An Open-Label, Phase 2 Trial Evaluating the Efficacy and Safety of Daratumumab in Subjects With Relapsed/Refractory Acute Myelogenous Leukemia or High-Risk Myelodysplastic Syndrome
Phase: PHASE2
Conditions: High Risk Myelodysplastic Syndrome, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia
Sponsor: M.D. Anderson Cancer Center

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MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2016‐0889 
Protocol Title 
An Open-label, Phase 2 Trial Evaluating the Efficacy and Safety 
of Daratumumab in Combination with Venetoclax in Subjects with 
Relapsed/Refractory Acute Myelogenous Leukemia, High-Risk 
Myelodysplastic Syndrome or T Acute Lymphoblastic 
Leukemia/Lymphoma 
Protocol Version 
07 
Version Date 
09/23/2020 
 
Protocol PI 
Gautam Borthakur 
Department 
Leukemia 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
133,917 
 
 

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2016-0889 
An Open-label, Phase 2 Trial Evaluating the Efficacy and Safety of Daratumumab 
in Combination with Venetoclax in Subjects with Relapsed/Refractory Acute 
Myelogenous Leukemia, High-Risk Myelodysplastic Syndrome or T Acute 
Lymphoblastic Leukemia/Lymphoma 
 
Short title:   
 
Daratumumab and venetoclax in AML/MDS 
 
Version 1:    
 
May 30, 2016 
Version 2: 
 
 
January 11, 2017 
Version 3: 
 
 
February 20, 2017 
Version 4: 
 
 
September 21, 2017 
Version 5:   
 
May 24, 2019 
Version 6: 
 
 
September 23, 2019 
Version 7: 
 
 
September 23, 2020 
 
MDACC IND #: 
 
133,917 
 
Sponsor-Investigator:   Gautam Borthakur, MD 
Co-Chair: 
 
 
Hagop Kantarjian, MD 
 
 
 
 
 
 
 
Drug and  
Funding Support:   
Janssen Scientific Affairs, LLC 
 
 

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Table of Contents 
1. 
Background ........................................................................................................................................... 6 
2. 
Study Population ................................................................................................................................... 9 
3. 
Study Objectives ................................................................................................................................... 9 
4. 
Hypothesis........................................................................................................................................... 10 
5. 
Study Design........................................................................................................................................ 10 
6. 
Eligibility Criteria ................................................................................................................................. 11 
A. 
Inclusion criteria:............................................................................................................................. 11 
B. 
Exclusion Criteria:............................................................................................................................ 12 
7. 
Dosage and Administration................................................................................................................. 13 
A. Treatment Schedule and Administration ........................................................................................... 14 
B. Dose Delays and Dose Modification ................................................................................................... 15 
C. Pre‐infusion medication ...................................................................................................................... 16 
D. Post‐infusion Medication ................................................................................................................... 16 
E. Management of Infusion‐related Reactions ....................................................................................... 17 
F. Permitted Therapies ............................................................................................................................ 19 
G. Prohibited Therapies .......................................................................................................................... 19 
H. Duration of Therapy ........................................................................................................................... 19 
8. 
Study Procedures ................................................................................................................................ 19 
A. 
Screening Procedures ..................................................................................................................... 19 
B. 
Daratumumab Interference with Indirect Antiglobulin Test (IAT) results ...................................... 20 
C. 
Clinic Visits ...................................................................................................................................... 21 
D. Follow‐up Period ................................................................................................................................. 21 
9. 
Criteria for Response for Acute Leukemias and MDS ......................................................................... 21 
10. 
Exploratory Studies ......................................................................................................................... 22 
11. 
Statistical Considerations ................................................................................................................ 22 
12. 
Adverse Events and Reporting Requirements ................................................................................ 25 
A. 
Adverse Events ................................................................................................................................ 25 
B. 
Serious Adverse Event (SAE) Reporting .......................................................................................... 26 
C. 
Reporting to FDA ............................................................................................................................. 27 
13. Reporting SAE to Janssen Scientific Affairs, LLC .................................................................................... 28 

