A Phase IB/II Study of Venetoclax (ABT-199) in Combination With Liposomal Vincristine or Vincristine Sulfate in Patients With Relapsed or Refractory T-Cell or B-Cell Acute Lymphoblastic Leukemia
Phase: PHASE1
Conditions: Recurrent Adult Lymphoblastic Lymphoma, Recurrent B Acute Lymphoblastic Leukemia, Recurrent B Lymphoblastic Lymphoma, Recurrent T Acute Lymphoblastic Leukemia, Recurrent T Lymphoblastic Lymphoma, Refractory B Acute Lymphoblastic Leukemia, Refractory B Lymphoblastic Lymphoma, Refractory T Acute Lymphoblastic Leukemia, Refractory T Lymphoblastic Lymphoma
Sponsor: ECOG-ACRIN Cancer Research Group

 
EA9152 
1 
A Phase Ib/II Study of Venetoclax (ABT-199) in Combination with 
Liposomal Vincristine or Vincristine Sulfate in Patients with Relapsed or 
Refractory T-cell or B-cell Acute Lymphoblastic Leukemia 
STUDY CHAIR: Neil Palmisiano M.D., M.S. 
STUDY CO-CHAIR: David Claxton, M.D. 
STUDY STATISTICIAN: Ju-Whei Lee, Ph.D. 
LABORATORY CO-CHAIRS: Adolfo Ferrando, M.D., Ph.D. 
 Elisabeth Paietta, Ph.D. 
LEUKEMIA COMMITTEE CO-CHAIR: Selina Luger, M. D. 
LEUKEMIA COMMITTEE CHAIR: Mark Litzow, M.D. 
Version Date:  July 20, 2022 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
Phase I – Limited Institutions:  
 
April 26, 2018 
PA121 / Thomas Jefferson University (ECOG-
ACRIN) 
 
ADDENDA 
Addendum #1 – Prior to Activation 
NY016 / Memorial Sloan Kettering Cancer Center 
(ECOG-ACRIN) 
 
Addendum #2 
Addendum #3 
PA075 / University of Pennsylvania/Abramson 
Cancer Center (ECOG-ACRIN) 
 
Addendum #4 
Addendum #5 
PA042 / Penn State Cancer Institute (ECOG-
ACRIN) 
 
Addendum #6 
Addendum #7 
CT018 / Yale University (ECOG-ACRIN) 
 
Addendum #8 
WI013 / Medical College of Wisconsin (ECOG-
ACRIN) 
 
Addendum #9 
Addendum #10 
MN026 / Mayo Clinic (ECOG-ACRIN) 
 
Addendum #11 
NJ066 / Rutgers University (ECOG-ACRIN) 
 
 
IL036 / Northwestern University (ECOG-ACRIN) 
 
 
MD017 /Johns Hopkins University (ECOG-ACRIN) 
 
 
Phase II – US Sites only: 
 
 
ALLIANCE / Alliance for Clinical Trials in Oncology  
 
NRG / NRG Oncology 
 
 
SWOG / SWOG 
 
 
 
 
Agents 
NSC# 
Supply 
ABT-199 
766270 
AbbVie 
Vincristine sulfate liposomes injection (Marqibo) 
NOTE: Liposomal Vincristine is no longer being 
manufactured as of April, 2022. 
748728 
Commercial 
Vincristine Sulfate 
67574 
Commercial 
IND #: Study Exempt from IND Requirements per 21 CFR 312.2(b) 
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Table of Contents 
Schema ...................................................................................................................... 7 
Schema ...................................................................................................................... 8 
1. Introduction ........................................................................................................ 9 
1.1 
Current Therapy for Relapsed or Refractory Acute Lymphoblastic 
Leukemia ................................................................................................... 9 
1.2 
BCL-2 and Apoptosis ................................................................................. 9 
1.3 
Venetoclax ............................................................................................... 11 
1.4 
Rationale for Study .................................................................................. 13 
2. Objectives ......................................................................................................... 15 
2.1 
Primary Endpoints ................................................................................... 15 
2.2 
Secondary Endpoints ............................................................................... 15 
2.3 
Exploratory/Correlative Studies .............................................................. 15 
3. Selection of Patients ......................................................................................... 16 
3.1 
Eligibility Criteria – Phase I (Arms A, B, C) – Step 0 ................................. 16 
3.2 
Eligibility Criteria – Phase I (Arms A, B, C) – Step 1 ................................. 16 
3.3 
Eligibility Criteria – Phase II (Arm D) – Step 0 ......................................... 20 
3.4 
Eligibility Criteria – Phase II (Arm D) – Step 1 ......................................... 20 
4. Registration Procedures .................................................................................... 23 
4.1 
Preregistration to Phase I (Arms A, B, C) – Step 0 ................................... 27 
4.2 
Registration to Phase I (Arms A, B, C) – Step 1 ....................................... 28 
4.3 
Preregistration to Phase II (Arm D) – Step 0 ........................................... 29 
4.4 
Registration to Phase II (Arm D) – Step 1 ................................................ 30 
4.5 
Data Query Portal ................................................................................... 32 
4.6 
Instructions for Patients who Do Not Start Assigned Protocol Treatment33 
5. Treatment Plan ................................................................................................. 34 
5.1 
Administration Schedule – Phase I .......................................................... 34 
5.2 
Administration Schedule – Phase II ......................................................... 38 
5.3 
Adverse Event Reporting Requirements ................................................. 40 
5.4 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Venetoclax (ABT-199, NSC 766270) ........................................................ 51 
5.5 
Dose Modifications ................................................................................. 54 
5.6 
Supportive Care ....................................................................................... 55 
5.7 
Duration of Therapy ................................................................................ 57 
5.8 
Duration of Follow-up ............................................................................. 57 
6. Measurement of Effect ..................................................................................... 58 
6.1 
Complete Remission (CR) ........................................................................ 58 
6.2 
Complete Remission incomplete (CRi) .................................................... 58 
6.3 
Partial Remission (PR) ............................................................................. 58 
6.4 
Stable Disease (SD) .................................................................................. 58 
6.5 
Relapse .................................................................................................... 58 
6.6 
Progressive Disease (PD) ......................................................................... 59 

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6.7 
Response Criteria for Lymphomatous Extramedullary Disease, 
Lymphoblastic Lymphoma55 .................................................................. 59 
7. Study Parameters .............................................................................................. 60 
7.1 
Phase I Therapeutic Parameters ............................................................. 60 
7.2 
Phase II Therapeutic Parameters ............................................................ 62 
7.3 
Biological Specimen Submissions ............................................................ 64 
8. Drug Formulation and Procurement ................................................................. 65 
8.1 
Venetoclax (ABT-199) NSC 766270 ......................................................... 65 
8.2 
Liposomal Vincristine (Marqibo) NSC 748728 ........................................ 68 
8.3 
Vincristine Sulfate NSC 67574 ................................................................. 70 
9. Statistical Considerations .................................................................................. 73 
9.1 
Phase I ..................................................................................................... 73 
9.2 
Phase II .................................................................................................... 74 
10. Specimen Submissions ...................................................................................... 78 
10.1 Submissions to the ECOG-ACRIN Leukemia Laboratory at MD Anderson 
Cancer Center .......................................................................................... 78 
10.2 Use of Specimens in Research ................................................................ 80 
10.3 ECOG-ACRIN Sample Tracking System .................................................... 80 
10.4 Sample Inventory Submission Guidelines ............................................... 81 
11. Leukemia Correlative Studies ........................................................................... 82 
11.1 PHASE I ONLY: Immunophenotype ......................................................... 82 
11.2 Molecular and Transcriptional Analysis of Adult ALL and Prognosis of 
Response to Combination Therapy – Adolfo Ferrando, MD, PhD .......... 82 
11.3 BH3 Profiling of Adult Lymphoblastic Leukemias Relapsed After or 
Refractory to Therapy ............................................................................. 83 
11.4 Lab Data Transfer Guidelines .................................................................. 84 
12. Electronic Data Capture .................................................................................... 85 
12.1 Records Retention ................................................................................... 85 
13. Patient Consent and Peer Judgment ................................................................ 85 
14. References ........................................................................................................ 85 
Appendix I  Patient Thank You Letter ...................................................................... 89 
Appendix II  Patient Pill Diary - Venetoclax ............................................................. 90 
Appendix III  ECOG Performance Status .................................................................. 95 
Appendix IV  Instructions for Reporting Pregnancies on a Clinical Trial ................. 96 
Appendix V  CYP3A Inhibitors and Inducers and P-Glycoprotein (PGP) Medications98 
Appendix VI  EA9152 Venetoclax Study Drug Request Form and EA9152 
Investigational Product Destruction Record ................................................... 101 
 

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STUDY CHAIR 
Neil Palmisiano, M.D., M.S. 
Thomas Jefferson University and Hospital 
834 Chestnut Street Suite 315 
Philadelphia, PA 19123  
Phone: (215) 503-6412 
E-mail: Neil.palmisiano@jefferson.edu 
 
STUDY CO-CHAIR 
David Claxton, M.D. 
Penn State Cancer Institute 
500 University Drive, MC-H056 
Hershey, PA 17033  
Phone: (717) 531-8678 
E-mail: dclaxton@pennstatehealth.psu.edu 
 
STUDY CHAIR LIAISON 
Ariel Kobylak, CCRP 
Sidney Kimmel Cancer Center 
Thomas Jefferson University and Hospital  
Jefferson Cancer Research Liaison Office (RLO) 
1015 Chestnut Street Suite 700 
Philadelphia, PA 19107  
Phone: (215) 955-5769 
E-mail: ariel.kobylak@jefferson.edu 
 
 
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INSTITUTION CONTACT INFORMATION 
Thomas Jefferson University (PA121) 
Investigator: Neil Palmisiano, M.D., M.S. 
Nurse/CRA: Ariel Kobylak 
Phone: 215-503-6412 
Phone: 215-955-9923 
Email: Neil.Palmisiano@jefferson.edu 
Email: ariel.kobylak@jefferson.edu 
Memorial Sloan Kettering Cancer Center (NY016) 
Investigator:  Jae Park, M.D.; Martin 
Tallman, M.D.; Mark Geyer 
Nurse/CRA: Marissa Smith, RN; Yunqi Yu 
Liu 
Phone: 212-639-
4048; 212-639-3842; 
212-639-3290 
 
Email: Parkj6@mskcc.org; 
Tallmanm@mskcc.org; geyerm@mskcc.org   
Email: smithm14@mskcc.org; 
yuliuy@mskcc.org  
University of Pennsylvania/Abramson Cancer Center (PA075) 
Investigator: Noelle Frey, M.D. 
Nurse/CRA: Doris Shank, RN 
Phone: 215-662-2867 
Phone: 215-662-4712  
Email: Noelle.Frey@uphs.upenn.edu  
Email: DorisM.Shank@uphs.upenn.edu   
Penn State Cancer Institute (PA042) 
Investigator: David Claxton, M.D. 
Nurse/CRA: Lea May, BSN, RN, OCN 
Nurse/CRA: Margaret Letteer, AN, RN 
Phone: 717-531-8870 
Phone: 717-531-0003 
ext. 0003 
Phone: 717-531-0003 
ext. 280471 
Email: dclaxton@pennstatehealth.psu.edu  
Email: lmay1@pennstatehealth.psu.edu 
 
Email: mletteer@pennstatehealth.psu.edu  
Yale University (CT018) 
Investigator: Nikolai Podoltsev, M.D., Ph.D. 
Nurse/CRA: Tanya Malak, CCRC 
Phone: 203-988-5441 
Phone: 203-273-3544 
Email: Nikolai.podoltsev@yale.edu  
Email: Tanya.malak@yale.edu 
Medical College of Wisconsin (WI013) 
Investigator: Ehab Atallah, M.D. 
Nurse/CRA: Katy Schroeder, BSN, RN, 
OCN 
Phone: 414-805-4600 
Phone: 414-805-8843 
Email: eattallah@mcw.edu   
Email: kbschroeder@mcw.edu  
Mayo Clinic (MN026) 
Investigator: Mark Litzow, M.D. 
Nurse/CRA: Jeffrey Hirvela  
Phone: 507-284-0288 
Phone: 507-538-4212 
Email: litzow.mark@mayo.edu   
Email: hirvela.jeffrey@mayo.edu  
Rutgers University (NJ066) 
Investigator: Dale Schaar MD, PhD  
Nurse/CRA: Kathy Kafka  
Nurse/CRA: Manisha Patel 
Phone: 732-235-4537 
Phone: 732-235-6411 
Phone: 732-235-6411 
Email: schaardg@cinj.rutgers.edu 
Email: kafka@cinj.rutgers.edu 
Email: manchy@cinj.rutgers.edu 
Northwestern University (IL036) 
Investigator; Shira Dinner, MD  
Study Coordinador 
Phone: 312 695-2120 
Phone: 312-695-1301 
Email: Shira.Dinner@nm.org 
Email: cancertrials@northwestern.edu 
Johns Hopkins University (MD017) 
Investigator: Jonathan Webster, M.D. 
Nurse/CRA: Colin Huck 
Phone: 410-614-9106 
Phone: 410-614-3725 
Email: jwebst17@jhmi.edu 
Email: chuck1@jhmi.edu 
 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately at 
1-866-651-2878 to receive 
further instruction and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org 
Contact the CTSU Help Desk with 
any OPEN-related questions by 
phone or email: 1-888-823-5923, 
or ctsucontact@westat.com.. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. 
Please see the data 
submission section of the 
protocol for further instructions.  
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS). 
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 
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Schema 
1.
If patient demonstrates CR or CRi at the day 42 or 70 bone marrow biopsies, they may continue on combination therapy or proceed to HSCT if deemed fit for transplant and advised by treating physician. Patient may proceed to HSCT at any point at 
treating physician’s discretion (if not at day 42 or 70).
2.
Subsequent arm will open for accrual only if < 1 DLT is observed in prior cohort. DLTs will be monitored days 1-42.
3.
If patient does not demonstrate any signs of progression, they may continue on combination therapy as long as they are receiving benefit per treating physician. Patients, if in CR/CRi by the end of cycle 2 may continue on combination or single agent at 
the discretion of treating physician.
4.
Bone marrow and peripheral blood specimens must be submitted for mandatory central review.
R
E
G
I
S
T
R
A
T
I
O
N
Step 1:
Phase I
HSCT1
Day 42
Bone Marrow 
Biopsy
Arm A Level 1, Cycle 1 (42 days)
Venetoclax 20mg d1, 50mg d2, 100mg 
d3, 200mg d4, 400mg d5-42 (oral) 
Liposomal vincristine 2.25mg/m2 weekly 
x4 starting d15 IV
Arm B Level 2, Cycle 1 (42 days)
Venetoclax 50mg d1, 100mg d2, 200mg 
d3, 400mg d4, 600mg d5-42 (oral) 
Liposomal vincristine 2.25mg/m2 weekly 
x4 starting d15 IV
Arm C Level 3, Cycle 1 (42 days)
Venetoclax 100mg d1, 200mg d2, 400mg 
d3, 600mg d4, 800mg d5-42 (oral)
Liposomal vincristine 2.25mg/m2 weekly x4 
starting d15 IV
< 1 DLT2
< 1 DLT2
Phase I Dose Escalation Accrual Goal: 3 - 18 patients
Day 70
Bone Marrow 
Biopsy
Repeat cycle 2 until 
progression3 or 
withdrawal from study
Long-Term
Follow-Up
HSCT1
If no PD
Arm A Level 1, Cycle 2 (28 days)
Venetoclax 400mg d43-70 (oral)
Liposomal vincristine 2.25mg/m2 
weekly x4 IV
Arm B Level 2, Cycle 2 (28 days)
Venetoclax 600mg d43-70 (oral)
Liposomal vincristine 2.25mg/m2 weekly 
x4 IV
Arm C Level 3, Cycle 2 (28 days)
Venetoclax 800mg d43-70 (oral)
Liposomal vincristine 2.25mg/m2 weekly x4 
IV
< 1 DLT2
< 1 DLT2
Long-Term
Follow-Up
S
L
O
T
-
R
E
S
E
R
V
A
T
I
O
N
P
R
E
-
R
E
G
I
S
T
R
A
T
I
O
N
Starting Dose
If PD
Step 0:4
 
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Schema 
1.
If patient demonstrates CR or CRi at day 28 or day 56 bone marrow biopsies, they may continue on combination therapy or proceed to HSCT if deemed fit for transplant and advised by treating physician. Patient may 
proceed to HSCT at any point at treating physician’s discretion (if not day 28 or 56).
2.
Patients will be classified by immunophenotype: B-cell ALL vs. T-cell ALL, with 28 patients as the accrual goal for each cohort.. 
3.
If patient does not demonstrate any signs of progression, they may continue on combination therapy as long as they are receiving benefit per treating physician. Patients, if in CR/Cri by the end of cycle 2 may continue 
on combination or single agent venetoclax at the discretion of the treating physician. 
4.
Bone marrow and peripheral blood specimens collected for the purpose of banking.
5.
In the event of liposomal vincristine shortage or discontinuation, patients actively undergoing treatment will be switched permanently to vincristine sulfate. 
NOTE:  Liposomal Vincristine is no longer being manufactured
R
E
G
I
S
T
R
A
T
I
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Step 1:
Phase II
HSCT1
Day 28
Bone Marrow Biopsy
Arm D, Cycle 1 (28 days)5
Venetoclax 600mg
Liposomal vincristine 
2.25mg/m2 weekly x4 
starting d1 IV or vincristine 
sulfate 1.4mg/m2 x4 
(capped at 2mg) starting 
d1 IV
If no PD
Arm D, Cycle 25
Venetoclax 600mg 
Liposomal vincrstiine 
2.25mg/m2 weekly x4 
starting d1 IV or vincristine 
sulfate 1.4mg/m2 once 
every 4 weeks (capped at 
2mg) starting d1 IV
Day 56 or 84
Bone Marrow Biopsy
Repeat cycle 2 until 
progression3 or 
withdrawal from study
Long-Term
Follow-Up
HSCT1
Classify2
• B-cell ALL vs. 
T-cell ALL
Phase II Accrual Goal: 56 patients 
If no PD
If PD
If PD
Long-Term
Follow-Up
P
R
E
-
R
E
G
I
S
T
R
A
T
I
O
N
Step 0:4
 
