Clinical trial NCT04070768
Conditions: Acute Myeloid Leukemia
Keywords: relapsed refractory CD33+
Sponsor: John Quigley
Start date: 2019-09-06; Completion date: 2024-02-20
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase Ib Study to determine the Maximum Tolerated Dose (MTD) of Venetoclax in combination with Gemtuzumab Ozogamicin(GO) in subjects with relapsed/refractory acute myeloid leukemia. Using a standard 3+3 design, subjects will receive once cycle of combination therapy. After one cycle of combination therapy, subjects showing response will continue on to one cycle of consolidation therapy with GO\\Veneoclax. Subjects who respond to combination therapy will continue on maintenance Venetoclax until progression or unacceptable toxicity.

Dose-limiting toxicity, defined as an adverse event related (possible, probably, or definite) to Venetoclax and/or Gemtuzumab fulfilling one of the following criteria:

criteria:

* Hematologic toxicity: treatment-related grade 3 or worse neutropenia and/or thrombocytopenia due to bone marrow hypocellularity present at the end of cycle one (day 28) with an additional 28 days allowed for count recovery (i.e. present at day 56); specifically grade 3 or worse neutropenia or thrombocytopenia with the bone marrow documented to be free of leukemic infiltration. Note: patients who enter the study with grade 3 or worse cytopenias will not be evaluable for hematologic dose-limiting toxicities.
* Non-hematologic toxicity: any grade 3 or worse treatment-related toxicity occurring within the first cycle (excluding grade 3-4 infections during cycle one).

The study will also evaluate the Overall Response Rate, Anti-leukemic activity, Relapse-free Survival (RFS), event-free survival (EFS) , and overall survival (OS). The study will evaluate quality of life using the European Organization for the Research and Treatment of Cancer 30 item questionnaire (EORTC QLQ-C30).

Detailed description:

Arms: arm 1: Gemtuzumab Ozogamicin(GO) + Venetoclax
Interventions: intervention 1: Gemtuzumab Ozogamicin intervention 2: Venetoclax
Intervention descriptions: intervention 1: Gemtuzumab Ozogamicin 3mg/m\^2, Days 1,4,7 intervention 2: Venetoclax, 100,200,400, or 600mg Daily Dose

Protocol documents:
Prot_SAP_000.pdf: 
  
Clinical Study Protocol 
 
 
 
 
BTCRC-AML17-113 
 
Phase Ib study of the safety and efficacy of Gemtuzumab Ozogamicin (GO) and Venetoclax  
in patients with relapsed or refractory CD33+ acute myeloid leukemia: 
Big Ten Cancer Research Consortium BTCRC-AML17-113 
 
 
Sponsor Investigator 
John Quigley, MD 
University of Illinois Cancer Center (UICC) 
 
Co-Investigators 
Pritesh Patel, MD (UICC) 
Karen Sweiss, PharmD (UICC) 
& 
Brian Parkin, MD 
AdventHealth Orlando 
 
Statistician 
Gregory S. Calip, PhD (UICC) 
 
Trial Management  
Big Ten CRC Administrative Headquarters at Hoosier Cancer Research Network, Inc. 
7676 Interactive Way, Suite 120 
Indianapolis, IN 46278 
 
 
Trial Support  
Pfizer Inc. 
Pfizer reference number: WI234149 
 
AbbVie Inc. 
Reference Number: 11644 
 
 
Investigational New Drug (IND) Number: 
141995 
 
 
Initial Protocol Version Date: 06DEC2018 
 
Protocol Amendment Version Date: 
05MAY2020  
06AUG2020  
29MAR2021  
09JUN2022 (current) 
 


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PROTOCOL SIGNATURE PAGE 
 
Phase Ib study of the safety and efficacy of Gemtuzumab Ozogamicin (GO) and Venetoclax in patients 
with relapsed or refractory CD33+ acute myeloid leukemia 
 
 
VERSION DATE:  09JUN2022 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to the 
ethical principles stated in the latest version of the Declaration of Helsinki, the applicable guidelines for 
good clinical practices, whichever provides the greater protection of the individual.  I will accept the 
monitor’s overseeing of the study.  I will promptly submit the protocol to applicable ethical review 
board(s). 
 
 
 
 
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SYNOPSIS 
TITLE 
Phase Ib study of the safety and efficacy of Gemtuzumab Ozogamicin 
(GO) and Venetoclax in patients with relapsed or refractory CD33+ acute 
myeloid leukemia
PHASE 
Ib 
OBJECTIVES 
Primary Objective: To assess the maximum tolerated dose of Venetoclax 
when administered with Gemtuzumab Ozogamicin (GO) in patients with 
AML. 
 
Secondary Objectives: To assess the efficacy of this combination in 
achieving overall response rate (ORR) and anti-leukemic activity; 
characterize any adverse effects of GO in combination with Venetoclax; 
and estimate the relapse-free, event-free and overall survival.  
 
Exploratory Objectives: To assess the effects of therapy on quality of life; 
assess genomic minimal residual disease (MRD) to determine the kinetics 
of response and association with relapse-free survival.
STUDY DESIGN 
Dose-escalation study (Cohorts 1-3) to determine whether there is a dose-
limiting toxicity.
KEY ELIGIBILITY 
CRITERIA  
Eligible patients, 18–75 yrs, will have relapsed/refractory AML, as defined 
by the World Health Organization classification; ECOG Performance score 
0–2; adequate organ function; and do not meet exclusion criteria including 
WBC >25 × 109/L (hydroxyurea permitted to decrease WBC count), 
unresolved ≥grade 2 clinically significant nonhematologic toxicities from 
prior anticancer therapy or unresolved ≥grade 2 DIC, other active 
malignancy within 1 year before study entry, major organ dysfunction, 
active infections, or pregnancy or breastfeeding.
STATISTICAL 
CONSIDERATIONS 
Standard 3+3 design 
TOTAL  
NUMBER OF 
SUBJECTS 
N = 15-24 (n = 9-18, plus 6). 
ESTIMATED 
ENROLLMENT 
PERIOD 
18 months 
ESTIMATED STUDY 
DURATION  
30 months 
 
 


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TABLE OF CONTENTS 
 
Schema ........................................................................................................................................................ 6 
1. 
Background and Rationale ................................................................................................................ 10 
1.1 
AML Background ..................................................................................................................... 10 
1.2 
Investigational Treatment ......................................................................................................... 10 
1.3 
Rationale ................................................................................................................................... 12 
2. 
Study Objectives and Endpoints ........................................................................................................ 13 
2.1 
Objectives ................................................................................................................................. 13 
2.2 
Endpoints .................................................................................................................................. 14 
3. 
Eligibility Criteria .............................................................................................................................. 15 
3.1 
Inclusion Criteria ...................................................................................................................... 15 
3.2 
Exclusion Criteria ..................................................................................................................... 16 
4. 
Subject Registration........................................................................................................................... 17 
5. 
Treatment Plan................................................................................................................................... 18 
5.1 
Dose Escalation Rules............................................................................................................... 18 
5.2 
Definition of Dose-limiting Toxicities...................................................................................... 18 
5.3 
Dose Cohorts ............................................................................................................................. 19 
5.4 
Induction (Cycle 1) and Consolidation (Cycle 2): .................................................................... 19 
5.5 
Maintenance Phase: (see also section 6.2.2, Tables 7, 8) ......................................................... 20 
5.6 
Transplant-eligible Patients ...................................................................................................... 21 
5.7 
Pre-medication and Hydration .................................................................................................. 21 
5.8 
Concomitant Medications ......................................................................................................... 22 
5.9 
Supportive Care ........................................................................................................................ 24 
6. 
Toxicities and Dose Delays/Dose Modifications .............................................................................. 25 
6.1 
Toxicity ..................................................................................................................................... 25 
6.2 
Dose delays/modifications ........................................................................................................ 26 
6.3 
Protocol Therapy Discontinuation ............................................................................................ 28 
6.4 
Study Stopping Rules ................................................................................................................ 28 
7. 
Study Calendar & Evaluations .......................................................................................................... 30 
7.1 
Safety Follow-up Evaluations ................................................................................................... 32 
7.2 
Long Term Follow-up Evaluations ........................................................................................... 32 
8. 
Biospecimen Studies and Procedures ................................................................................................ 32 
8.1 
Correlative Studies .................................................................................................................... 32 
8.2 
Source and Timing of Biospecimen Collections ...................................................................... 34 
8.3 
Storage of Biospecimens........................................................................................................... 34 
8.4 
Banking of Leftover Biospecimens .......................................................................................... 34 
8.5 
Banking Samples for Future Unspecified Research ................................................................. 35 
8.6 
Confidentiality of Biospecimens............................................................................................... 35 
9. 
Criteria for Disease Evaluation ......................................................................................................... 35 
9.1 
Definitions of Response to Treatment in AML ........................................................................ 35 
9.2 
Definitions of Survival Endpoints for AML ............................................................................. 36 
10. 
Drug Information .......................................................................................................................... 36 
10.1 
Venetoclax (ABT-199) ............................................................................................................. 36 
10.2 
Gemtuzumab Ozogamicin (MYLOTARG™) .......................................................................... 37 
11. 
Adverse Events ............................................................................................................................. 39 


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11.1 
Definitions................................................................................................................................. 39 
11.2 
Reporting................................................................................................................................... 40 
11.3 
Sponsor-Investigator Responsibilities ...................................................................................... 43 
11.4 
IND Safety Reports Unrelated to This Trial ............................................................................. 43 
12. 
Statistical Methods ........................................................................................................................ 43 
12.1 
Study Design ............................................................................................................................. 43 
12.2 
Endpoints .................................................................................................................................. 43 
12.3 
Sample Size and Accrual .......................................................................................................... 44 
12.4 
Assessment of Safety ................................................................................................................ 44 
12.5 
Assessment of Efficacy ............................................................................................................. 44 
12.6 
Statistical Analysis Plans .......................................................................................................... 45 
13. 
Trial Management ......................................................................................................................... 46 
13.1 
Data and Safety Monitoring Plan (DSMP) ............................................................................... 46 
13.2 
University of Illinois Cancer Center Data Safety Monitoring Committee ............................... 46 
13.3 
Data Quality Oversight Activities ............................................................................................. 46 
13.4 
Compliance with Trial Registration and Results Posting Requirements .................................. 47 
14. 
Data Handling and Record Keeping ............................................................................................. 47 
14.1 
Data Management ..................................................................................................................... 47 
14.2 
Case Report Forms and Submission ......................................................................................... 47 
14.3 
Record Retention ...................................................................................................................... 47 
14.4 
Confidentiality .......................................................................................................................... 48 
15. 
Ethics............................................................................................................................................. 48 
15.1 
Institutional Review Board (IRB) Approval ............................................................................. 48 
15.2 
Ethical Conduct of the Study .................................................................................................... 48 
15.3 
Informed Consent Process ........................................................................................................ 48 
16. 
References ..................................................................................................................................... 50 
Appendix I – ECOG Performance Status ................................................................................................. 52 
Appendix II – New York Heart Association Classification ...................................................................... 53 
Appendix III – Prohibited and Cautionary Medications ........................................................................... 54 
Appendix IV – Cairo Bishop Guidelines .................................................................................................. 55 
Appendix V – Quality of Life and Fatigue Questionnaires ...................................................................... 56 
 
List of tables 
Table 1  Venetoclax Ramp-up Schedule ...................................................................................................18 
Table 2  Induction (Cycle 1) and Consolidation (Cycle 2) Venetoclax and Gemtuzumab  
Administration ...........................................................................................................................................21 
Table 3  Maintenance Venetoclax Administration (Cycles 3+) ................................................................21 
Table 4  Dose adjustments of Venetoclax in the presence of Posaconazole or other strong CYP3A  
inhibitors ....................................................................................................................................................22 
Table 5  Gemtuzumab Delay/Discontinuation ..........................................................................................25 
Table 6  Gemtuzumab Schedule for Dose Interruptions ...........................................................................25 
Table 7  Dose Duration Reduction for Venetoclax Toxicity (Maintenance) ............................................25 
Table 8  Venetoclax Dosing Regimen Modifications ...............................................................................26 
 
 


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SCHEMA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*If patients have grade 3 thrombocytopenia or neutropenia after holding venetoclax for 4 weeks, remove 
from study. 
BMBx after 1 maintenance cycle 
End of consolidation 
BMBx (D28) 
End of induction 
BMBx (D28)
Relapsed or Refractory AML patients who have received 3 or fewer lines of therapy 
Induction with Gemtuzumab + Venetoclax 
Gemtuzumab 3 mg/m2 Days 1, 4, and 7 
Daily Venetoclax 
Significant Residual Leukemic 
Blasts (less than PR)
CRi 
CR or PR 
Remove from study 
Hold Venetoclax 
for up to 4 weeks 
Platelets 50 to 99 x 109/L 
and ANC ≥ 1.0 x 109/L* 
Platelets ≥100 x 109/L 
and ANC ≥ 1.0 to x 109/L 
Consolidation 
Gemtuzumab 3 mg/m2 Days 1 and 4 
Daily Venetoclax
Maintenance 
Daily Venetoclax 
PR 
CR/CRi* 
Significant Residual Leukemic 
Blasts (less than PR) 
Remove from study 
Maintenance 
Venetoclax 
Maintenance 
Venetoclax 
Cr/CRi or PR and 
Venetoclax well tolerated
Increase in leukemic blasts 
Remove from study 
Continue maintenance 


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ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
AHQ 
Administrative Headquarters 
ANC 
absolute neutrophil count 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
aPTT 
Activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BCL-2 
B-cell lymphoma-2 gene 
BH3 
BCL-2 homology 3 domain 
BM 
bone marrow 
BMP 
basic metabolic panel 
BSA 
body surface area 
BTCRC 
Big Ten Cancer Research Consortium 
C1D1 
Cycle 1 day 1 
CBC 
complete blood cell count 
CI 
Confidence interval 
CLL 
chronic lymphocytic leukemia 
CLM 
Correlative Laboratory Manual 
CNS 
Central nervous system 
CR 
complete remission 
CRc 
complete cytogenetic response 
CRi 
complete remission with incomplete hematologic recovery 
CRp 
complete response with incomplete platelet recovery 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
dL 
Deciliter 
DLT 
dose-limiting toxicity 
DSMC 
Data Safety Monitoring Committee 
DSMP 
Data Safety Monitoring Plan 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 


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eGFR 
Estimated Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
FLT3 
FMS-like tyrosine kinase-3 
GO 
Gemtuzumab Ozogamicin 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HepC 
Hepatitis C 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
Hr 
Hour 
HR 
Hazard ratio 
HMA 
hypomethylating agent 
IB 
Investigator’s Brochure 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
Intra uterine device 
IV 
Intravenous 
Kg 
Kilogram 
Lb 
Pound 
LDAC 
low-dose cytarabine 
LDH 
lactate dehydrogenase 
LMWH 
low-molecular-weight heparin 
LSCs 
leukemia stem cells 
MCL-1 
myeloid cell leukemia-1 
Mg 
Milligram 
Min 
Minute 
mL 
Milliliter 
MOMP 
mitochondrial outer membrane permeabilization 
MRD 
minimal residual disease 
MTD 
maximum tolerated dose 
N/A 
Not applicable 
NCCN 
National Comprehensive Cancer Network 


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NCI 
National Cancer Institute 
NDC 
National Drug Code 
NS 
Normal saline 
ORR 
overall response rate 
OS 
overall survival 
PFS 
progression-free survival 
PK 
Pharmacokinetics 
PR 
partial remission 
PT 
Prothrombin time 
RFS 
relapse-free survival 
RP2D 
Recommend phase 2 dose 
RR 
response rate 
SAE 
serious adverse event 
SCT 
stem cell transplant 
SD 
stable disease 
TLS 
tumor lysis syndrome 
UI-Health 
University of Illinois Health 
ULN 
upper limit of normal 
UPIRSO 
unanticipated problems involving risk to subjects or others 
US 
United States 
USP 
United States Pharmacopeia 
VOD 
veno-occlusive disease 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
Wt 
Weight 


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1. 
BACKGROUND AND RATIONALE 
1.1 
AML Background 
AML is predominantly a disease of the elderly, yet the results of therapy are dismal for these patients, 
others deemed ineligible for standard cytotoxic induction chemotherapy, and especially for patients with 
previously treated relapsed/refractory AML. Very few such patients survive more than 2 years.1 
Refractoriness to AML treatment, or relapse, are caused by quiescent leukemia stem cells (LSCs) that are 
resistant to conventional chemotherapy. Targeted AML therapy for such infirm, usually elderly, patients 
seeks to exploit therapeutic differences between LSCs and normal hematopoietic stem cells to eradicate 
leukemia, with the aim of providing meaningful survival prolongation, and maintaining or improving their 
quality of life. 
 
