include 
refrigerated (not frozen) gel packs or gel insulators. 
It is recommended to ship samples via FedEx overnight (for a delivery by 3 pm or earlier the next 
day) or FedEx 2-day (with a morning delivery). During extreme heat, ship via FedEx overnight (for 
a delivery ideally by 10.30 am, or 3 pm the next day). 
4. Frozen samples should be batch shipped on dry ice via FedEx following collection. The shipment 
should contain enough dry ice to last at least 72 hours. 
5. On the day of shipment, email the sample shipment information to City of Hope Pathology Core 
(DL-PATHCORE-BiospecimenSupport@COH.org). 
6. Ship samples with a copy of the correlative tissue form (Appendix X) and a copy of the pathology 
report to: 
Karen Miller 
COH Pathology Core 
City of Hope National Medical Center 
1500 E. Duarte Road 
Familian Science (Building 084), Room 1207 
Duarte, CA 91010 
T: 626-218-8408 
Email: DL-PATHCORE-BiospecimenSupport@COH.org 
 
 


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APPENDIX F-2: CORRELATIVE TISSUE FORM (FOR ALL SITES) 
 
A copy of this form should accompany the sample shipments to COH Pathology Core. 
Non-COH sites: refer to Appendix F-1 for shipping instructions to COH Pathology Core. 
 
COH IRB number: 18119 
Shipping date (MM-DD-YYYY):   ________/________/________ 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
Date of collection/ biopsy (MM-DD-YYYY):    ________/________/________ 
Time point:     
  Baseline       
  Progression 
Diagnosis: 
Tissue type (FFPE scrolls, slides, biopsies): 
Number of scrolls: 
Number of slides: 
 
 
 
 
 
 
CRA/Study Coordinator/Nurse Printed Name:   
CRA/Study Coordinator/Nurse Signature:   
Contact Number: 
 
 
 
 
 
 
 
 
 
 


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APPENDIX G-1: VENETOCLAX PILL DIARY INSTRUCTIONS 
Remember to bring this diary, all pill bottles, and any unused pills to each clinic visit. 
Call your study doctor or nurse immediately if you are having any new or worsening side effects.  
Study drug Instructions – When and How: 
o Take venetoclax once a day by mouth 
o Take the pills with a meal and water at approximately the same time each day  
o Swallow pills; do not chew them or crush them 
o Do not skip any doses unless your doctor tells you to. 
o Do not drink grapefruit juice, eat grapefruit, Seville oranges or marmalades, or starfruit while you are 
taking venetoclax. 
When to stop taking venetoclax 
o Do not stop taking venetoclax unless your doctor tells you to. 
What if I miss a scheduled dose? 
o If less than 8 hours have passed from the scheduled time, then take the missed dose as soon as you 
remember.   
o If more than 8 hours have passed from the scheduled time, then skip the missed dose. Wait for your 
next scheduled dose. Do not take extra medicine to make up the missed dose. 
What if I vomit after taking venetoclax? 
o If you vomit your pills, write this down in your pill diary.   
o Wait until the next scheduled dose; do not take extra medicine to make up the vomited dose.  
 
Additional Instructions: 
o Bring this diary, all pill bottles, and any unused pills to each clinic visit.  
o Keep your study drug in the original container until you take it. 
o Do NOT throw away empty pill bottles or unused pills. 
o Your dose may be adjusted based on your side effects 
 
Contact Information 
Study Doctor 
Phone: 
 
Name: 
Study Nurse 
Phone: 
 
Name: 
Backup Study Nurse  
Phone: 
 
Name: 
 
 
 


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APPENDIX G-2: VENETOCLAX PILL DIARY (CYCLE 1) 
 
Call your study doctor or nurse immediately if you are having any new or worsening side effects.  
Your study doctor or nurse will tell you what to do. 
Your dose may be adjusted based on your side effects. 
Day 
Week  
Day 
Date 
Time 
# Pills 
Taken 
Comments 
1 
 
 
 
___:___AM/PM   
Planned # pills___ 
2 
 
 
 
___:___AM/PM 
 
Planned clinic day. DO NOT take your pill(s) until the study team 
tells you to do so.  
Planned # pills___ 
3 
 
 
 
___:___AM/PM   
Planned # pills___ 
4 
 
 
 
___:___AM/PM   
Planned # pills___ 
5 
 
 
 
___:___AM/PM   
Planned # pills___ 
6 
 
 
 
___:___AM/PM   
Planned # pills___ 
7 
 
 
 
___:___AM/PM   
Planned # pills___ 
 
Day 
Week  
Day 
Date 
Time 
# Pills 
Taken 
Comments 
8 
 
 
 
___:___AM/PM  
 
Planned clinic day. DO NOT take your pill(s) until the study team 
tells you to do so.  
Planned # pills___ 
9 
 