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A. 
Management of Safety Data ........................................................................................................... 28 
B. Adverse Events of Special Interest ...................................................................................................... 28 
C. Unlisted (Unexpected) Adverse Event/Reference Safety Information ............................................... 29 
D. Special Reporting Situations ............................................................................................................... 29 
E. Pregnancy ............................................................................................................................................ 30 
F. Maintenance of Safety Information .................................................................................................... 31 
G. Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Janssen Medicinal 
Products to Janssen Scientific Affairs, LLC .............................................................................................. 31 
H. SAEs, Adverse Events of Special Interest and Special Reporting Situations ....................................... 32 
I. 
Non‐Serious AEs .............................................................................................................................. 33 
J. PQC Reporting ...................................................................................................................................... 33 
K. Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Non‐
Janssen Medicinal Products .................................................................................................................... 33 
L. Transmission Methods ........................................................................................................................ 33 
14.  Drug Destruction Policy ........................................................................................................................ 34 
15. References ............................................................................................................................................ 34 
Table 7: Schedule of Study Events .............................................................................................................. 37 
 
 
 

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Tables: 
 
Table 1: 
Venetoclax dosing guidelines 
Table 2: 
Infusion rates for daratumumab administration   
 
Table 3: 
Daratumumab-Related Toxicity Management   
 
Table 4:   
Stopping boundaries for futility monitoring 
 
 
Table 5:   
Early stopping boundaries for toxicity monitoring  
 
Table 6:  
Operating characteristics for efficacy and toxicity  
monitoring   
 
 
 
 
 
 
Table 7:  
Schedule of Study Events   
 
 
 
 
 
 
Appendix A: Classification of Asthma Severity 
Appendix B: Corticosteroid Comparison Chart 
Appendix C: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Criteria 
Appendix D: Leukemia-specific Adverse Event Recording and Reporting Guidelines 
 
 
 

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1. Background 
Acute Myelogenous Leukemia (AML) and High-Risk Myelodysplastic 
Syndrome (HR-MDS) 
Long term outcomes in acute myeloid leukemia (AML) remain uniformly poor except 
in few cytogenetically and molecularly favorable subcategories.[1, 2] Despite 
progress in the understanding of leukemia pathophysiology, 20-40% of patients do 
not achieve remission with the standard induction chemotherapy and 50-70% of first 
complete remission patients are expected to relapse within 3 years.[3] The 
prognosis following AML relapse remains uniformly poor. High dose cytarabine (Ara-
C) based therapy has been the cornerstone of salvage chemotherapy for relapsed or 
refractory AML for many years. The complete response rate in first salvage is 
approximately 30-50%. Addition of other cytotoxic agents such as mitoxantrone or 
etoposide has not improved complete response rates but may be associated with 
increased toxicities. Regimens incorporating clofarabine or cladribine with or without 
high dose Ara-C (HDAC) may improve remission rates but have not resulted in 
survival benefit.[4-6] 
 
The same is true for patients with high risk myelodysplastic syndrome (HR-MDS). 
Front-line treatment with hypomethylating agents improves survival[7] but relapse of 
disease is the norm and survival among patients with relapsed HR-MDS is 
abysmally poor.[8]  
 
Genomic sequencing has improved our understanding of ‘primary or driver’ 
mutations as well as ‘secondary or cooperating’ mutations in AML and MDS. These 
studies have also revealed clonal complexity of these diseases with existence of 
multiple clones with variety of mutations.[9] While targeting ‘driver’ mutations is an 
attractive strategy, the complex landscape of interacting mutations makes it difficult 
to envisage a strategy exclusively based on targeting mutations alone to be 
successful. Clinically this is supported by the fact that responses with kinase 
inhibitors targeting FLT3, MEK etc. are generally short lasting.[10] On the other hand 
20-30% of patients with AML get cured of disease with chemotherapy based 
approaches (nucleoside analog and anthracycline based). Thus rational potentiation 
of chemotherapy effect on leukemia cells holds a promise of improving long term 
outcome in AML and MDS and not being restricted by presence of mutational 
events. Treatment directed against antigens expressed in leukemia cells offer such a 
mutation agnostic target. 
 