In September 2017, the FDA approved GO for treatment of adult patients with CD33-positive, newly 
diagnosed or relapsed/refractory, AML. GO’s novel mechanism of action in combination with Venetoclax, 
a drug that has recently proved to be efficacious with manageable toxicities, will be investigated in this 
study.  
1.2 
Investigational Treatment 
1.2.1 Gemtuzumab Ozogamicin (GO) 
GO consists of a humanized anti-CD33 monoclonal antibody linked to calicheamicin, a potent antitumor 
enediyne antibiotic. GO binds to CD33, an antigen expressed on the surface of more than 90% of AML 
blast cells. Binding of GO is followed by internalization and intracellular release of calicheamicin, leading 
to DNA damage and subsequent mitochondria-dependent apoptosis. 
 
The original FDA approval for GO was based on phase II studies of 9 mg/m2 given on days 1 and 14 in 
277 patients with AML in first relapse, where it showed good tolerability, an overall response rate (ORR 
= complete remission (CR) and complete response with incomplete platelet recovery (CRp)) of 26%, and 
a median relapse-free survival (RFS) of approximately 6 months in patients aged >60 yrs (review2). To 
reduce the hematological and hepatic toxicities seen with this dose and schedule,3 a French Cooperative 
group performed a phase II trial of GO 3 mg/m2 given on days 1, 4, and 7, in patients with relapsed AML 
(n = 57).4 The rationale for lower dosing was based on responses observed with doses of 1–4 mg/m2 in 
the initial phase 1 study of GO. The administration of fractionated doses of GO was derived from 
observations of rapid re-expression of CD33 on the cell surface after an initial exposure (review5). The 
ORR was 33%, and median survival improved to 11 months, with a marked reduction in adverse effects 
(e.g., median duration of >grade 2 thrombocytopenia fell to 21 days).  
 
In a randomized phase III Cooperative group trial this GO dosing and schedule was next combined with 
a standard AML chemotherapy regimen (“7+3”) and compared to “7+3” alone—resulting in significant 
gains in 2 year event-free survival (EFS), overall survival (OS) and RFS, despite no difference in initial 
CR rates.6 These benefits were confirmed in a recent meta-analysis as extending to 6 years in AML 
patients with low or intermediate risk cytogenetics,7 suggesting addition of GO increases the eradication 
of LSC, particularly in more “mature” AML with CD33-expressing LSC (reviews8,9).  
 
Note that patients in CR or CRp after induction received two further consolidation cycles of 
Gemtuzumab Ozogamicin (3 mg/m2 on day 1) according to their initial randomization, in combination 
with daunorubicin and cytarabine.6 


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There are at least three recognized mechanisms of AML resistance to GO and calicheamicin (reviews5,9) 
including (i) decreased blast CD33 expression, related to common polymorphisms in CD33 splicing;10,11 
(ii) upregulation of drug transporters that re-export calicheamicin (e.g., p-glycoprotein5,12); and (iii), 
decreased apoptosis due to deficient activation of mitochondrial outer membrane permeabilization 
(MOMP), inhibiting the release of cytochrome c, subsequent caspase activation and blast cell death.5,13 
Of interest, apoptosis induced by GO (calicheamicin effect) is both CD95/Fas and p53 independent, is 
dependent on the pro-apoptotic proteins Bax/Bak, and strongly inhibited by overexpression of the anti-
apoptotic proteins BCL-2 or BCL-XL.13 Conversely, GO-related apoptosis is increased by drugs that 
appear to induce MOMP, such as PK11195.12 
1.2.2 Venetoclax 
Recent studies indicate that LSCs have a unique metabolic phenotype, with low levels of reactive oxygen 
species, a reliance on mitochondrial oxidative phosphorylation (rather than aerobic glycolysis), and 
aberrant overexpression of the B-cell lymphoma-2 gene (BCL-2). Inhibition of BCL-2 selectively targets 
mitochondrial energy metabolism in LSCs, and, due to their unique inability to upregulate glycolysis for 
adenosine triphosphate (ATP) production, induces cell death in LSCs but not in hematopoietic stem 
cells.14  
 
Venetoclax (ABT-199) is a recently developed BCL-2 homology 3 domain (BH3) mimetic, binding BCL-
2, and dislodging it from binding to Bak and Bax, to allow apoptosis.15 Thus it should specifically impact 
LSCs. Venetoclax is orally bioavailable, has demonstrated potent anti-leukemic activity in AML cell lines 
and primary patient samples, including LSCs, and is now being intensively studied in various hematologic 
malignancies, including AML.16,17 Notably, this BH3 mimetic has been granted FDA approval for 
treatment of previously treated chronic lymphocytic leukemia (CLL18) patients with 17p deletion after a 
phase II study showed an overall response rate of nearly 80%. 
 
As with most AML therapies, use of BH3 mimetics as monotherapy for AML is unlikely to be curative: 
acquired ABT-199 resistance rapidly occurs due to, for example, upregulation of other anti-apoptotic 
proteins such as BCL-XL or myeloid cell leukemia-1 (MCL-1), and their inhibition is then required to 
prevent glycolysis and induce LSC death in vitro.19 In accord with these observations, in in vivo studies, 
a recent phase II trial of ABT-199 monotherapy resulted in a CR rate of 19% in previously treated 
relapsed/refractory (“high risk”) AML patients, but median time to relapse was only 75 days.20 Thus, 
unlike in CLL, where BCL-2 is of primary importance, there is heterogeneous use of antiapoptotic proteins 
by AML LSCs, and more broad-based targeting using a LSC-targeting BH3 mimetic in combination with 
chemotherapies known to target LSCs (such as GO) may be more efficacious.15,20  
 
To date, early phase trials have demonstrated that in AML patients ineligible for standard “7+3” induction 
therapy, the addition of Venetoclax to standard “less intensive therapies” improves response rates while 
maintaining a tolerable safety profile. In an ongoing phase II study of Venetoclax (400 or 800 mg) in 
combination with standard dosing of the hypomethylating agents (HMA) Decitabine or Azacitidine in de 
novo AML patients, the ORR was over 70%. This lead to FDA breakthrough designation in January 2016 
for “Venetoclax use in combination with HMAs in treatment-naive patients ineligible for standard 
therapy”.21 In another early phase study Lin et al. combined Venetoclax with low-dose cytarabine (LDAC) 
and observed improved overall survival rates when compared with single agent LDAC.22 In these reported 
studies (n = 74) the most common grade 3/4 adverse events were those typically seen in AML-febrile 


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neutropenia, hypokalemia, and pneumonia.20-22 Of note, no reports suggested increased risk of 
hepatotoxicity or thrombocytopenia. 
 
Of interest, patients destined to respond to ABT-199 monotherapy in the phase II trial above20 were 
retrospectively identified based on “BH3 profiling” of their pretreatment AML blasts. BH3 profiling is a 
well-published assay to determine mitochondrial sensitivity to BH3 peptides, reflecting cancer cell 
“priming” or dependency on BCL-2 (in this case), BCL-XL, and/or MCL-1 for apoptosis protection. 
Importantly, BH3 profiling also strongly predicts LSC chemosensitivity.20,23 
1.3 
Rationale 
Based on previous studies, we propose a phase Ib dose-finding study of Venetoclax in combination with 
staggered dosing of GO for refractory/relapsed CD33+ AML patients, as a combination therapy that has 
several important synergies. 
1. By targeting BCL-2 proteins that protect AML cells from apoptosis, Venetoclax should increase 
the efficacy of GO, overcoming the resistance of leukemic cells to calicheamicin. 
2. They should have synergistic effects in eradicating LSCs (although they may target separate LSC 
populations). 
3. The combination should potentially target both low-, intermediate-, and high-risk AML patients 
(this population). 
4. Staggered dosing of GO may compensate for the low expression of CD33/slow uptake of GO in 
some patients with AML.12 
Most importantly, we believe this combination can provide meaningful survival prolongation in this 
vulnerable population, while maintaining or improving their quality of life. 
1.3.1 Rationale for enrolling patients into cohort 3 who are resistant to venetoclax 
Since the combination of venetoclax and hypomethylating agents (HMA) was granted accelerated 
approved by the FDA in November of 2018,24 its use in the front-line setting – as well as its off-label use 
in the relapsed/refractory AML (R/R AML) setting – has increased.  
 
However, there is a rationale for using venetoclax with gemtuzumab ozogamicin (GO) in venetoclax-
refractory patients. GO induces anti-leukemic activity by causing DNA scission in leukemic cells, which 
activates an apoptotic pathway that results in mitochondrial outer membrane permeabilization (MOMP).25 
In many AML samples BCL-2 overexpression occurs, decreasing MOMP.13 The rationale for use of 
venetoclax in BTCRC AML17-113 is to counteract this mechanism of apoptotic resistance.  
 
It is not clear how AML cells become resistant to venetoclax. One significant mechanism of resistance in 
CLL cells is that they undergo mutations in the BCL-2 gene which reduce binding by venetoclax.26 
However whether this particular mechanism of resistance occurs in AML is unknown. Studies on small 
numbers of patients receiving venetoclax-based combinations in AML have been performed. One such 
study looked at 25 patients, out of a total of 81 treated patients, who experienced adaptive resistance to 
venetoclax and HMA or low dose cytarabine. Of these 25 patients, 5 developed an increase in FLT3-ITD 
mutational burden, while 15 developed TP53 mutations/deletions.27 Notably, GO is known to have 
reduced activity in the context of TP53 mutations (TP53 upregulates the pro-apoptotic proteins NOXA, 
PUMA, BAX, BIM), whereas FLT3-ITD mutations do not have a clinically meaningful effect on GO 
efficacy.28 
 


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Thus while BCL-2:venetoclax interactions may still be occurring in venetoclax-resistant AML cells, it 
appears other mechanisms are likely preventing these cells from undergoing apoptosis, for example, 
upregulation of MCL-1 or BCL-XL.29 One may (simplistically) model intrinsic apoptosis as being 
prevented by the summation of these 3 important proteins, MCL-1, BCL-XL and BCL-2, thus the binding 
of BCL-2 by venetoclax should still aid apoptotic stimuli in that it reduces the total amount of anti-
apoptotic proteins in venetoclax-resistant cells. As an example of this the downregulation of MCL-1 by 
omacetaxine has been shown to overcome venetoclax resistance, resensitizing leukemia cells to BCL-2 
inhibition by venetoclax. In addition, calicheamicin is a potent driver of apoptosis, in contrast to HMA, 
which, at the doses used in the venetoclax/HMA regimen, are not directly cytotoxic.30 Thus, by using 
Gemtuzamab to increase the apoptotic stimulus, requiring increased levels of anti-apoptotic proteins, 
previously venetoclax-resistant leukemia cells should be induced to undergo apoptosis.  
 
In sum, we hypothesize that recruiting patients into BTCRC AML17-113 cohort 3 who are resistant to 
venetoclax is a therapeutically rational choice for the following reasons: 
(1) This cohort uses a dose of venetoclax, 600 mg, higher than the dose given with HMA (400 mg). 
Greater downregulation of BCL-2 should expose AML cells to greater apoptotic pressure.  
(2) GO should provide a greater stimulus to apoptosis, and the continued use of venetoclax means GO 
should provide this stimulus without being inhibited by BCL-2.  
(3) As TP53 mutations or deletions decrease the efficacy of GO, patients with AML who have been 
exposed to venetoclax AND who have developed TP53 mutations/deletion are likely not good 
candidates for this trial. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objective 
 Assess the maximum tolerated dose (MTD) of Venetoclax when administered with GO in patients 
with AML. 
2.1.2 Secondary Objectives 
 Estimate the efficacy of the combination in achieving ORR after first two cycles (overall response 
rate includes CR/CRi). 
 Estimate the efficacy of the combination in achieving anti-leukemic activity (CR/CRi/PR). 
 Characterize any adverse effects of GO in combination with Venetoclax. 
 Estimate the relapse-free, event-free and overall survival.  
 Longitudinal quantitative assessment of the effects of therapy on quality of life (QOL), degree of 
fatigue, and physical function. 
2.1.3 Exploratory Objectives 
 Longitudinal assessment of genomic minimal residual disease (MRD) to determine the kinetics of 
response and the association with relapse-free survival. 
 Explore the impact of CD33 variants, and the degree of CD33 expression on leukemic blasts, on 
the response rates and relapse-free survival. 
 Explore the relationship between leukemic blast BH3 profiling and response rates. 