 
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1. 
Introduction 
1.1 
Current Therapy for Relapsed or Refractory Acute Lymphoblastic Leukemia 
Despite the fact that multi-agent chemotherapy regimens like Hyper-CVAD 
induce remissions in greater than 90% of adults with acute lymphoblastic 
leukemia, only a minority of patients are cured of their disease.[1-3] Five year 
survival rates of all comers approach 40%, and when patients are refractory to 
primary treatment or for those unable to proceed to allogeneic hematopoietic 
stem cell transplant (allo-HSCT) after relapse, the prognosis is dismal.[1] For fit 
patients after relapse, therapy directed toward inducing a complete remission so 
that an allogeneic stem cell transplant can performed currently offers the best 
chance of long-term disease control or cure. However, traditional re-induction 
strategies, like liposomal vincristine or other combination chemotherapies, 
achieve a complete remission only 20-30% of the time, leaving many fit patients 
without the option of transplant.[4, 5]  
Recently, blinatumomab, a bi-specific T-cell engager antibody targeted towards 
CD19 and CD3, and inotuzumab ozogamicin, an anti-CD22 monoclonal antibody 
linked to a calicheamicin-family antibiotic, have been developed for use in 
relapsed B-cell ALL. In this setting, blinatumomab demonstrates significant 
activity with CR or CRh rates approaching 70% of patients.[6] However, its 
difficult administration schedule (continuous infusion for 4 weeks) along with 
significant neurotoxic side effects and a still-short overall survival of 9.8 months 
argue for alternate strategies. Inotuzumab reported the results of its phase 3 
three trial, and again, while CR rates were high 81%, overall survival remained 
poor (average overall survival of 7.7 months). The study failed to meet its CR co-
primary endpoint, though it did allow for significantly more (41% vs 11%) patients 
to proceed to allo-HSCT. Chimeric antigen receptor therapy has been recently 
approved by the FDA, however, is only available in specialized centers and 
limited to treat those under the age of 25.[7] 
While new therapies are being developed for relapsed B-cell ALL, relapsed T-cell 
disease remains with few treatment options.[8, 9] Currently, nelarabine, a pro-
drug analogue of deoxygaunosine causing impairment of DNA synthesis, is the 
only T-ALL specific therapy approved by the FDA. The drug’s activity was 
demonstrated in a phase II open label trial and showed CR or CRi rates of 31%, 
but with dose-limiting neurotoxicity seen in 1/3 of patients. Though these new 
regimens are encouraging, better therapies are still clearly needed for this 
disease. 
1.2 
BCL-2 and Apoptosis  
One of the several hallmarks of cancers is the ability to evade programmed cell 
death. The careful organization of upstream regulators and downstream effectors 
of apoptosis allows for the precise dismantling of a cell in response to a wide 
variety of stimuli including external signaling via the FAS or TNF pathways, and 
internal signals in response to DNA damage or cytokine deprivation. This later 
pathway, or the intrinsic pathway, is tightly regulated by BCL-2 superfamily of 
proteins and culminates in the release of cytochrome-C from “stressed” cells’ 
mitochondria by the creation of pores in its outer membrane, a process denoted 
as mitochondrial outer membrane permeabilization (MOMP). (Please see 
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The BCL-2 family of proteins regulates MOMP through inhibitory and promotional 
interactions between different members of the superfamily. Members share BCL-
2-like homology domains 1-4 (BH1-BH4) which help govern their interactions and 
function. The supergroup can be divided by each protein’s effect on the fate of 
the cell: sensitizers, activators, suppressors and effectors of apoptosis. In resting 
state, suppressors of apoptosis (BCL-2, BCL-xL, MCL1, BCL-W) bind to the 
effectors (BAX or BAK) and activators (BID and BIM) and suppress their activity. 
In response to cell damage, the production of sensitizers and activators is 
induced. Sensitizers bind directly to anti-apoptotic proteins which causes their 
disassociation from effector and activator proteins. In turn, activators bind to 
effectors, inducing a conformational change in effectors that allows for their 
oligomerization. This oligomerization creates pores in mitochondria that are 
responsible for MOMP and the release of cytochrome-C. In turn, cyctochrome-C 
complexes with Apaf-1 which itself oligomerizes into a heptamer known as the 
apoptosome and recruits and activates caspase 9. Caspase 9 in turn activates 
other subsequent effector caspases to proteolytically dismantle the cell.[10, 11] 
Upstream of the intrinsic pathway, the central tumor suppressor p53 helps 
orchestrates the cell signals leading to apoptosis. For example, the release of 
p53 from MDM-2 by DNA damage initiates a broad cascade including the rapid 
translocation of p53 to the mitochondria. Evidence suggests that p53 can interact 
directly with Bak among others in the BCL-2 family, causing a release of 
inhibitory proteins BCL-2/BCL-xL and can complex with BCL-2/BCL-xL which 
functionally sequesters them. Additionally, p53 acts as a transcription factor for 
the initiator proteins including PUMA and NOXA, which bind to BCL-xL and allow 
for the release of Bax to form its effector oligomers. It is postulated that through 
these downstream effects, p53-deficient cells are rendered chemotherapy-
resistant. Cytokine withdrawal can also upregulate initiators of apoptosis, namely 
Bim and PUMA via Forkhead Box O (FOXO) transcription factors.[10-12]   
The relative expression of BCL-2 family proteins is temporally and geographically 
regulated in non-malignant cells during growth and differentiation. This program 
in lymphocytes demonstrates the complex interactions that can exist between 
superfamily members. BCL-2 expression in critical for development of B and T 
lymphoid progenitors from hematopoietic stem cells.[13] Early T-cells 
demonstrate high levels of expression of BCL-2 relative to BCL-xL at CD4-CD8- 
(double negative stage) but down regulates BCL-2 in favor of BCL-xL during 
CD4+CD8+ stage[14-18] BCL-2 expression rises as T-cells further differentiate 
into single positive thymocytes (CD4+CD8- or CD4-CD+)[15, 18] and then is 
maintained in memory T-cells.[19] On antigen binding, co-stimulation of the T-cell 
receptor with CD28 upregulates BCL-xL.[20] Similarly during b-cell ontogenesis, 
high levels of BCL-2 are seen early only (pro-B stage), are markedly lower in 
intermediate stages of differential and again are upregulated in the memory b-
cell.[21, 22] 
Proof for a central role of the BCL-2 superfamily in malignancies, and especially 
hematologic malignancies has been provided by decades of basic science 
research. BCL-2 was first discovered in the late 1970’s as part of the 
translocation 14:18 that is a hallmark of follicular lymphoma. Seminal studies 
demonstrated that cell lines that have upregulated anti-apoptosis protein like 
BCL-2 or MCL-1 do not themselves become cancerous, but, allow otherwise 
lethal mutations in the cell cycle to propagate. Additionally, upregulation of these 

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inhibitory proteins by various means in a wide variety of tumor subtypes renders 
them relatively chemotherapy resistant.[11] 
1.3 
Venetoclax 
1.3.1 
Mechanism of action 
Venetoclax (ABT-199) is a highly-selective, orally-bioavailable BCL-2 
inhibitor rationally designed from prior anti-BCL-2 drugs to spare the 
inhibition of BCL-xL.[23] Previous compounds in the family, like 
navitoclax, induced apoptosis in circulating platelets in an on target 
fashion (ie, sequestering BCL-xL) which resulted in dose-limiting and 
dose-dependent thrombocytopenia.[24] Using time-resolved 
fluorescence resonance energy transfer (TR-FRET) binding assays, 
the affinity of venetoclax for BCL-2 was found to be sub-nanomolar (Ki 
< 0.010 nM) and between 2,000-20,000 times less avid for BCL-xL 
and BCL-W, with essentially no affinity for MCL-1 (Ki>444).[23] In vitro 
testing of venetoclax has demonstrated remarkable sensitivity of 
patient chronic lymphocytic leukemia samples, with a LC50 10.0 ± 3.2 
nM compared to healthy donor T-cells and granulocytes (2.5 ± 2.8 µM 
and >4 µM) respectively. Researchers have shown sensitivity to a 
wide variety of other dependent cell lines including, diffuse large b-cell 
lymphomas, acute myeloid leukemias, acute lymphoblastic leukemias, 
and multiple myelomas.[25-27]  
The Letai group has pioneered an approach to determine the 
mitochondrial priming of a cell line for apoptosis and therefore predict 
its sensitivity to BCL-2 inhibitors like venetoclax.   
This technique, termed BH3 profiling, is a multifaceted interrogation of 
the relative state of the BCL-2 superfamily proteins of a particular cell 
sample by utilizing the principle that groups of activator, sensitizers 
and suppressor BH3 proteins bind preferentially to each other.[25, 28-
31]. Cells are made permeable exposed systematically to synthetic 
BH3 domains derived from various activating and sensitizing classes 
of proteins. Fundamentally, the greater the amount of these synthetic 
proteins needed to achieve MOMP, the less well “primed” a cell is to 
undergo cell death. Several classes of priming have been described, 
ranging from those incapable of apoptosis (i.e., cells that lack BAX 
and/or BAK through mutation or otherwise) to those nearly on the 
verge of cell death (i.e., highly primed). Importantly, these assays can 
also determine the anti-apoptotic proteins that a cell sample depends 
on for survival. For instance, cells that display increased MOMP in 
response to NOXA, a sensitizer BH3 protein which binds only to MCL-
1, are thought to be dependent on MCL-1 for survival. This addiction 
can be confirmed by exposure to anti-MCL-1 drugs causing apoptosis 
but not anti-BCL-2 drugs. In another example, the Letai group 
investigated the priming of a variety primary AML samples by 
exposing them to a fixed concentration of BAD, which preferentially 
binds to and overwhelms BCL-2-mediated inhibition of apoptosis, and 
also a fixed dose of venetoclax. A very close correlation of 
cytochrome C release by BAD and venetoclax was seen (Spearman r 
=0.935, p<0.0001), demonstrating the on target effects of the drug. In 
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venetoclax demonstrated significantly greater sensitivity than those 
blocked from apoptosis with BCL-xL or MCL-1.    
Recently, dynamic BH3 profiling, which predicts response to 
chemotherapy drugs, has also been described. Here, samples are 
exposed to a test drug and then treated similarly with exogenous BH3 
peptides. Results are compared to untreated samples. Cells who 
become significantly more primed (i.e., require less BH3 peptide to 
initiate apoptosis) are considered sensitive to the agent. For example, 
lung cancer cell lines with EGFR exon 19 mutations sensitive to 
gefitinib and with a T790M mutation which renders resistant to 
gefitinib but sensitive to a WZ4002 were examined using this method. 
As expected, the exon 19 EGFR cell lines demonstrated a significant 
increase in priming with both gefitinib and WZ4002, while the T790F 
lines showed only an increase in priming with response to WZ4002. 
The correlation between increase in priming at 16 hours and cell 
death at 72 hours as measured by annexin V/PI was impressively 
strong (Spearman r 0.82 95%CI:0.46-0.95). [32] 
1.3.2 
Clinical Efficacy in Hematologic Malignancies 
Early clinical experience in various hematologic malignancies with 
venetoclax has been published.[33-38] Escalating doses of 
venetoclax (50mg-600mg) in combination with rituximab in patients 
with relapsed/refractory CLL have shown to be well-tolerated and to 
have impressive preliminary activity.[35] Of the 18 evaluable patients 
reported in a phase I study, 78% of subjects had at least a PR, with 
38% having a CR/CRi. Toxicity was acceptable, with hematologic 
toxicities and nausea predominating. Grade 3/4 neutropenia, 
thrombocytopenia and anemia were found in 43%,16%, and 11% 
respectively. One death occurred during dose escalation of ABT-199 
(at 50mg) on account of uncontrolled tumor lysis (due to 
hyperkalemia), prompting more aggressive monitoring as well as a 
lower starting dose (20mg). In a subsequent study with more intense 
TLS-mitigating measures, venetoclax (20mg to 600mg) was given 
with bendamustine and rituximab in patients with relapsed/refractory 
CLL with none developing clinical or laboratory signs of TLS [36]. 
Patients experienced similar rates of hematologic and non-
hematologic toxicity as the prior study. As a single agent (dose rage 
20mg-1200mg) in relapsed/refractory AML or as frontline therapy for 
pts unfit for intensive therapy, ABT-199 was again well tolerated with 
the most common treatment-emergent AEs being nausea (14/32, 
44%), diarrhea (12/32, 38%), fatigue (9/32, 28%), neutropenia 8/32, 
25%). and vomiting (8/32, 25%).[34] Grade 3/4 AEs (in ≥3 pts) were 
limited to febrile neutropenia (8/32, 25%), anemia (3/32, 9%) and 
pneumonia (3/32, 9%). There were no reported events of clinical or 
laboratory tumor lysis syndrome and no AEs leading to death. CR/CRi 
was seen in 15.5% (5/32) of those tested. The largest study reported 
to date demonstrated the efficacy of venetoclax in patients with 
relapsed or refractory deletion 17p CLL.[38] 107 patients were 
enrolled across 31 centers world-wide in this single arm study using a 
graduated dosing schedule to mitigate the risk of tumor lysis 
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weeks by International Workshop for Chronic Lymphocytic Leukemia 
(IWCLL) criteria, showed that 77% of patients achieved at least a 
partial remission of disease, with 10% attaining a complete response. 
As seen in previous studies, neutropenia (43 of 107[40%], anemia (19 
[18%]), and infection (21 [20%]) were the most common grade 3-4 
adverse events. Few (9%) experienced dose interruption or dose 
reduction for neutropenia. No deaths or serious adverse events 
related to tumor lysis were seen. The outcomes of this study led to 
accelerated FDA approval for venetoclax in deletion 17p CLL.  
1.4 
Rationale for Study 
The use of ABT-199 in combination with cytotoxic agents in ALL is attractive 
mechanistically, as BCL-2 upregulation is thought to induce chemotherapy 
resistance and BCL-2 inhibition may lower the apoptotic threshold of a cell.[10]  
In addition, work to date with BH3 profiling of primary B-ALL and ETP-cells has 
demonstrated the BCL2 dependence of these subtypes [30, 39]. Preclinical 
synergy data with other BH3-mimetics in T-ALL and B-ALL has been 
demonstrated with an array of agents including steroids, anthracyclines, 
asparaginase, TKIs and vincristine.[39-42] The combination of vincristine and 
ABT-737, for example, demonstrated strong to very strong synergy with median 
combination indices ranging from 0.09-0.9, among both T and B ALL cell 
lines.[42] Mice xenografted with MLL patient samples and treated with venetoclax 
and a combination of vincristine, peg-asparginase and dexamethasone showed 
marked synergy.[44] In this model, ABT-199 alone and VXR alone had minimal 
effect on circulating blasts, however, the combination reduced leukemia burden 
by more than 70%. In one patient sample tested, the combination eradicated ALL 
in mice below the level of detection.  
Diverse T-ALL cell lines treated with ABT-199 demonstrated significant response 
with IC50 values ranging from 13.9nM – 10uM, with cells line expressing 
immature phenotypes more sensitive to the drug. This work was extended to 
patient samples, where again, cells expressing immature T-cell markers (i.e., 
lacking CD4 and CD8) demonstrated cell kill with lower IC50 concentrations and 
higher caspase activity after exposure to a fixed dose of ABT-199.[30, 41] In B-
cell ALL, BCL-2 may be more uniformly expressed, with B- ALL samples being 
inhibited at low concentrations of ABT-199 (IC50 0.1-3.0 nM).[40] In vivo, 
treatment of mice xenografted with LOUCY cell lines, B-cell precursor ALL, early 
pre-T-cell ALL and MLL-rearranged, patient-derived ALL samples with ABT-199 
results significantly reduced tumor burden when compared to controls.[45-47] 
Recently, Bourquin et al published their investigation of BCL-2 inhibition in vitro 
and in vivo testing of a wide variety of ALL samples.[48] They interrogated 68 
ALL samples, many from highly resistant patients in co-culture with bone marrow 
stromal cells with the intent of determining the feasibility of real-time drug-
response profiling. In vitro testing demonstrated strong sensitivity to single agent 
venetoclax across early pre-T ALL, T-ALL and a variety of b-cell precursor ALL. 
In vivo, venetoclax demonstrated significant synergy with vincristine and 
dexamethasone, significantly delaying disease progression for multiple samples 
over either agent alone.   
The study of venetoclax alone and in combination in acute myeloid leukemia has 
helped inform the dose and schedule proposed in this clinical trial. In order to 
mitigate the risk of tumor lysis, fixed, intra-patient dose escalation designs have 
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been utilized.[34, 49, 50] In a single agent phase II study, venetoclax 800mg was 
found to be safe, with no toxicity related deaths, and no reports of clinical tumor 
lysis syndrome. An elderly, upfront phase Ib/II trial found the recommended 
phase II dose of the combination of venetoclax and low-dose cytarabine to be 
600mg, with prolonged (> 42 days), grade 4 thrombocytopenia being the 
predominant dose limiting toxicity.[49] However, another group studying 
venetoclax in combination with azacitidine, did not see dose-limiting 
thrombocytopenia at up to 800mg.[50] Of note, no trial in AML has reported 
significant TLS. 
Liposomal Vincristine, Marqibo®, is a lipid-encapsulated nanoparticle formulation 
of vincristine, and was developed to have improved pharmacokinetic and side-
effect profile over naked vincristine.[51] The drug gained FDA approval for ALL in 
second relapse after a phase II trial demonstrated significant activity.[4] In this 
study, sixty-five heavily pre-treated patients were treated with 2.25mg/m2 of 
liposomal vincristine weekly.Thirteen (20%) achieved a CR/CRi, and an 
additional 15% had either a partial response or bone marrow blast response 
(defined as morphologic response with incomplete platelet and neutrophil 
recovery). The formulation demonstrated response in patients who notably had 
all previously been exposed to vincristine in prior treatment regimens. The 
majority of serious adverse events where related to neuropathy and constipation, 
occurring in 25% and 12% of subjects respectively.  
Especially in patients with relapsed disease, the combination of venetoclax and 
liposomal vincristine is a promising treatment strategy as these agents have non-
overlapping toxicity profiles. Given this tolerability along with the significant pre-
clinical data supporting the potential synergy of BCL-2 inhibition with vincristine, 
we propose a phase Ib/II clinical trial to explore the safety and preliminary 
efficacy of the combination in B- and T-ALL. 
Please note: As of April 2022, the removal of liposomal vincristine from the 
market in the US necessitates substitution of vincristine sulfate for liposomal 
vincristine.  Section 5.2 of this protocol details the administration differences for 
vincristine sulfate. Section 9.2 documents additional toxicity monitoring instituted 
to ensure patients’ safety in the phase II portion of this trial. 
 
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2. 
Objectives 
2.1 
Primary Endpoints 
2.1.1 
Phase I: 
2.1.1.1 
To determine the maximum tolerated dose of venetoclax in 
combination with liposomal vincristine/vincristine sulfate in 
patients with relapsed or refractory T-cell and B-cell ALL. 
NOTE: 
Liposomal Vincristine is no longer being 
manufactured. 
2.1.1.2 
Safety assessment and toxicity characterization after 
treatment of venetoclax in combination with liposomal 
vincristine in patients with relapsed or refractory T-cell and 
B-cell ALL. 
2.1.2 
Phase II: 
2.1.2.1 
To determine the preliminary efficacy of venetoclax in 
combination with liposomal vincristine/vincristine sulfate to 
induce CR+CRi in patients with relapsed or refractory T-
cell and B-cell ALL. 
2.2 
Secondary Endpoints 
2.2.1 
Phase II: 
2.2.1.1 
To determine the progression free survival, overall survival 
and toxicity after the combination treatment in patients with 
relapsed or refractory T-cell and B-cell ALL. 
2.2.1.2 
To determine the rate of MRD negativity rate of the 
combination 
2.3 
Exploratory/Correlative Studies  
2.3.1 
Phase II: 
2.3.1.1 
To determine if genetic signature as determined by next 
generation sequencing can predict response to 
combination. 
2.3.1.2 
To determine if immunophenotype of ALL is associated 
with response to combination. 
2.3.1.3 
To determine if the BH3 profile is associated with response 
to combination. 
2.3.1.4 
To determine if relative expression of BCL-2 measure by 
flow cytometry is associated with response to combination. 
NOTE: 
Exploratory biomarker testing of banked specimens will not occur until 
an amendment to this treatment protocol (or separate correlative 
science protocol) is reviewed and approved in accordance with 
National Clinical Trials Network (NCTN) policies. 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit. All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Eligibility Criteria – Phase I (Arms A, B, C) – Step 0 
3.1.1 
Patient must be considered a potential candidate for the trial. 
NOTE: 
Enrollment to Step 0 may occur prior to or following 
completion of the assessments to verify patient eligibility 
for Step 1 registration. Bone marrow and/or peripheral 
blood specimens collected during Step 0 or prior to 
treatment on Step 1 must be submitted for central review in 
order for the patient to be considered evaluable. Results 
will not be reported to the site and will not impact patient 
participation in the trial. 
3.2 
Eligibility Criteria – Phase I (Arms A, B, C) – Step 1 
3.2.1 
Patients must have a diagnosis of: 
A) Relapsed or refractory B-cell or T-cell ALL after multi-agent 
chemotherapy. 
B) Patients with < 5% blasts may enroll on trial in phase I portion 
provided that minimal residual disease (MRD) is present at > 10-3 
as tested on an assay with minimum sensitivity of 10-4. 
OR 
C) Relapsed lymphoblastic lymphoma 
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3.2.2 
Age ≥ 18 years  
3.2.3 
ECOG performance status 0-2 
3.2.4 
Adequate liver function with AST/ALT less than 3X upper limit of 
normal and total bilirubin less than 2 mg/dL within 10 days prior to first 
dose of study agent. 
3.2.5 
Circulating WBC count must not be above 25 x109/L at the time of 
registration. 
3.2.5.1 
Patients with WBC count above 25 x109/L are eligible if 
they have started steroids or hydroxyurea per institutional 
guidelines. Please see Section 5.6.2 for additional details. 
3.2.6 
Glomerular filtration rate (GFR) of at least 40 mL/min within 7 days 
prior to first dose of study agent. 
3.2.7 
Patients of childbearing potential must not be pregnant or breast-
feeding due to risk of fetal harm by the chemotherapeutic agents 
prescribed in this protocol. 
3.2.8 
All patients of childbearing potential must have a blood test or urine 
study with a minimum sensitivity 25 IU/L or equivalent units of HCG 
within 2 weeks prior to registration to rule out pregnancy. 
A patient of childbearing potential is defined as anyone, regardless of 
sexual orientation or whether they have undergone tubal ligation, who 
meets the following criteria: 1) has achieved menarche at some point, 
2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) 
has not been naturally postmenopausal for at least 24 consecutive 
months (i.e., has had menses at any time in the preceding 24 
consecutive months). 
Patient of childbearing potential? ______ (Yes or No) 
Date of blood or urine test: ___________ 
3.2.9 
Patients must not expect to conceive or father children by using  
accepted and highly effective method(s) of contraception or by 
abstaining from sexual intercourse for the duration of their 
participation in the study and for 30 days after the last dose of 
venetoclax. 
Should a patient or a partner of a patient become pregnant or suspect 
they are pregnant while participating in this study, the treating 
physician should be notified immediately. 
3.2.10 
No evidence of prior solid malignancy except adequately treated non-
melanoma skin cancer, in situ cervical carcinoma, or any surgically- or 
radiation-cured malignancy continuously disease free for ≥ 2 years so 
as not to interfere with interpretation of radiographic response. 
3.2.11 
Patients with isolated testicular or CNS relapsed disease are not 
eligible. 
3.2.12 
Patients must not have Burkitt’s lymphoma/leukemia based on the 
WHO criteria. 
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3.2.13 
Patients must not have active central nervous system (CNS) 
leukemia, as defined by unequivocal morphologic evidence of 
lymphoblasts in the cerebrospinal fluid (CSF) or the use of CNS-
directed local treatment for active disease within the prior 28 days. 
Prophylactic intrathecal chemotherapy is allowed. Previously treated 
CNS disease with documented clearance of the CSF will be allowed. 
3.2.14 
Patients will not be enrolled if they received prior chemotherapy within 
2 weeks before registration to step 1with the following exceptions: to 
reduce the circulating lymphoblast count or palliation or for ALL 
maintenance (mercaptopurine, methotrexate, vincristine, thioguanine, 
and/or tyrosine kinase inhibitors). 
3.2.15 
Patients may be enrolled with a prior allogeneic hematopoietic stem 
cell transplant (HSCT) but the transplant date must be at least 90 
days before date of registration to step 1. Patient must be off 
immunosuppression and without active GVHD prior to registration to 
step 1 if previous HSCT. 
3.2.16 
Patients cannot have poorly controlled chronic viral infections 
including Hepatitis B, C, or HIV. HIV positive patients are allowed on 
this study if they have a CD4 count ≥ 400, and are on a stable antiviral 
regimen.  
3.2.17 
Patients with NYHA Class III or IV heart failure, uncontrolled angina, 
severe uncontrolled ventricular arrhythmias, or electrocardiographic 
evidence of acute ischemia may not be enrolled. 
3.2.18 
Patients with serious medical or psychiatric illness that in the opinion 
of the primary investigator is likely to interfere with study participation 
may not be enrolled. 
3.2.19 
Patients must not be taking any other experimental medications within 
21 days prior to registration. Clinical trial medications that are FDA 
approved will be allowed within 14 days prior to registration. 
3.2.20 
Patients should not have received the following within 7 days prior to 
the first dose of study drug: 
• 
Strong and Moderate CYP3A inhibitors (see Appendix V for 
details); 
• 
Strong and Moderate CYP3A inducers (see Appendix V for 
details) 
See Section 5.6.3 for discussion of the use of azole anti-fungals. 
3.2.21 
Patients must not have grade 3 or higher peripheral neuropathy or 
history of grade 3 or higher peripheral neuropathy. Patients with 
familial demyelinating disease like Charcot-Marie-Tooth disease are 
also excluded. 
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Physician Signature 
 
Date 
OPTIONAL: 
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use the eligibility checklist as source documentation. 
 