CD 38 as target in AML therapy 
Conventional perception is that the leukemia initiating cell resides in the CD34+/38- 
fraction of cells. However the phenotype of LIC is more heterogeneous as shown in 
the study of LIC in NPM1 mutated AML that is associated with low CD34 
expression.[11] In this study many of the LICs resided within the CD34-/38+ 
population. Similarly in progression from chronic myelomonocytic leukemia (CMML) 
to AML, there is substantial expansion of the Lin-/CD34+/CD38+ progenitor cell 
population.[12] This population is highly proliferative, resistant to apoptosis and has 

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enhanced myeloid colony formation/replating ability. Thus targeting CD 38 is a viable 
therapeutic option in myeloid malignancies. 
 
T Acute Lymphoblastic Leukemia/Lymphoma (T-ALL, T-LBL) 
In T-cell ALL and T-cell LBL, the neoplasm is characterized by malignant expansion 
of immature lymphoblasts committed to the T-cell lineage. T-ALL and T-LBL are 
widely thought of as the same disease type differing only by the amount of 
involvement in the bone marrow. Infiltration above 25% is considered T-ALL and 
below 25% is T-LBL[13]. They are a heterogeneous group of diseases with regard to 
immunophenotyping, cytogenetics molecular genetic abnormalities, and clinical 
features including response to therapy. 
 
Although ALL is relatively more common in children, it can also affect adults. T-ALL 
and T-LBL account for approximately 12% to 15% of childhood and 25% of adult 
ALL cases. Molecular subtypes of T-ALL with Notch mutations are found in about 
50% to 60% of children and adults with T-ALL [13, 14]. 
 
Treatment for T-LBL has moved from traditional lymphoma protocols to treatments 
designed for ALL[13]. Treatment results in newly diagnosed adult patients with ALL 
have improved in the past decade with an increase of complete remission (CR) rates 
to between 85% and 90% and overall survival (OS) rates to between 40% and 50% 
with the developments of intensified and targeted chemotherapies and stem cell 
transplantation (SCT)[13]. The 5-year overall survival of T-ALL has improved to 
between 48% and 56%[15, 16]. T-ALL represents one of the most favorable 
subgroups of adult ALL. Mortality rates of T-ALL patients have significantly 
decreased over the last decades because of advances in the treatment of this 
aggressive subset of ALL. The 5-year OS rates are approximately 35% to 40% in 
adults and 75% to 85% for children and adolescents[17]. Despite the progress in the 
treatment results of newly diagnosed T-ALL or T-LBL, approximately half of these 
patients relapse within the first 2 years or fail to achieve a CR and have an 
extremely poor prognosis. 
 
Response rates of 50% are achievable among relapsed or refractory T-ALL/T-LBL 
patients treated with high or intermediate doses of cytarabine-based combination 
therapy, but remissions are of short duration. 
 
Response rates of 50% are achievable among relapsed or refractory T-ALL/T-LBL 
patients treated with high or intermediate doses of cytarabine-based combination 
therapy, but remission. Given the historically poor clinical outcomes for the majority 
of patients with relapsed T-ALL/T-LBL, there is a clear need for new treatment 
options. 
 
CD38 as target in T-acute lymphoblastic leukemia/lymphoma 
In a study from Children’s Hospital of Philadelphia, CD 38 expression was confirmed 
by flowcytometry in all T-ALL/LBL samples including those of early T-cell precursor 
ALL.[18] In that study the investigators report that daratumumab monotherapy was 

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effective in patient-derived xeneograft models developed from 14 of 15 patients with 
T-ALL. 
 