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 Explore the relationship between leukemic blast expression of anti-apoptosis proteins (BCL-2, 
BCL-XL and MCL-1) and response rates.  
2.2 
Endpoints 
2.2.1 Primary Endpoint 
 Dose-limiting toxicity, defined as an adverse event related (possible, probably, or definite) to 
Venetoclax and/or Gemtuzumab fulfilling one of the following criteria: 
o Hematologic 
toxicity: 
treatment-related 
grade 
3 
or 
worse 
neutropenia 
and/or 
thrombocytopenia due to bone marrow hypocellularity present at the end of cycle one (day 28) 
with an additional 28 days allowed for count recovery (i.e. present at day 56); specifically 
grade 3 or worse neutropenia or thrombocytopenia with the bone marrow documented to be 
free of leukemic infiltration. Note: patients who enter the study with grade 3 or worse 
cytopenias will not be evaluable for hematologic dose-limiting toxicities.  
o Non-hematologic toxicity: any grade 3 or worse treatment-related toxicity occurring within the 
first cycle (excluding grade 3-4 infections during cycle one).  
2.2.2 Secondary Endpoints 
 Overall response rate (CR/CRi), as defined by the revised IWG criteria31. See Section 9.1. 
 Anti-leukemic activity (CR/CRi/PR), as defined by the revised IWG criteria31. See Section 9.1. 
 Adverse effects will be characterized using the CTCAE v5 criteria. 
 Relapse-free survival (RFS), event-free survival (EFS, and overall survival (OS). See Section 9.2 
 The European Organization for the Research and Treatment of Cancer 30 item questionnaire 
(EORTC QLQ-C30), The Functional Assessment of Cancer Therapy Fatigue (FACT-Fatigue) 
questionnaire, two-minute walk test, and timed chair stands will be performed at trial entry and 
every other month for 1 year.32  
2.2.3 Correlative/ Exploratory Endpoints 
 Genomic MRD with droplet digital PCR (ddPCR) will be measured to determine kinetics of 
response and the association with relapse-free survival at the end of cycles 1 and 2, at 6 months 
and 12 months, and if there is evidence of relapse. (Sub-PI is Dr. Brian Parkin [see ref. 33].) 
 CD33 DNA polymorphisms will be measured at presentation and at relapse. 
 Leukemic blast CD33 expression will be measured at presentation and at relapse. 
 “BH3 profiling”34 of AML blasts will be performed at presentation and at relapse.  
 BCL-2, BCL-XL, and MCL-1 protein levels in PB or BM blasts will be measured at presentation 
and after 6 days (i.e., Cycle 1 Day +3) of Venetoclax therapy.  
 
 


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3. 
ELIGIBILITY CRITERIA 
Study entry is open to adults regardless of gender or ethnic background. While there will be every effort 
to seek out and include women and minorities, the patient population is expected to be no different than 
that of other cancer studies at the hospitals participating in this trial. 
3.1 
Inclusion Criteria 
Subjects must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health information. 
NOTE: HIPAA authorization may be included in the informed consent or obtained separately. 
 
2. Ages 18 to 75 years at the time of consent. 
 
3. ECOG Performance Status of 0-2 within 7 days prior to registration; see Appendix I. 
 
4. Patients must have AML, as defined,35 that is relapsed or refractory. Prior therapy including 
chemotherapy, immunotherapy, biological or targeted therapy (e.g. FMS-like tyrosine kinase-3 
(FLT3) inhibitors, other kinase inhibitors, azacitidine, ATRA) is allowed.  
 
5. CD33 expression (by flow or IHC) in at least 20% of the leukemia blasts per local pathologist.36 
 
6. Prior cancer treatment must be completed at least 21 days prior to registration and the subject must 
have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to 
≤Grade 1 or baseline. 
 
7. Demonstrate adequate organ function as defined in the table below; all screening labs to be 
obtained within 28 days prior to registration.  
 
System 
Laboratory Value 
Renal
Calculated creatinine clearance 
≥30 cc/min using the  
Cockcroft-Gault formula
Hepatic
Bilirubin
≤1.5 × upper limit of normal (ULN)
Aspartate aminotransferase (AST) 
≤2 × ULN
Alanine aminotransferase (ALT) 
≤2 ×ULN
 
8. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 
days prior to registration. NOTE: Females are considered of child bearing potential unless they 
are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months 
 
9. Females of childbearing potential and males must be willing to use effective contraception during 
treatment and for at least 30 days after the last dose of Venetoclax. Females will be advised to use 
effective contraception for at least 6 months after the last dose of Gemtuzumab and males for at 
least 3 months after the last dose of Gemtuzumab.   
 


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10. As determined by the enrolling physician or protocol designee, ability of the subject to understand 
and comply with study procedures for the entire length of the study 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Patients with history of prior use of GO or Venetoclax 
NOTE: Starting with dose cohort 3, prior therapy with venetoclax is allowed, provided patients 
do not have evidence of p53 deletion or mutations. If the dose cohort is de-escalated to dose 
cohort 2 due to toxicity in cohort 3, prior exposure to venetoclax will continue to be allowed, 
provided patients do not have evidence of p53 deletion/mutations.  
 
2. History of myeloproliferative neoplasm [MPN] including myelofibrosis, essential 
thrombocythemia, polycythemia vera, CML with or without BCR-ABL1 translocation, and AML 
with BCR-ABL1 translocation. 
 
3. More than three lines of prior therapy. A line of therapy consists of ≥1 complete cycle of a single 
agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of 
various regimens (e.g., 3-6 cycles of initial therapy with bortezomib-dexamethasone [VD] 
followed by stem cell transplantation [SCT], consolidation, and lenalidomide maintenance is 
considered 1 line).37 
 
4. WBC >25 × 109/L. Cytoreduction is required (hydroxyurea as per local standard of care). 
 
5. Acute promyelocytic leukemia. 
 
6. Unresolved ≥grade 2 clinically significant nonhematologic toxicities from prior anticancer therapy 
or unresolved disseminated intravascular coagulation ≥ grade 2 per CTCAE v5 criteria. 
 
7. History of other malignancies within 1 year prior to study entry, with the exception of: adequately 
treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; basal cell carcinoma of 
the skin or localized squamous cell carcinoma of the skin; previous malignancy confined and 
surgically resected (or treated with other modalities), with curative intent. 
 
8. Investigational drug within 4 weeks of study entry.  
 
9. History of CHF requiring treatment, left ventricular ejection fraction ≤ 50%, cardiac insufficiency 
grade III or IV per New York Heart Association classification (NYHA; see Appendix II), or 
chronic stable angina 
 
10. Patients who are HIV positive.  
 
11. Known CNS involvement with AML. 
 
12. Previous hematopoietic stem cell transplant within 2 months. 
 


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13. Previous history of veno-occlusive disease/sinusoidal obstruction syndrome. 
 
14. Patients who are positive for hepatitis B or C infection with the exception of those with an 
undetectable viral load within 3 months. Subjects with serologic evidence of prior vaccination to 
HBV [i.e., HBs Ag-, and anti-HBs+] may participate. 
 
15. Active uncontrolled infection or severe systemic infection. Enrollment is possible after control of 
infection, at discretion of the treating physician. 
 
16. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is 
being treated on study). 
 
17. Patients who have received strong and/or moderate CYP3A inducers or inhibitors within 7 days 
prior to the initiation of study treatment unless deemed necessary by the treating physician. (See 
Section 5.8.2 and Appendix III) 
 
18. Patients who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment. 
 
19. Malabsorption syndrome or other condition that precludes enteral route of administration. 
 
20. Psychological, familial, sociological, or geographical condition that would preclude study 
compliance and follow-up. 
 
21. Unable or unwilling to undergo a screening bone marrow study.  
 
22. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may 
increase the risk associated with study participation or investigational product administration or 
may interfere with the interpretation of study results and, in the judgment of the investigator, would 
make the patient inappropriate for enrollment in this study. 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through Big Ten Cancer Research Consortium (Big Ten CRC) 
Administrative Headquarters’(AHQ) electronic data capture (EDC) system. A subject is 
considered registered when an ‘On Study’ date is entered into the EDC system. 
 
Registration will occur after the patient has signed the patient consent and eligibility is confirmed, 
but before any treatment has been administered. To be eligible for registration to this study, the 
patient must meet each of the criteria listed on the eligibility checklist. A copy of the eligibility 
checklist will be retained at the participating center. Subjects must begin therapy within 5 business 
days of registration.  
 
Venetoclax dose levels will be assigned at registration.  
 


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If a patient signs consent and is registered to the study and is later found to be unable to begin the 
planned study treatment, for whatever reason, the patient will be removed from study and treated 
at the physician’s discretion. The patient will be considered a screen/baseline failure and be 
replaced. Further data will not be collected if the patient has not begun study treatment at the time 
of removal from trial. The reason for removal from study will be clearly indicated in EDC. 
If a patient begins treatment, and then treatment is discontinued for whatever reason, the patient 
must be followed per section 7.2. 
5. 
TREATMENT PLAN 
This will be a single arm, open-label multicenter study of the combination of Venetoclax and GO 
in patients with AML. It will be an initial dose-escalation phase Ib study (Cohorts 1-3); using a 
standard 3+3 design to determine the maximum tolerated dose. There will be an induction and a 
consolidation cycle followed by a maintenance phase.  
5.1 
Dose Escalation Rules 
 Three to six subjects will initially be enrolled at dose level 1. If none of the 3 subjects 
experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional three 
subjects will be enrolled at dose level 2. If none of the 3 subjects at dose level 2 experience a 
dose limiting toxicity (DLT), an additional three subjects will be enrolled at dose level 3. If all 
subjects in dose level 3 complete the first cycle of therapy without DLT, 3 more subjects will 
be enrolled into dose level 3 to ensure only 0-1 of 6 subjects have a DLT. There will be no 
further escalation beyond dose level 3. 
 
 Alternatively, if 1 of the first 3 subjects within any given dose cohort experiences a DLT, an 
additional 3 subjects will be enrolled at that dose level. If only 1 of the total 6 subjects in a 
dose level experience a DLT, the study will proceed to the next dose level as planned. If 2 of 
the total 6 subjects in any given dose cohort experience a DLT, the next lower dose level will 
be explored and considered the maximum tolerated dose (MTD) if no more than 1 of 6 subjects 
experience a DLT. If this occurs in cohort 1, the dose will be decreased to cohort -1 and if 2 or 
more DLTs are reached in dose level -1, the study will be put on hold and a protocol 
amendment will be considered. [see Section 6.4 for “Stopping Rules”] 
 
 The MTD for Venetoclax in combination with Gemtuzumab Ozogamicin is defined as the dose 
level at which fewer than 33% of subjects experience a dose limiting toxicity (DLT), and 
specifically is the dose level at which less than 2 out of 6 subjects experience DLT. That dose 
will be the recommended Phase II dose (RP2D). 
 
 Once the RP2D has been identified, we will expand this cohort to include an additional six 
patients to further evaluate the efficacy and safety profile of the RP2D. 
5.2 
Definition of Dose-limiting Toxicities 
Dose-limiting toxicities (DLTs) are defined as an adverse event related (possible, probable or 
definite) to Venetoclax and/or Gemtuzumab Ozogamicin fulfilling one of the following criteria: 
o Hematologic toxicity: treatment-related grade 3 or worse neutropenia and/or 
thrombocytopenia due to bone marrow hypocellularity present at the end of cycle one (day 
28) with an additional 28 days allowed for count recovery (i.e. present at day 56); 


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specifically grade 3 or worse neutropenia or thrombocytopenia with the bone marrow 
documented to be free of leukemic infiltration. Note: patients who enter the study with grade 
3 or worse cytopenias will not be evaluable for hematologic dose-limiting toxicities. 
o Non-hematologic toxicity: any grade 3 or worse treatment-related toxicity occurring within 
the first cycle (excluding grade 3-4 infections during cycle one).  
 
NOTE: Events that can be clearly attributed to disease progression, concurrent illness or the 
effects of other medications will not be classified as DLTs.  
 
DLTs will be counted based on the number of patients with a DLT at a given dose level, not the 
absolute number of DLTs. No single patient can trigger more than one DLT. Intra-patient dose 
escalation is not permitted. 
5.3 
Dose Cohorts 
 
Cohort 
Number of 
Subjects 
Venetoclax 
Daily Dose (mg) 
Gemtuzumab Ozogamicin 
IV on Days +1, +4, +7 
–1 
3-6 
100 
3 mg/m2 
(up to one 4.5 mg vial) 
1 (start) 
3-6 
200 
2 
3-6 
400 
3 
3-6 
600 
 
5.4 
Induction (Cycle 1) and Consolidation (Cycle 2): 
Cycle 1: Gemtuzumab Ozogamicin (GO) 3 mg/m2 IV infusion (up to one 4.5 mg vial) will be 
given on days +1, +4, and +7 in combination with daily oral administration of Venetoclax during 
Induction. Based on previous studies,21,22 Venetoclax dose will start at 200 mg daily with dose 
escalation planned over 3 cohorts to identify the recommended phase 2 dose (RP2D). Dose cohort 
3 will use the maximum dose of Venetoclax of 600 mg orally daily. Because of evidence of tumor 
lysis syndrome (TLS) with Venetoclax use in previous CLL studies,18 we will use a 3-day stepwise 
ramp up in cycle 1 to the target dose for all cohorts (see Table 1).20-22 Patients should expect to be 
hospitalized throughout Induction/Cycle 1, although medically stable patients may be discharged 
from the hospital under close supervision at the discretion of the treating physician. Patients do 
not have to be hospitalized during the first week of consolidation if the treating physician wishes 
to administer Gemtuzumab (C2D1 and D4) in the outpatient clinic. 
 
Table 1. Venetoclax Ramp-up schedule  
Day 
Cohort 1 (mg) 
Cohort 2 (mg) 
Cohort 3 (mg) 
–2
50
50
100
–1
100
100
200
0
100
200
400
1–28
200
400
600


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Clinical and hematological responses will be assessed after the end of both the induction and 
consolidation cycles. Bone marrow assessment will occur on day 28 regardless of absolute 
neutrophil count (ANC) or platelet recovery. 
 
After induction, patients demonstrating complete remission or partial remission will continue to 
consolidation. Patients in CRi (ANC < 1.0 × 109/L or platelets < 100 × 109/L) will stop Venetoclax 
for up to four weeks to allow for cytopenia recovery. If the ANC recovers to ≥ 1.0 × 109/L and the 
platelets recover to ≥100 × 109/L, consolidation will ensue. If there is not full ANC AND platelet 
recovery to the aforementioned levels, consolidation will be omitted, and patients will enter the 
maintenance phase with Venetoclax alone provided they do not have any grade 3-4 cytopenias. 
The previously assigned Venetoclax dose will be resumed and the maintenance rules for 
Venetoclax dose adjustments or discontinuation will apply (see section 6.2.2). If however patients 
have a grade 3-4 cytopenia despite holding Venetoclax for four weeks, they will be removed from 
study [NOTE: this applies to both induction and consolidation.] 
 
Cycle 2: The second cycle (consolidation) will consist of GO 3 mg/m2 IV infusion (up to one 4.5 
mg vial) on days +1, and +4, in addition to daily oral administration of Venetoclax at the assigned 
dose. A bone marrow assessment will occur on day 28 regardless of cytopenias and those with CR, 
CRi, or at least a partial remission will continue onto maintenance therapy with Venetoclax alone. 
The previously assigned Venetoclax dose will be resumed and the maintenance rules for 
Venetoclax dose adjustments or discontinuation will apply (see section 6.2.2). 
 