 
 
___:___AM/PM 
 
Planned # pills___ 
10  
 
 
___:___AM/PM  
 
Planned # pills___ 
11  
 
 
___:___AM/PM  
 
Planned # pills___ 
12  
 
 
___:___AM/PM  
 
Planned # pills___ 
13  
 
 
___:___AM/PM  
 
Planned # pills___ 
14  
 
 
___:___AM/PM  
 
Planned # pills___ 
 
Day 
Week  
Day 
Date 
Time 
# Pills 
Taken 
Comments 
15  
 
 
___:___AM/PM  
 
Planned clinic day. DO NOT take your pill(s) until the study team 
tells you to do so.  
Planned # pills___ 
16  
 
 
___:___AM/PM 
 
Planned # pills___ 
17  
 
 
___:___AM/PM  
 
Planned # pills___ 
18  
 
 
___:___AM/PM  
 
Planned # pills___ 
19  
 
 
___:___AM/PM  
 
Planned # pills___ 
20  
 
 
___:___AM/PM  
 
Planned # pills___ 
21  
 
 
___:___AM/PM  
 
Planned # pills___ 
 
Subject ID#: 
Patient Initials (F, M, L): 
Institution:  
Cycle #: 
Cycle start date: 
 
 Safety Lead-in    
 Phase 2 
Participant/Caregiver Signature (please sign when submitting your diary): 
Date: ____/______/_____ 


Venetoclax and Romidepsin for R/R Mature T-cell lymphoma 
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Day 
Week 
Day 
Date 
Time 
# Pills 
Taken 
Comments 
22  
 
 
___:___AM/PM  
 
Planned clinic day. DO NOT take your pill(s) until the study team 
tells you to do so.  
Planned # pills___ 
23  
 
 
___:___AM/PM 
 
Planned # pills___ 
24  
 
 
___:___AM/PM  
 
Planned # pills___ 
25  
 
 
___:___AM/PM  
 
Planned # pills___ 
26  
 
 
___:___AM/PM  
 
Planned # pills___ 
27  
 
 
___:___AM/PM  
 
Planned # pills___ 
28  
 
 
___:___AM/PM  
 
Planned # pills___ 
 
 
 
 
Study Team ONLY:  # of Pill Bottles Returned: ________    # of Pills Returned: ________ 
Compare with drug diary entries made by participant/guardian.  If there is a discrepancy (in the # of bottles or the 
# of pills returned), please reconcile (initials & date):____________________________ 
 
 
 
 
 
 
 
 
Subject ID#: 
Patient Initials (F, M, L): 
Institution:  
Cycle #: 
Cycle start date: 
 
 Safety Lead-in    
 Phase 2 
Participant/Caregiver Signature (please sign when submitting your diary): 
Date: ____/______/_____ 


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APPENDIX G-3: VENETOCLAX PILL DIARY (CYCLE 2+) 
 
 
Call your study doctor or nurse immediately if you are having any new or worsening side effects.  
Your study doctor or nurse will tell you what to do. 
Your dose may be adjusted based on your side effects. 
 
Day 
Week  
Day 
Date 
Time 
# Pills 
Taken 
Comments 
1 
 
 
___:___AM/PM   
Planned # pills___ 
2 
 
 
___:___AM/PM 
 
Planned # pills___ 
3 
 
 
___:___AM/PM   
Planned # pills___ 
4 
 
 
___:___AM/PM   
Planned # pills___ 
5 
 
 
___:___AM/PM   
Planned # pills___ 
6 
 
 
___:___AM/PM   
Planned # pills___ 
7 
 
 
___:___AM/PM   
Planned # pills___ 
 
Day 
Week  
Day 
Date 
Time 
# Pills 
Taken 
Comments 
8 
 
 
___:___AM/PM  
 
Planned # pills___ 
9 
 
 
___:___AM/PM 
 
Planned # pills___ 
10 
 
 
___:___AM/PM  
 
Planned # pills___ 
11 
 
 
___:___AM/PM  
 
Planned # pills___ 
12 
 
 
___:___AM/PM  
 
Planned # pills___ 
13 
 
 
___:___AM/PM  
 
Planned # pills___ 
14 
 
 
___:___AM/PM  
 
Planned # pills___ 
 
Day 
Week  
Day 
Date 
Time 
# Pills 
Taken 
Comments 
15 
 
 
___:___AM/PM  
 
Planned # pills___ 
16 
 
 
___:___AM/PM 
 
Planned # pills___ 
17 
 
 
___:___AM/PM  
 
Planned # pills___ 
18 
 
 
___:___AM/PM  
 
Planned # pills___ 
19 
 
 
___:___AM/PM  
 
Planned # pills___ 
20 
 
 
___:___AM/PM  
 
Planned # pills___ 
21 
 
 
___:___AM/PM  
 
Planned # pills___ 
 
 
Subject ID#: 
Patient Initials (F, M, L): 
Institution:  
Cycle #: 
Cycle start date: 
 