Daratumumab 
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high 
affinity to a unique epitope on CD38, a transmembrane glycoprotein. It is currently 
approved for the treatment of patients with multiple myeloma who have received at 
least three prior lines of therapy including a proteasome inhibitor and an 
immunomodulatory agent or who are double-refractory to a PI and an 
immunomodulatory agent. The drug is not approved for the indication being studied, 
AML and HR-MDS. It is a targeted immunotherapy directed towards tumor cells that 
express high levels of CD38, such as multiple myeloma, lymphoma and B- and T-
cell ALL and potentially subsets of AML.  Daratumumab has multiple mechanisms of 
action (MoA), including antibody-dependent cell-mediated cytotoxicity (ADCC) and 
complement-dependent cytotoxicity (CDC). Importantly, daratumumab-induced 
ADCC and CDC do not appear to be affected by the presence of bone marrow 
stromal cells, indicating that daratumumab can effectively induce the killing of 
malignant cells in a tumor-preserving bone marrow microenvironment. In vivo 
studies have shown that daratumumab is highly active and interrupts xenograft 
tumor growth at low doses.[19] 
 
Clinical Study Summary 
In humans, daratumumab is tolerated well. Maximum tolerated dose (MTD) has not 
been reached following intravenous (IV) infusions up to 24 mg/kg monotherapy and 
16 mg/kg in combination studies. The most frequently reported adverse events 
(AEs) across the daratumumab program have been infusion-related reactions (IRRs) 
following single agent therapy. Among all subjects treated in ongoing studies 
(monotherapy and combination therapy), IRRs have been reported in 49% of 
subjects. (Reference: Appendix G, Investigator’s Brochure). 
 
Daratumumab will be provided at no cost to the patient. 
 
Venetoclax  
Venetoclax (Venclexta™) is a selective and orally bioavailable small-molecule 
inhibitor of BCL-2, an anti-apoptotic protein. Venetoclax is approved for treatment of 
chronic lymphocytic leukemia (CLL) and in combination with azacitidine, decitabine 
or low-dose cytarabine to treat older adults with AML. Venetoclax helps restore the 
process of apoptosis by binding directly to the BCL-2 protein, displacing pro-
apoptotic proteins like BIM, triggering mitochondrial outer membrane 
permeabilization and the activation of caspases.  
 
In nonclinical studies, venetoclax has demonstrated cytotoxic activity in tumor cells 
that overexpress BCL-2. Pre-clinical studies in T-ALL, particularly a high-risk 
subtype of early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), using 
BH3 profiling, have revealed BCL-2 dependence with exquisite in vitro sensitivity to 

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the BCL-2–selective antagonist venetoclax.[20, 21]. Limited clinical experience also 
suggests that venetoclax is active against T-ALL.[22] 
 
Venetoclax is highly bound to human plasma protein with unbound fraction in 
plasma <0.01 across a concentration range of 1-30 μM (0.87-26 μg/mL). The 
population estimate for the terminal elimination half-life of venetoclax was 
approximately 26 hours. The pharmacokinetics of venetoclax does not change over 
time. 
 
Concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during 
ramp-up phase is contraindicated. Concomitant use of venetoclax with strong 
CYP3A inhibitors increases venetoclax exposure (i.e., Cmax and AUC) and may 
increase the risk for tumor lysis syndrome at initiation and during ramp-up phase. 
For patients who have completed the ramp-up phase and are on a steady daily dose 
of venetoclax, reduce the venetoclax dose by at least 75% when strong CYP3A 
inhibitors must be used concomitantly. 
 
Concomitant use of venetoclax with moderate CYP3A inhibitors or P-gp inhibitors 
should be avoided. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, 
reduce the venetoclax dose by at least 50%. These patients will be monitored more 
closely for signs of toxicities and will resume the venetoclax dose that was used prior 
to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of 
the inhibitor. 
 