After day 28, in the absence of leukemia in the BM, where there is a grade 3-4 cytopenia 
(thrombocytopenia or neutropenia), Venetoclax should be held for up to four weeks to allow 
recovery of counts to platelets ≥ 50 x 109/L and ANC ≥1.0 x 109/L (to allow entry into Maintenance 
Phase). Those who continue to have a grade 3-4 cytopenia will be taken off study. 
 
Patients with treatment failure (see Section 9.1) will be taken off study. Please note that any patient 
with residual disease (with at least PR) may move onto consolidation regardless of blood counts. 
5.5 
Maintenance Phase: (see also section 6.2.2, Tables 7, 8) 
Please note that any patient with residual disease (with at least PR) may move onto maintenance 
regardless of blood counts. 
 
Patients who enter a maintenance phase require platelets ≥ 50 x 109/L and an ANC ≥ 1.0 × 109/L. 
If a subject presents with a Grade 4 cytopenia for more than 1 week during Maintenance phase, 
unless it is thought to be due to the underlying disease, venetoclax dosing should be interrupted 
until platelets ≥ 50 x 109/L and ANC ≥ 1.0 x 109/L. 
 
During Maintenance, for subjects, in CR/CRi, receiving venetoclax who required >1 interruption 
or delay of study drug administration for grade 4 cytopenias, venetoclax, at dose prescribed for 
that cohort, should be administered for 21 days out of 28 days during each of the subsequent cycles. 
If, despite these modifications, a subject continues to have persistent grade 4 cytopenias, 
venetoclax should be administered for 14 days out of 28 days during each of the subsequent cycles. 


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If grade 3 cytopenias (i.e., ANC < 1.0 x 109/L and/or platelets < 50 x 109/L) persist please discuss 
with PI, however those who still continue to have a grade 4 cytopenia should be taken off study. 
 
Venetoclax therapy will be continued daily at the previously assigned dose for as long as patients 
continue to benefit or until disease progression or unacceptable toxicity.  
 
Patients who enter the maintenance phase in partial remission should have a bone marrow 
assessment after the first month of maintenance therapy (cycle 3). Those with an improved 
response should continue with maintenance Venetoclax. Those with stable disease should continue 
treatment if the drug is well-tolerated and if the primary hematologist believes that Venetoclax is 
of benefit. If there is disease progression, patients should be taken off study.  
5.6 
Transplant-eligible Patients 
Patients deemed suitable for transplant may be removed from the study at any point, at the 
discretion of the treating physician. We suggest a period of 2-3 months between the last dose of 
Gemtuzumab and the beginning of any HSCT conditioning regimen. In view of the infrequent 
association of VOD with Gemtuzumab use, we recommend the consideration of alternatives to 
TBI/TMI-containing protocols, which may increase the risk of VOD, for these patients. 
Ultimately, the final decision is deferred to the site PI.  
5.7 
Pre-medication and Hydration 
Gemtuzumab: 
Premedicate with acetaminophen 650 mg orally and diphenhydramine 50 mg orally or 
intravenously one hour (±15 min) prior to the administration and methylprednisolone 1 mg/kg or 
an equivalent dose of an alternative corticosteroid within 30 minutes (±10 min) prior to the infusion 
of GO.  
 
Additional doses of acetaminophen and diphenhydramine may be administered every 4 hours after 
the initial pretreatment dose. It is advised to repeat the same dose of methylprednisolone or an 
equivalent corticosteroid for any sign of an infusion reaction (e.g., fever, chills, hypotension or 
dyspnea) during the infusion or within 4 hours after the initial pretreatment dose.  
 
NOTE: For patients with hyperleukocytosis (leukocyte count greater than 25 x 109/L), 
cytoreduction (hydroxyurea) is required prior to starting treatment. 
 
Venetoclax: 
Venetoclax can cause rapid reduction in tumor thereby increasing the risk for TLS, despite the 
initial ramp-up phase. To mitigate risk of TLS, patients should receive 1.5 – 2 L hydration (oral or 
IV) daily in addition to use of a uric acid-lower agent starting at D-2 and continued until physician 
discretion.  
 
Per the National Comprehensive Cancer Network (NCCN) guideline, Venetoclax is classified as 
having a minimal to low emetic risk (<30% frequency of emesis). Antiemetic medications for 
breakthrough nausea will be prescribed at the primary investigator’s discretion.  
 


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If a patient misses a dose of Venetoclax within 8 hours of the scheduled dose, the patient should 
take the missed dose and then resume the normal daily dosing schedule. If a dose is missed by 
more than 8 hours, the patient should not take the missed dose and resume the daily dosing 
schedule the following day. If a patient vomits after a dose, no additional dose should be taken. 
 
NOTE: For patients with hyperleukocytosis (leukocyte count greater than 25 x 109/L), 
cytoreduction (hydroxyurea) is required prior to starting treatment. 
 
Table 2. Induction (Cycle 1) and Consolidation (Cycle 2) Venetoclax and Gemtuzumab 
Administration 
Drug 
Dose1 
Route 
Schedule 
Cycle 
Length 
Venetoclax3 
Assigned dose2 
Orally 
Days 1-28  
(Cycle 1: Day -2, -1, 0)2 
28 days 
Gemtuzumab 
3 mg/m2 
(up to one 4.5 mg vial)
Infusion 
Cycle 1: Days 1, 4, and 7 
Cycle 2: Days 1, 4 
1Body surface area (BSA) should be recalculated when weight changes by ≥ 10% according to the 
Mosteller formula. 
2Please see Table 1 stepwise ramp-up schema 
3Venetoclax tablets should be taken orally once daily with a meal and water. Do not chew, crush or 
break tablets. NOTE: Diaries will be provided for self-administration of Venetoclax when subjects 
are outpatient. On days when both venetoclax and gemtuzumab are given, it is preferred that 
subjects take venetoclax 1 hour prior to the GO infusion. However, variations from this guidance 
will not be considered as protocol deviations.
 
Table 3. Maintenance Venetoclax Administration (Cycles 3+) 
Drug 
Dose 
Route 
Schedule 
Cycle 
Length 
Venetoclax1 
Assigned 
dose 
Orally 
Days 1-28 
28 days 
1Venetoclax tablets should be taken orally once daily with a meal and water. Do not chew, crush 
or break tablets. NOTE: Diaries will be provided for self-administration of Venetoclax when 
subjects are outpatient. 
5.8 
Concomitant Medications 
5.8.1 Allowed Concomitant Medications 
All treatments the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care. 
 
Appropriate use of transfusions is recommended. Please refer to Supportive Care section for 
further details.  
 
Due to potential interference of azole antifungals with Venetoclax metabolism, non-azole 


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antifungals are recommended if antifungal prophylactic medications are used during prolonged 
episodes of grade 4 neutropenia (Induction phase).  
5.8.2 Prohibited Concomitant Medications 
Please see Appendix III for a table of prohibited and cautionary medications.   
 
In general, hematopoietic growth factors should not be used unless deemed to be necessary by the 
treating physician (see also section 5.7).  
 
Strong CYP3A Inhibitors 
Venetoclax is predominantly metabolized by CYP3A4/5 therefore concomitant use with strong 
CYP3A inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, 
lopinavir, ritonavir, ritonavir-boosted nirmatrelvir [Paxlovid], telaprevir, posaconazole, 
voriconazole) at initiation should be avoided. If use is deemed medically necessary by the treating 
physician (recognizing that this may increase the risk of tumor lysis syndrome), see Table 4 for 
dosing instructions. For patients who have completed the ramp-up phase and are on a steady daily 
dose of Venetoclax, see Table 4 for steady dose instructions38,39 – note that Posaconazole requires 
greater dose reductions than other strong CYP3A inhibitors. If the strong CYP3A inhibitor is 
discontinued, resume the Venetoclax dose that was used prior to initiating the CYP3A inhibitor 2 
to 3 days after discontinuation.39 
 
Table 4: Dose adjustments of Venetoclax in presence of Posaconazole or other strong 
CYP3A inhibitors 
Cohort
Assigned VEN 
Daily Dose (mg) 
Ramp-up day 
VEN dose with 
Posaconazole 
Daily Dose (mg) 
VEN dose with all 
other strong 
CYP3A inhibitors
Daily Dose (mg) 
-1 
100 
D-2
10
10
D-1
10
10
D0
10
20
Steady dose 
20 
30 
1 
200 
D-2
10
10
D-1
20
20
D0
30
30
Steady dose
40
50
2 
400 
D-2 
10 
10 
D-1
20
20
D0
50
50
Steady dose 
70 
100 
3 
600 
D-2
20
20
D-1
40
50
D0 
70 
100 
Steady dose
100
150
 


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Moderate CYP3A inhibitors and P-gp substrates 
Avoid use of moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin (not levofloxacin), 
diltiazem, dronedarone, fluconazole (>200mg), verapamil). Venetoclax should be administered 
using caution with substrates or inhibitors of P-gp. Studies indicate that venetoclax may increase 
the concentration of P-gp substrates. Narrow therapeutic substrates should be administered six 
hours prior to venetoclax administration.40 If concurrent use cannot be avoided, reduce the 
Venetoclax dose by at least 50%.  Resume the Venetoclax dose that was used prior to initiating 
the CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor.  
 
CYP3A Inducers 
Avoid use of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) 
or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). 
5.9 
Supportive Care 
Monitoring for tumor lysis is recommended and aggressive hydration and allopurinol prophylaxis 
should be implemented (see section 5.6.) 
 
It is recommended that the patient’s fluid status and hepatic and renal function and blood glucose 
levels be carefully monitored during the drug administration period. 
 
Venous Access: A central venous access device is strongly recommended for this study. 
 
Blood Product Support: Appropriate use of all blood products is recommended. Use of 
cytomegalovirus (CMV) negative products is strongly encouraged for patients documented to be 
CMV negative and who may later undergo bone marrow transplantation. 
 
Blood products should be irradiated following the current FDA guidelines found at: 
http://www.fda.gov/cber/gdlns/gamma.html 
 
Hematopoietic Growth Factors: Filgrastim (G-CSF) may be used at the treating physician’s 
discretion, provided bone marrow evaluation demonstrates no evidence of AML, to enhance 
neutrophil recovery when clinically indicated. The routine use of filgrastim in clinically well 
patients awaiting count recovery is not recommended. 
 
Prevention of Fungal Infections: Antifungal prophylaxis can reduce morbidity and fungal 
infection-related mortality in severely neutropenic chemotherapy recipients. Evidence for benefit 
is strongest for those conditions associated with > 15% rate of systemic fungal infection such as 
prolonged neutropenia, as observed in AML patients and stem cell transplant (SCT) recipients and 
is recommended for study patients during Induction. Hospitalized patients who require prophylaxis 
should receive micafungin, or other non-azole agents (see section 5.8 above). 
 
Management of Fever and Neutropenia: Patients with an ANC < 500/μL (or < 1000/μL and falling) 
and an oral temperature > 38°C twice in 24 hours or > 38.3°C once, should have empiric systemic 
antibiotics initiated immediately after appropriate cultures are drawn. The specific choice of 
empiric antibiotics should be guided by the resistance patterns seen at the individual institution.  
The antibiotic regimen chosen for febrile neutropenia should contain activity against gram-


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negative organisms and Pseudomonas aeruginosa in particular. Note: aminoglycosides increase 
the risk of nephrotoxicity.  
 
The persistence of fever for > 3 days despite broad spectrum antibiotic therapy or the emergence 
of a new fever in a neutropenic patient warrants investigation for invasive fungal infection and 
initiation of empiric antifungal therapy. Antifungal options include echinocandins (micafungin, 
capsofungin, and anidulafungin), amphotericin B (or lipid amphotericin products), as well as 
combination therapy. Azole antifungal medications should be avoided, if possible. The choice of 
specific agent(s) and length of therapy will be dictated by the suspected or confirmed fungal 
species, site of infection, and clinical status. Consultation with an Infectious Disease physician is 
recommended. 
 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests before 
and at regular intervals during their participation in this study as specified in Study Calendar & 
Evaluations. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation as specified in Study Calendar & 
Evaluations.  
 
The intent of the study design is for all patients to complete induction, consolidation and 
maintenance with the exception of those who experience an unacceptable toxicity or if the 
investigator determines that discontinuation of treatment is in the best interest of the patient. Please 
see sections 6.2.1 and 6.2.2 below for individual drug exceptions that are applicable throughout 
the entire study.   
6.1 
Toxicity 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade 
adverse events. DLTs are defined in detail in section 5.2 
6.1.1 Hematologic Toxicity  
DLT definition: Grade 3-4 or worse neutropenia or thrombocytopenia occurring after day 56 due 
to bone marrow hypocellularity and with the bone marrow documented to be free of leukemic 
infiltration. 
6.1.2 Non-hematologic Toxicity  
DLT definition: Defined as any grade 3 or worse treatment-related toxicity (excluding grade 4 
infections) occurring within the first 56 days.  
 
In general, dose interruptions for grade 3 or 4 non-hematologic toxicities occurring after day 56 
will be at the discretion of the primary oncologist. Please see the individual drug sections below 
for further detail on dose modifications and special exceptions [tables 5,6, 8]. 
 


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6.2 
Dose delays/modifications 
During induction and consolidation, there will be no dose reductions of study drugs for 
hematologic toxicity. For patients in CRi after day 28 of induction, Venetoclax may be held for up 
to four weeks, to allow for platelet or ANC recovery. Note CBC will be performed at least twice 
weekly and consolidation should start as soon as platelets recover to 100 x 109/L and ANC 
recovers to 1.0 x 109/L. If platelets or ANC do not recover within 4 weeks, patients will not receive 
further GO and will enter the Venetoclax maintenance phase. Patients who enter the maintenance 
phase must have platelets ≥ 50 x 109/L and an ANC ≥ 1.0 × 109/L. If there is a grade 3 or worse 
cytopenia present after holding Venetoclax for up to 4 weeks, patients will be removed from study.  
 
At the end of consolidation, Venetoclax may be held again for up to four weeks, maintenance 
phase can be started as soon thrombocytopenia or neutropenia improves to less than a grade 3 
toxicity, unless there is still residual disease in the bone marrow, in which case treatment can 
proceed regardless of ANC/platelet count. NOTE: If a grade 3 cytopenia persists after 4 weeks of 
holding Venetoclax for up to 4 weeks following induction or consolidation, patients will be 
removed from study.  
6.2.1 Gemtuzumab 
Table 5. Gemtuzumab Delay/Discontinuation 
Event 
Gemtuzumab Action 
Persistent Thrombocytopenia 
Discontinue if platelets do not recover to ≥ 100 x 10
9/L 
after temporary cessation of Venetoclax for four weeks 
Persistent neutropenia 
Discontinue if ANC does not recover to ≥ 1.0 x 10
9/L after 
temporary cessation of Venetoclax for four weeks 
VOD 
Discontinue 
Total bilirubin > 2 × ULN, or 
AST and/or ALT > 2.5 × ULN 
Interrupt until recovery of total bilirubin to ≤2 times ULN 
and AST and/or ALT to ≤2.5 times ULN. 
 