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3.3 
Eligibility Criteria – Phase II (Arm D) – Step 0 
3.3.1 
Patient must be considered a potential candidate for the trial. 
NOTE: 
Enrollment to Step 0 may occur prior to or following 
completion of the assessments to verify patient eligibility 
for Step 1 registration. 
3.4 
Eligibility Criteria – Phase II (Arm D) – Step 1 
3.4.1 
Relapsed or refractory B-cell or T-cell ALL, including lymphoblastic 
lymphoma, after at least one line of chemotherapy. 
3.4.2 
Patients with prior venetoclax treatment for ALL will be excluded. 
3.4.3 
Age ≥ 18 years.  
3.4.4 
ECOG performance status 0-2. 
3.4.5 
Adequate liver function with AST/ALT less than 3X upper limit of 
normal and total bilirubin less than 2 mg/dL within 10 days prior to first 
dose of study agent. 
3.4.6 
Circulating WBC count must not be above 25 x109/L at the time of 
registration to step 1. 
3.4.6.1 
Patients with WBC count above 25 x109/L are eligible if 
they have started steroids or hydroxyurea per institutional 
guidelines. Please see Section 5.6.2 for additional details. 
3.4.7 
GFR of at least 40 mL/min within 7 days prior to first dose of study 
agent. 
3.4.8 
Patients must not be pregnant or breast-feeding due to risk of fetal 
harm by the chemotherapeutic agents prescribed in this protocol. 
3.4.9 
All patients of childbearing potential must have a blood test or urine 
study with a minimum sensitivity 25 IU/L or equivalent units of HCG 
within 2 weeks prior to registration to rule out pregnancy. 
A patient of childbearing potential is defined as anyone, regardless of 
sexual orientation or whether they have undergone tubal ligation, who 
meets the following criteria: 1) has achieved menarche at some point, 
2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) 
has not been naturally postmenopausal for at least 24 consecutive 
months (i.e., has had menses at any time in the preceding 24 
consecutive months). 
Patient of childbearing potential? ______ (Yes or No) 
Date of blood or urine test: ___________ 
3.4.10 
Patients must not expect to conceive or father children by using  
accepted and highly effective method(s) of contraception or by 
abstaining from sexual intercourse for the duration of their 
participation in the study and for 30 days after the last dose of 
venetoclax. 
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Should a patient or partner of a patient become pregnant or suspect 
she is pregnant while participating in this study, the treating physician 
should be informed immediately. 
3.4.11 
No evidence of prior malignancy except adequately treated non-
melanoma skin cancer, in situ cervical or breast carcinoma, or  
chemotherapy-surgically- or radiation-cured malignancy continuously 
disease free for ≥ 2 years. 
3.4.12 
Patients with isolated testicular or CNS relapsed disease are not 
eligible. 
3.4.13 
Patients must not have Burkitt’s lymphoma/leukemia based on the 
WHO criteria. 
3.4.14 
Patients must not have active central nervous system (CNS) 
leukemia, as defined by unequivocal morphologic evidence of 
lymphoblasts in the cerebrospinal fluid (CSF) or the use of CNS-
directed local treatment for active disease within the prior 28 days. 
Prophylactic intrathecal chemotherapy is allowed. Previously treated 
CNS disease with documented clearance of the CSF will be allowed 
and once cleared, prophylactic intrathecal chemotherapy can be 
continued. 
3.4.15 
Patients will not be enrolled if they received prior chemotherapy within 
2 weeks before enrollment with the following exceptions: to reduce the 
circulating lymphoblast count or palliation (i.e., steroids or 
hydroxyurea), for ALL maintenance (mercaptopurine, methotrexate, 
vincristine, thioguanine, and/or tyrosine kinase inhibitors). 
3.4.16 
Patients may be enrolled with a prior allogeneic hematopoietic stem 
cell transplant (HSCT) but the transplant date must be at least 90 
days before date of enrollment. Patient must be off 
immunosuppression and without active GVHD prior to enrollment if 
previous HSCT. Low-dose steroids (10mg or less) are allowed. 
3.4.17 
Patients cannot have poorly controlled chronic viral infections 
including Hepatitis B, C, or HIV. HIV positive patients with 
undetectable viral load are allowed.  
3.4.18 
Patients with NYHA Class III or IV heart failure, uncontrolled angina, 
severe uncontrolled ventricular arrhythmias, or electrocardiographic 
evidence of acute ischemia may not be enrolled. 
3.4.19 
Patients with serious medical or psychiatric illness that in the opinion 
of the primary investigator is likely to interfere with study participation 
may not be enrolled. 
3.4.20 
Patients must not be participating in any other clinical trial or taking 
any other experimental medications within 21 days prior to 
registration. 
3.4.21 
Patients must not have received the following within 7 days prior to 
the first dose of study drug or while on study treatment: 
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• 
Strong and Moderate CYP3A inhibitors (see Appendix V for 
details); 
• 
Strong and Moderate CYP3A inducers (see Appendix V for 
details) 
See Section 5.6.3 for discussion of the use of azole anti-fungals. 
3.4.22 
Patients must not have grade 3 or higher peripheral neuropathy or 
history of grade 3 peripheral neuropathy. Patients with familial 
demyelinating diseases like Charcot-Marie-Tooth disease also 
excluded. 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
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4. 
Registration Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System (RUMS), OPEN, Rave,); 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and 
certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug 
shipment, or as the CI on the DTL must be rostered at the enrolling site with a 
participating organization (i.e., Alliance). 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
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Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorresources/default.htm. For questions, please contact 
the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations. 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by emailing the email address above or calling 1-888-651-
CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 

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• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
Downloading Site Registration Documents:  
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff must be associated 
with the LPO or a PO on the protocol. Site registration forms may be downloaded from 
the EA9152 protocol page located on the CTSU members’ website. 
• 
Log on to the CTSU members’ website Go to https://www.ctsu.org and log in to the 
members’ area using your CTEP-IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol EA9152 
• 
Click on Documents, select the Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB initiative, IRB data will load 
automatically to the CTSU as described above.) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website. 
To access the Regulatory Submission Portal log on to the CTSU members’ website 
Regulatory Submission Portal: www.ctsu.org (members’ area)  Regulatory  
Regulatory Submission 
Institutions with patients waiting that are unable to use Regulatory Submission the Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE:  
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 