2. Venetoclax will be obtained from commercial source and is the 
responsibility of the patient and/or insurance company.  Study 
Population 
Patients with relapsed/refractory acute myelogenous leukemia, high-risk 
myelodysplastic syndrome, or relapsed/refractory T-ALL/T-LBL. 
3. Study Objectives 
Primary Objectives 
The primary objective of this study is to assess response rate as determined by the 
International Working Group recommendations in AML, MDS[23, 24] and in adult 
patients with relapsed/refractory T-ALL/T-LBL. 
 
Secondary Objectives 
The secondary objectives of this study are to assess: 
 Safety and tolerability 
 Time on treatment 
 Overall survival  
 Progression free survival 

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 Long-term response rate 
 
Exploratory Objective 
To explore biomarkers predictive of response or resistance to therapy including 
expression of CD38 at study entry and at relapse and response rate based on CD38 
expression level. 
4. Hypothesis 
For relapsed/refractory AML/high risk MDS and relapsed/refractory T-ALL/T-LBL, the 
primary hypothesis is that daratumumab in combination with venetoclax will improve 
the overall response rate from the historical rate of 15% by at least 10% (i.e., 25% 
response rate). 
5. Study Design 
This is a single center, Phase 2, open-label study of daratumumab and venetoclax in 
subjects with relapsed/refractory AML, high risk MDS and relapsed/refractory T-
ALL/T-LBL. Subjects in a cohort of 6 with up to 36 subjects will be enrolled to receive 
daratumumab and venetoclax. Each cycle will be 4 weeks (28 days). Daratumumab 
will be administered at 16mg/kg weekly for the first 2 cycles (8 weeks) of treatment, 
followed by every 2 weeks for 4 cycles (or 16 weeks) weeks and then every 4 weeks 
until progression or up to 1 year of treatment whichever comes earlier.  Venetoclax 
administration will follow the schedule indicated in package insert for administration 
in AML. (www.rxabbvie.com/pdf/venclexta.pdf) Venetoclax will be administered for 
21 days in each cycle and clinician will use appropriate judgement about number of 
days of venetoclax beyond cycle 1, based on disease status and blood counts. 
Tumor lysis syndrome (TLS) prophylaxis during dose ramp-up of venetoclax will be 
per label of venetoclax for use in AML.  
On days of daratumumab dosing, the subject will receive pre-infusion medications 
and on the 2 days after receiving daratumumab dosing, the subject will receive post-
infusion corticosteroid prophylaxis for IRR. See Section 7C and D. 
MDACC Investigational New Drug (IND) office will review interim safety data with 
Principal Investigator (and statistician if needed) at a predetermined interim safety 
analyses interval as indicated next. The first analysis will occur after the first 6 
subjects are treated for at least 1 cycle. Enrollment will be temporarily halted after 
first six subjects have been enrolled and treated. If deemed safe, enrollment will 
resume and safety monitoring will be conducted in cohort size of 6 thereafter, as 
detailed in the Statistical Considerations section. We will also implement a Bayesian 
futility monitoring for overall response rate in cohort size of 6. However, enrollment 
will not need to be held. As enrollment is expected to be at 1-2 patients a month this 
would not substantially impact futility monitoring.  