The scheduled dose will be omitted if there is a delay of 3-6 days between sequential infusions. 
Table 6. Gemtuzumab Schedule for Interruptions 
Time from missed dose 
Action 
<3 days
Give missed dose
3-6 days
Skip dose
≥7 days
Off study
 
 


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6.2.2 Venetoclax39, 41 
Table 7. Dose Duration Reduction for Venetoclax Toxicity (Maintenance) 
Venetoclax 
toxicity event 
Current (cohort) 
dosing regimen 
Modification of 
dosing regimen 
1st event
28 days
28 days
2nd event
28 days 
21 days
3rd event
21 days
14 days
4th event
14 days
discontinue
 
There will be no dose reductions of Venetoclax for hematologic toxicity during cycles 1 and 2. Patients 
who are in CRi after either cycle may temporarily discontinue Venetoclax for up to four weeks to allow 
for platelet or ANC recovery. Patients who enter the maintenance phase must have platelets ≥ 50 x 109/L 
and an ANC ≥ 1.0 × 109/L 
 
If a dose reduction is required, please follow the guidelines in Table 7. Missed Venetoclax doses are not 
to be made up.  
 
Table 8. Venetoclax Dosing Regimen Modifications  
Toxicity 
Occurrence 
Action 
Tumor Lysis Syndrome (TLS) 
TLS defined by the 
Cairo-Bishop 
criteria; see 
Appendix IV 
Any 
Implement standard TLS treatment (increase IVF). 
Withhold Venetoclax if TLS labs do not improve by 
25% within 24 hours. Resume once TLS labs 
improve. 
Non-Hematologic Toxicities (Consolidation and Maintenance only) 
Grade 3 or 4 non- 
hematologic 
toxicities 
1st occurrence 
Withhold Venetoclax. Once the toxicity has resolved 
to Grade 1 or baseline, resume at same dose.
2nd and 
subsequent 
occurrences 
Withhold Venetoclax. Once the toxicity has resolved 
to Grade 1 or baseline, resume at a reduced dosing 
duration (see Table 7). 
Hematologic Toxicities (Maintenance only) 
Grade 4 neutropenia 
with or without 
fever; or Grade 4 
thrombocytopenia 
1st occurrence 
Interrupt Venetoclax. To reduce infection risks 
associated with neutropenia, G-CSF may be 
administered if clinically indicated, provided there is 
bone marrow confirmation of leukemia clearance. 
Once the toxicity has resolved to Grade 2 or baseline, 
resume at the same dose duration (Table 7).
2nd occurrence 
Interrupt Venetoclax. Consider using G-CSF as 
clinically indicated. Once the toxicity has resolved to 
Grade 2 or baseline, follow dose duration reduction 
guidelines (Table 7). 


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3rd and 
subsequent 
occurrences 
Interrupt Venetoclax. Consider using G-CSF as 
clinically indicated. If toxicity remains at grade 3, 
may discuss with PI regarding treatment options. If 
grade 4 toxicity persists, remove from study (Table 7).
Consider discontinuing Venetoclax if toxicities recur despite two dose duration reductions 
 
6.3 
Protocol Therapy Discontinuation 
In addition to discontinuation due to therapy-related toxicities as outlined in section 6.1, a subject 
will also be discontinued from protocol therapy and then followed up per protocol under the 
circumstances outlined below. The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF) and should also be discussed with the study 
sponsor-investigator. 
 Documented disease progression  
 Unacceptable toxicity 
 The treating physician believes a change of therapy would be in the best interest of the subject 
 Follow-up bone marrow biopsy demonstrates either significant residual leukemic blasts or 
significant cytoreduction with a high percentage residual leukemic blasts, but BM study is 
deemed by the hematopathologist to demonstrate less than a partial response. 
 Bone marrow biopsy during maintenance phase shows stable disease but the treating 
hematologist believes that the Venetoclax is no longer of benefit. 
 DLT as defined above or if there is grade 3 neutropenia or thrombocytopenia after holding 
Venetoclax for four weeks at the end of cycles 1 or 2 
 Patient is unable to comply with protocol requirements 
 The subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons. If a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be contacted for further scheduled 
study assessments. The outcome of that discussion should be documented in both the medical 
records and in the eCRF. 
 A female subject becomes pregnant  
 Development of a second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment which would interfere with this study. 
 If protocol therapy is interrupted for ≥ 30 days.  
 Lost to follow up. If a research subject cannot be located to document survival, the subject may 
be considered “lost to follow-up.” All attempts to contact the subject must be documented.  
 
If a subject decides to withdraw from the study (and not just from protocol therapy) all efforts 
should be made to complete the final study assessments. The site study team should contact the 
subject by telephone or through a clinic visit to determine the reason for the study withdrawal. If 
the reason for withdrawal is an adverse event, it will be recorded on the eCRF. 
6.4 
Study Stopping Rules 
This is a phase I trial with a 3+3 study design. Subjects will be monitored for DLTs lasting no later 
than Day 56; however, if all patients in a dose cohort have recovered from DLTs prior to Day 56, 
dose escalation may proceed. If a DLT occurs in 1 of the 3 subjects in a given dose cohort, the 
dose cohort will be expanded to 6 subjects. If 2 of the total 6 subjects in any given dose cohort 


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experience a DLT, the next lower dose level will be explored and considered the maximum 
tolerated dose (MTD), if no more than 1 of 6 subjects experience a DLT. If this occurs in cohort 
1, the dose will be decreased to cohort -1 and if 2 or more DLTs are reached in dose level -1, the 
study will be put on hold and a protocol amendment will be considered. 


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7. 
STUDY CALENDAR & EVALUATIONS  
Cycle = 28 days
Screen 
Induction2, 3 
Consolidation2,3 
Maintenance
Phase2,3
Follow up4 
Cycle 1 
Cycle 2  
Cycles 3+ 
Safety 
F/U 
Long-term 
Follow up
-28 
days1
Ramp 
up 
D1 
D15 
D28 
D1 
D15 
D28 
D1 
D15 
30 days 
post Tx 
Q 2 months 
(±14 days)4 
REQUIRED ASSESSMENTS 
Informed Consent
X
Medical history, Prior therapy, trial awareness5
X
Physical exam, ECOG Performance status
X
X
X
X
X
X
X
C3
X
X
Vital signs (temp, HR, BP)
X
X
X
X
X
X
X
C3
X
X
Height (screening only), weight
X
X
X
X
X
X
C3
X
Con meds, AEs, venetoclax drug diary review6
X
X
X
X
X
X
X
C3
X
X
QLQ-C30, FACT-Fatigue, walk test, chair stands 
X12
X
Q213
X12
EKG, Echocardiogram
X
LABORATORY ASSESSMENTS 
Pregnancy test (serum or urine) WOCBP7
-7d
Hepatitis B/C and HIV screen
X
Complete Blood Cell Count with diff (CBC)
X
X8
X8
X8
X
X8
X8
X
X
X
X
X
Basic Metabolic Panel (BMP), Uric Acid
X
X8
X8
X8
X8
X8
X
X
X
Albumin, ALT, AST, bili, alk phos, T protein, LDH 
X
X8
X8
X8
X8
X
X
X
PT/INR PTT, fibrinogen 
X 
X8 
X8 
X8 
 
 
 
 
 
 
 
 
DISEASE ASSESSMENT 
Bone Marrow Aspirate and Biopsy9 
-14d1,9 
 
 
 
X 
 
 
X 
C3 (if PR) 
C79, C139, relapse 
 
TREATMENT EXPOSURE 
Gemtuzumab Ozogamicin (IV)
1,4,7 
1,4 
Venetoclax (PO)
-2,-1,0
D1-28
D1-28
D1-28
CORRELATIVE STUDIES (SPECIMEN COLLECTION)
Buccal Swab
X12
Whole Blood10
X10,11
D310
X10
X10
C710, C1310, relapse
Bone Marrow Aspirate11
X11,12
X11
X11
C711, C1311, relapse
BANKING SAMPLES (SPECIMEN COLLECTION)
Whole Blood, Serum and Plasma14
X
X
X
C7, C13, relapse
FOLLOW-UP 
Survival status, subsequent therapy 
X15


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1: Screening assessment needs to be completed within 28 days. Exception: Bone marrow aspirate needs to be collected within 14 days prior to 
initiation of treatment. 
2: See section 5 for treatment plan. 
3: A window of ±3 days will be applied to all cycle 1 and 2 treatment visits; a ±7-day window will apply for maintenance visits. 
4: Subjects without documented disease progression will be followed for disease progression every 2 months (±14 days) for 6 months. Once 
disease progression is documented, subjects will enter a survival follow up period: every 2 months for 6 months from the time of documented 
progression. 
5: Medical history will capture genetic sequencing results/cytogenetics report, prior substance abuse, organ transplant, history of liver disease and 
family history of cancer.  
6: Drug diary review will be performed on Day 1, prior to dispensing the next cycle of venetoclax. 
7: For women of childbearing potential (WOCBP): urine or serum βhCG, within 7 days prior to study registration. If a urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. 
8: CBC should be performed daily while subjects are in the hospital. Basic metabolic panel (calcium, carbon dioxide, chloride, creatinine, glucose, 
potassium, sodium, urea nitrogen), coags and uric acid measurements will be performed at least every 8 hours during the ramp up and every 8-12 
hours during Cycle 1 Days 1-3 to monitor for tumor lysis syndrome. Subsequently, recommend basic metabolic panel and liver function tests be 
performed at least three times weekly during the induction phase. Uric acid should be evaluated at further intervals at the discretion of the 
investigator. Recommend measuring coags weekly during the remainder of the induction phase. During consolidation, recommend measuring 
these labs daily while patient is in hospital and at least weekly when outpatient, at the discretion of the treating physician. During maintenance, 
recommend measuring these labs at least once every two weeks when outpatient, at the discretion of the treating physician. 
9: Bone Marrow Aspirate and Biopsy and/or evaluation of extramedullary site with immunophenotyping, cytochemistry, and cytogenetics 
(karyotype ± FISH): to be completed at pre-treatment (within 14 days), Day 28 ± 3 days during cycles 1 and 2, and ± 14 days pre-treatment cycle 7 
day 1 (i.e. ~6 mo), pre-treatment cycle 13 day 1 (i.e. ~12 mo), and relapse. Patients in PR at the end of consolidation should have a repeat BM 
assessment after one month of maintenance. 
10: Whole blood to be collected pre-treatment, Cycle 1 Day +3 (±1 day), end of induction, end of consolidation, pre-treatment cycle 7 day 1 (i.e. 
~6 mo), pre-treatment cycle 13 day 1 (i.e. ~12 mo), and relapse. See section 8.  See Correlative Laboratory Manual (CLM) for collection, labeling, 
processing, and shipping instructions. 
11: Bone marrow aspirate to be collected pre-treatment, end of induction, end of consolidation, pre-treatment cycle 7 day 1 (i.e. ~6 mo), pre-
treatment cycle 13 day 1 (i.e. ~12 mo), and relapse. See CLM for collection, labeling, processing, and shipping instructions. Left-over samples will 
be banked for potential future studies, with patient consent. See section 8. 
12: Pre-treatment evaluation includes buccal swab, whole blood collection, QOL (QLQ-C30, FACT-Fatigue), walk test, and chair stands. Pre-
treatment bone marrow aspirate will be collected at screening. Aspirate collection for correlative studies is required prior to therapy.  
13: QOL (QLQ-C30, FACT-Fatigue), walk test and chair stands to be performed pre-treatment, at the end of consolidation, every other cycle 
starting with Cycle 4 and throughout long term follow up.  
14: Whole Blood, Serum and Plasma for banking to be collected pre-treatment, end of induction, end of consolidation, pre-treatment cycle 7 day 1 
(i.e. ~6 mo), pre-treatment cycle 13 day 1 (i.e. ~12 mo), and relapse. See CLM for collection, labeling, processing, and shipping instructions. 
15: It is suggested that patients should not receive HSCT conditioning within 2-3 months of last Gemtuzumab dose and that total body irradiation 
(TBI)/ total marrow irradiation (TMI) as part of a HSCT conditioning regimen be avoided, if possible, per discretion of the site PI.  


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7.1 
Safety Follow-up Evaluations 
A safety follow-up visit will occur when subjects permanently stop study treatment for whatever 
reason (toxicity, progression, or at discretion of site investigator) and will be performed 30 days 
(±7 days) after the last dose of treatment. Subjects who have an ongoing ≥ grade 2 or serious AE 
(SAE) at this visit will continue to be followed until the AE resolves to ≤ Grade 1 or baseline, is 
deemed clinically insignificant, and/or until a new anti-cancer treatment starts, whichever is 
earlier. 
7.2 
Long Term Follow-up Evaluations 
All subjects will be followed until documented disease progression. Subjects who discontinue 
treatment for any reason without documented disease progression will be followed for disease 
progression every 2 months (±14 days) for 6 months.  
 
Once disease progression is documented, subjects will enter a survival follow up period every 2 
months (±14 days) for 6 months from the time of documented progression.   
 
Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. 
 
8. 
BIOSPECIMEN STUDIES AND PROCEDURES   
8.1 
Correlative Studies 
 
8.1.1 Longitudinal assessment of genomic minimal residual disease (MRD) with droplet digital PCR 
(ddPCR) will determine the kinetics and depth of response and its association with RFS and OS. 
ddPCR is a novel technology capable of detecting gene mutations in as few as 1 in 50,000 cells, 
providing a highly sensitive platform for AML MRD measurement.42 DNA extracted from pre-
treatment patient bone marrow or peripheral blood mononuclear cells (PBMC) will undergo 
targeted deep sequencing of recurrently mutated genes in AML and/or whole exome sequencing 
to identify somatically-acquired leukemia-associated gene mutations. These mutations will be 
confirmed to be somatic by Sanger resequencing of both tumor and germline (derived from buccal 
swab) DNA. ddPCR will then detect these mutations in serial post-treatment samples (4 time 
points: end of induction, end of consolidation, and at 6 months and 12 months) using genomic 
DNA from bone marrow and/or PBMC as well as plasma-based cell-free DNA to determine the 
presence of genomic MRD at each time point. Both the rate and maximal level of reduction of 
leukemia-associated gene mutations will be correlated with RFS and OS. The measurement of 
multiple genes per patient will allow assessment of clonal dynamics in the MRD state and the 
relative clearance of leukemic versus pre-leukemic cells (defined as clones containing all gene 
mutations identified pre-treatment or those containing only a subset of those gene mutations, 
respectively). These experiments will be performed at the laboratory of Dr. Brian Parkin. 
  