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• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status: 
You can verify your site’s registration status on the members’ side of the CTSU website. 
• 
Log on to the CTSU members’ website ; 
• 
Click on the Regulatory tab at the top of your screen; 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status shown only reflects institutional compliance with site registration 
requirements as outlined above. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Treatment should start within seven days after registration.  
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in 
conjunction with the Registration system in the Oncology Patient Enrollment Network 
(OPEN). Prior to discussing protocol entry with the patient, all site staff must use the 
CTSU OPEN Slot Reservation System to insure that a slot on the protocol is available to 
the patient. Once a slot- reservation confirmation is obtained, site staff may then proceed 
to enroll the patient to this study.  
Requirements for OPEN access: 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
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NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is provided on the OPEN tab of the CTSU 
members’ side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Preregistration to Phase I (Arms A, B, C) – Step 0 
NOTE: 
Patients who are only preregistered must not begin treatment. 
4.1.1 
Protocol Number  
4.1.2 
Site/Investigator Identification  
• 
Institution CTEP ID 
• 
Treating Investigator 
• 
Consenting Person 
• 
Site Registrar 
• 
Network Group Credit 
• 
Credit Investigator 
4.1.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1. 
4.1.5 
Additional Requirements  
4.1.5.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office – Boston. 
4.1.5.2 
Bone marrow and/or peripheral blood specimens must be 
submitted for central review as outlined in Section 10. 
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4.1.5.3 
Biological specimens are to be submitted for defined 
laboratory research studies and/or future undefined 
research per patient consent as outlined in Section 10. 
4.2 
Registration to Phase I (Arms A, B, C) – Step 1 
4.2.1 
Protocol Number  
4.2.2 
Site/Investigator Identification  
• 
Institution CTEP ID 
• 
Treating Investigator 
• 
Consenting Person 
• 
Site Registrar 
• 
Network Group Credit 
• 
Credit Investigator 
4.2.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.2.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.2. 
4.2.5 
Additional Requirements  
4.2.5.1 
Patients must provide a signed and dated, written informed 
consent form. 
4.2.5.2 
Biological specimens are to be submitted for defined 
laboratory research studies and/or future undefined 
research per patient consent as outlined in Section 10. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office – Boston. 
4.2.5.3 
Medidata Rave is a clinical data management system 
being used for data collection for this trial/study. Access to 
the trial in Rave is controlled through the CTEP-IAM 
system and role assignments. To access Rave via 
iMedidata, site staff will need to be registered with CTEP 
and have a valid and active CTEP-IAM account; and 
assigned one of the following Rave roles on the relevant 
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Lead Protocol Organization (LPO) or Participating 
Organization roster at the enrolling site: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator. Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm 
for registration types and documentation required. To hold 
Rave CRA role or Rave CRA (Lab Admin) role, the user 
must hold a minimum of an AP registration type. To hold 
the Rave Site Investigator role, the individual must be 
registered as an NPIVR or IVR. Associates can hold read-
only roles in Rave. 
Upon initial site registration approval for the study in RSS, 
all persons with Rave roles assigned on the appropriate 
roster will be sent a study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select 
Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by 
clicking on the link in the upper right pane of the iMedidata 
screen. If an eLearning is required and has not yet been 
taken, the link to the eLearning will appear under the study 
name in iMedidata instead of the Rave EDC link; once the 
successful completion of the eLearning has been 
recorded, access to the study in Rave will be granted, and 
a Rave EDC link will display under the study name. 
Users that have not previously activated their 
iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive 
a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the 
CTSU website, Rave tab under the Rave resource 
materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by 
e-mail at ctsucontact@westat.com. 
4.3 
Preregistration to Phase II (Arm D) – Step 0 
NOTE: 
Patients who are only preregistered must not begin treatment. 
4.3.1 
Protocol Number  
4.3.2 
Site/Investigator Identification  
• 
Institution CTEP ID 
• 
Treating Investigator 
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• 
Consenting Person 
• 
Site Registrar 
• 
Network Group Credit 
• 
Credit Investigator 
4.3.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.3.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.3. 
4.3.5 
Additional Requirements  
4.3.5.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office – Boston. 
4.3.5.2 
Biological specimens are to be submitted for defined 
laboratory research studies and/or future undefined 
research per patient consent as outlined in Section 10. 
4.4 
Registration to Phase II (Arm D) – Step 1 
4.4.1 
Protocol Number  
4.4.2 
Site/Investigator Identification  
• 
Institution CTEP ID 
• 
Treating Investigator 
• 
Consenting Person 
• 
Site Registrar 
• 
Network Group Credit 
• 
Credit Investigator 
4.4.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
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• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.4.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.4. 
4.4.5 
Classification Factor 
4.4.5.1 
Patient will be classified by immunophenotype: B-cell vs. 
T-cell. 
4.4.6 
Additional Requirements  
4.4.6.1 
Patients must provide a signed and dated, written informed 
consent form. 
4.4.6.2 
Biological specimens are to be submitted for defined 
laboratory research studies and/or future undefined 
research per patient consent as outlined in Section 10. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office – Boston. 
4.4.6.3 
Medidata Rave is a clinical data management system 
being used for data collection for this trial/study. Access to 
the trial in Rave is controlled through the CTEP-IAM 
system and role assignments. To access Rave via 
iMedidata, site staff will need to be registered with CTEP 
and have a valid and active CTEP-IAM account; and 
assigned one of the following Rave roles on the relevant 
Lead Protocol Organization (LPO) or Participating 
Organization roster at the enrolling site: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator. Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm 
for registration types and documentation required. To hold 
Rave CRA role or Rave CRA (Lab Admin) role, the user 
must hold a minimum of an AP registration type. To hold 
the Rave Site Investigator role, the individual must be 
registered as an NPIVR or IVR. Associates can hold read-
only roles in Rave. 
Upon initial site registration approval for the study in RSS, 
all persons with Rave roles assigned on the appropriate 
roster will be sent a study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select 
Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the 
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“accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by 
clicking on the link in the upper right pane of the iMedidata 
screen. If an eLearning is required and has not yet been 
taken, the link to the eLearning will appear under the study 
name in iMedidata instead of the Rave EDC link; once the 
successful completion of the eLearning has been 
recorded, access to the study in Rave will be granted, and 
a Rave EDC link will display under the study name. 
Users that have not previously activated their 
iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive 
a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the 
CTSU website, Rave tab under the Rave resource 
materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by 
e-mail at ctsucontact@westat.com. 
4.5 
Data Query Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics. 
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on 
the Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
NOTE: 
Some Rave protocols may not have delinquent form details or reports 
specified on the DQP. A protocol must have the Calendar functionality 
implemented in Rave by the Lead Protocol Organization (LPO) for 
delinquent form details and reports to be available on the DQP. Site 
staff should contact the LPO Data Manager for their protocol 
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4.6 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
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5. 
Treatment Plan 
5.1 
Administration Schedule – Phase I 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
In the phase I portion of this trial, venetoclax will be given orally in a tablet 
formulation once daily in 3 dose arms with a fixed, standard dose of intravenous 
(IV) liposomal vincristine 2.25mg/m2 weekly starting after a 2 week lead-in phase 
of venetoclax.  
Venetoclax will be dosed as follows: 
• 
Cohort 1 (Arm A) ‒ 20, 50, 100, 200 mg on Days 1, 2, 3, 4 and 400 mg on 
Days 5 ‒ 70 
• 
Cohort 2 (Arm B) ‒ 50, 100, 200, 400 mg on Days 1, 2, 3, 4 and 600 mg on 
Days 5 ‒ 70 
• 
Cohort 3 (Arm C) ‒ 100, 200, 400, 600 mg on Days 1, 2, 3, 4 and 800 mg on 
Days 5 ‒ 70 
In order to mitigate the risk of tumor lysis syndrome (TLS), fixed intra-patient 
dose escalation (per company standards) will be employed, as well as TLS 
prophylaxis starting 3 days prior to venetoclax dosing. Patients will be admitted to 
the hospital for TLS monitoring during dose escalation (days 1-6). See Section 
5.6.2. 
Three (3) patients will be enrolled in the initial dose arm (Arm A). If none of the 
initial three (3) patients experience a dose limiting toxicity (DLT), then an 
additional three (3) patients will be enrolled at the next dose arm (Arm B). If for 
any dose arm, one (1) patient experiences a DLT, then an additional three (3) 
patients will be enrolled at that dose arm. Escalation will continue until > 33% of a 
particular dose arm experiences a DLT. The next lower dose arm to that which 
caused the DLTs will be considered the recommended phase II dosing schema 
(RP2D) and implemented for Arm D. If < two (2) patients experience a DLT in 
dosing arm C, then dosing arm C will be used in the phase II portion of this trial. 
The table below illustrates the dose escalation plan based on observed DLTs for 
any given group of patients on the same treatment arm.  
Number of Observed DLTs 
Action 
0/3 patients 
Escalate to the next dose arm 
1/3 patients 
Add 3 more patients at current dose arm 
>1/3 patients 
Dose in previous arm is MTD* 
1/6 patients 
Escalate to the next dose arm 
≥2/6 patients 
Dose in previous arm is MTD* 
* Discontinue the trial if occurs at the initial dose level. MTD refers to maximum 
tolerated dose. 
The maximum tolerated dose (MTD) must be confirmed with six (6) patients. If 
only 0/3 patients with DLT in the MTD, three (3) additional patients will be 
enrolled into this dose level to better characterize the safety of this phase I 
portion dose. The MTD of venetoclax determined in the phase I portion will be 
the recommended dose for venetoclax used in combination with liposomal 
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vincristine in the phase II portion of this study. A minimum of three (3) patients 
and a maximum of eighteen (18) patients will be treated in the phase I portion of 
the study. 
Patients will receive venetoclax per their assigned dose arm schedule, Arm A, B, 
or C below. After a two-week lead-in phase, patients will also be initiated on 
weekly liposomal vincristine 2.25mg/m2 IV x 4 weeks (Cycle 1 = 42 days). A bone 
marrow biopsy will be performed on Day 42 +/- 2 days. Cycle 2 may be held up 
to two weeks (14 days) for results of day 42 bone marrow biopsy, and should this 
occur, oral venetoclax should be continued. All patients will continue onto a 
second 28-day cycle of the combination therapy (Cycle 2 = 28 days). Patients 
with progressive disease will be off treatment. A bone marrow biopsy will be 
performed at day 70 +/- 2 days. Patients who achieve at least a stable disease 
response can remain on a 28-day cycle of combination therapy until disease 
progression, or withdrawal from trial. If patients achieve CR/CRi, patient may 
continue on combination therapy or single agent venetoclax therapy after the 
completion of cycle 2 at the discretion of the treating physician. All subsequent 
cycles will follow the cycle 2 regimen for combination therapy over 28 days. At 
the discretion of the treating physician, a patient who achieves CR or CRi may 
proceed to HSCT at any time. Dose modifications occurs per Section 5.5 are 
allowed starting in Cycle 2 (i.e., after day 42 of DLT monitoring window). The 4th 
weekly dose (day 36) of liposomal vincristine may be held for treatment emergent 
adverse events in cycle 1, at the discretion of the site investigator. This should be 
discussed with the study chair prior to liposomal vincristine dose being held. 
Patients must have taken at least 75% of venetoclax doses and 75% of liposomal 
vincristine doses during the DLT period to be considered evaluable for MTD. 
Those patents not meeting this requirement and not showing any DLT will need 
to be replaced for MTD determination. 
The provided medication diary should be distributed to patients to document 
venetoclax administration schedules (see Appendix II). 
NOTE: 
Marqibo (vinCRIStine sulfate LIPOSOME injection) has different 
dosage recommendations than vinCRIStine sulfate injection. Verify 
drug name and dose prior to preparation and administration to avoid 
overdosage. 
5.1.1 
Arm A 
Cycle 1: 
Venetoclax: orally in a tablet formulation once daily at 20, 50, 100, 
200 mg on Days 1, 2, 3, 4 and 400 mg on Days 5 ‒ 42. 
Liposomal Vincristine: 2.25mg/m2 IV weekly x 4 starting Day 15. The 
4th weekly dose (day 36) may be held at the discretion of the site 
investigator in the first cycle. 
NOTE: 
All patients should proceed to Cycle 2 receiving 
combination therapy unless they have progressive disease 
or they achieve CR or CRi and proceed to HSCT. Patients 
may continue on combination therapy until HSCT can be 
arranged. 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
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Cycle 2: 
Venetoclax: orally in a tablet formulation once daily at 400 mg on 
Days 43 ‒ 70. 
Liposomal Vincristine: 2.25mg/m2 IV weekly x 4. 
NOTE: 
Patients should avoid consuming food and beverages 
containing grapefruit juice or Seville oranges for the 
duration of the study due to CYP3A4/5 inhibition. 
If patients achieve CR/CRi, patient may continue on 
combination therapy or single agent venetoclax therapy 
after the completion of cycle 2 at the discretion of the 
treating physician. 
NOTE: 
Dose reduction of liposomal vincristine is allowed during 
cycle two per package insert guidelines at investigator’s 
discretion. 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
5.1.2 
Arm B 
Cycle 1: 
Venetoclax: orally in a tablet formulation once daily at 50, 100, 200, 
400 mg on Days 1, 2, 3, 4 and 600 mg on Days 5 ‒ 42. 
Liposomal Vincristine: 2.25mg/m2 IV weekly x 4 starting Day 15. The 
4th weekly dose (day 36) may be held at the discretion of the site 
investigator in the first cycle. 
NOTE: 
All patients should proceed to Cycle 2 receiving 
combination therapy unless they have progressive disease 
or they achieve CR or CRi and proceed to HSCT. Patients 
may continue on combination therapy until HSCT can be 
arranged. 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
Cycle 2: 
Venetoclax: orally in a tablet formulation once daily at 600 mg on 
Days 43 ‒ 70. 
Liposomal Vincristine: 2.25mg/m2 IV weekly x 4. 
NOTE:  
Patients should avoid consuming food and beverages 
containing grapefruit juice or Seville oranges for the 
duration of the study due to CYP3A4/5 inhibition. 
If patients achieve CR/CRi, patient may continue on 
combination therapy or single agent venetoclax therapy 
after the completion of cycle 2 at the discretion of the 
treating physician 
NOTE: 
Dose reduction of liposomal vincristine is allowed during 
cycle two per package insert guidelines at investigator’s 
discretion. 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
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5.1.3 
Arm C 
Cycle 1: 
Venetoclax: orally in a tablet formulation once daily at 100, 200, 400, 
600 mg on Days 1, 2, 3, 4 and 800 mg on Days 5 ‒ 42. 
Liposomal Vincristine: 2.25mg/m2 IV weekly x 4 starting Day 15. The 
4th weekly dose (day 36) may be held at the discretion of the site 
investigator in the first cycle. 
NOTE: 
All patients should proceed to Cycle 2 receiving 
combination therapy unless they have progressive disease 
or they achieve CR or CRi and proceed to HSCT. Patients 
may continue on combination therapy until HSCT can be 
arranged. 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
Cycle 2: 
Venetoclax: orally in a tablet formulation once daily at 800 mg on 
Days 43 ‒ 70. 
Liposomal Vincristine: 2.25mg/m2 IV weekly x 4. 
NOTE:  
Patients should avoid consuming food and beverages 
containing grapefruit juice or Seville oranges for the 
duration of the study due to CYP3A4/5 inhibition.   
If patients achieve CR/CRi, patient may continue on 
combination therapy or single agent venetoclax therapy 
after the completion of cycle 2 at the discretion of the 
treating physician. 
NOTE: 
Dose reduction of liposomal vincristine is allowed during 
cycle two per package insert at investigator’s discretion. 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
5.1.4 
Dose Limiting Toxicity (DLT) 
Prior trials have shown serious, non-hematologic adverse events for 
venetoclax to be grade 3/4 tumor lysis syndrome, grade 3/4 nausea, 
and grade 3/4 diarrhea. Grade 3/4 peripheral neuropathy and 
constipation have been seen in administration of liposomal vincristine. 
For the purposes of this trial, any adverse event occurring ≤ 42 days 
of first dose of study drug that meets the following qualifications and is 
potentially related to study medication or combination will be 
considered a dose limiting toxicity: 
• 
Non-hematologic Grade 3 adverse events that do not resolve to ≤ 
Grade 2 within 7 days. Optimal medical therapy for nausea, 
vomiting, and diarrhea must be employed before these would be 
considered a DLT. Alopecia of any grade will not be considered a 
DLT. Recurrent (i.e., if venetoclax was held and restarted) non-
hematologic grade 3 AEs will be considered a DLT with the 
exception of electrolyte abnormalities. 
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• 
Grade 3 or 4 electrolyte abnormalities that do not result in clinical 
sequelae and that resolve to ≤Grade 2 with optimal medical 
management within 72 hours will not be considered DLTs. 
• 
Non-hematologic Grade 4 adverse events. 
• 
Any type of grade 3-4 hypersensitivity reaction (i.e.: allergic 
reaction, anaphylaxis, serum sickness, skin disorders, etc.), that 
necessitates discontinuation of study drug. 
• 
Hematologic: 
Prolonged myelosuppression defined as persistence of ≥Grade 4 
neutropenia or thrombocytopenia AND marrow cellularity of 5% or 
less in the absence of persistent ALL (i.e. >5% of nucleated cells 
are leukemic blasts in bone marrow) that persists at least 42 days 
after the initiation of Cycle 1 of therapy. Persistent cytopenias that 
were present at cycle 1, day 1 that persist until day 42 in the 
absence of active disease will not be considered a DLT (i.e., 
cytopenia must be treatment-emergent). Infections will not be 
considered DLTs (including neutropenic fever), unless the 
investigator determines that the infection or neutropenic fever 
resulted from the degree or duration of myelosuppression in the 
absence of persistent leukemia 
• 
Grade 3 or greater peripheral neuropathy not present at study 
entry that does not resolve to ≤ Grade 2 within 7 days with the 4th 
dose of vincristine held on day 36. 
While the phase I portion is ongoing, the study team will meet weekly 
via teleconference to review and discuss DLTs and the overall trial 
conduct. Toxicities will be assessed and graded according to NCI 
Common Terminology Criteria for Adverse Events (CTCAE). No 
patients can be enrolled in a subsequent dose cohort until all patients 
of the previous cohort have completed the 42 days of cycle 1. If a 
patient never starts the study drug, withdraws prior to Day 42 (of cycle 
1) for non-DLT reasons, is lost to follow up prior to Day 42, or does 
not receive 75% of study medications, this slot will be made available 
for replacement.  
Dose modifications are not allowed during cycle 1 of the phase I 
portion of this trial. If study drugs are felt required to be held (for non-
hematologic grade 3 treatment emergent adverse events), the study 
chair will be notified prior to doses being held. Patients must take at 
least 75% of venetoclax doses and 75% of liposomal vincristine doses 
to be considered evaluable for MTD decision. 
5.2 
Administration Schedule – Phase II 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
The phase II portion of this trial will be a single arm, open-label trial of the 
combination of the RP2D of venetoclax and vincristine sulfate. As of amendment 
11, no new patients should be started on liposomal vincristine on trial, and any 
patient currently receiving liposomal vincristine should be switched to vincristine 
sulfate at the beginning of their next cycle or as the drug supply requires, 
whichever comes first. 
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No lead-in phase of venetoclax will be required. Patients will be initiated on daily 
venetoclax at the MTD (600mg) and vincristine sulfate 1.4mg/m2 (capped at 2mg)  
weekly x 4 weeks to substitute for liposomal vincristine 2.25mg/m2 x 4 weeks 
(Cycle 1 = 28 days). A bone marrow biopsy will be performed on Day 28 +/- 2 
days. Subsequent cycles may be held up to 2 weeks (14 days) to allow for 
peripheral blood count recovery and bone marrow interpretation (see Section 5.5 
for additional dose modification guidelines).Patients who achieve at least a stable 
disease response will continue onto a second 28-day cycle of the combination 
therapy (Cycle 2 = 28 days). Patients with progressive disease will be taken off 
treatment. A bone marrow biopsy will be performed at day 56 +/- 2 days (note: if 
cycle 2 is held for blood count recovery, the first day of cycle 2 should be 
considered day 29 for purposes of second bone marrow biopsy). Patients who 
achieve at least a stable disease response can remain on combination therapy 
until disease progression or withdrawal from trial. All subsequent cycles will 
follow the cycle 2 regimen for combination therapy over 28 days, unless a dose 
modification occurs per Section 5.5. At the discretion of the treating physician, a 
patient who achieves CR or CRi may proceed to HSCT at any time. Dose 
reductions for cytopenias in patients during cycle 1 are strongly discouraged. 
Study treatment may be held for up to 14 continuous days in the event of an 
adverse event. The dose of liposomal vincristine or conventional vincristine 
sulfate may be given up to 2 days after scheduled date in order to accommodate 
infusion center holidays or patient preference. 
Patients will be classified according to ALL phenotype (B-cell vs T-cell) based on 
the immunophenotyping provided by enrolling sites. 
The provided medication diary should be distributed to patients to document 
venetoclax administration schedules (see Appendix II). 
NOTE: 
Liposomal vincristine has different dosage recommendations than 
vincristine sulfate injection. Verify drug name and dose prior to 
preparation and administration to avoid overdosage. 
5.2.1 
Arm D 
Cycle 1: 
Venetoclax 600mg: orally in a tablet formulation once daily, Days 1-
28. 
Liposomal Vincristine: 2.25mg/m2 IV weekly x 4 starting on Day 1. 
OR, 
Conventional vincristine sulfate 1.4mg/m2 IV weekly x 4 (capped at 
2mg). 
NOTE: 
All patients should proceed to Cycle 2 unless they have 
progressive disease or they achieve CR or CRi and 
proceed to HSCT.  
Dose modifications for venetoclax and liposomal vincristine 
or conventional vincristine sulfate per Section 5.5.2 are 
allowed during Cycle 1. 
Patients may switch from liposomal vincristine to 
conventional vincristine sulfate in the middle of a cycle 
(including cycle 1).  Once a patient switches, patients must 
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continue with conventional vincristine sulfate for the 
duration of trial. 
NOTE: 
Liposomal Vincristine is no longer being 
manufactured. 
Cycle 2 and Beyond: 
Venetoclax 600mg: orally in a tablet formulation once daily 1-28 per 
cycle. 
Liposomal Vincristine: 2.25mg/m2 IV weekly x 4 starting on Day 1 of 
each cycle. 
OR, 
Conventional vincristine sulfate 1.4mg/m2 IV (capped at 2mg) every 4 
weeks (C1D1). Please note change in frequency from cycle 1 and 
phase I dosing with liposomal vincristine. 
NOTE:  
Patients should avoid consuming food and beverages 
containing grapefruit juice or Seville oranges for the 
duration of the study due to CYP3A4/5 inhibition.  
If patients achieve CR/CRi, patient may continue on 
combination therapy or single agent venetoclax therapy 
after the completion of cycle 2 at the discretion of the 
treating physician. 
Dose reduction or elimination of liposomal vincristine or 
vincristine sulfate is allowed during cycle two per package 
insert guidelines at investigator’s discretion. 
Patients may switch from liposomal to conventional 
vincristine sulfate in the middle of a cycle (including cycle 
1).  Once a patient switches, patients must continue with 
conventional vincristine sulfate for the duration of trial. 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
5.3 
Adverse Event Reporting Requirements 
All toxicity grades described in this protocol and all reportable adverse events 
on this protocol will be graded using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
5.3.1 
Purpose 
Adverse event (AE) data collection and reporting, which are a 
required part of every clinical trial, are done so investigators and 
regulatory agencies can detect and analyze adverse events and risk 
situations to ensure the safety of the patients enrolled, as well as 
those who will enroll in future studies using similar agents. 
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5.3.2 
Routine Reporting of Adverse Events (Medidata Rave) 
Adverse events are reported in a routine manner at scheduled times 
during a trial using the Medidata Rave clinical data management 
system. Please refer to Section 4 of the protocol for more information 
on how to access the Medidata Rave system and the EA9152 forms 
packet for instructions on where, when and what adverse events are 
to be reported routinely on this protocol. 
5.3.3 
Expedited Reporting of Adverse Events (CTEP-AERS) 
In addition to routine reporting, certain adverse events must be also 
reported in an expedited manner for timelier monitoring of patient 
safety and care. The remainder of this section provides information 
and instructions regarding expedited adverse event reporting. 
5.3.4 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of an agent in humans, whether or not 
considered agent related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to protocol 
treatment. 
Unlikely 
The AE is doubtfully related to protocol 
treatment. 
Possible 
The AE may be related to protocol treatment. 
Probable 
The AE is likely related to protocol treatment. 
Definite 
The AE is clearly related to protocol treatment. 
• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List): An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND. Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports 
• 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
• 
Dose Limiting Toxicity (DLT): The appearance of side effects 
occurring ≤ 42 days of the first dose of study agent that are 
possibly severe enough to prevent further increase in dosage or 
strength of treatment agent, or to prevent continuation of 
treatment at any dosage level. Any adverse event occurring on the 
phase I portion of the study that meets the E9152 definition of DLT 
must be reported via CTEP-AERS 
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• 
Hospitalization (or prolongation of hospitalization): For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
• 
Life Threatening Adverse Event: Any AE that places the subject 
at immediate risk of death from the AE as it occurred.   
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they 
may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in 
this definition. 
5.3.5 
Expedited Adverse Event Reporting Procedure 
Adverse events requiring expedited reporting will use CTEP’s Adverse 
Event Reporting System (CTEP-AERS). CTEP’s guidelines for CTEP-
AERS can be found at http://ctep.cancer.gov 
A CTEP-AERS report must be submitted electronically via the CTEP-
AERS Web-based application located at http://ctep.cancer.gov., so 
that ECOG-ACRIN and all appropriate regulatory agencies will be 
notified of the event in an expeditious manner. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (857-504-2990) 
• 
the FDA (1-800-FDA-1088) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe. 
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
Many factors determine the requirements for expedited reporting of 
adverse events on each individual protocol. The instructions and 
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5.3.6 
Steps to determine if an adverse event is to be reported in an 
expedited manner – Arms A, B, C, and D 
5.3.6.1 
Guidelines for reporting adverse events OCCURRING 
WHILE ON PROTOCOL TREATMENT AND WITHIN 30 
DAYS of the last administration of the investigational 
agent/IND exempt. 
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the 
table below in Section 5.3.7. 
Yes 
No 
Identify the type and 
grade of the event 
using the CTCAE. 
Determine if the patient 
was hospitalized for  
≥ 24 hours for the event. 
With this information, 
review the chart in Section 
5.3.7 to determine if event 
requires expedited 
reporting 
Refer to Section 5.3.8 to 
determine if the event 
meets the protocol specific 
reporting requirements for 
this study. If so, report the 
event via CTEP-AERS. 
Refer to Section 5.3.8 to determine 
if the event meets the protocol 
specific reporting requirements for 
this study. If so, report the event via 
CTEP-AERS. 
Is the event 
reportable? 
No 
Yes 
Refer to Section 5.3.8 to determine if the event meets the 
criteria as an exception to reporting on this protocol. If it 
does not, report the event via CTEP-AERS. 
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5.3.6.2 
Guidelines for reporting adverse events OCCURRING 
GREATER THAN 30 DAYS after the last administration of 
the investigational/IND exempt agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.3.7, AND has an 
attribution of possible, probably or definite, OR meets the 
protocol specific requirements in Section 5.3.8, the 
following events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 3, 4 and Grade 5 AEs  
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational/IND exempt 
agent with an attribution of possible, probable 
or definite must be reported via CTEP-AERS 
even if the patient is off study. 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
5.3.7 
Expedited Reporting Requirements for protocol EA9152 
Investigational/IND exempt Agents: Venetoclax 
Commercial Agents: Liposomal vincristine, Vincristine sulfate 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational/IND Exempt Agent/Intervention.1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration 
of investigational/IND exempt agent/intervention. 
 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether 
or not they are considered related to the investigational/IND exempt agent(s)/intervention (21 
CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour; 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
• 
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
• 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of 
investigational/IND exempt agent/intervention and have an attribution of possible, probable, or 
definite require reporting as follows:   
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
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5.3.8 
Additional instructions, requirements and exceptions for protocol 
EA9152 
Additional Instructions 
• 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the AEMD 
Help Desk at aemd@tech-res.com or 301-897-7497. This will 
need to be discussed on a case-by-case basis. 
• 
Reporting a death on study: A death occurring while on study 
treatment or within 30 days of the last dose of study treatment 
requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be 
provided. 
NOTE: 
A death due to progressive disease should be 
reported as a Grade 5 “Disease progression” under 
the System Organ Class (SOC) “General disorder and 
administration site conditions”. Evidence that the 
death was a manifestation of underlying disease (e.g. 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
EA9152 specific expedited reporting requirements: 
• 
Dose Limiting Toxicities (Phase I arms only – Arms A, B, and 
C) 
For the purposes of this trial, any adverse event (per NCI 
Common Terminology Criteria for Adverse Events (CTCAE)) 
occurring within 42 days of first dose of study agent that meets 
the following qualifications and is potentially related to study 
medication or combination will be considered a dose limiting 
toxicity and must be reported initially via CTEP-AERS within 24 
hours, followed by a complete report via CTEP-AERS within 5 
calendar days, including the following: 
• 
Non-hematologic Grade 3 adverse events that do not resolve 
to ≤ Grade 2 within 7 days. Optimal medical therapy for 
nausea, vomiting, and diarrhea must be employed before 
these would be considered a DLT. Alopecia of any grade will 
not be considered a DLT. Recurrent (i.e. if venetoclax was 
held and restarted) non-hematologic grade 3 AEs will be 
considered a DLT with the exception of electrolyte 
abnormalities. 
• 
Grade 3 or 4 electrolyte abnormalities that do not result in 
clinical sequelae and that resolve ≤ Grade 2 with optimal 
medical management within 72 hours will not be considered 
DLTs. 
• 
Non-hematologic Grade 4 adverse events. 
• 
Any type of Grade 3-4 hypersensitivity reaction (i.e.: allergic 
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reaction, anaphylaxis, serum sickness, skin disorders, etc.), 
that necessitate discontinuation of study drug. 
• 
Prolonged myelosuppression defined as persistence of  
≥ Grade 4 neutropenia or thrombocytopenia AND marrow 
cellularity of 5% or less in the absence of persistent ALL (i.e.  
> 5% of nucleated cells are leukemic blasts in bone marrow) 
that persists at least 42 days after the initiation of Cycle 1 of 
therapy. Persistent cytopenias that were present at cycle 1, 
day 1 that persist until day 42 in the absence of active 
disease will not be considered a DLT (i.e., cytopenia must be 
treatment-emergent). Infections will not be considered a DLT 
(including neutropenic fever), unless the investigator 
determines that the infection or neutropenic fever resulted 
from the degree or duration of myelosuppression in the 
absence of persistent leukemia 
• 
Grade 3 or greater peripheral neuropathy not present at study 
entry that does not resolve to < grade 2 within 7 days with the 
4th dose of vincristine held on day 36. 
• 
Pregnancies (All Arms – A, B, C, and D): Pregnancies and 
suspected pregnancies (including a positive or inconclusive 
pregnancy test, regardless of age or disease state) occurring 
while the female patient is on venetoclax, or within 28 days of the 
female patient’s last dose of venetoclax, are considered 
immediately reportable events. The pregnancy, suspected 
pregnancy, or positive/ inconclusive pregnancy test must be 
reported via CTEP-AERS within 24 hours of the Investigator’s 
knowledge. Please refer to Appendix IV for detailed instructions 
on how to report the occurrence of a pregnancy as well as the 
outcome of all pregnancies. 
 
EA9152 specific expedited reporting exceptions: 
For study, the adverse events listed below do not require expedited 
reporting via CTEP-AERS: 
• 
Myelosuppression that causes a delay of < 14 days in initiating 
cycle 2 
• 
Grade 4 neutropenia that is attributable to underlying disease or 
persisting < 6 weeks from the start of a cycle that is not 
attributable to the underlying disease 
• 
Any hematologic toxicities not meeting definition for dose-limiting 
toxicity 
5.3.9 
Other recipients of adverse event reports and supplemental data 
ECOG-ACRIN will forward CTEP-AERS reports to the appropriate 
regulatory agencies and pharmaceutical company. 
ECOG-ACRIN may call a site for additional or supplemental 
information regarding a serious adverse event. Any additional written 
AE information requested by ECOG-ACRIN MUST be uploaded to the 
Supplemental Data Folder in Medidata Rave. 
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Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.3.10 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported as 
follows: 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol). Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis on the Adverse Event Form or Late 
Adverse Event Form in the appropriate Treatment Cycle or 
Post Registration folder in Medidata Rave 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
NOTE: 
When reporting attribution on the AE Form, assess 
the relationship between the secondary malignancy 
and the current protocol treatment ONLY (and NOT 
relationship to any anti-cancer treatment received 
either before or after protocol treatment). 
3. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
4. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
5. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the CTEP-
AERS report should not be used to report recurrence or 
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NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG-ACRIN Second Primary Form 
must be submitted for the most recent trial. ECOG-ACRIN 
must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if 
available) even if ECOG-ACRIN was not the patient's most 
recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the ECOG-ACRIN 
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5.4 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Venetoclax 
(ABT-199, NSC 766270) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for more information. Frequency is provided based on 1298 patients. 
Below is the CAEPR for Venetoclax (ABT-199). 
Version 2.1, May 8, 20191 
 
Adverse Events with Possible 
Relationship to Venetoclax (ABT-199) 
(CTCAE 5.0 Term) 
[n= 1298] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
 
 
 
Febrile neutropenia 
 
GASTROINTESTINAL DISORDERS 
 
Constipation 
 
Diarrhea 
 
 
Nausea 
 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
 
 
 
Fever 
 
INFECTIONS AND INFESTATIONS 
Infection2 
 
 
INVESTIGATIONS 
 
Lymphocyte count decreased 
 
Neutrophil count decreased 
 
 
 
Platelet count decreased 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Hypocalcemia 
 
 
Hypokalemia 
 
 
Hypophosphatemia 
 
 
 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
NERVOUS SYSTEM DISORDERS 
 
Headache 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
VASCULAR DISORDERS 
 