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6. Eligibility Criteria 
A. Inclusion criteria: 
1. Understand and voluntarily sign an informed consent form. 
2. Age >/=18 years at the time of signing the informed consent form.  
3. Diagnosis of AML [other than acute promyelocytic leukemia (APL)] with 
refractory/relapsed disease; patients with relapsed/refractory high-risk 
[(intermediate-2 or higher by International Prognostic Scoring System (IPSS) 
and/or >/= 10% blasts)] MDS will also be eligible. (Treatment approach for 
relapsed/refractory AML is very similar to that of high risk MDS), or diagnosis 
of relapsed/refractory T-ALL/T-LBL.   
4. All non-hematological toxicity of previous cancer therapy should have 
resolved to </= grade1 (except alopecia or other toxicities not involving major 
organs). 
5. Eastern Cooperative Oncology Group (ECOG) performance status of </= 2 at 
study entry. 
6. Laboratory test results within these ranges: 
 Serum creatinine </= 2 mg/dL and estimated glomerular filtration rate or 
creatinine clearance >/= 40 ml/min 
 Total bilirubin </= 2 mg/dL 
 Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
</=3 x upper limit of normal (ULN) 
7. Women of childbearing potential must be practicing a highly effective method 
of birth control consistent with local regulations regarding the use of birth 
control methods for subjects participating in clinical studies: e.g., established 
use of oral, injected or implanted hormonal methods of contraception; 
placement of an intrauterine device or intrauterine system; barrier methods: 
condom with spermicidal foam/gel/film/cream/suppository or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/ 
cream/suppository; male partner sterilization (the vasectomized partner 
should be the sole partner for that subject); true abstinence (when this is in 
line with the preferred and usual lifestyle of the subject) during and after the 
study (3 months after the last dose of daratumumab for women). 
8. A man who is sexually active with a woman of childbearing potential and has 
not had a vasectomy must agree to use a barrier method of birth control e.g., 
either condom with spermicidal foam/gel/film/cream/suppository or partner 
with occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository, and all men must also not donate sperm 
during the study and for 3 months after receiving the last dose of study drug. 
9. AML relapse > 6 months since autologous or allogeneic stem cell 
transplantation, provided there is no active graft-versus-host disease (GVHD) 
> grade 1; no treatment with high dose steroids for GVHD (up to 20 mg 
Prednisolone or equivalent); no treatment with immunosuppressive drugs with 
the exception of low dose cyclosporine and tacrolimus (blood levels of 0.5-0.6 
µg/mL). 

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B. Exclusion Criteria: 
1. White blood cell count more than 25 × 109 /L prior to initiation of venetoclax. 
2. Pregnant or breast feeding females.  
3. Cancer chemotherapy within 2 weeks prior to start of daratumumab treatment 
(exception hydroxyurea). Use of hydroxyurea to control proliferative disease 
will be allowed prior to starting therapy on study and for 7 days during cycle 1-
3 (Maximum daily dose of 7gm). 
4. Subject has received daratumumab or other anti-CD38 therapies previously. 
5. Subject has received a cumulative dose of corticosteroids more than the 
equivalent of >/= 140 mg of prednisone within the 2 week period before Cycle 
1, Day 1. 
6. Subject has known chronic obstructive pulmonary disease (COPD) with a 
Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. 
NOTE: FEV1 testing is required for patients suspected of having COPD and 
subjects must be excluded if FEV1 <50% of predicted normal. 
7. Subject has a history of another malignancy within 5 years before Cycle 1, 
Day 1 (exceptions are squamous and basal cell carcinomas of the skin and 
carcinoma in situ of the cervix, or malignancy that in the opinion of the 
investigator, with concurrence with the IND office and supporter's medical 
monitor, is considered cured with minimal risk of recurrence).   
8. Subject is known to be seropositive for hepatitis B (defined by a positive test 
for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, 
subjects who are HBsAg negative but positive for antibodies to hepatitis B 
core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-
HBs]) must be screened using real-time polymerase chain reaction (PCR) 
measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR 
positive will be excluded. EXCEPTION: Subjects with serologic findings 
suggestive of HBV vaccination (anti-HBs positivity as the only serologic 
marker) AND a known history of prior HBV vaccination, do not need to be 
tested for HBV DNA by PCR.  
9. Subjects who are seropositive for hepatitis C (except in the setting of a 
sustained virologic response [SVR], defined as aviremia at least 12 weeks 
after completion of antiviral therapy) will be excluded. 
10. Subject has clinically significant cardiac disease, including: 
 myocardial infarction within 1 year before Cycle 1, Day 1, or unstable or 
uncontrolled disease/condition related to or affecting cardiac function (e.g., 
unstable angina, congestive heart failure, New York Heart Association 
Class III-IV) 
 Cardiac arrhythmia (CTCAE Version 4.03 Grade 2 or higher) or clinically 
significant ECG abnormalities.  
 Screening 12-lead ECG showing a baseline QT interval as corrected by 
Fridericia’s formula (QTcF) >470 msec. 
11. Subject has known severe allergies, hypersensitivity, or intolerance to 
monoclonal antibodies or human proteins, or their excipients (refer to the 