 Safety Lead-in    
 Phase 2 
Participant/Caregiver Signature (please sign when submitting your diary): 
Date: ____/______/_____ 


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Day 
Week 
Day 
Date 
Time 
# Pills 
Taken 
Comments 
22  
 
 
___:___AM/PM  
 
Planned # pills___ 
23  
 
 
___:___AM/PM 
 
Planned # pills___ 
24  
 
 
___:___AM/PM  
 
Planned # pills___ 
25  
 
 
___:___AM/PM  
 
Planned # pills___ 
26  
 
 
___:___AM/PM  
 
Planned # pills___ 
27  
 
 
___:___AM/PM  
 
Planned # pills___ 
28  
 
 
___:___AM/PM  
 
Planned # pills___ 
 
 
 
 
Study Team ONLY:  # of Pill Bottles Returned: ________    # of Pills Returned: ________ 
Compare with drug diary entries made by participant/guardian.  If there is a discrepancy (in the # of bottles or the 
# of pills returned), please reconcile (initials & date):____________________________ 
 
 
 
 
 
 
 
 
 
 
Subject ID#: 
Patient Initials (F, M, L): 
Institution:  
Cycle #: 
Cycle start date: 
 
 Safety Lead-in    
 Phase 2 
Participant/Caregiver Signature (please sign when submitting your diary): 
Date: ____/______/_____ 


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APPENDIX H-1: DCC REGISTRATION COVERSHEET 
COH Protocol #18119: A Phase 2 Study of Venetoclax with Safety Lead-in for Treatment of 
Relapsed/Refractory Mature T-cell Lymphomas 
 
 
Data Coordinating Center  
City of Hope 
1500 Duarte Road 
Duarte, CA 91010  
Tel:  626-218-7904  
Email:  DCC@coh.org (use #secure# in subject line) 
Site Principal Investigator  
Name: 
Address: 
 
 
Phone:  
Fax:  
e-mail: 
CRA/Study Coordinator:     
Contact Number:   
Patient’s Initials: (F M L): 
Institution: 
Medical Record No: 
Investigator/Treating Physician: 
Patient’s DOB: 
IRB approval valid until (date): 
Sex: 
______Male 
______Female 
Date Informed Consent Signed: 
Projected start date of treatment: 
Race 
Ethnicity 
Method of 
Payment:_______________________ 
 
Black 
 Hispanic 
Codes: 
 
Caucasian 
 Non-Hispanic 
01 Private 
06 Military or Veterans 
Adm. sponsored 
 
Asian 
 Other_________________ 
02 Medicare 
07 Self-pay (no 
insurance) 
 
American Indian 
 
03 Medicare & 
private ins. 
08 No means of 
payment  (no insurance) 
 
Native Hawaiian/Pacific 
Islander 
04 Medicaid 
09 Unknown 
 
Other_______________
____________________ 
05 Medicaid & Medicare 
 


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APPENDIX H-2: SAE/UP REPORTING COVERSHEET 
NOTIFICATION OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT 
For Use by Participating Institutions Only 
THIS FORM ALONG WITH A COPY OF THE MEDWATCH 3500 OR IRB REPORTING FORM MUST BE EMAILED TO DCC@COH.ORG 
WITHIN 24 HOURS OF KNOWLEDGE OF ONSET OF SERIOUS ADVERSE EVENT OR UNANCTICIPATED PROBLEM 
COH Protocol #18119- Participating Site IRB # ___________ 
From: 
Date: 
Phone No.: 
Email: 
Reporting Investigator: 
Event:  
Participant ID: 
Institution: 
Date Event Met Reporting Criteria (as defined in protocol):   
 
Type of Report: 
 Initial    Follow-up 
CTCAE Grade:   
 G1/mild    G2/moderate     G3/severe    G4/life threatening   
 G5 
Attribution to Venetoclax: 
 Unrelated   Unlikely   Possible    Probable   Definite 
Attribution to Romidepsin: 
 Unrelated   Unlikely   Possible    Probable   Definite 
Historical/Known Correlation to 
Agent Venetoclax: 
 Expected    Unexpected   
Historical/Known Correlation to 
Agent Romidepsin: 
 Expected    Unexpected   
Meets Definition of Serious AE:      Serious      Non-serious 
Meets Definition of 
Unanticipated Problem: 
   UP      Not a UP 
Has the event been reported to 
the following institution’s IRB? 
   No      Yes; Date:_____/____/_____ 
 
Authorized Investigator Signature:   
Date:____/____/____