Hypertension 
 
1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
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PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
Adverse events reported on venetoclax (ABT-199) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that venetoclax 
(ABT-199) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Hemolysis; Thrombotic thrombocytopenic 
purpura 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (coronary artery disease); 
Heart failure; Myocardial infarction; Sinus tachycardia; Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
GASTROINTESTINAL DISORDERS - Abdominal pain; Belching; Dry mouth; Dyspepsia; 
Dysphagia; Gastrointestinal disorders - Other (Crohn's disease); Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema 
limbs; Flu like symptoms; General disorders and administration site conditions - Other (general 
physical heath deterioration); General disorders and administration site conditions - Other 
(multiple organ dysfunction syndrome); Injection site reaction; Non-cardiac chest pain; Pain; 
Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (hepatic function abnormal) 
IMMUNE SYSTEM DISORDERS - Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Infusion related reaction; 
Injury, poisoning and procedural complications - Other (laceration) 
INVESTIGATIONS - Aspartate aminotransferase increased; Blood bilirubin increased; Weight 
loss 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Dehydration; Hyperglycemia; 
Hyperkalemia; Hyperphosphatemia; Hyperuricemia; Hypoalbuminemia; Hypomagnesemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Myelodysplastic syndrome; Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (acute myeloid leukemia); Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Intracranial hemorrhage; Ischemia 
cerebrovascular; Nervous system disorders - Other (neuropathy peripheral); Peripheral sensory 
neuropathy; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Dysuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Ovarian rupture 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Aspiration; 
Dyspnea; Epistaxis; Hypoxia; Nasal congestion; Oropharyngeal pain; Pleural effusion; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (asphyxia) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Eczema; Pruritus; Rash acneiform; 
Rash maculo-papular 
VASCULAR DISORDERS - Hypotension; Thromboembolic event 

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NOTE: 
Venetoclax (ABT-199) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 

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5.5 
Dose Modifications  
Dose modifications during cycle 1 of the phase I portion of this trial are not 
allowed. 
5.5.1 
Venetoclax 
During cycle 1 of the phase I portion of this trial, venetoclax should not 
be held for hematologic toxicities unless meeting DLT criteria. 
Venetoclax may be held for non-hematologic grade 3 adverse events 
which will be considered a DLT if they do not resolve within 7 days 
(see Section 5.1.4). Any temporary or permanent discontinuation of 
study drug should be discussed with study chair in real time if 
possible. After cycle one of the phase I portion, venetoclax may be 
reduced for toxicity at the discretion of the investigator with the 
following guidelines. 
During the phase II portion of the trial, venetoclax may be reduced for 
toxicity at the discretion of the investigator. The following table may 
serve as a guideline for suggested dose reduction: 
Dose Modification Guidelines for Adverse Events 
Adverse Event 
Occurrence 
Dosage Modification 
Grade 4 neutropenia with or without 
infection; or grade 4 
thrombocytopenia 
Prior to achieving 
remission or clinically 
significant response 
In most instances, do not interrupt 
venetoclax 
First occurrence after 
achieving remission or 
clinically significant 
response 
Delay subsequent cycle of 
combination up to 2 weeks prior to 
initiation of subsequent cycle 
Subsequent occurrence 
after achieving remission 
or clinically significant 
response 
 
Reduce venetoclax duration by 7 
days during each of the subsequent 
cycles, such as D1- 14 or D1-21 
days instead of D1-28 days. 
Grade 3 or 4 nonhematologic 
toxicities 
Any occurrence 
Interrupt venetoclax if not resolved 
with supportive care. 
Upon resolution to Grade 1 or 
baseline level, may resume 
venetoclax at the same dose. 
5.5.2 
Liposomal Vincristine 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
Liposomal vincristine will be administered to patients weekly. Starting 
from cycle 2 of the phase 1 portion and cycle 1 of the phase II portion, 
liposomal vincristine will be dose modified at the discretion of the 
treating physician with the following prescribing information as a 
guideline. 
• 
For Grade 3 or 4 (severe symptoms; limiting self-care activities of 
daily living [ADL]) or persistent Grade 2 (moderate symptoms; 
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limiting instrumental ADLs) peripheral neuropathy: interrupt 
liposomal vincristine.  
• 
If the peripheral neuropathy remains at Grade 3 or 4: 
discontinue liposomal vincristine.  
• 
If the peripheral neuropathy recovers to Grade 1 or 2: reduce 
liposomal vincristine dose to 2 mg/m2.  
• 
If the patient has persistent Grade 2 peripheral neuropathy after 
the first dose reduction to 2 mg/m2: interrupt liposomal vincristine 
for up to 7 days.  
• 
If the peripheral neuropathy increases to Grade 3 or 4: 
discontinue liposomal vincristine.  
• 
If the peripheral neuropathy recovers to Grade 1: reduce 
liposomal vincristine dose to 1.825 mg/m2.  
• 
If the patient has persistent Grade 2 peripheral neuropathy after 
the second dose reduction to 1.825 mg/m2: interrupt liposomal 
vincristine for up to 7 days.  
• 
If the peripheral neuropathy increases to Grade 3 or 4: 
discontinue liposomal vincristine.  
• 
If the peripheral neuropathy recovers to Grade 1: reduce 
liposomal vincristine dose to 1.5 mg/m2. 
5.5.3 
Vincristine sulfate (conventional)  
Vincristine sulfate will be dose modified at the discretion of the 
treating physician with the following prescribing information as a 
guideline. 
• 
For neurotoxicity characterized as areflexia only, give 100% of the 
vincristine sulfate dose.  For grade 1 motor neuropathy including 
abnormal ability to button or write, give 100% of the vincristine 
sulfate dose. For grade 2 motor neuropathy, hold until recovery 
and then reduce dose of vincristine sulfate to 50% of planned 
dose.  For grade 3 motor neuropathy, hold until recover to < grade 
2.  
• 
For other Grade 3 related nonhematological/organ toxicity, hold 
vincristine sulfate until resolution.  
• 
Grade 4 other related nonhematological/organ toxicity, discontinue 
vincristine sulfate. 
5.6 
Supportive Care  
5.6.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
Please reference Appendix V for a list of CYP3A Inhibitors and 
Inducers and medications affecting P-Glycoprotein (PGP). If the 
treating physician and patient decide that any of the medications listed 
here are to be used for best patient care, please consult the study 
chair. 
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5.6.2 
Tumor Lysis Prophylaxis and Monitoring 
In previous clinical trials, venetoclax has been associated with life 
threating tumor lysis. Careful monitoring for tumor lysis based on 
tumor burden will be instituted. Prior to initiation of study drug, 
circulating WBC count must not be above 25 x109/L. Patients with 
leukocyte count above 25 x109/L should start steroids or hydroxyurea 
per institutional guidelines, and these medications should be 
discontinued before Day 1 of study drug if possible. If at least 4 days 
hydroxyurea or dexamethasone has been utilized without reduction in 
blasts, patient may start trial after discussion with the study chair. 
Hydrea or steroids may be reinstituted if deemed necessary by 
treating physician to control counts after Day 6. 
Phase I: 
Given the high risk of tumor lysis inherent to ALL, patients should be 
monitored as inpatients for intensive laboratory monitoring during the 
intrapatient dose escalation of venetoclax (days 1-6). Serum 
chemistries, uric acid, LD (TLS labs) should be drawn within 4 hours 
pre-dose as well as every 8 hours (+/- 2 hours) during hospitalization. 
Additionally, tumor lysis labs should be drawn prior to first dose of 
combination and then every 24 hours for 3 days afterwards (i.e. days 
15-18) only if patient remains at risk for tumor lysis per treating 
physician. Three days prior to initiation of study drug, patients should 
start uric acid lowering therapy with allopurinol unless prior allergic 
reaction or intolerance prevents its use. Oral hydration with at least 2L 
of fluids should be encouraged for all patients daily during 
administration of drug. If appropriate oral hydration cannot be 
ensured, IV fluids should be administered at the discretion of the 
treating provider. Documentation of the review of tumor lysis labs 
required in study procedures must occur before the patient is 
instructed to take subsequent doses of venetoclax by clinical research 
staff during the first week of single agent venetoclax and the first cycle 
of combination of drugs. Sites that utilize a day hospital may monitor 
patients in this setting as opposed to traditional inpatient provided that 
all laboratory measures and evaluations can be completed in the 
timeframes listed within this protocol. 
Phase II: 
Given low rates of tumor lysis syndrome (TLS) seen in phase I portion 
of this trial and in acute leukemias in general treated with venetoclax, 
inpatient administration will NOT be required unless WBC >20 at 
C1D1.  Daily tumor lysis labs should be drawn on D1-3 and 
institutional protocol for TLS prophylaxis and management should be 
followed. Oral hydration with at least 2L of fluids should be 
encouraged for all patients daily during administration of drug. If 
appropriate oral hydration cannot be ensured, IV fluids should be 
administered at the discretion of the treating provider. Documentation 
of the review of tumor lysis labs required in study procedures must 
occur before the patient is instructed to take subsequent doses of 
venetoclax by clinical research staff during the first week of cycle 1. 
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5.6.2.1 
If laboratory TLS, please reference the venetoclax 
package insert for supportive care guidelines: 
Withhold the next day’s dose of venetoclax. If resolved 
within 24-48 hours of last dose, resume at the same dose. 
• 
For any blood chemistry changes requiring more than 
48 hours to resolve, resume at a reduced dose of 
venetoclax. 
• 
For any events of clinical TLS, resume at a reduced 
dose of venetoclax following resolution. 
5.6.3 
Use of Anti-fungal Azoles 
Many patients with ALL are prescribed azole anti-fungal medications 
(i.e., fluconazole, vorinconazole, posaconazole, isavuconazonium 
sulfate) as prophylaxis or treatment for invasive fungal infections. 
Standard dose reductions for use of azole antifungals per venetoclax 
PI are strongly recommended. 
5.6.4 
Drug Interactions 
Please see Section 8.1.11 and for potential drug interactions involving 
venetoclax and liposomal or conventional vincristine sulfate. 
5.7 
Duration of Therapy  
Patients will receive protocol therapy unless: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event, submit forms according to the instructions in the 
EA9152 Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered.  
• 
Progression of disease. 
5.8 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated, and for survival for 5 years from the date of registration to step 1. All 
patients must also be followed through completion of all protocol therapy if it 
exceeds 5 years of treatment.  
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6. 
Measurement of Effect 
Response to combination therapy will be determined by patient bone marrow samples 
that will be locally analyzed [54]. 
6.1 
Complete Remission (CR)  
Requires that all of the following be present for at least 4 weeks. 
• 
Peripheral Blood Counts  
• 
Neutrophil count ≥ 1.0 x 109/L. 
• 
Platelet count ≥ 100 x 109/L. 
• 
Reduced hemoglobin concentration or hematocrit has no bearing on 
remission status. 
• 
Leukemic blasts must not be present in the peripheral blood. 
• 
Bone Marrow Aspirate and Biopsy  
• 
Cellularity of bone marrow biopsy must be > 20% with maturation of all 
cell lines. 
• 
≤ 5% blasts. 
• 
Extramedullary leukemia, such as CNS or soft tissue involvement, must not 
be present. 
• 
An MRD negative response must meet the criteria for CR or CRi and have 
any residual disease <0.01% based on original testing technique. 
6.2 
Complete Remission incomplete (CRi)  
Requires that all the same response criteria in peripheral blood and bone marrow 
as CR with the exception of one of the following 
• 
Incomplete platelet recovery (platelets > 75 but < 100 x 109/L (> 75,000 but  
< 100,000/mm3) independent of platelet transfusions)  
• 
Incomplete neutrophil count recovery > .75 but < 1 x 109/L (> 750 but  
< 1000/mm3). 
6.3 
Partial Remission (PR)  
Requires that all of the criteria for complete remission be satisfied except that the 
bone marrow may contain > 5% blasts but < 25% blasts. 
6.4 
Stable Disease (SD) 
Failure to achieve at least a PR, but with no evidence of progression as defined 
as an increase of peripheral blood or bone marrow blasts of more than 10% from 
nadir during study. 
6.5 
Relapse  
Relapse following complete remission (CR) and complete remission incomplete 
(CRi) is defined as: 
• 
Peripheral Blood Counts  
• 
Reappearance of blasts in the blood. 
• 
Bone Marrow Aspirate and Biopsy  
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• 
Presence of > 5% blasts, not attributable to another cause (e.g., bone 
marrow regeneration). 
• 
If there are no circulating blasts and the bone marrow contains 5% to 
20% blasts, then a repeat bone marrow performed ≥ 1 week later 
documenting more than 5% blasts is necessary to meet the criteria for 
relapse. 
6.6 
Progressive Disease (PD) 
Progressive disease is defined as a 50% increase in blasts in the marrow, 
depending on blast percentage at baseline: 
• 
For patients with < 5% blasts at baseline, there must be an increase to ≥ 10% 
blasts. 
• 
For patients with 5% to 10% blasts at baseline, there must be a ≥ 50% 
increase to > 10% blasts. 
• 
For patients with 10% to 20% blasts at baseline, there must be a ≥ 50% 
increase to ≥ 20% blasts. 
6.7 
Response Criteria for Lymphomatous Extramedullary Disease, Lymphoblastic 
Lymphoma55 
A PET/CT that includes the neck, chest, abdomen and pelvis is the preferred 
method of evaluation at diagnosis and after two cycles of combination therapy. If 
a patient at enrollment has a negative bone marrow and only extramedullary 
disease, i.e. lymphoblastic lymphoma, then response will be assessed by PET 
CT by day 84. A bone marrow biopsy to look for MRD will be required at this time 
point. 
Complete Response: Complete resolution of lymphomatous enlargement by CT. 
For patients with a previous positive PET scan, a post-treatment residual mass of 
any size is considered a CR as long as it is PET negative. 
Partial Response: > 50% decrease in the sum of the product of the great 
perpendicular diameters (SPD) of the largest site of involvement (usually 
mediastinum). For patients with a previous positive PET scan, a post treatment 
residual mass must be positive in at least one previously involved site. 
Progressive disease: > 25% increase in the SPD of the largest site of 
involvement. For patients with a previous positive PET scan, a post treatment 
residual mass must be positive in at least one previously involved site. 
No Response/Stable disease: Fits criteria for neither PR nor PD. 
 
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7. 
Study Parameters 
7.1 
Phase I Therapeutic Parameters  
1. Prestudy CBC with differential, LFTs, and Tumor Lysis Labs must be done ≤ 10 days before first dose of study 
medication. 
2. All required prestudy chemistries should be done ≤ 10 days before first dose of study medication - unless specifically 
required on Day 1 as per protocol. If abnormal, they must be repeated within 48 hours before first dose of study 
medication. 
3. Pre-study bone marrow biopsy and aspirate must be completed ≤ 2 weeks prior to registration to step 0. If more than 
14 days have elapsed from bone marrow and aspirate to cycle 1, day 1, these studies would need to be repeated 
only if necessary in the opinion of the investigator. 
Test and Observations 
Prior to 
Cycle 1 
Treatment 
Off-
Treatment 
Visitk 
Follow
-Upm 
Cycle 1,  
Day 1 
Cycle 1, 
Days 15-18 
Cycle 2, 
Day 1 
Cycle 2, 
Days 2-28 
Cycle X, 
Day 1l 
Physical Exam  
X 
X 
  
X 
  
X 
 X 
 
Peripheral Neuropathy Assessment 
X 
X 
  
X 
  
X 
X 
 
CBC with Differentiala,b 
X 
Xo 
X 
Xp 
Xp 
Xp 
X 
X 
Serum or Urine Pregnancy Testg, 
X 
 
 
 
 
 
 
 
Comprehensive Metabolic Panelb,c 
X 
Xo 
X 
X 
Xq 
Xq 
 
 
Urinalysisd 
X 
 
 
 
 
 
 
 
Tumor Lysis Labs b,e, f 
X 
Xo 
Xe 
X 
Xq 
Xq 
 
 
HIV, HBC, HCVb,h 
X 
 
 
 
 
  
 
 
PET CT/CT Chest/Abdomen/Pelvisi 
X 
 
 
 
 
X 
 
 
CSF Samplingj 
 Xj 
 
 
 
 
 
 
 
Bone Marrow Biopsy and Aspirate 
X 
 
 
 Xn 
 
 Xn 
X 
 Xm 
a. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct required for protocol therapy must be done < 24 
hours prior to the first dose of venetoclax in each treatment cycle. 
b. All study procedures and blood samples collected for pretreatment laboratory tests may be collected and analyzed no more than 10 days prior to 
dosing. Chemistry results must be reviewed and confirm that subject’s liver function tests and other safety labs still meet inclusion criteria prior to 
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administration of venetoclax dose. They should be seen and evaluated more often if clinically indicated for the management of toxicities, at the 
discretion of the treating physician investigator. 
c. Chemistry laboratory analysis includes albumin, urea or BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, direct and total bilirubin, 
glucose, total protein, sodium, potassium, chloride, HCO3 (CO2; venous blood), calcium, phosphorous. Once disease progression occurs, these 
labs are no longer required to be completed. 
d. Urinalysis will be done as clinically indicated. Urinalysis tests to include gross examination including specific gravity, protein, glucose and blood. 
A microscopic evaluation will also be performed, as clinically indicated, to include WBC/HPF, RBC/HPF and any additional findings. 
e. Tumor lysis labs include LDH, uric acid, fibrinogen and coagulation studies in addition to chemistries. TLS labs on days 17 and 18 are required 
only if evidence of TLS on day 15 and 16 labs. If the patient has already undergone tumor lysis with single agent venetoclax in the opinion of the 
investigator, days 16-18 TLS labs are optional. 
f. 
Please see tumor lysis monitoring guidelines in Section 5.6.2. 
g. Patients of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 
within 2 weeks prior to Step 1 registration.  
h. At screening, testing should be performed for HIV antibody, hepatitis C antibody, and HBs antigen utilizing local standard informed consent 
procedures prior to this laboratory collection. These tests could be repeated later during the course of the study, if clinically indicated. 
i. 
As clinically indicated and if solid disease at time of study entry. Patients with LBL at registration would need to have response assessment 
before starting cycle three. PET-CT imaging is strongly preferred, but CT C/A/P will be an acceptable alternative if PET-CT is not feasible. 
j. 
As clinically indicated after initial screening to Lumbar Puncture. CNS sampling to document no active CNS disease should be done within 28 
days of enrollment. 
k. End of Study Assessment will be done within 6 weeks (+/- 1 week) of the last dose of study treatment.  
l. 
If patient continues receiving study drug after cycle 2, the cycle length will remain 28 days for each additional cycle and indicated tests should be 
completed on day 1 of each consecutive treatment cycle. 
m. Patient will be followed for survival every 6 months until 5 years after study registration to step 1. Follow-up bone marrow biopsies should also 
be performed at relapse, unless the patient received HSCT. If the patient comes off treatment for a reason other than progression, they will be 
followed for response until progression, for which bone marrow biopsy and aspirate will be performed on the follow up schedule of q6 months. 
Biopsies - other than those done prior to start of Cycle 1 and at relapse - do not need to be submitted to the EA LTB, per Section 7.2.  
n. Bone marrow biopsies may be performed at +/- 2 days of designated schedule.  
o. Inpatient admission for tumor lysis monitoring is required for days 1-6 of cycle 1. Please see Section 5.6.2 for additional details and 
requirements. 
p. Complete blood counts should be monitored at least twice weekly if patient is requiring transfusion therapy as outpatient.  
q. Subsequent monitoring of serum chemistries tumor lysis labs should be at least weekly for cycle 2, and then afterwards at the discretion of the 
treating physician. 
 