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latest version of the Investigator Brochure), or known sensitivity to 
mammalian-derived products. 
12. Subject has any concurrent medical condition or disease (e.g., active 
systemic infection, laboratory abnormalities) that is likely to interfere with 
study procedures or results, or that in the opinion of the investigator would 
constitute a hazard for participating in this study. 
13. Exclude patients with known Kell antibodies. 
 
7. Dosage and Administration 
Daratumumab will be administered at 16mg/kg for the first 2 Cycles (one time 
per week for 8 weeks) of treatment, followed by every 2 weeks for 4 cycles (or 16 
weeks) and then every 4 weeks until progression or up to 1 year whichever 
comes earlier. All cycles are 4 weeks (28 days). The first visit of a cycle should 
be 4 weeks (+/- 3 days) after the start of the previous cycle, except in case of 
toxicities, see Section 7B. Every effort should be made to keep subjects on the 
planned dosing schedule. 
 
Preparation 
Infusion solution will be prepared as a 1000 mL (first dose) or 500-mL (second 
and subsequent doses) dilution of daratumumab in sterile, pyrogen-free 0.9% 
NaCl. Preparation of infusion bags should be done on the day of the planned 
infusion. Daratumumab must be administered as an IV infusion given through a 
well-functioning IV catheter by using an infusion pump (Table 2). The study drug 
must be filtered by using an inline filter (0.2 μM) during the infusion. Manuals with 
detailed descriptions for preparation and administration of daratumumab will be 
supplied to pharmacy. 
 
Venetoclax administration will follow following schedule for Cycle 1: 
 
Table 1: Venetoclax dosing guidelines 
 
 
Day 1 
Day2 
Day3 
Day 4-21 
Not on 
mod/strong 
CYP inhibitor 
or Pgp 
inhibitor  
100 mg  
200 mg  
400 mg  
400 mg  
On moderate 
CYP inhibitor 
or Pgp 
inhibitor  
50 mg  
100 mg  
200 mg  
200 mg  
On strong 
CYP inhibitor 
excluding 
posaconazole  
10 mg  
20 mg  
50 mg  
100 mg  

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Receiving 
posaconazole  
10 mg  
20 mg  
50 mg  
70 mg  
  
For Cycle 2 onwards venetoclax will be dosed on days 1-21 at the dose intended 
to be administered on days 4-21 in cycle 1, but will start at that dose from Day1. 
Clinical judgement will be used to reduce the number of days of venetoclax 
administration based on disease status, ongoing clinically relevant issues e.g. 
infection, renal dysfunction etc.   
  
Tumor lysis syndrome (TLS) prophylaxis during dose ramp-up of venetoclax will 
be per label of venetoclax for use in AML. 
A. Treatment Schedule and Administration (Daratumumab) 
Daratumumab will be administered as an intravenous (IV) infusion (Table 2). 
Each subject’s dose will be calculated based on the subject’s weight rounded to 
the nearest kilogram. The dose of daratumumab will remain constant throughout 
the study, unless the patient’s weight changes more than 10% from baseline. All 
infusions will be planned as outpatient visits. If needed, infusion can be done in 
the in-patient setting. Subjects will receive pre-infusion medications and post-
infusion medications as detailed in Sections 7C and D. 
 
Table 2. Infusion rates for daratumumab administration 
 
Dilution 
volume 
Initial rate 
(first hour) 
Rate increment 
Maximum 
rate 
First infusion 
1000 ml 
50ml/hr 
50 ml/hr every hr 
200 ml/hr 
Second infusiona 
500 ml 
50 ml/hr 
50 ml/hr every hr 
200 ml/hr 
Subsequent 
infusionb 
500 ml 
100 ml/hr 
50 ml/hr every hr 
200 ml/hr 
a. Escalate only if there were no Grade 1 (mild) or greater infusion reactions during the first 3 
hours of the first infusion. 
b. Escalate only if there were no Grade 1 (mild) or greater infusion reactions during a final 
infusion rate of ≥ 100 mL/hr in the first two infusions. 
 