8.1.2 Association of CD33 cell-surface expression and CD33 single nucleotide polymorphisms 
(SNP) and somatic mutations with response to the combination of GO and Venetoclax will be 
determined based on serial genomic MRD levels, CR, and RFS. The presence of splice acceptor 
SNPs that lead to alterative splicing of CD33 that eliminates the IgV portion of the molecule to 


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which GO binds has recently been shown to adversely influence clinical effectiveness of GO in 
trials including GO alone or in combination with chemotherapy.11 In order to study the impact of 
such CD33 variants in this trial, all coding exons and adjacent intronic sequences of CD33 will be 
sequenced from genomic DNA extracted from pre-treatment samples and paired buccal swabs to 
identify germline SNPs and acquired somatic mutations. Similar sequencing will be performed on 
any relapsed specimens as well to determine emergence of secondarily-acquired CD33 mutations. 
The presence of isoform altering mutations will be confirmed with isoform specific qPCR of 
mRNA extracted from pre-treatment samples. Finally, cell surface expression of CD33 isoforms 
including or lacking the IgV region will be determined using flow cytometry with isoform specific 
antibodies (anti-CD33 clones P67.6 and HIM3-4, respectively).43 These experiments will be 
performed at the laboratory of Dr. Brian Parkin. 
 
8.1.3 Identification of clonal evolution and secondarily acquired mutations in refractory and 
relapsed patient samples may reveal mechanisms underlying treatment failure. For patients 
who do not respond to the induction and consolidation cycles of the investigational therapy or who 
relapse after initial response, whole exome sequencing may be performed on germline controls 
(derived from buccal swabs), pre-treatment tumor samples, and tumor samples obtained at the time 
of treatment failure in order to identify the presence of primary or secondary acquisition of 
mutations that may be related to the mechanisms of treatment failure. For relapsed patients, ddPCR 
will be used to track mutations acquired or enriched in the relapse clone into the pre-treatment and 
CR samples in order to determine if the relapsed clone acquired the mutations after treatment or if 
a minor preexisting clone was enriched as a result of treatment. These experiments will be 
performed at the laboratory of Dr. Brian Parkin. 
 
8.1.4 BCL-2 Family Protein Analysis prior to, and after Venetoclax exposure may reveal adaptive 
changes in anti-apoptotic protein expression. Leukocytes isolated from pretreatment and Day+3 
(C1D3) peripheral blood will be analyzed by semi-quantitative Western blot analysis for BCL-2, 
BCL-XL and MCL-1 expression.16 If sufficient samples are available then PBMNC samples from 
pretreatment and Day+3 will also be permeabilized, incubated with fluorescent antibodies to BCL-
2, BCL-XL and MCL-1, and expression measured by flow cytometry.20 Analysis will also be 
performed on relapse samples (if this occurs). These experiments will be performed at the 
University of Illinois in the laboratory of Dr. John Quigley. 
 
8.1.5. BH3 profiling predicts response to therapy. 
Thawed BM samples from pretreatment and, potentially, relapse samples will be permeabilized, 
incubated with various BH3 peptides and subsequently mitochondrial cytochrome C release 
measured by flow cytometry analyses.16 These experiments will be performed at the University of 
Illinois in the laboratory of Dr. John Quigley. 
 
8.1.6 Quality of life, fatigue, and physical function will be assessed at baseline and every other 
month for one year to measure the effects of therapy.32 Quality of life (QOL) will be assessed 
using the European Organization for the Research and Treatment of Cancer 30 item questionnaire 
(EORTC QLQ-C30). The questionnaire is scored from 0 to 100, higher scores positively correlate 
with a better QOL. The Functional Assessment of Cancer Therapy Fatigue (FACT-Fatigue) 
questionnaire consists of 13 items with scores ranging from 0 to 52, higher scores positively 


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correlate with less fatigue. Objective physical measures will consist of a two-minute walk test, and 
timed chair stands. See Appendix V for sample questionnaires.  
8.2 
Source and Timing of Biospecimen Collections 
8.2.1 Buccal swab:  
Patients will have buccal mucosal cells collected prior to treatment using two buccal swabs to 
provide germline DNA. See Correlative Laboratory Manual (CLM) for collection, labeling, 
processing, and shipping instructions. 
8.2.2 Bone marrow aspirate:  
Bone marrow aspirate material will be collected will be collected prior to treatment, at the end of 
the induction cycle (Cycle 1 Day 28 ± 3 days), at the end of the consolidation cycle (Cycle 2 Day 
28 ± 3 days), at pre-treatment cycle 7 day 1 (i.e. ~6 months after initial treatment) (± 14 days), at 
pre-treatment cycle 13 day 1 (i.e. ~12 months after initial treatment) (± 14 days), and at any time 
of suspected relapse. Leukocytes from the bone marrow aspirate will be isolated by Ficoll gradient 
centrifugation and cryopreserved for use in the correlative studies described. See CLM for 
collection, labeling, processing, and shipping instructions. 
8.2.3 Peripheral blood:  
Peripheral blood samples will be collected prior to treatment, at Cycle 1 Day +3 (± 1 day), at the 
end of the induction cycle (Cycle 1 Day 28 ± 3 days), at the end of the consolidation cycle (Cycle 
2 Day 28 ± 3 days), at pre-treatment cycle 7 day 1 (i.e. ~6 months after initial treatment) (± 14 
days), at pre-treatment cycle 13 day 1 (i.e. ~12 months after initial treatment) (± 14 days), and at 
any time of suspected relapse. Correlative peripheral blood samples will preferentially be obtained 
during clinically indicated peripheral blood draws. Plasma will be isolated and frozen, and 
leukocytes will be isolated by Ficoll gradient centrifugation and cryopreserved for use in the 
correlative studies described.  See CLM for collection, labeling, processing, and shipping 
instructions. 
8.3 
Storage of Biospecimens 
8.3.1 Specimen Processing and Storage:  
Buccal swabs will be stored at -20° until DNA extraction. Plasma will be isolated from peripheral 
blood tubes and stored in aliquots at -80°. Bone marrow aspirates and peripheral blood samples 
will undergo Ficoll gradient centrifugation and mononuclear cells with be aliquoted and 
cryopreserved in liquid nitrogen. These samples will be stored in the central lab for use in the 
correlative studies outlined in this protocol as well as for future research. 
 
Please refer to the Correlative Laboratory Manual (CLM) for all sample collection, processing, 
labeling, and shipping instructions. 
8.4 
Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples collected for study-specific 
correlative research. Hoosier Cancer Research Network (HCRN), as Administrative 
Headquarters for the Big Ten CRC, will manage the banked samples. Samples will be banked 


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indefinitely in the Hoosier Cancer Research Network Biorepository and used for future 
unspecified cancer-related research. 
8.5 
Banking Samples for Future Unspecified Research 
Subject consent will be obtained to collect additional blood samples for future unspecified Big 
Ten Cancer Research Consortium studies. HCRN will manage the banked samples. Samples will 
be banked indefinitely in the HCRN Biorepository. 
8.6 
Confidentiality of Biospecimens 
Samples will be identified by a subject’s study number assigned at the time of registration to the 
trial. Any material issued to collaborating researchers will be anonymized and only identified by 
the subject’s study number. 
 
9. 
CRITERIA FOR DISEASE EVALUATION 
9.1 
Definitions of Response to Treatment in AML 
Disease will be assessed according to the International Working Group Criteria31. 
 
Category 
Definition 
Treatment Success categories 
Complete remission (CR) 
Bone marrow blasts < 5%; absence of blasts with Auer rods; absence 
of extramedullary disease; absolute neutrophil count > 1.0 x 109/L 
(1000/µL); platelet count > 100 x 109/L (100,000/µL); independent 
of red cell transfusions 
CR with incomplete 
recovery (CRi) 
All CR criteria except for residual neutropenia < 1.0 x 109/L 
(1000/µL) or thrombocytopenia < 100 x 109/L (100,000/µL) 
Partial remission (PR) 
All hematologic criteria of CR; decrease of bone marrow blast 
percentage to 5% to 25%; and decrease of pretreatment bone marrow 
blast percentage by at least 50% 
Treatment Failure categories 
Resistant Disease 
Failure to achieve CR or CRi or failure to achieve CR, CRi, or PR; 
only includes patients surviving ≥ 7 days following completion of 
initial treatment, with evidence of persistent leukemia by blood 
and/or bone marrow examination
Death in aplasia 
Deaths occurring ≥ 7 days following completion of initial treatment 
while cytopenic; with an aplastic or hypoplastic bone marrow 
obtained within 7 days of death, without evidence of persistent 
leukemia 
Death from indeterminate 
cause 
Deaths occurring before completion of therapy, or < 7 days following 
its completion; or deaths occurring ≥ 7 days following completion of 
initial therapy with no blasts in the blood, but no bone marrow 
examination available 


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Relapse 
Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood; or 
development of extramedullary disease 
Adapted from International Working Group Criteria31
In patients with abnormal cytogenetics at diagnosis, CR (or CRi) will be delineated as above plus 
evidence of complete cytogenetic response (also known as CRc)—defined as a reversion to normal 
cytogenetics.  
9.2 
Definitions of Survival Endpoints for AML 
 
Overall Survival 
All evaluable patients entered into trial; measured from the date of entry to the 
date of death from any cause; patients not known to have died at last follow-
up are censored on the date they were last known to be alive 
Relapse-free Survival 
Only patients achieving CR or CRi; measured from the date of achievement of 
a remission until the date of relapse or death from any cause; patients not 
known to have relapsed or died at last follow-up are censored on the date they 
were last examined 
Event-free Survival 
All patients entered into trial; measured from the date of entry to the date of 
treatment failure, disease relapse, or death from any cause; patients not known 
to have any of these events are censored on the date they were last examined 
Adapted from European LeukemiaNet.44
 
10. 
DRUG INFORMATION 
10.1 
Venetoclax (ABT-199) 
10.1.1 Pharmacological Properties and FDA-Approved Indication 
Venetoclax is a BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic 
leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at 
least one prior therapy. 
10.1.2 How Supplied 
AbbVie will supply Venetoclax at no charge to subjects participating in this clinical trial. 
 
Drug Packaging configurations: 10mg 16 tablets/card, 50mg 1×8 blister card, 100mg 1×8 blister 
cards, 100mg 2×8 blister cards, 100mg 120 count bottles. 
 
Venetoclax 10 mg film-coated tablets are round, biconvex shaped, and pale yellow. 
 
Venetoclax 50 mg film-coated tablets are oblong, biconvex shaped, and beige.  
 
Venetoclax 100 mg film-coated tablets are oblong, biconvex shaped, and pale yellow.   
10.1.3 Preparation 
Venetoclax is taken 1 time a day with a meal and water at about the same time each day. 


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10.1.4 Storage and Stability 
Store at 15 to 25 degrees C (59-77 degrees F) 
10.1.5 Handling and Disposal 
Subjects will be instructed to do the following when given Venetoclax to take home: 
 Keep Venetoclax in a safe place, away from other family members’ medications and away 
from any food or drinks.  
 Store the medication at room temperature in a dry location – avoid storing medication in 
the bathroom. 
 Store Venetoclax in its original container, which may be a blister pack  
 Keep the medication out of reach from children and pets.  
 Return damaged or unused Venetoclax to the study physician 
10.1.6 Dispensing 
Venetoclax must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Venetoclax should be stored in a secure area according to 
local regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects.  
10.1.7 Adverse events 
The most common adverse reactions (≥20%) in clinical trials were neutropenia, diarrhea, nausea, 
anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Warnings include 
Tumor Lysis Syndrome and neutropenia. Refer to the package insert for a comprehensive list of 
adverse events. 
 
Please refer to the latest version of the prescribing information which can be found at 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/, and/or on the manufacturer’s website. 
10.2 
Gemtuzumab Ozogamicin (MYLOTARG™) 
10.2.1 Pharmacological Properties and FDA-Approved Indication 
Gemtuzumab Ozogamicin is a CD33-directed antibody-drug conjugate indicated for:  
 
treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults  
 
treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients 
2 years and older  
10.2.2 How Supplied 
Pfizer will supply Gemtuzumab Ozogamicin at no charge to subjects participating in this clinical 
trial. 
 
MYLOTARG (Gemtuzumab Ozogamicin) for Injection is a white to off-white lyophilized cake 
or powder supplied in a carton (NDC 0008-4510-01) containing one 4.5 mg single-dose vial. 
10.2.3 Preparation 
Use appropriate aseptic technique for the reconstitution and dilution procedures. Protect the 
reconstituted and diluted MYLOTARG solution from light.  


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Reconstitution 
 
MYLOTARG is a cytotoxic drug. Follow applicable special handling and disposal 
procedures.1 
 
Calculate the dose (mg) and number of vials of MYLOTARG required. 
 
Prior to reconstitution, allow drug product vials to reach ambient temperature for 
approximately 5 minutes. 
 
Reconstitute each vial with 5 mL of Sterile Water for Injection, USP to obtain a concentration 
of 1 mg/mL of MYLOTARG that delivers 4.5 mL (4.5 mg). 
 
Gently swirl the vial to aid dissolution. DO NOT SHAKE. 
 
Inspect the reconstituted solution for particulates and discoloration. The reconstituted 
solution may contain small white to off-white, opaque to translucent, and amorphous to fiber-
like particles. 
 
MYLOTARG contains no bacteriostatic preservatives.  
 
Use reconstituted solution immediately or after being refrigerated at 2–8°C (36–46°F) for up 
to 1 hour. Protect from light. Do not freeze. 
Dilution 
 
Calculate the required volume of the reconstituted solution needed to obtain the appropriate 
dose according to patient body surface area. Withdraw this amount from the vial(s) using a 
syringe. Protect from light. Discard any unused reconstituted solution left in the vial. 
Doses must be mixed to a concentration between 0.075 mg/mL to 0.234 mg/mL according to 
the following instructions: 
 
Doses less than 3.9 mg must be prepared for administration by syringe. Add the reconstituted 
MYLOTARG solution to a syringe with 0.9% Sodium Chloride Injection to a final 
concentration between 0.075 mg/mL to 0.234 mg/mL. PROTECT FROM LIGHT.  
 
Doses greater than or equal to 3.9 mg are to be diluted in a syringe or an IV bag in an 
appropriate volume of 0.9% Sodium Chloride Injection to ensure a final concentration 
between 0.075 mg/mL to 0.234 mg/mL. PROTECT FROM LIGHT.  
 
Gently invert the infusion container to mix the diluted solution. Do not shake. 
 
Following dilution with 0.9% Sodium Chloride Injection, MYLOTARG solution should be 
infused immediately. If not used immediately, store at room temperature (15–25°C; 59–
77°F) for up to 6 hours, which includes the 2-hour infusion time and 1-hour, if needed, to 
allow the refrigerated diluted solution to equilibrate to room temperature. The diluted 
solution can be refrigerated at 2–8°C (36–46°F) for up to 12 hours which includes up to 1-
hour in the vial post-reconstitution. Protect from light and do not freeze. 
Administration 
 
Use an in-line 0.2 micron polyethersulfone (PES) filter for infusion of MYLOTARG. 
 
Protect the intravenous bag from light using a light-blocking cover during infusion. The 
infusion line does not need to be protected from light. 
 
Infuse the diluted solution over 2 hours. 
 
Do not mix MYLOTARG with, or administer as an infusion with, other medicinal products. 