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7.2 
Phase II Therapeutic Parameters 
1. Prestudy CBC with differential, LFTs, and Tumor Lysis Labs must be done ≤ 10 days before first dose of study 
medication. 
2. All required prestudy chemistries should be done ≤ 10 days before first dose of study medication - unless specifically 
required on Day 1 as per protocol. If abnormal, they must be repeated within 48 hours before first dose of study 
medication. 
3. Pre-study bone marrow biopsy and aspirate must be completed ≤ 2 weeks prior to registration to step 0. If more than 
14 days have elapsed from bone marrow and aspirate to cycle 1, day 1, these studies would need to be repeated 
only if necessary in the opinion of the investigator. 
Test and Observations 
Prior to 
Cycle 1 
Treatment 
Off-
Treatment 
Visitk 
Follow
-Upm 
Cycle 1,  
Day 1 
Cycle 1, 
Days 15 
Cycle 2, 
Day 1 
Cycle 2, 
Days 2-28 
Cycle X, 
Day 1l 
Physical Exam  
X 
X 
  
X 
  
X 
 X 
 
Peripheral Neuropathy Assessment 
X 
X 
  
X 
  
X 
X 
 
CBC with Differentiala,b 
X 
Xo 
X 
Xp 
Xp 
Xp 
X 
X 
Serum or Urine Pregnancy Testg, 
X 
 
 
 
 
 
 
 
Comprehensive Metabolic Panelb,c 
X 
Xo 
X 
X 
Xq 
Xq 
 
 
Urinalysisd 
X 
 
 
 
 
 
 
 
Tumor Lysis Labs b,e, f 
X 
Xo 
X 
X 
Xq 
Xq 
 
 
HIV, HBC, HCVb,h 
X 
 
 
 
 
  
 
 
PET CT/CT Chest/Abdomen/Pelvisi 
X 
 
 
 
 
X 
 
 
CSF Samplingj 
 Xj 
 
 
 
 
 
 
 
Bone Marrow Biopsy and Aspirate 
X 
 
 
 Xn 
 
 
X 
 Xm 
a. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct required for protocol therapy must be done < 24 
hours prior to the first dose of venetoclax in each treatment cycle. 
b. All study procedures and blood samples collected for pretreatment laboratory tests may be collected and analyzed no more than 10 days prior to 
dosing. Chemistry results must be reviewed and confirm that subject’s liver function tests and other safety labs still meet inclusion criteria prior to 
administration of venetoclax dose. They should be seen and evaluated more often if clinically indicated for the management of toxicities, at the 
discretion of the treating physician investigator. 
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c. Chemistry laboratory analysis includes albumin, urea or BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, direct and total bilirubin, 
glucose, total protein, sodium, potassium, chloride, HCO3 (CO2; venous blood), calcium, phosphorous. Once disease progression occurs, these 
labs are no longer required to be completed. 
d. Urinalysis will be done as clinically indicated. Urinalysis tests to include gross examination including specific gravity, protein, glucose and blood. 
A microscopic evaluation will also be performed, as clinically indicated, to include WBC/HPF, RBC/HPF and any additional findings. 
e. Tumor lysis labs include LDH, uric acid, fibrinogen and coagulation studies in addition to chemistries. TLS labs on days 17 and 18 are required 
only if evidence of TLS on day 15 and 16 labs. If the patient has already undergone tumor lysis with single agent venetoclax in the opinion of the 
investigator, days 16-18 TLS labs are optional. 
f. 
Please see tumor lysis monitoring guidelines in Section 5.6.2. 
g. Patients of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 
within 2 weeks prior to Step 1 registration.  
h. At screening, testing should be performed for HIV antibody, hepatitis C antibody, and HBs antigen utilizing local standard informed consent 
procedures prior to this laboratory collection. These tests could be repeated later during the course of the study, if clinically indicated. 
i. 
As clinically indicated and if solid disease at time of study entry. Patients with LBL at registration would need to have response assessment 
before starting cycle three. PET-CT imaging is strongly preferred, but CT C/A/P will be an acceptable alternative if PET-CT is not feasible. 
j. 
As clinically indicated after initial screening to Lumbar Puncture. CNS sampling to document no active CNS disease should be done within 28 
days of enrollment. 
k. End of Study Assessment will be done within 6 weeks (+/- 1 week) of the last dose of study treatment.  
l. 
If patient continues receiving study drug after cycle 2, the cycle length will remain 28 days for each additional cycle and indicated tests should be 
completed on day 1 of each consecutive treatment cycle. 
m. Patient will be followed for survival every 6 months until 5 years after study registration to step 1. Follow-up bone marrow biopsies should also 
be performed at relapse, unless the patient received HSCT. If the patient comes off treatment for a reason other than progression, they will be 
followed for response until progression, for which bone marrow biopsy and aspirate will be performed on the follow up schedule of q6 months. 
Biopsies - other than those done prior to start of Cycle 1 and at relapse - do not need to be submitted to the EA LTB, per Section 7.2.  
n. Bone marrow biopsies may be performed at +/- 2 days of designated schedule.  
o. TLS should be monitored on C1D1-3 with TLS labs as above.  
p. Complete blood counts should be monitored at least twice weekly if patient is requiring transfusion therapy as outpatient.  
q. Subsequent monitoring of serum chemistries tumor lysis labs should be at least weekly for cycle 2, and then afterwards at the discretion of the 
treating physician 
 
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7.3 
Biological Specimen Submissions  
Specimens are to be submitted as outlined in Section 10. 
All specimens submitted must be entered and tracked via the online ECOG-
ACRIN Sample Tracking System (STS). 
Biological Materials6 
Prior to Start of 
Treatment1,2 
Relapse 
PHASE I ONLY: MANDATORY for Central Review 
Bone Marrow Aspirate (heparin, first pull) 
X 
 
Peripheral Blood (heparin, green or purple, EDTA top tubes, 30-40mL) 
X 
 
Bone Marrow/Peripheral Blood Smears (Wright-Giesma stained) 
X 
 
Submit from patients who answer ‘Yes’ to ‘I agree to have my samples collected and I agree that 
my samples and related information may be used for laboratory studies.’ 
Bone Marrow Aspirate (heparin, first pull)4,5 
X (Phase II) 
X 
Peripheral Blood (heparin, green or purple, EDTA top tubes, 30-40mL)5 
X (Phase II) 
X 
Submit from patients who answer ‘Yes’ to ‘I agree to provide additional samples for research.’ 
Peripheral Blood (red top tubes, 15-20mL) 
X 
 
Buccal Rinse2 
X 
 
1. Preregistration bone marrow and/or peripheral blood specimens are to be submitted for defined laboratory 
research studies and undefined future research per patient consent. 
2. Buccal rinse is strongly encouraged to be collected at baseline, but can be collected at any other time 
during the study if necessary. 
3. The laboratory will accept any amount of bone marrow as long as it represents the first pull. Ideally, 2-3-mL 
of aspirate from a separate aspiration site should be submitted. If bone marrow at the time of relapse is not 
collected, then peripheral blood collection is sufficient as long as circulating absolute blast count is >1000. 
4. Leftover specimens from the defined laboratory research studies will be stored for future undefined 
research studies from patients who answer ‘Yes’ to ‘My samples and related information may be kept in a 
Biobank for use in future health research.’ 
5. Specimens are to be submitted to the ECOG-ACRIN Leukemia Laboratory at MD Anderson Cancer Center. 
 
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8. 
Drug Formulation and Procurement 
8.1 
Venetoclax (ABT-199) NSC 766270 
8.1.1 
Other Names  
Venclexta, Venclyxto, ABT-199. 
8.1.2 
Classification  
Antineoplastic Agent, BCL-2 Inhibitor. 
8.1.3 
Mode of Action  
Venetoclax selectively inhibits the anti-apoptotic protein BCL-2, which 
mediates tumor cell survival and has been associated with 
chemotherapy resistance. Venetoclax binds directly to the BCL-2 
protein, displacing pro-apoptotic proteins and restoring the apoptotic 
process. 
8.1.4 
Storage and Stability  
The clinical supply should be stored at 15° to 25°C (59° to 77°F). 
8.1.5 
Dose Specifics  
Arm A: 20, 50, 100, 200 mg on Days 1, 2, 3, 4 and 400 mg on Days 5 
‒ 70+ 
Arm B: 50, 100, 200, 400 mg on Days 1, 2, 3, 4 and 600 mg on Days 
5 ‒ 70+ 
Arm C: 100, 200, 400, 600 mg on Days 1, 2, 3, 4 and 800 mg on 
Days 5 ‒ 70+ 
Arm D: 600mg Day 1 until study completion 
8.1.6 
Preparation  
Venetoclax is available in a tablet formulation. 
Excipients:  
Copovidone, colloidal silicon dioxide, polysorbate 80, sodium stearyl 
fumarate, calcium phosphate dibasic 
Coating Composition:  
10 mg and 100 mg tablet coating contains iron oxide yellow, polyvinyl 
alcohol, polyethylene glycol, talc, and titanium oxide. 
50 mg tablet coating contains iron oxide yellow, iron oxide red, iron 
oxide black, polyvinyl alcohol, titanium dioxide, polyethylene glycol 
and talc. 
8.1.7 
Route of Administration  
Venetoclax should be taken orally with food and water. Patients 
should avoid consuming food and beverages containing grapefruit 
juice or Seville oranges for the duration of the study due to CYP3A4/5 
inhibition. 
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8.1.8 
Incompatibilities  
Not applicable. 
8.1.9 
Availability  
Venetoclax is provided free of charge by AbbVie and will be 
distributed by Patwell. 
Phase I Drug Orders: 
Venetoclax will be supplied in the following configurations: 
• 
2x8 blister card of 10mg tablets (16 tablets total) 
• 
1x8 blister card of 50mg tablets (8 tablets total) 
• 
1 bottle with 120 100mg tablets (120 tablets total) 
Different configurations should be ordered depending on the arm to 
which the patient is assigned. Suggested orders based on arm 
assignment may be found on the EA9152 Venetoclax Drug Request 
Form. 
Phase I Initial Orders: Following submission of the required 
regulatory documents and patient registration to Step 1, Arm A, B or 
C, a supply of venetoclax may be ordered from the ECOG-ACRIN 
Drug Team. Institutions must email the completed EA9152 Venetoclax 
Phase I Drug Request Form to the ECOG-ACRIN Drug Team at 
DrugOrder@ecog-acrin.org. A copy of the EA9152 Venetoclax Phase 
I Drug Request Form is available for download from the EA9152 
Study Specific Tools section on the website (www.ecog.org). Please 
see Appendix VI for instructions on how to download this document. 
Phase I Reorders: 
Institutions should keep in mind that shipments take 3 business days 
from the date the drug request is received by Patwell. Reorders using 
the EA9152 Venetoclax Phase I Drug Request Form should be 
emailed to the ECOG-ACRIN Drug Team at DrugOrder@ecog-
acrin.org. Once the reorder is approved, the drug will be received on 
site within 2-3 business days. Shipments will be made from Patwell on 
business days only. There will be no weekend or holiday delivery 
of drugs. 
Phase II Drug Orders: 
3 x 120-ct bottles of Venetoclax 100mg = 2 cycles of treatment 
will be dispensed to a site as per drug order form  
Phase II Initial Orders: Following submission of the required 
regulatory documents and patient registration to Step 1, Arm D, a 
supply of venetoclax may be ordered from the ECOG-ACRIN Drug 
Team. Institutions must email the completed EA9152 Venetoclax 
Phase II Drug Request Form to the ECOG-ACRIN Drug Team at 
DrugOrder@ecog-acrin.org. A copy of the EA9152 Venetoclax Phase 
II Drug Request Form is available for download from the EA9152 
Study Specific Tools section on the website (www.ecog.org) and the 
CTSU website under the study specific Pharmacy Tab. Please see 
Appendix VI for instructions on how to download this document. 
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Phase II Reorders: 
Institutions should keep in mind that shipments take 3 business days 
from the date the drug request is received by Patwell. Reorders using 
the EA9152 Venetoclax Phase II Drug Request Form should be 
emailed to the ECOG-ACRIN Drug Team at DrugOrder@ecog-
acrin.org. Once the reorder is approved, the drug will be received on 
site within 2-3 business days. Shipments will be made from Patwell on 
business days only. There will be no weekend or holiday delivery 
of drugs. 
Drug Inventory Records: 
Investigational Product Records at Investigational Site(s): It is the 
responsibility of the Investigator to ensure that a current record of 
investigational production disposition is maintained at each study site 
where investigational product is inventoried and disposed. Records or 
logs must comply with applicable regulations and guidelines. The 
EA9152 Investigational Product Destruction Record must be 
submitted to document any unused venetoclax at the completion of 
the study. Please see Appendix VI for instructions on how to 
download this document. 
Drug Destruction and Return: 
At the completion of each patient’s treatment at your institution, all 
unused drugs, partially used, or empty containers must be destroyed 
at the site according to the institution’s policy for drug destruction. 
Please maintain appropriate records of the disposal, including dates 
and quantities. 
8.1.9.1 
Drug Accountability: 
All NCI studies using an oral agent must maintain Oral 
Drug Accountability Record Forms (DARF) to track study-
supplied agents. The NCI Investigational Agent 
Accountability Record Form for Oral Agents should be 
utilized to track the disposition of venetoclax. This form is 
available on the CTEP website at 
http://ctep.cancer.gov/forms. 
8.1.10 
Side Effects  
See Section 5.4 for side effects. 
8.1.11 
Potential Interactions 
Venetoclax is metabolized primarily by CYP3A4 and is a substrate of 
P-glycoprotein. CYP3A4 inhibitors should not be used during days 1-
21 of cycle 1 until patients begin receiving final venetoclax dose with 
no evidence of TLS. Medications that are moderate/strong inhibitors 
or inducers of 3A4 are contraindicated on this study, and may require 
removal from study if necessary to initiate these medications. See 
Appendix V for a list of these medications. See Section 5.6.3 for 
institution of azole anti-fungals. Alternative agents with weak or no 
CYP3A4 effects should be considered. Due to venetoclax being a 
substrate of P-glycoprotein, medications affecting P-glycoprotein are 
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also contraindicated (this medication list is also included in Appendix 
V). A comprehensive list of inhibitors, inducers, and substrates may 
be found at http://medicine.iupui.edu/clinpharm/ddis/. This website is 
continually revised and should be checked frequently for updates. 
8.1.12 
Nursing/Patient Implications  
Instruct patients to take venetoclax tablets with a meal and water at 
approximately the same time each day. The tablets should be 
swallowed whole and not chewed, crushed, or broken. At least 8.5 
cups of water (2 L) should be consumed every day starting 2 days 
before the first dose and throughout the ramp-up phase, especially 
the first day of each dose increase. Patients should avoid grapefruit 
products, Seville oranges, and starfruit during treatment. If a patient 
misses a dose within 8 hours of the time it is usually taken, the patient 
should take the missed dose as soon as possible and resume the 
normal daily dosing schedule. If a patient misses a dose by more than 
8 hours, the patient should not take the missed dose and should 
resume the usual dosing schedule the next day. If a patient vomits 
following dosing, no additional dose should be taken that day and the 
next prescribed dose should be taken at the usual time. 
8.2 
Liposomal Vincristine (Marqibo) NSC 748728 
NOTE: 
Liposomal Vincristine is no longer being manufactured. 
8.2.1 
Other Names  
Marqibo, Vincristine sulfate liposome injection. 
8.2.2 
Classification  
Antineoplastic agent, Vinca Alkaloid. 
8.2.3 
Mode of Action  
Vincristine is a cell cycle specific agent that binds to tubulin, leading to 
microtubule depolymerization and cellular apoptosis. The liposomal 
formulation increases the half-life, allowing for enhanced activity. 
8.2.4 
Storage and Stability  
Store intact kit (containing vincristine vial, sphingomyelin/cholesterol 
liposome vial, and sodium phosphate vial) refrigerated at 2 degrees C 
to 8 degrees C; do not freeze. Once prepared and diluted, liposomal 
vincristine is stable for no more than 12 hours at room temperature. 
8.2.5 
Dose Specifics  
Arm A: 2.25mg/m2 IV weekly starting Day 15 
Arm B: 2.25mg/m2 IV weekly starting Day 15 
Arm C: 2.25mg/m2 IV weekly starting Day 15 
Arm D: 2.25mg/m2 IV weekly starting Day 1 
8.2.6 
Preparation  
Marqibo (vinCRIStine sulfate LIPOSOME injection) is vincristine 
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administration. Marqibo is prepared from the components in the 
Marqibo Kit. Liposomal vincristine takes approximately 60 to 90 
minutes to prepare. The preparer should have dedicated 
uninterrupted time to prepare the medication due to the extensive 
monitoring of temperature and time required for the preparation. 
Refer to the FDA-approved package insert for complete preparation 
information. Below is a list of items required by the pharmacy to 
prepare Marqibo: 
• 
Marqibo Kit 
• 
Water bath 
• 
Calibrated thermometer (0°C to 100°C) 
• 
Calibrated electronic timer 
• 
Sterile venting needle or other suitable device equipped with a 
sterile 0.2 micron filter 
• 
1 mL or 3 mL sterile syringe with needle, and 
• 
5 mL sterile syringe with needle. 
The manufacturer will provide the water bath, calibrated thermometer, 
and calibrated electronic timer to the medical facility at the initial order 
of Marqibo and will replace them every 2 years. All syringes and 
needles should be used from the preparing pharmacy’s standard 
supply. 
After preparation, each single-dose vial of Marqibo (vinCRIStine 
sulfate LIPOSOME injection) contains 5 mg/31 mL (0.16 mg/mL) 
vincristine sulfate 
8.2.7 
Route of Administration  
Intravenous infusion over 1 hour 
8.2.8 
Incompatibilities  
Do not use with in-line filters. Do not mix with other drugs. 
8.2.9 
Availability  
Commercially available supply 
8.2.10 
Side Effects  
Below are the most commonly reported adverse events related to 
vinCRIStine sulfate LIPOSOME injection. Please refer to the package 
insert for the comprehensive list of adverse events. 
The most common adverse reactions (>30%) from previous 
clinical trials were: 
• 
Constipation (57%) 
• 
Nausea (52%) 
• 
Pyrexia (43%) 
• 
Fatigue (41%) 
• 
Peripheral neuropathy (39%) 
• 
Febrile neutropenia (38%) 
• 
Diarrhea (37%) 
• 
Anemia (34%) 
• 
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The most common grade 3 or higher toxicities reported: 
• 
Febrile Neutropenia (31%) 
• 
Neutropenia (18%) 
• 
Anemia (17%) 
• 
Thrombocytopenia (17%) 
• 
Pneumonia (8%) 
• 
Septic shock (6%) 
• 
Staphylococcal bacteremia 
(6%) 
• 
Peripheral sensory and motor 
neuropathy (17%) 
• 
Constipation (5%) 
• 
Ileus (6%) 
• 
Asthenia (5%) 
• 
Respiratory distress (6%) 
• 
Respiratory failure (5%) 
• 
Pyrexia (15%) 
• 
Fatigue (12%) 
• 
Pain (8%) 
• 
Abdominal pain (8%) 
• 
Aspartate aminotransferase 
increased (7%) 
• 
Hypotension (6%) 
• 
Mental status changes (4%) 
• 
Cardiac arrest (6%) 
• 
Renal and urinary disorders (7%) 
• 
Musculoskeletal and connective 
tissue disorders (8%) 
 
8.2.11 
Potential Interactions 
Liposomal vincristine is metabolized primarily by CYP3A4. 
Medications that are moderate/strong inhibitors or inducers of 3A4 are 
contraindicated on this study, and will require removal of patient from 
study if necessary to initiate these medications. See Appendix V for a 
list of these medications. Alternative agents with weak or no CYP3A4 
effects should be considered. 
8.2.12 
Nursing/Patient Implications  
Liposomal vincristine is NOT to be given intrathecally, and could result 
in death.   
NOTE: 
Marqibo (vinCRIStine sulfate LIPOSOME injection) has 
different dosage recommendations than vinCRIStine sulfate 
injection. Verify drug name and dose prior to preparation 
and administration to avoid overdosage. 
8.2.13 
References  
Marqibo (vincristine liposomal) [prescribing information]. Rockford, IL: 
Talon Therapeutics Inc; April 2017. 
8.3 
Vincristine Sulfate NSC 67574 
8.3.1 
Other names 
Oncovin R, Vincasar PFS R, vincristine sulfate, VCR, leucocristine, 
LCR. 
8.3.2 
Classification 
Vinca alkaloid (tubulin inhibitor). 
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8.3.3 
Mode of Action 
Vincristine binds to tubulin, a protein that forms microtubules, thus 
interfering with spindle formation during metaphase and causing 
cessation of cellular mitosis. 
8.3.4 
Storage and Stability 
Store refrigerated between 2°–8°C (36°–46°F). Discard unused 
solution. Protect from light. Store Upright. 
8.3.5 
Dose Specifics 
For Cycle 1, 1.4 mg/m2 (capped at 2 mg) IV on day 1 given weekly for 
4 doses.. For Cycle 2, 1.4 mg/m2 (capped at 2 mg) IV on day 1 given 
every 4 weeks. Dose modifications are necessary in patients with 
hepatic insufficiency. Please refer to Section 5.5.3 for dose 
modification information. 
8.3.6 
Preparation 
Please refer to institutional SOP or package insert for preparation and 
BUD (beyond use dating). 
8.3.7 
Administration 
Please refer to institutional SOP or package insert for administration 
guidelines. Please note that this drug is a VESICANT and should 
ONLY be given by intravenous route. May be FATAL if given by other 
routes. 
8.3.8 
Compatibilities 
This drug is compatible in NSS and D5W.  Refer to institutional 
policies or package insert for VCR and compatible solutions. 
8.3.9 
Availability 
Vincristine is commercially available as 1 mg (1mg/mL) single-use vial 
or 2 mg (2mg/2mL) single-use vial. 
8.3.10 
Side Effects 
1. Hematologic: Leukopenia (mild and rare), thrombocytopenia 
(rare), anemia. 
2. Dermatologic: Alopecia; skin and soft tissue damage if 
extravasated (the manufacturer recommends subcutaneous 
injection of hyaluronidase and application of heat to help disperse 
the drug); rash. 
3. Gastrointestinal: Nausea, vomiting (rare); constipation (see 
neurological side effects); abdominal pain (cramps); anorexia; 
diarrhea. Fatal ascending paralysis follows intrathecal 
administration. 
4. Hepatic: Elevations of SGOT and SGPT (mild and transient). 
5. Neurologic: Peripheral neuropathy (loss of deep tendon reflexes, 
paresthesias, paralysis); autonomic neuropathy (constipation, 
paralytic ileus, urinary retention, orthostasis); ataxia; myalgias; 
cortical blindness; headache; seizures. 
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6. Pulmonary: Bronchospasm (acute shortness of breath), more 
common when administered with mitomycin. 
7. Ocular: Diplopia; ptosis; photophobia; cortical blindness (see 
neurologic); optic atrophy. 
8. Other: Severe pain in the jaw, pharynx, bones, back and limbs 
following injection; syndrome of inappropriate antidiuretic hormone 
(SIADH); fever; pancreatitis (rare). 
8.3.11 
Nursing Implications 
1. Vesicant - Refer to extravasation protocol if inadvertent infiltration 
occurs. The manufacturer recommends local injection of 
hyaluranidase and warm compress to the area of leakage if 
extravasation occurs. 
2. Monitor for neurotoxicities - numbness, tingling, ataxia, loss of 
deep tendon reflexes, etc. 
3. Monitor for constipation and treat promptly. May require 
prophylactic stool softeners and/or laxatives. 
4. Precautions must be taken to prevent inadvertent intrathecal 
administration. ISMP recommends preparing vincristine in a mini 
bag to ensure safety. 
NOTE: 
Please refer to the commercially-available package 
labeling for more information. 
8.3.12 
References 
Byrd RA, Rohrbaugh TM, Raney RB, Norris DG. Transient cortical 
blindness secondary to vincristine therapy in childhood malignancies. 
Cancer 47:37-40, 1981. 
Drug Package Insert 
McRae MP, King JC. Compatibilities of antineoplastic, antibiotic and 
corticosteroid drugs in intravenous admixtures. Am J Hosp Pharm 
33:1010-1013, 1976. 
Chauncey TR, Shanel JL, Fox JH. Vincristine neurotoxicity. JAMA 
254:507, 1985. ECOG 2/91 
 
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9. 
Statistical Considerations 
9.1 
Phase I 
The primary objective of the phase I portion of this trial is to determine the 
maximum tolerated dose (MTD), safety and toxicity of venetoclax that can be 
administered in combination with liposomal vincristine during the phase II portion 
in patients with relapsed or refractory T-cell and B-cell ALL. The venetoclax dose 
cohorts examined are described as follows: 
• 
Cohort 1 (Arm A): 20, 50, 100, 200 mg on Days 1, 2, 3, 4 and 400 mg on 
Days 5 ‒ 70 
• 
Cohort 2 (Arm B): 50, 100, 200, 400 mg on Days 1, 2, 3, 4 and 600 mg on 
Days 5 ‒ 70 
• 
Cohort 3 (Arm C): 100, 200, 400, 600 mg on Days 1, 2, 3, 4 and 800 mg on 
Days 5 ‒ 70 
Venetoclax will be first given to the patients based on an intra-patient dose 
escalation scheme (as described above) in a 2-week lead-in phase, then in 
combination with a fixed, standard dose of intravenous liposomal vincristine for 
28 days. A bone marrow biopsy will be performed at day 42 +/- 2 days. All 
patients should proceed to Cycle 2 (28-day of combination therapy) unless they 
have progressive disease or they achieve CR or CRi and proceed to HSCT. A 
second bone marrow biopsy will be performed at day 70 +/- 2 days (the end of 
Cycle 2). Patients who achieve at least a stable disease response can remain on 
a 28-day cycle of combination therapy until disease progression or withdrawal 
from trial. At the discretion of the treating physician, a patient who achieves CR 
or CRi may proceed to HSCT at any time. In addition, patients who enter CR/CRi 
who develop side effects thought related to liposomal vincristine may continue on 
single agent venetoclax therapy at the discretion of treating physician after cycle 
2. 
9.1.1 
Statistical Analysis Plan 
The phase I portion of this study will use a standard 3+3 design 
according to the rules outlined below, with patients enrolled in cohorts 
of 3. 
Number of Observed DLTs 
Action 
0/3 
Escalate to the next dose cohort 
1/3 
Add 3 more patients at current dose cohort 
> 1/3 
Dose in previous cohort is MTD* 
1/6 
Escalate to the next dose cohort 
≥ 2/6 
Dose in previous cohort is MTD* 
* Discontinue the trial if occurs at the initial dose level 
Dose limiting toxicities (DLT) are defined in Section 5.1.4 of this 
protocol document. The table below summarizes the probabilities of 
dose escalation (that is, of 0/3 DLTs or of 1/3 + 0/3 DLTs) for a range 
of true DLT rates. 
True DLT Rate 
10% 
20% 
30% 
40% 
50%  
Probably of Dose Escalation 
91% 
71% 
49% 
31% 
17% 
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Upon completion of the trial, frequency of patients experiencing 
toxicities will be summarized by dose level, among patients who 
receive at least one dose of study drug. The DLTs will also be 
reviewed and tabulated by dose level, among patients evaluable for 
DLTs. Toxicities will be assessed and graded according to the CTCAE 
version 5.0. 
9.1.2 
Sample Size 
A minimum of 3 patients and maximum of 18 patients will be treated in 
the phase I portion of this trial. 
9.1.3 
Projected Accrual and Duration 
The accrual rate is expected to be 38 patients per year. 
Consequently, the accrual of 3 patients per cohort is projected to take 
approximately 1 month. Given the 3 patients in a cohort need to be 
followed for 42 days and toxicity data need to be reviewed before the 
next cohort can be opened, this evaluation can be up to 2 months. It 
is, thus, expected that the accrual together with evaluation for each 
cohort of 3 patients will be up to 3 months. With the maximum of 18 
patients enrolled into the phase I part, the duration of the phase I part 
might take up to 18 months 
9.1.4 
Monitoring Plan 
While the phase I study is ongoing, the study team will meet weekly 
via teleconference to review and discuss DLTs and the overall trial 
conduct. 
9.2 
Phase II 
The phase II portion of this trial will be a single arm, open-label trial of the 
combination of the venetoclax  and liposomal vincristine or vincristine sulfate. 
As conventional vincristine sulfate will be substituted for liposomal vincristine due 
to discontinuation of the latter, the grades 3-4 motor and sensory neuropathy will 
be closely monitored at each interim analysis for patients who starts protocol 
treatment with conventional vincristine sulfate. Frequency and percentage will be 
used to report combined grade 3-4 motor and sensory neuropathy events. A 90% 
binomial confidence interval will be estimated for these events combined as well. 
It is expected that the target combined rate would be 35% If the lower limit of the 
90% confidence interval is above the expected rate of 35% the results will be 
discussed with the study team and NCI for accrual suspension.  Should this 
threshold be reached, subsequent amendment of the protocol will be considered 
to decrease the dose of venetoclax. 
Patients will be classified in phase II according to ALL phenotype (B-cell vs T-
cell) tested by the site. The primary endpoint of this phase II portion is CR+CRi 
rate (with respect to the best response) by the end of Cycle 3. Secondary 
endpoints include progression-free survival, overall survival, and toxicity. 
Correlative markers are also going to be explored for their association with 
response; currently, studies of genetic signature, intracellular BCL-2 expression, 
BH3 profiling and immunophenotype of ALL are planned. 
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9.2.1 
Statistical Analysis Plan 
As the dose schedule is different between Phase I and Phase II, all 
analyses (except for the toxicity analysis) on Phase II will be 
performed on enrolled, eligible patients who started the phase II 
combination therapy (i.e., excluding those to be treated at the MTD on 
the phase I portion of the trial) and had phenotype (B-cell vs T-cell) 
information available. All patients starting phase II treatment will be 
included in the toxicity analysis regardless of eligibility. 
A 90% confidence interval will be computed for the CR+CRi rate (the 
primary endpoint, defined in Section 6) achieved by the end of Cycle 3 
for each patient cohort (B-cell or T-cell). 
Progression-free survival (PFS) is defined as the time from study 
registration (to step 1) to documented disease progression or death 
from any cause, whichever occurs first. Patients who have not 
experienced an event of interest by the time of analysis will be 
censored at the date of last disease evaluation showing they are 
progression-free. Overall survival (OS) is defined as the time from 
study registration (to step 1) to death from any cause. Patients who 
have not experienced death at the time of final analysis will be 
censored at the date of last contact. For each patient cohort (B-cell or 
T-cell), PFS and OS distributions will be estimated using the Kaplan-
Meier method, and the median OS and PFS along with its 
corresponding 90% confidence interval will be reported.  
Toxicity incidences assessed and graded according to the CTCAE 
version 5.0, will be tabulated by patient cohort. 
In the event that there are missing data, no imputation of the missing 
data will be conducted. We will assume that data are missing at 
random and will conduct all analyses as originally planned because 
we do not anticipate an excess of missing data. 
9.2.2 
Sample Size 
For each stratum (B-cell or T-cell ALL, tested by the sites), a sample 
size of 25 eligible patients achieves a 87% power to detect a 
difference of 25% between historical complete response rate of 
liposomal vincristine alone by 90 days (20%, O’Brien et al. (2013)) 
and the complete response rate in our phase II portion receiving the 
combination treatment by the end of Cycle 3 (45%), using a one-sided 
binomial test with the type I error of 5%. The null hypothesis will be 
rejected if >/= 9 patients in either stratum are found to have achieved 
a CR or a CRi by the end of Cycle 3. 
Assuming a total of 10% of patients will be ineligible or never start the 
combination treatment of the phase II portion, the number of patients 
needed for the phase II portion is inflated to 28 patients per stratum, 
making the total accrual goal of the phase II study 56 patients.  
9.2.3 
Projected Accrual and Duration 
With 28 patients planned for each cohort and a yearly accrual of 24 
patients for the B-cell and 8 patients for the T-cell ALL, it is projected 
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that the phase II accrual duration takes approximately 14 months and 
42 months, respectively, for the B-cell and the T-cell cohorts. 
9.2.4 
Monitoring Plan 
9.2.4.1 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for 
all ECOG-ACRIN studies. Reports of these analyses are 
sent to the ECOG-ACRIN Principal Investigator or Senior 
Investigator at the participating institutions. Expedited 
reporting of certain adverse events is required, as 
described in Section 5.3. 
9.2.5 
Correlative Studies 
Correlative markers are going to be explored for their association with 
efficacy measures; currently, studies of intracellular BCL-2 
expression, immunophenotype of ALL, and genetic signature are 
planned. Correlative analyses will be performed on all patients 
included in the phase II efficacy analysis, and have the lab data 
available. 
Intracellular BCL-2 expression by flow cytometry will be dichotomized 
into two groups by the median (low vs. high). Univariate Cox 
proportional hazards (PH) models will be used to evaluate the 
association of the BCL-2 expression at baseline and 
immunophenotype (B-cell and T-cell ALL) with OS and PFS, 
separately. Logistic regression models will be used to investigate the 
association of the BCL-2 expression at baseline and 
immunophenotype with response (CR/CRi/PR vs. others by the end of 
Cycle 3). Multivariable Cox PH modelling and logistic regression 
modelling will also be used to adjust for the effect of covariates that 
are possibly associated with these efficacy outcomes. 
As to the association of genetic signature and response to the 
combination therapy, data analysis will be performed by the Ferrando 
Lab (as described in Section 11.2). For BH3 profiling, the statistical 
analysis will be performed by a team to be determined, and the 
analysis plan (as described in Section 11.3) is subject to change 
depending on the methodology used by the team. 
NOTE: 
An amendment for any correlative science studies to be 
performed on biological specimens will be submitted to 
CTEP, NCI for review and approval according to NCTN 
guidelines. Amendments to the protocol and/or proposals 
for use of banked bone marrow or peripheral blood 
specimens will include the appropriate background, 
experimental plans with assay details, and a detailed 
statistical section. Specimens for testing will not be 
released until the appropriate NCI approvals have been 
obtained. 
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9.2.6 
Gender and Ethnicity 
Both men and women of all races and ethnic groups are eligible for 
this study. The anticipated accrual in subgroups defined by gender, 
race, and ethnicity is: 
Racial 
Categories 
Ethnic Categories 
Total 
Hispanic or 
Latino 
Non Hispanic or 
Latino 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
1 
0 
1 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
1 
1 
Black or African American 
1 
0 
2 
2 
5 
White 
3 
4 
19 
23 
49 
Total 
4 
4 
22 
26 
56 
The accrual targets in individual cells are not large enough for 
definitive subgroup analyses. Therefore, overall accrual to the study 
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10. 
Specimen Submissions 
PHASE I ONLY: Bone marrow aspirates and/or peripheral blood must be submitted at 
preregistration for the centralized review described in Section 11.1. 
Bone marrow aspirates and peripheral blood are to be submitted from consenting 
patients for the defined laboratory research studies described in Section 11.2. 
Peripheral blood and buccal rinse are to be submitted from consenting patients for future 
undefined research studies. 
It is required that all specimens submitted on this trial be entered and tracked using the 
ECOG-ACRIN Sample Tracking System (STS) (see Section 10.3). An STS shipping 
manifest form is to be included with every submission. 
All specimens must be clearly labeled with the ECOG-ACRIN protocol number 
(EA9152), ECOG-ACRIN patient sequence number, patient’s initials, date of collection 
and specimen type. 
10.1 
Submissions to the ECOG-ACRIN Leukemia Laboratory at MD Anderson Cancer 
Center 
10.1.1 
Specimen Preparation Guidelines 
The following are to be submitted: 
1. Heparinized bone marrow aspirate (the laboratory will accept any 
amount as long as it represents a first pull). Ideally, 2-3mL of 
aspirate from a separate aspiration site should be submitted.  
For patients with an inaspirable bone marrow (‘dry tap’), or if a 
bone marrow has been done previously and the patient refuses to 
have another aspiration done, call the EA Leukemia Laboratory at 
(713) 745 -7846 or (713) 563-1943 to discuss the case and the 
possibility for submitting peripheral blood only. Be prepared to 
report the WBC count and the blast count in the peripheral blood at 
the time of the call. Patients without bone marrow or circulating 
disease, especially in the case of lymphoblastic lymphoma, may 
submit peripheral blood after discussion with the study chair. 
• 
Submit at baseline and relapse from patients who answer 
“Yes” to “I agree to have my samples collected and I agree 
that my samples and related information may be used for 
laboratory studies.” 
2. Heparinized or EDTA peripheral blood (four (4) green or purple 
top tubes, 30-40mL). 
• 
Submit at baseline and relapse from patients who answer 
“Yes” to “I agree to have my samples collected and I agree 
that my samples and related information may be used for 
laboratory studies.” 
3. Two (2) red top tubes of peripheral blood (15-20mL). 
• 
Submit at baseline from patients who answer ‘Yes’ to “I agree 
to provide additional samples for research.” 
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4. MANDATORY AT ALL TIME POINTS: A copy of the institutional 
pathology report on the bone marrow must be submitted via 
Medidata Rave. The pathology report must include cytogenetic 
results and any results from fluorescence-in-situ (FISH) 
hybridization and/or molecular studies done at the submitting 
institution. 
Please fax to the EA Leukemia Laboratory at (713) 563-6506. 
5. Buccal Cell Specimens 
• 
Preferably, Scope, a commercial brand mouthwash, or normal 
saline in a small sealed bottle can be given to the patient for a 
mouthwash.  
• 
Aseptic techniques must be used to collect buccal cells from 
patients on site and buccal cells must not be contaminated 
with cells from any other source. Patients should not brush 
their teeth or consume food within an hour prior to buccal cell 
collection.   
• 
If mouthwash (e.g., Scope) or normal saline is used, the 
patient should pour approximately 10cc of mouthwash or 
saline into his/her mouth and vigorously swish it against the 
cheeks for 10 seconds and deliver the solution into a labeled 
50mL sterile polypropylene test tube or a sterile urine cup. 
Among mouthwashes, the Scope brand fares best in collecting 
buccal cells for the preparation of high-quality DNA in high 
yield.  
• 
It is important that buccal cells do not dry out during shipping. 
Institutions are advised to seal the container containing the 
buccal cells tightly. Ship containers on cool packs, together 
with the patient’s peripheral blood and bone marrow 
specimens. 
• 
Submit from patients who answer "Yes” to “I agree to provide 
additional samples for research.” 
NOTE: 
Buccal rinse is strongly encouraged to be 
collected prior to the start of treatment, but can be 
collected at any other time during the study, if 
necessary. 
10.1.2 
Shipping Procedures 
The EA Leukemia Laboratory must be notified by telephone or 
email the day of shipment for ALL shipments, including follow up 
submissions. 
The laboratory must be aware that specimens are forthcoming as 
immediate processing is essential to the integrity of the specimens. 
Telephone: (713)745-7846 or (713) 563-1943 
For questions regarding the shipment, Dr. Loghavi can be reached via 
email (sloghavi@mdanderson.org) or by calling her cell phone (310-
990-3703). 
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Heparinized bone marrow and peripheral blood or EDTA specimens, 
coagulated blood in red top tubes and buccal cells must be sent fresh 
(on the day of collection) on cool packs (do not freeze and do not use 
ice cubes)Monday –Thursday by overnight courier (preferably Federal 
Express) to arrive within 24 hours. 
Friday shipments are ill advised, similarly shipping before 
holidays is often problematic, due to closures or courier delivery 
problems. The laboratory is closed Saturday, Sunday and 
holidays. 
Ship using the CBPF’s FedEx account using the FedEx on-line ship 
manager 
Ship to: 
ECOG-ACRIN Leukemia Bank 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room 
G1.3598 
1515 Holcombe Boulevard 
Houston, TX 77030 
Phone: Toll Free (713)-745-7846 or (713) 563-1943 
Fax: (713) 563-6506 
Email: UM-EALB@mdanderson.org 
An STS shipping manifest form must be generated and shipped with 
all specimen submissions.   
Please enter all information into the STS, including time and date of 
specimen collection and peripheral blood WBC count and blast count. 
10.2 
Use of Specimens in Research 
Bone marrow and peripheral blood specimens will be distributed to Dr. Adolfo 
Ferrando at Columbia University. See Section 11 for the description of the 
laboratory research studies to be performed. 
Specimens submitted will be processed to maximize their utility for current and 
future research projects. DNA, RNA, serum, and plasma (if appropriate) will be 
isolated from the submitted peripheral blood specimens. 
Specimens from patients who consented to allow their specimens to be used for 
future approved research studies will be retained in the ECOG-ACRIN Leukemia 
Bank (LB). Specimens will be de – identified prior to distribution for any approved 
research studies. 
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study. 
10.3 
ECOG-ACRIN Sample Tracking System 
It is required that all specimens submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
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When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Important: Please note that the STS software creates pop-up windows, you will 
need to enable pop-ups within your web browser while using the software. A user 
manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html 
Please take a moment to familiarize yourself with the software prior to using the 
system. 
An STS generated shipping manifest form should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
Study Specific Notes 
Generic Specimen Submission Form (#2981v3) will be required only if STS is 
unavailable at time of specimen submission. Notify the laboratory of the shipment 
by faxing a copy of the completed form to the laboratory. 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.4 
Sample Inventory Submission Guidelines  
Inventories of all specimens submitted will be tracked via the ECOG-ACRIN STS 
and receipt and usability verified by the receiving laboratory. Inventories of 
specimens forwarded and utilized for the approved laboratory research studies 
will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis in an electronic format defined by 
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11. 
Leukemia Correlative Studies 
11.1 
PHASE I ONLY: Immunophenotype 
Immunophenotyping has become an essential part of the diagnostic work-up of 
all leukemia patients. In fact, the diagnosis of leukemia without 
immunophenotypic characterization is no longer acceptable. ECOG-ACRIN has, 
therefore, developed a model system for antigenic data collection that requests 
specimens from all patients entered on ECOG-ACRIN leukemia treatment trials 
be studied by the ECOG-ACRIN Leukemia Laboratory at MD Anderson Cancer 
Center. In addition to establishing the leukemia subtype, this centralized testing 
and data collection has allowed that research questions of clinical relevance to 
be applied to a growing database (e.g., definition of prognostically significant 
antigen expression levels to eventually yield specific treatment subcategories). 
Depending on the study protocol and tissue availability, anti-coagulated (heparin, 
EDTA, ACD) peripheral blood or bone marrow or both are to be submitted to the 
EA Leukemia Laboratory. 
In addition to the study of abnormal hematopoietic cells, the focus of research on 
circulating serum factors in patients with leukemia or myelodysplasia has 
increased. Two tubes of coagulated peripheral blood (red top tubes) are 
requested for future research studies that may aim at identifying pathogenetic, 
diagnostic, or prognostic factors associated with leukemia or myelodysplasia.  
Serum and cells from peripheral blood or bone marrow from patients entered on 
studies of hematologic malignancies are stored in ECOG-ACRIN's Leukemia 
Laboratory for EA9152 embedded and future laboratory studies. The bank 
provides the scientific community a source of leukemia specimens that are 
collected, processed, and maintained following quality control and quality 
assurance guidelines. An amendment or proposal for any correlative science 
studies to be performed on biological specimens will be submitted to CTEP for 
review according to NCTN guidelines. Amendments to the protocol and/or 
proposals for use of banked specimens will include the appropriate background, 
experimental plans with assay details, and a detailed statistical section. 
Specimens will not be released until the appropriate NCI approvals are in place.  
11.2 
Molecular and Transcriptional Analysis of Adult ALL and Prognosis of Response 
to Combination Therapy – Adolfo Ferrando, MD, PhD 
Gene expression profiling (GEP) and the analysis of driver mutations has helped 
to sub-classify malignancies, including adult ALL, as well as provide valuable 
information in regards to prognosis. The Ferrando group has previously identified 
prognostic expression patterns and mutations of interest in previous studies 
across various ALL subtypes.[52,53] A transcriptional signature prognostic of 
response to therapy will be investigated using RNAseq gene expression profiling 
data from diagnostic specimens. Towards this goal, we will divide the cohort into 
a test set composed of 2/3 of the specimens and a validation set consisting of the 
remaining 1/3 of the cases. Genes significantly associated with the strongest 
response to therapy in the test set will be identified by t-test with correction for 
multiple comparisons. Top scoring genes will be further selected based on their 
sensitivity and specificity for the prognosis of clinical response using a leave-one-
out cross-validation approach. Finally, the selected panel of genes prognostic of 
response to therapy identified in the test set will be evaluated in the validation set 
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of specimens using a K-mean clustering approach. Matched RNAseq data from 
specimens obtained at diagnosis and at the time of relapse will be analyzed to 
explore the underlying mechanisms mediating disease progression. Specifically 
supervised analysis using paired t-test with correction for multiple comparisons 
will be used to identify differentially expressed genes at diagnosis and relapse. 
Functional characterization of these signatures will be addressed via functional 
annotation using DAVID and via GSEA using the MsigDB collection of annotated 
gene-sets. 
11.3 
BH3 Profiling of Adult Lymphoblastic Leukemias Relapsed After or Refractory to 
Therapy 
With the intent of BH3 profiling (as described in Section 1.3.1), the study will 
bank specimens of bone marrow at the time of study entrance and relapse. 
As described above, the intrinsic apoptotic pathway is governed by the BCL-2 
superfamily of proteins, which can be subdivided based on their function into four 
groups: activators, sensitizers, repressors and effectors of apoptosis. The 
repressor class, of which BCL-2, BCL-Xl, and MCL-1 among others, are 
members, is responsible for preventing cells from undergoing apoptosis in 
opposition to upstream, pro-apoptotic signaling. Using the unique binding 
patterns of various activator and sensitizer BH3 peptides, the dependency of a 
particular cell line on a repressor can be inferred. For example, it is established 
that the sensitizer protein NOXA-A binds to and inhibits only MCL-1. Therefore, if 
a cell line undergoes apoptosis in the presence of additional, exogenous NOXA-
A, that cell line thought to be MCL-1 dependent for its survival. 
BH3 profiling is the term used to describe the investigation of the relative state, 
also called “priming,” of a particular cell line in regards to its closeness to 
undergoing apoptosis as well as on which anti-apoptotic protein or proteins a 
sample is dependent. In this way, a sample’s BH3 profile can also predict 
response to BCL-2 inhibitors among other chemotherapeutic agents.   
One method of BH3 profiling determines the degree of priming by measuring the 
change in mitochondrial outer membrane polarization in response to variety of 
conditions that can include synthetic BH3 proteins or chemotherapy. Frozen 
patient samples before treatment and after relapse are thawed, resuspended, 
and viability determined. Viable cells are then made permeable with digitonin, 
which allows for uniform exposure to various exogenous BH3 peptides, and are 
subsequently treated with JC-1. JC-1 stains mitochondria and fluoresces 
proportionally to the degree of polarization of mitochondria, which is then 
analyzed and reported by FACS as a median fluorescence intensity (MFI). 
The MFI of positive controls, which uniformly depolarize mitochondria, and 
negative control peptides, which result in no additional depolarization, are 
compared to the MFI of the sample after the addition of synthetic BH3 sensitizer 
proteins. The comparison of these is described by the following formula as % 
primed:  
% priming = (1-(MFIsample – MFIpositive)/(MFInegative – MFIpositive)) x 100 
Percent priming for responders (CR, CRi and PR) versus non-responders, as 
defined by response criteria in Section 6.1-6.4 will be calculated for samples after 
exposure to a variety of BH3 proteins, including NOXA-A, HRK, BIM, BID. 
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PFS will be tested for correlation with % priming by log-rank test for trend. In 
addition, a receiver operation characteristic curve to test whether BH3 profiling 
can predict CR to the regimen will be performed. 
NOTE: 
An amendment for any BH3 profiling to be performed on biological 
specimens will be submitted to CTEP, NCI for review and approval 
according to NCTN guidelines. Specimens for testing will not be 
released until the appropriate NCI approvals have been obtained. 
11.4 
Lab Data Transfer Guidelines  
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office - Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the Investigator.  