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10.2.4 Storage and Stability 
Refrigerate (2–8°C; 36–46°F) MYLOTARG vials and store in the original carton to protect from 
light. Do not freeze. 
10.2.5 Handling and Disposal 
MYLOTARG is a cytotoxic drug. Follow applicable special handling and disposal procedure. 
10.2.6 Dispensing 
MYLOTARG must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. MYLOTARG should be stored in a secure area according to 
local regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to study subjects. 
10.2.7 Adverse events 
The most common adverse reactions (greater than 15%) in clinical trials were hemorrhage, 
infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, 
and mucositis. Warnings include infusion-related reactions and hemorrhage. Refer to the package 
insert for a comprehensive list of adverse events. 
Please refer to the latest version of the prescribing information that can be found at 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/, and/or on the manufacturer’s website. 
 
11. 
ADVERSE EVENTS 
11.1 
Definitions 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests 
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study regimen 
by the site investigator. 
11.1.2 Serious Adverse Event (SAE) 
An SAE is an adverse event that: 
 Results in death.  


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 Is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing hospitalization. 
NOTE: Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional therapy, 
resection of primary tumor, or elective surgery, will not be considered serious adverse 
events. 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
11.1.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, package insert, or when it is not included in the 
informed consent document as a potential risk. Unexpected also refers to AEs that are mentioned 
in the IB as occurring with a class of drugs or are anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
11.1.4 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
Unrelated 
The Adverse Event is not related to the drug(s)  
Unlikely 
The Adverse Event is doubtfully related to the drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  
Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
 
11.2 
Reporting 
11.2.1 Adverse Events 
 Adverse events (AEs) will be recorded from the time of consent until 30 days after treatment 
discontinuation of study drugs or until a new anti-cancer treatment starts, whichever occurs 
first. 


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 AEs will be recorded regardless of whether or not the event(s) are considered related to the 
study drugs.  
 All AEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within the EDC system. 
 All AEs considered related to study drugs will be followed until resolution to ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever is earlier. 
11.2.2 Reporting of Pregnancy 
Although pregnancy is not considered an adverse event, it is the responsibility of investigators or 
their designees to report any pregnancy or lactation in a subject (spontaneously reported to them), 
including the pregnancy of a male subject’s female partner that occurs during the trial or within 
120 days of completing the trial, or 30 days following cessation of treatment if the subject initiates 
new anticancer therapy, whichever is earlier. All subjects and female partners of male subjects 
who become pregnant must be followed to the completion/termination of the pregnancy. All 
pregnancies must be reported within 24 hours to BTCRC AHQ on the BTCRC Pregnancy 
Reporting form (See Documents/Info tab in the EDC). 
 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health 
of infant) must also be reported. 
 
Such events must be reported within 24 hours to BTCRC AHQ on the BTCRC Pregnancy 
Reporting form (See Documents/Info tab in the EDC). BTCRC AHQ will report the event within 
24 hours to Pfizer Global Safety (Attn: Worldwide Product Safety; FAX 1-866-997-8322) and 
AbbVie (Fax 1-866-997-8322; PPDINDPharmacovigilance@abbvie.com). 
11.2.3 Site Requirements for Reporting SAEs and Non-Serious Events of Clinical Interest to 
BTCRC Administrative Headquarters 
 SAEs will be reported from time of signed informed consent until 30 days after discontinuation 
of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first.  
 SAEs will be reported on the SAE Submission Form and entered in the SAE tab in the EDC 
system within 24 hours of discovery of the event.  
 SAEs will be reported whether or not they are related to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within the EDC system.  
 All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 1 or 
baseline and/or deemed clinically insignificant and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 Non-serious Events of Clinical Interest (including tumor lysis syndrome) will be reported to 
BTCRC AHQ and will be handled in the same manner as SAEs.  
 Additionally, any serious adverse event, considered by an investigator to be related to either 
study drug, which is brought to the attention of the investigator at any time outside of the 30-
day time period specified in the previous paragraph, also must be reported immediately to 
BTCRC AHQ.  


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The site will electronically submit the completed BTCRC SAE Submission Form (see 
Documents/Info tab in the EDC) to BTCRC AHQ within 24 hours of discovery of the event 
(safety@hoosiercancer.org). The investigator is responsible for informing the IRB and/or the 
Regulatory Authority of the SAE as per local requirements. 
 
The original copy of the BTCRC SAE Submission Form and the email correspondence must be 
kept within the study file at the study site. 
 
Once the SAE has resolved, sites must submit a follow up SAE Submission Form within a 
reasonable timeframe to BTCRC AHQ electronically to safety@hoosiercancer.org. 
11.2.4 BTCRC AHQ Requirements for Reporting SAEs to Pfizer 
BTCRC AHQ will submit all SAEs received from sites to Pfizer within 24 hours of receipt of the 
BTCRC SAE Submission Form and to regulatory authorities (FDA) per federal guidelines.  
 
BTCRC AHQ will submit all SAE reports and any other relevant safety information to: 
 
Pfizer U.S. Clinical Trial Department 
Facsimile number:  1-866-997-8322 
 
BTCRC AHQ will provide follow-up information to Pfizer as it is received from a site. 
11.2.5 BTCRC AHQ Requirements for Reporting SAEs to AbbVie 
For any subject receiving Study Product, BTCRC AHQ will submit all SAEs received from sites 
to AbbVie within 24 hours of receipt of the BTCRC SAE Submission Form and to regulatory 
authorities (FDA) per federal guidelines. 
 
BTCRC AHQ will submit all SAE reports and any other relevant safety information to AbbVie at: 
Facsimile number: +1 (847)-938-0660 
Email: PPDINDPharmacovigilance@abbvie.com 
 
BTCRC AHQ will provide follow-up information to AbbVie as it is received from a site. 
11.2.6 BTCRC AHQ Responsibilities for Reporting SAEs to FDA 
BTCRC AHQ has been designated to manage the Investigational New Drug Application (IND) 
associated with this protocol on behalf of the sponsor-investigator. BTCRC AHQ will cross-
reference this submission to Pfizer and AbbVie’s parent INDs at the time of submission. 
Additionally, BTCRC AHQ will submit a copy of these documents to Pfizer and AbbVie at the 
time of submission to FDA. 
 
BTCRC AHQ will be responsible for all communication with the FDA in accordance with 
21CFR312 which includes but is not limited to the 7 and 15 Day Reports, as well as an Annual 
Progress Report. Additionally, BTCRC AHQ will submit a copy of these reports to Pfizer and 
AbbVie at the time of submission to FDA. 


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11.3 
Sponsor-Investigator Responsibilities 
BTCRC AHQ will send a SAE summary to the sponsor-investigator within 1 business day of 
receipt of SAE Submission Form from a site. The sponsor-investigator will promptly review the 
SAE summary and assess for expectedness and relatedness. 
11.4 
IND Safety Reports Unrelated to This Trial 
AbbVie and Pfizer will provide Big Ten CRC AHQ with IND safety reports from external studies 
that involve the study drug(s) per their guidelines. Big Ten CRC AHQ will forward the safety 
reports to the sponsor-investigator who will review these reports and determine if revisions are 
needed to the protocol or consent. Big Ten CRC AHQ will forward these reports to participating 
sites within 1 business day of receiving the sponsor-investigator’s review. Based on the sponsor-
investigator’s review, applicable changes will be made to the protocol and informed consent 
document (if required). All IND safety reports will also be made available to sites via the EDC 
system. 
 
Upon receipt from BTCRC AHQ, site investigators (or designees) are responsible for submitting 
these safety reports to their respective IRBs, as per their IRB policies. 
 
12. 
STATISTICAL METHODS 
12.1 
Study Design 
This will be a single arm, open-label multicenter study of the combination of Venetoclax and Gemtuzumab 
Ozogamicin (GO) in patients with relapsed or refractory AML. It will be an initial dose-escalation phase 
Ib study (Cohorts 1-3), using a 3+3 design to determine whether there is a dose-limiting toxicity. There 
will be a 28-day induction and then a 28-day consolidation cycle, followed by a maintenance phase. 
12.2 
Endpoints 
12.2.1 Definition of Primary Endpoint 
 Dose-limiting toxicity, defined as an adverse event related (possible, probably, or definite) to 
Venetoclax and/or Gemtuzumab fulfilling one of the following criteria: 
o Hematologic 
toxicity: 
treatment-related 
grade 
3 
or 
worse 
neutropenia 
and/or 
thrombocytopenia due to bone marrow hypocellularity present at the end of cycle one (day 28) 
with an additional 28 days allowed for count recovery (i.e. present at day 56); specifically 
grade 3 or worse neutropenia or thrombocytopenia with the bone marrow documented to be 
free of leukemic infiltration. Note: patients who enter the study with grade 3 or worse 
cytopenias will not be evaluable for hematologic dose-limiting toxicities.  
o Non-hematologic toxicity: any grade 3 or worse treatment-related toxicity occurring within the 
first cycle (excluding grade 3-4 infections during cycle one).  
12.2.2 Definition of Secondary Endpoints  
 Overall response rate (CR/CRi), as defined by the revised IWG criteria24. See Section 9.1. 
 Anti-leukemic activity (CR/CRi/PR), as defined by the revised IWG criteria24. See Section 9.1. 
 Adverse effects will be characterized using the CTCAE v5 criteria. 
 Relapse-free survival (RFS), event-free survival (EFS, and overall survival (OS). See Section 9.2 


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 The European Organization for the Research and Treatment of Cancer 30 item questionnaire 
(EORTC QLQ-C30), The Functional Assessment of Cancer Therapy Fatigue (FACT-Fatigue) 
questionnaire, two-minute walk test, and timed chair stands will be performed at trial entry and 
every other month for 1 year.32  
12.2.3 Definition of Exploratory Endpoints  
 Genomic MRD with droplet digital PCR (ddPCR) will be measured to determine kinetics of 
response and the association with relapse-free survival at the end of cycles 1 and 2, at 6 months 
and 12 months, and if there is evidence of relapse. (Sub-PI is Dr. Brian Parkin [see ref. 33].) 
 CD33 DNA polymorphisms will be measured at presentation and at relapse. 
 Leukemic blast CD33 expression will be measured at presentation and at relapse. 
 “BH3 profiling”34 of AML blasts will be performed at presentation and at relapse.  
 BCL-2, BCL-XL, and MCL-1 protein levels in PB or BM blasts will be measured at presentation 
and after 6 days (i.e., Cycle 1 Day +3) of Venetoclax therapy.  
12.3 
Sample Size and Accrual 
A standard “3 + 3” design will be used to establish the maximum tolerated dose. The maximum tolerated 
dose is defined as the dose level at which fewer than 33% of subjects experience a dose limiting toxicity. 
An expansion cohort of 6 patients will be carried out at the maximum tolerated dose, which will be the 
recommended Phase II dose.  
 
This study is a traditional ‘3 + 3’ design without de-escalation, a specified A + B dose finding study with 
parameters of A = B = 3, cL = 0, cU = 2, and CU = 1. The associated target quantiles for our study are ΓA = 
0.35 and ΓA = 0.26. Hence, the dose selected by this design has a toxicity rate below 0.26 and above CU/(A 
+ B) on average. In simulation studies, the apparent selected dose with our targeted N=18-24 (n=9-18, 
plus 6) selects a dose with toxicity rate near 0.2. In this scenario, the ‘3 + 3’ design ΓU = (CU + 1)/(A + B) 
= 2/(3 + 3) = 0.33 is our upper bound. To evaluate the quality of estimation of the target dose per average 
sample size increase, we reviewed simulation studies of this design under conditions of A = B = 3 with 
values of change (Δ) of either 0.35 or 0.70. Within the average sample size range of 16.2 to 21.8, between 
78% and 89% correct dose recommendations were achieved, where tendencies of higher Δ resulted in 
greater percent correct dose recommendations [see ref. 45 for further review]. 
12.4 
Assessment of Safety 
Patients evaluable for toxicity are those who receive at least one dose of Venetoclax and one dose of GO. 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade adverse 
events per the defined Study Calendar for toxicity assessment schedule. 
12.5 
Assessment of Efficacy 
All subjects with disease who received at least one dose of study drug and have had their disease re-
evaluated (or die beforehand), will be included in the efficacy analysis. Per the analysis plan described in 
section 12.8.2 for all time-to-event outcomes (e.g., survival) identified as secondary endpoints, cumulative 
incidence and hazard functions will be estimated as conditional survival probabilities until first meeting 
the defined outcome criteria for efficacy: 
 ORR (CR/CRi) and anti-leukemic activity (CR/CRi/PR) after 2 cycles. See Section 9.1.  
 Relapse-free and event-free survival  
 Overall survival in subjects 


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12.6 
Statistical Analysis Plans 
12.6.1 Analysis Plans for Primary Objective 
DLTs will be presented by dose of Venetoclax when administered with Gemtuzumab Ozogamicin. 
12.6.2 Analysis Plans for Secondary Objectives 
Descriptive characteristics of all adverse effects of GO in combination with Venetoclax (using CTCAE 
v5 criteria) will be reported; and the efficacy of the combination in achieving ORR (includes CR/CRi) 
and anti-leukemic activity (includes CR/CRi/PR), as defined by the revised IWG criteria24), RFS, EFS, 
and OS in subjects. The effects of therapy on quality of life, fatigue, and physical function at D0 (trial 
entry) and the end of every other month for 1 year (see section 8.1) will be reported and analyzed using 
generalized linear modeling. 
 
All time-to-event outcomes (e.g. survival) will be calculated using Kaplan Meier methods and exploratory 
log-rank tests will be used to compare treatment effect between groups based on genomic MRD, CD33 
DNA polymorphisms, BH3 profiling and anti-apoptosis protein levels in PB MBCs at presentation and 
after 1 week of Venetoclax.  
 
Sample size permitting: Hazard ratios (HR) and 95% CIs will be produced. Time-to-event outcomes with 
a competing or semi-competing risk (e.g. CIR) will be analyzed using cumulative incidence curves and 
exploratory comparisons between arms will be made using Grey’s test. Rate ratios and 95% CIs will be 
presented. Chi squared tests will be used to assess the treatment effect between cohorts for all categorical 
variables and t-tests or Mann Whitney tests will be applied for continuous measures as appropriate. 
12.6.3 Other Planned Analyses 
Descriptive characteristics of patients will be reported in tabular form along with the dates of trial opening 
and closing, indicating the total number of patients enrolled and accounting for all patients considered for 
entry (flow diagram). Patients found to be ineligible will be indicated along with their reasons for 
ineligibility and whether they received any study therapy. Of the included subjects, the number of patients 
who were evaluable for toxicity and response (secondary objectives, see section 12.2.2) will be reported. 
 
Drug administration by dose level will be reported in tables detailing the total number of patients treated, 
number of doses or cycles received at dose level, and the number of incomplete cycles, including brief 
descriptions of what happened in dose escalation if intermediate dose levels or deviations from study 
protocol resulted. Any dose holds, reductions, and delays, and permanent discontinuation of study 
treatments will be summarized with reasons for each. Finally, summaries of dose intensity will be 
estimated, including how many patients were able to receive each planned dose intensity of Venetoclax 
administered with Gemtuzumab Ozogamicin. 
 