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12. 
Electronic Data Capture 
Please refer to the EA9152 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
12.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being 
studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office – Boston prior to destroying 
any source documents. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
References 
1. 
O'Brien S, Thomas D, Ravandi F et al. Outcome of adults with acute lymphocytic 
leukemia after second salvage therapy. Cancer 2008;113:3186-3191. 
2. 
Kantarjian HM, Thomas D, Ravandi F et al. Outcome of adults with acute 
lymphocytic leukemia in second or subsequent complete remission. Leuk 
Lymphoma 2010;51:475-480. 
3. 
Kantarjian HM, O’Brien S, Smith TL et al. Results of Treatment With Hyper-CVAD, a 
Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia. Journal of Clinical 
Oncology 2000;18:547-547. 
4. 
O'Brien S, Schiller G, Lister J et al. High-Dose Vincristine Sulfate Liposome 
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Aguayo A, Cortes J, Thomas D et al. Combination therapy with methotrexate, 
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6. 
Topp MS, Gökbuget N, Zugmaier G et al. Phase II Trial of the Anti-CD19 Bispecific 
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7. 
Maude SL, Frey N, Shaw PA et al. Chimeric Antigen Receptor T Cells for Sustained 
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9. 
Parikh SA and Litzow MR. Philadelphia chromosome-negative acute lymphoblastic 
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11. Delbridge ARD and Strasser A. The BCL-2 protein family, BH3-mimetics and cancer 
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12. Hemann MT and Lowe SW. The p53-Bcl-2 connection. Cell Death Differ 
2006;13:1256-1259. 
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Lymphoid Cells From the Hematopoietic Stem Cell. Blood 1997;89:853. 
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16. Grillot DA, Merino R and Nd G. Bcl-XL displays restricted distribution during T cell 
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thymocytes. Proc Natl Acad Sci U S A 1995;92:4763-4767. 
18. Veis DJ, Sentman CL, Bach EA and Korsmeyer SJ. Expression of the Bcl-2 protein 
in murine and human thymocytes and in peripheral T lymphocytes. The Journal of 
Immunology 1993;151:2546-2554. 
19. Grayson JM, Zajac AJ, Altman JD and Ahmed R. Cutting Edge: Increased 
Expression of Bcl-2 in Antigen-Specific Memory CD8+ T Cells. The Journal of 
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20. Boise LH, Minn AJ, Noel PJ et al. CD28 costimulation can promote T cell survival by 
enhancing the expression of Bcl-XL. Immunity 1995;3:87-98. 
21. Li YS, Hayakawa K and Hardy RR. The regulated expression of B lineage 
associated genes during B cell differentiation in bone marrow and fetal liver. J Exp 
Med 1993;178:951. 
22. Merino R, Ding L, Veis DJ et al. Developmental regulation of the Bcl-2 protein and 
susceptibility to cell death in B lymphocytes. EMBO J 1994;13:683-691. 
23. Souers AJ, Leverson JD, Boghaert ER et al. ABT-199, a potent and selective BCL-2 
inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013;19:202-
208. 
24. Zhang H, Nimmer PM, Tahir SK et al. Bcl-2 family proteins are essential for platelet 
survival. Cell Death Differ 2007;14:943-951. 
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25. Pan R, Hogdal LJ, Benito JM et al. Selective BCL-2 Inhibition by ABT-199 Causes 
On Target Cell Death in Acute Myeloid Leukemia. 2013;4:362-375. 
26. Touzeau C, Dousset C, Le Gouill S et al. The Bcl-2 specific BH3 mimetic ABT-199: 
a promising targeted therapy for t(11;14) multiple myeloma. Leukemia 2014;28:210-
212. 
27. Khan N, Zhou L, Babar J et al. ABT199 and ONC201 in Diffuse Large B Cell 
Lymphoma Cell Lines. Blood 2015;126:5129. 
28. Brunelle JK, Ryan J, Yecies D et al. MCL-1 dependent leukemia cells are more 
sensitive to chemotherapy than BCL-2 dependent counterparts. J Cell Biol 
2009;187:429. 
29. Chonghaile TN, Sarosiek KA, Vo T et al. Pretreatment Mitochondrial Priming 
Correlates with Clinical Response to Cytotoxic Chemotherapy. Science 
2011;334:1129. 
30. Chonghaile TN, Roderick JE, Glenfield C et al. Maturation Stage of T-cell Acute 
Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and 
Sensitivity to ABT-199. Cancer Discovery 2014;4:1074-1087. 
31. Deng J, Carlson N, Takeyama K et al. BH3 Profiling Identifies Three Distinct 
Classes of Apoptotic Blocks to Predict Response to ABT-737 and Conventional 
Chemotherapeutic Agents. 2007;12:171-185. 
32. Montero J, Sarosiek K, DeAngelo J et al. Drug-Induced Death Signaling Strategy 
Rapidly Predicts Cancer Response to Chemotherapy. Cell 2015;160:977-989. 
33. De Vos S, Flowers C, Wang D et al. Interim results from a dose-escalation study of 
the BCL-2 inhibitor venetoclax (ABT-199/GDC-0199) plus bendamustine (B) and 
rituximab (R) in patients (pts) with relapsed/refractory (R/R) Non-Hodgkin's 
Lymphoma (NHL). ASCO Meeting Abstracts 2015;33:8535. 
34. Konopleva M, Pollyea DA, Potluri J et al. A Phase 2 Study of ABT-199 (GDC-0199) 
in Patients with Acute Myelogenous Leukemia (AML). Blood 2014;124:118-118. 
35. Ma S, Seymour JF, Lanasa MC et al. ABT-199 (GDC-0199) combined with 
rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic 
leukemia (CLL): Interim results of a phase 1b study. ASCO Meeting Abstracts 
2014;32:7013. 
36. Salles GA, Boyd TE, Morschhauser F et al. Preliminary Results of a Phase 1b 
Study (GO28440) Combining GDC-0199 (ABT-199) with Bendamustine/Rituximab 
in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic 
Leukemia. Blood 2014;124:3337-3337. 
37. Davids MS, Seymour JF, Gerecitano JF et al. Phase I study of ABT-199 (GDC-
0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): 
Responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at 
higher cohort doses. ASCO Meeting Abstracts 2014;32:8522. 
38. Stilgenbauer S, Eichhorst B, Schetelig J et al. Venetoclax in relapsed or refractory 
chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 
study. 2016;17:768-778. 
39. Del GM, Schlis KD, Sallan SE et al. BCL-2 dependence and ABT-737 sensitivity in 
acute lymphoblastic leukemia. Blood 2008;111:2300. 
40. Konopleva M, Benito JM, Harutyunyan KG et al. Acute Lymphoblastic Leukemia Is 
a Bcl-2 Dependent Disease: Proteomic Profiling and Pre-Clinical Efficacy Of a 
Selective Bcl-2 Antagonist ABT-199. Blood 2013;122:3919-3919. 

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41. Peirs S, Matthijssens F, Goossens S et al. ABT-199 mediated inhibition of BCL-2 as 
a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood 
2014;124:3738-3747. 
42. Kang MH, Kang YH, Szymanska B et al. Activity of vincristine, L-ASP, and 
dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-
mimetic ABT-737 in vitro and in vivo. Blood 2007;110:2057-2066. 
43. Benito J, Godfrey L, Kojima K et al. MLL-Rearranged Acute Lymphoblastic 
Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the 
BCL-2-Specific Antagonist ABT-199. Cell Rep 2015;13:2715-2727. 
44. Chonghaile TN, Roderick JE, Glenfield C et al. Maturation Stage of T-cell Acute 
Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and 
Sensitivity to ABT-199. Cancer Discov 2014;4:1074-1087. 
45. Peirs S, Matthijssens F, Goossens S et al. ABT-199 mediated inhibition of BCL-2 as 
a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood 
2014;124:3738-3747. 
46. Khaw SL, Suryani S, Evans K et al. Venetoclax responses of pediatric ALL 
xenografts reveal sensitivity of MLL-rearranged leukemia. Blood 2016;128:1382-
1395. 
47. Frismantas V, Dobay MP, Rinaldi A et al. Ex vivo drug response profiling detects 
recurrent sensitivity patterns in drug resistant ALL. Blood 2017. 
48. DiNardo C, Pollyea D, Pratz K et al. A Phase 1b Study of Venetoclax (ABT-
199/GDC-0199) in Combination with Decitabine or Azacitidine in Treatment-Naive 
Patients with Acute Myelogenous Leukemia Who Are ≥ to 65 Years and Not Eligible 
for Standard Induction Therapy. Blood 2015;126:327. 
49. Wei A, Strickland SA, Roboz GJ et al. Safety and Efficacy of Venetoclax Plus Low-
Dose Cytarabine in Treatment-Naive Patients Aged ≥ 65 Years with Acute Myeloid 
Leukemia. Blood 2016;128:102. 
50. Pathak P, Hess R and Weiss MA. Liposomal vincristine for relapsed or refractory 
Ph-negative acute lymphoblastic leukemia: a review of literature. 2014;5:18-24. 
51. Tzoneva G, Perez-Garcia A, Carpenter Z et al. Activating mutations in the NT5C2 
nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nat Med 
2013;19:368-371. 
52. Van Vlierberghe P, Ambesi-Impiombato A, De Keersmaecker K et al. Prognostic 
relevance of integrated genetic profiling in adult T-cell acute lymphoblastic 
leukemia. Blood 2013;122:74-82. 
53. Cheson BD, Bennet JM, Kopecky KJ et al. Revised Recommendations of 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute 
Myeloid Leukemia. Bloomfield Journal of Clinical Oncology 2003; 21:24, 4642-4649. 
54. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Acute 
Lymphoblastic Leukemia; 2019 [updated May 15 2019]. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. 
 
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or Vincristine Sulfate in Patients with Relapsed or Refractory T-cell or B-cell Acute 
Lymphoblastic Leukemia 
Appendix I 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

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Lymphoblastic Leukemia 
Appendix II 
 
Patient Pill Diary - Venetoclax 
 
Pill Calendar Directions 
1. Take your scheduled dose of each pill. 
2. Venetoclax tablets should be taken with a meal and water at approximately the same 
time each day. The tablets should be swallowed whole and not chewed, crushed, or 
broken.  
3. At least 8.5 cups of water (2 L) should be consumed every day starting 2 days before 
the first dose and throughout the treatment, especially the first day of each dose 
increase. 
4. You should avoid grapefruit products, Seville oranges, and starfruit during treatment.  
5. If you miss a dose within 8 hours of the time it is usually taken, you should take the 
missed dose as soon as possible and resume the normal daily dosing schedule. If 
you miss a dose by more than 8 hours, you should not take the missed dose and 
should resume the usual dosing schedule the next day.  
6. If you vomit after taking the pill, you should not take another pill be that day. The next 
prescribed dose should be taken at the usual time 
7. Please bring the empty bottle or any leftover tablets and your pill calendar to your 
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Patient Pill Calendar 
This is a calendar on which you are to record the time and number of tablets you take each day. 
You should take your scheduled dose of each pill. Note the times and the number of tablets that 
you take each day. If you develop any side effects, please record them and anything you would 
like to tell the doctor in the space provided. Bring any unused tablets and your completed pill 
calendar to your doctor’s visits. 
 
DAY 
Date 
Month      Day       Year 
Time 
capsules 
taken 
Number 
of 
capsules 
taken 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
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8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
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DAY 
Date 
Month      Day       Year 
Time 
capsules 
taken 
Number 
of 
capsules 
taken 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
28 
 
 
 
 
 
 
Patient Signature: ____________________________ 
Date: _________________ 
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This is a calendar on which you are to record the time and number of tablets you take each day. 
You should take your scheduled dose of each pill. Note the times and the number of tablets 
that you take each day. If you develop any side effects, please record them and anything you 
would like to tell the doctor in the space provided. Bring any unused tablets and your completed 
pill calendar to your doctor’s visits. 
Cycle 2+: Arm _____ - Dose Level ______ (_______ mg) 
DAY 
Date 
Month      Day       Year 
Time 
capsules 
taken 
Number 
of 
capsules 
taken 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
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12 
 
 
 
 
 
 
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DAY 
Date 
Month      Day       Year 
Time 
capsules 
taken 
Number 
of 
capsules 
taken 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
Patient Signature: ____________________________ 
Date: _________________ 
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Lymphoblastic Leukemia 
Appendix III 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 

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Lymphoblastic Leukemia 
Appendix IV 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy 
test regardless of age or disease state) of a female patient while she is on venetoclax, or 
within 28 days of the female patient’s last dose of venetoclax must be reported in an 
expeditious manner. The outcome of the pregnancy and neonatal status must also be 
reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be 
reported via CTEP’s Adverse Event Reporting System (CTEP-AERs) 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy 
test need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, 
followed by a complete expedited CTEP-AERs report within 5 calendar days of the initial 24-
hour report. 
What other information do I need in order to complete the CTEP-AERs report for a 
pregnancy? 
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium 
and perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) 
“Pregnancy, puerperium and perinatal conditions” 
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
• 
The start date of the pregnancy should be reported as the calculated date of conception.   
• 
The potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event” section of 
the CTEP-AERs report.  
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the female patient until completion of the pregnancy and 
must report the outcome of the pregnancy and neonatal status via CTEP-AERs.  
• 
The decision on whether an individual female patient can continue protocol treatment will 
be made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office – Boston. Please contact the ECOG-ACRIN Operations Office – 
Boston to ask for a conference call to be set up with the appropriate individuals.   
• 
It is recommended the female patient be referred to an obstetrician-gynecologist, 
preferably one experienced in reproductive toxicity for further evaluation and counseling.  
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How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERs 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself. 
However, if the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-
AERs report should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions (formerly referred to as disabilities), congenital anomalies, or birth defects. For 
assistance in recording the grade or category of these events, please contact the CTEP 
AEMD Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed 
on a case by case basis.   
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
It must be reported via CTEP-AERs as Grade 4 “Pregnancy Loss” under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions”.   
A pregnancy loss should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A newborn death occurring during the first 28 
days after birth” that is felt by the investigator to be at least possibly due to the 
investigational/IND exempt agent/intervention. However, for this protocol, any neonatal 
death that occurs within 28 days of birth, without regard to causality, must be reported via 
CTEP-AERs AND any infant death after 28 days that is suspected of being related to the in 
utero exposure to venetoclax must also be reported via CTEP-AERs. 
It must be reported via CTEP-AERs as Grade 4 “Death neonatal” under the System Organ 
Class (SOC) “General disorder and administration site conditions”. 
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death 
Additional Required Forms: 
When submitting CTEP-AERs reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any 
additional medical information to CTEP (301-897-7404). This form is available on CTEP's 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReport
Form.pdf) 
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Lymphoblastic Leukemia 
Appendix V 
 
CYP3A Inhibitors and Inducers and P-Glycoprotein (PGP) Medications 
The medications or substances that are listed in the table below are strong or moderate 
inhibitors/inducers of CYP3A4. 
Strong and moderate inhibitors of CYP3A4 or PGP, and are contraindicated during this protocol. 
Excluded 
Anticancer therapies including chemotherapy, radiotherapy, or other investigational therapy, 
including targeted small molecule agents: Excluded 5 half-lives prior to first dose and throughout 
venetoclax administration 
Biologic agents (e.g., monoclonal antibodies) for anti-neoplastic intent: 
Excluded 30 days prior to first dose and throughout venetoclax administration 
Excluded during ramp-up phase and Cautionary at the Cohort Designated Dose:  
Strong and Moderate CYP3A inhibitors  
Exclude during ramp-up phase and consider alternative medications. If subject requires use of these 
medications at the cohort designated dose, use with caution and reduce the venetoclax dose by 50% for 
moderate inhibitors and at least 75% for strong inhibitors 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. 
Strong and Moderate CYP3A inducers 
Exclude during ramp-up phase and consider alternative medications. If subject requires use of these 
medications at the cohort designated dose, use with caution and contact AbbVie medical monitor for 
guidance. 
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 
Cautionary 
Warfarin** 
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 
P-gp inhibitors 
Amiodarone, azithromycin, captopril, carvedilol, dronedarone, felodipine, quercetin, quinidine, ronalzine, 
ticagrelor 
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Geftinib* 
Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/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 Star 
fruits. 
* 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. 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet. 
Venetoclax (Venclaxta) may interact with other drugs, which can cause side effects. For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial. It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study. When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort. It is 
helpful to bring your medication bottles or an updated medication list with you. 
Many health care providers can write prescriptions. You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in 
a clinical trial.  
These are the things that you and they need to know:  
Venetoclax (Venclaxta) must be used very carefully with other medicines that use certain liver 
enzymes. Before you enroll onto the clinical trial, your study doctor will work with your regular 
health care providers to review any medicines and herbal supplements that are considered 
strong inducers/inhibitors or substrates of CYP3A4. 
• 
Please be very careful! Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug. Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
• 
You should avoid consuming food and beverages containing grapefruit juice or Seville 
oranges for the duration of the study because it contains ingredients that could interact with 
your study drug.   
• 
Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine.  
Your study doctor’s name is  
_____________________________________ and he or she can be contacted at 
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STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental 
study drug___venetoclax (Venclaxta)___.  This clinical 
trial is sponsored by the NCI.  ___Venetoclax______ 
may interact with drugs that are processed by your liver.  
Because of this, it is very important to: 
 Tell your doctors if you stop taking any medicines or if 
you start taking any new medicines. 
 Tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or 
pharmacists) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal 
supplement. 
___Venetoclax_____ interacts with a specific liver 
enzyme called CYP3A4, and must be used very carefully 
with other medicines that interact with this enzyme.  
 Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care providers 
to review any medicines and herbal supplements that 
are considered strong inducers/inhibitors or 
substrates of CYP3A4.  
 Before prescribing new medicines, your regular health 
care providers should go to a frequently-updated 
medical reference for a list of drugs to avoid, or contact 
your study doctor.   
 Your study doctor’s name is  
_____________________________ and can be  
contacted at _________________________________.  

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Lymphoblastic Leukemia 
Appendix VI 
 
EA9152 Venetoclax Study Drug Request Form and EA9152 Investigational Product 
Destruction Record 
Downloading the EA9152 Venetoclax Study Drug Request Form and EA9152 
Investigational Product Destruction Record: These forms are available for download 
from the EA9152 protocol page located on the CTSU members’ website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol EA9152 
• 
Click on Documents tab, select the Pharmacy tab, and download and complete the 
forms provided. 
Rev. Add2