Tables of adverse effects displaying the worst grade by dose level will be reported, including columns or 
each grade and “any grade” adverse effects. Separate tables report hematological and non-hematological 
effects will be reported according to dose escalation. 
 
Descriptive tables reporting frequencies and means or medians of scores of the EORTC QLQ-C30 and 
FACT-Fatigue questionnaire, two-minute walk test, and timed chair stand will be created for D0 (trial 
entry) and subsequent months of follow up. Generalized linear modeling of continuous scores or ordinal 
values accounting for correlation and repeated will be performed to determine differences between groups 


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and characteristics considered to be potential confounding factors. Given a threshold value indicating a 
substantial degree of the outcome (i.e., quality of life, fatigue and physical function), generalized 
estimating equation models with a binomial distribution and unstructured correlation covariance will be 
used to produce odds ratios (OR) and robust 95% CI for the relation of dose and clinical characteristics to 
each outcome. 
 
13. 
TRIAL MANAGEMENT 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted in accordance with the University of Illinois Cancer Center’s Data and Safety 
Monitoring Plan (DSMP). The University of Illinois Cancer Center Data Safety and Monitoring 
Committee (DSMC) will review and make recommendations on this trial. BTCRC AHQ will provide the 
University of Illinois Cancer Center DSMC with periodic data reports to comply with the UICC DSMC 
review requirements.  
 
In addition, BTCRC AHQ oversight activities include: 
 Review of all adverse events requiring expedited reporting as defined in the protocol. 
 Provide trial accrual progress, safety information, and data summary reports to the sponsor-
investigator. 
 Submit data summary reports to the lead institution DSMC for review as per their DSMP. 
13.2 
University of Illinois Cancer Center Data Safety Monitoring Committee 
BTCRC AHQ will provide the UICC DSMC with the following: 
 Adverse event summary report 
 Audit results, if applicable 
 Data related to stopping/decision rules described in study design 
 Study accrual patterns  
 Protocol deviations 
 
The University of Illinois Cancer Center DSMC will review study data every quarter. Documentation of 
DSMC reviews will be provided to the sponsor-investigator and BTCRC AHQ. Issues of immediate 
concern by the DSMC will be brought to the attention of the sponsor-investigator and other regulatory 
bodies as appropriate. The sponsor-investigator will work with BTCRC AHQ to address the DSMC’s 
concerns. 
13.3 
Data Quality Oversight Activities  
Remote validation of the EDC system data will be completed on a continual basis throughout the life cycle 
of the study. A summary report (QC Report) of these checks together with any queries resulting from 
manual review of the eCRFs will be generated for each site and transmitted to the site and the site monitor. 
Corrections will be made by the study site personnel. 
 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects of the 
protocol are followed.  Additional for-cause visits may occur as necessary. Source documents will be 
reviewed for verification of agreement with data entered into the EDC system. It is important for the site 
investigator and their relevant personnel to be available for a sufficient amount of time during the 


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monitoring visits or audit, if applicable. The site investigator and institution guarantee access to source 
documents by BTCRC AHQ or its designee. 
 
The trial site may also be subject to quality assurance audit by Pfizer, AbbVie, or their designee as well 
as inspection by appropriate regulatory agencies. 
13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for submission 
to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. The sponsor-investigator has delegated 
responsibility to BTCRC AHQ for registering the trial and posting the results on clinicaltrials.gov. 
Information posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on appropriate trial 
locations and study site contact information. 
 
14. 
DATA HANDLING AND RECORD KEEPING 
14.1 
Data Management 
BTCRC AHQ will serve as the Clinical Research Organization for this trial. Data will be collected through 
a web based clinical research platform compliant with Good Clinical Practices and Federal Rules and 
Regulations. Other study institutions will be given a password to directly enter their own data onto the 
web site via electronic case report forms (eCRFs). BTCRC AHQ personnel will coordinate and manage 
data for quality control assurance and integrity. 
 
All data will be collected and entered into the EDC system by study site personnel from participating 
institutions. 
14.2 
Case Report Forms and Submission 
An electronic case report form (eCRF) is required and must be completed for each included subject. The 
completed dataset is housed at BTCRC AHQ and is the sole property of the sponsor-investigator’s 
institution. It should not be made available in any form to third parties, except for authorized 
representatives of appropriate Health/Regulatory Authorities, without permission from the sponsor-
investigator and BTCRC AHQ. After the initial publication, the complete data set will be available to all 
BTCRC institutions. 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/BTCRC AHQ, the investigator agrees to keep 
records, including the identity of all participating subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and detailed 
records of drug disposition. To comply with international regulations, the records should be retained by 
the investigator in compliance with regulations. 
 
During data entry, range and missing data checks will be performed on-line. The checks to be performed 
will be documented in the Data Monitoring Plan for the study. A summary report (QC Report) of these 


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checks together with any queries resulting from manual review of the eCRFs will be generated for each 
site and transmitted to the site and the site monitor. Corrections will be made by the study site personnel. 
This will be done on an ongoing basis. 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the subjects 
will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be 
made publicly available. Information collected will be maintained on secure, password protected 
electronic systems. Paper files that contain personal information will be kept in locked and secure locations 
only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator and his/her 
research associates, BTCRC AHQ, Pfizer, AbbVie, IRB, or government agencies, like the FDA, may 
inspect their medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
 
If the results of the study are published, the subjects’s identity will remain confidential. 
15. 
ETHICS 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol, including the final version of the informed consent form, must be approved in 
writing by an IRB. The investigator must submit written approval by the IRB to the BTCRC AHQ office 
before he or she can enroll any subject into the study.  
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in accordance 
with local requirements. In addition, the IRB must approve all advertising used to recruit subjects for the 
study. The protocol must be re-approved by the IRB annually, as local regulations require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be provided to the 
IRB according to local regulations and guidelines. 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the Declaration of 
Helsinki. Conduct of the study will be in compliance with ICH Good Clinical Practice, and with all 
applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written information about 
the nature, purpose, possible risks and benefits of the study. Subjects must also be notified they are free 
to discontinue from the study at any time. The subject should be given the opportunity to ask questions 
and allowed time to consider the information provided. 
 


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The subject’s signed and dated informed consent must be obtained before conducting any procedure 
specifically for the study. The site investigator must store the original, signed informed consent form. A 
copy of the signed informed consent form must be given to the subject. 
 
 


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16. 
REFERENCES 
1. Dombret, H, Gardin, C. Blood 2016, 127: 53 
2. Rowe, JM, Lowenberg, B. Blood 2013, 121: 4838–41 
3. Sievers, EL, Appelbaum, FR, et al. Blood 1999, 93: 3678–84 
4. Taksin, AL, Legrand, O, et al. Leukemia 2007, 21: 66–71 
5. Linenberger, ML. Leukemia 2005, 19: 176–82 
6. Caistagne, S, Pautas, C, et al. Lancet 2012 379, 9825: 1508–1516 
7. Hills, RK, Castaigne S, et al. Lancet Oncol 2014, 15: 986–96 
8. Pollyea, DA, Jordan, CT. Blood 2017, 129: 1627–1635 
9. Walter, RB, Appelbaum, FR, et al. Blood 2012, 119: 6198–6208 
10. Pollard, JA, Loken, M, et al. J Clin Oncol 2016, 34: 747–755 
11. Lamba, JK, Chauhan L, Shin M, et al. J Clin Oncol. 2017 35: 2674-2682. 
12. Walter, RB, Raden, BW, et al. Blood 2004, 103: 4276–4284 
13. Prokop, A, Wrasidlo, W, et al. Oncogene 2003, 22: 9107–9120 
14. Lagadinou, ED, Sach, A, et al. Cancer Stem Cell 2013, 12: 329–341 
15. Bhola, PD, Letai, A. Mol Cell 2016, 61:695–704 
16. Pan, R, Hogdal, LJ, et al., Cancer Discov 2014, 4: 363–375 
17. Pullarkat VA, Newman EM. Cancer Discov 2016, 6: 1082-1083. 
18. Roberts, AW, Davids, MS, et al., N Engl J Med 2016 374: 311–322 
19. Zhang, Q, Han, L et al., Blood 2016 128:101 (abstr) 
20. Konopleva, M, Pollyea, DA, et al., Cancer Discov 2016, 6: 1106–1117 
21. Pollyea, D, Dinardo, C et al. Lancet Oncol 2018, doi.org/10.1016/S1470–2045(18)30010-X 
22. Lin TL, Strickland SA, et al, 2016 June; Chicago, IL: ASCO; 2016. Abstract nr 7007 
23. Vo, TT, Ryan, J, et al., Cell 2012,151:344–55 
24. FDA Approves venetoclax in combination for AML in adults. FDA. Nov 21, 2018. Accessed 
Mar 4, 2021. https://www.fda.gov/drugs/fda-approves-venetoclax-combination-aml-adults. 
25. Haag, P, Viktorsson, K, et al. Exp Hematol. 2009 Jun;37(6):755-66.  
26. Blombery, P, Anderson, MA, et al. Cancer Discov. 2019 Mar;9(3):342-353.  
27. DiNardo, CD, Tiong, IS, et al. Blood. 2020 Mar 12;135(11):791-803.  
28. Fournier, E, Duployez, N, et al. Blood. 2020 Feb 20;135(8):542-546.  
29. Lin, KH, Winter, PS, et al. Sci Rep. 2016 Jun 10;6:27696. 
30. Sato, T, Issa, JPJ, and Kropf, P. Cold Spring Harb Perspect Med. 2017 May; 7(5): a026948.  
31. Cheson, BD, Bennett, JM, et al., J Clin Oncol 2003, 21: 4642–9 
32. Alibhai, SM, Breunis, H, et al., J Geriatr Oncol 2015, 6: 262–71 
33. Parkin, B, Ouillette, P, et al., Clin Cancer Res 2015, 21: 2045–2056 
34. Certo, M, Del Gaizo Moore, V, et al., Cancer Cell 2006, 9: 351–365 
35. Arber DA, Orazi A, Hasserjian R, et al., Blood 2016, 127: 2391–405. 
36. Amadori S, Suciu S, Selleslag D, et al., J Clin Oncol 2016;34(9):972–9 
37. Rajkumar, SV, Richardson, P, and San Miguel, JF. Blood. 2015 126:921–922. 
38. Agarwal, SK, DiNardo, CD, Potluri, J et al., Clin Ther. 2017; 39: 359–367 
39. Venclexta (Venetoclax) [package insert]. North Chicago, IL: AbbVie Inc; 2019. 
40. Agarwal, SK, Tong B et al. Adv Ther. 2018 35:2015-2023. 


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41. DiNardo, CD. et al. Blood. 2019 Jan;133(1):7-17. 
42. Parkin B, Londono-Joshi A, Kang Q, et al., J Clin Invest 2017;127:3484–3495. 
43. Laszlo GS, Harrington KH, Gudgeon CJ, et al., Oncotarget 2016; 7:43281–43294. 
44. Döhner H, Estey E, Grimwade D, et al., Blood 2017; 129:424. 
45. Hansen AR, Graham DM, et al. Cancer Control 2014; 21: 200 – 208.  
46. Oken MM, Creech RH, Tormey DC, et al., Am. J. Clin. Oncol 1982, 5: 649–55. 
47. Hunt SA, Abraham WT, Chin MH, et al., Circulation 2005, 112: e154–235.  
48. Coiffier B, Altman A, Pui CH, et al. J Clin Oncol 2008; 26: 2767. 
49. Rikli RE, Jones CJ et al., Journal of Aging and Physical Activity 1999, 7: 160 – 179. 
 
 
 


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Appendix I – ECOG Performance Status 
 
ECOG Score 
Performance Status 
0 
Asymptomatic 
1 
Symptomatic, fully ambulatory 
2 
Symptomatic, in bed < 50% of the day 
3 
Symptomatic, in bed > 50% of the day but not bedridden 
4 
Bedridden 
5 
Dead 
 
Adapted from ECOG Definitions46 
 


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Appendix II – New York Heart Association Classification 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations 
of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation 
of physical activity. They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart 
failure or the anginal syndrome may be present even at rest. 
If any physical activity is undertaken, discomfort is 
increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Adapted from the American Heart Association Guidelines47 
 
 


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Appendix III – Prohibited and Cautionary Medications 
 
Excluded throughout the study 
Strong CYP3A inducers – avasimibe, carbamazepine, enzalutamine, mitotane, phenytoin, rifampin, 
St. John’s wort 
 
Moderate CYP3A inducers - bosentan, efavirenz, etravirine, modafinil, nafcillin
Excluded during ramp-up phase and Cautionary at the Cohort Designated Dose 
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 (not 
levofloxacin), clotrimazole, crizotinib, cyclosporine, darunavir/ritonavir, diltiazem1, erythromycin, 
fluconazole (>200mg), 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, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan 
 
OATP1B1/1B3 substrates 
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, rosuvastatin, simvastatin acid, pitavastatin, 
pravastatin, repaglinide, telmisartan, valsartan, olmesartan 
 
BCRP inhibitors 
Geftinib
 
 
 
 
 


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Appendix IV – Cairo Bishop Guidelines 
 
Cairo-Bishop definition of laboratory tumor lysis syndrome: 
Either the presence of two or more of the following laboratory changes within 3 days before or seven 
days after cytotoxic therapy OR a 25% change above or below normal. 
Element 
Value 
Change from baseline 
Uric Acid 
≥476 µmol/L (8mg/dL) 
or 25% increase 
Potassium 
≥6.0 mmol/L (or 6mEq/L) 
or 25% increase 
Phosphorus 
≥1.45 mmol/L (4.5 mg/dL) for adults 
or 25% increase 
Calcium 
≤1.75 mmol/L (7mg/dL) 
or 25% decrease 
Adapted from the Guidelines for the management of pediatric and adult tumor lysis syndrome: an 
evidence-based review48 
 
 
 


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Appendix V – Quality of Life and Fatigue Questionnaires 
 
 
 
 
 


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http://www.facit.org/FACITOrg/Questionnaires  
 
 
Two minute walk test instructions 
 
Patients will need to walk for a total of two minutes and the unit of length will be measured in “feet.” 
Assistive devices can be used but should be kept consistent and documented from test to test. If physical 
assistance is required, this test should not be performed. Walking path (i.e. laps up and down hallway) 
should be predetermined and feasible to measure.  
* Adapted from NIH toolbox 
 
 
30 second chair stand test49 
 
Patients should start in the sitting position with back straight, arms crossed over chest and feet flat on the 
floor. The chair should be placed against a wall for stability. Observe 1-2 practice stands to ensure 
proper form and adequate balance. Once the patient is ready, measure the number of times he/she can 
rise to a full stand and then return to a fully seated position in 30 seconds. If the patient is more than half 
way up at the end of the 30 seconds, count this as a full stand.