Daratumumab will be administered as noted below: 
 Cycles 1 and 2: One time per week on Days 1, 8, 15, and 22.  On Days 8, 
15, and 22 (+1 day window).  
 Cycle 3 to 6: Once every 2 weeks, Days 1 and 15 (+/- 3 days). 
 Cycles 7+: Once every 4 weeks, Day 1 (+/- 7 days). 
 
These windows will be used for delays not related to toxicities. For delays caused 
by toxicities please refer to Table 3. 
 
For additional details for administration times and rates please refer to Table 2 
and Daratumumab package insert 
(https://www.janssenmd.com/pdf/darzalex/DARZALEX_PI.pdf).  

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All subjects should have vital signs monitored at the end of the infusion. If a 
subject experiences any significant medical event, then the investigator should 
assess whether the subject should stay overnight for observation. If the subject 
has not experienced a significant medical event but is hospitalized overnight only 
for observation, then the hospitalization should not be reported as a serious 
adverse event. 
 
 
B.  Dose Delays and Dose Modification  
a. Daratumumab 
Dose Modification 
No daratumumab dose modification (increase or decrease) will be permitted. 
 
Toxicity Management 
ONLY if any of the following criteria are met and the event is considered related 
to daratumumab then the next scheduled daratumumab infusion must be held to 
allow for recovery from toxicity.  
 
The criteria for a dose delay are as follows: 
 
Grade 3 or higher non-hematologic toxicities with the following exceptions:  
 Grade 3 nausea that responds to antiemetic treatment within 7 days 
 Grade 3 vomiting that responds to antiemetic treatment within 7 days 
 Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days 
 Grade 3 fatigue that was present at baseline or that lasts for <7 days after 
the last administration of daratumumab 
 Grade 3 asthenia that was present at baseline or that lasts for <7 days 
after the last administration of daratumumab 
 isolated Grade 3 or higher glutamyltransferase elevation 
 
If daratumumab administration does not commence within the prespecified 
window (Table 3) of the scheduled administration date (either for toxicity or 
extenuating circumstances), then the dose will be considered a missed dose. 
Administration may resume at the next planned dosing date.  
 
Table 3.  Daratumumab-related Toxicity Management 
Cycles 
Frequency 
Dose Miss 
Dosing Resumption 
1 -2 
Weekly  
(Q1W) 
>3 days 
next planned weekly dosing date 

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3-6 
Every 2 weeks 
(Q2W) 
>7 days 
next planned every 2 weeks 
dosing date 
7+ 
Every 4 weeks 
(Q4W) 
>14 days 
next planned every 4 weeks 
dosing date 
 
A missed dose will not be made up. If a dose is delayed (beyond the usual 
permissible window), then the dates of all subsequent doses must be 
adjusted. Any adverse event deemed to be related to daratumumab that 
requires a dose hold of more than 4 weeks (Cycle 1 to Cycle 6) or more than 6 
weeks (Cycle 7 and beyond) will result in permanent discontinuation of 
daratumumab.  
 
Interruption or Missed Doses 
Subjects missing >/= 3 consecutive planned doses of daratumumab for toxicity 
related to daratumumab should be withdrawn from the study.  For subjects 
missing >/= 3 consecutive planned doses of daratumumab with reasons other 
than toxicity should also be withdrawn, unless upon consultation with the IND 
office and review of the safety and efficacy, continuation is agreed upon.   
b. Venetoclax:  
Venetoclax dose reduction will follow its dose modification suggestions in acute 
myeloid leukemia from its package insert.   
Additional dose reductions and delays are allowed for venetoclax in cycle 1 and 
subsequent cycles if considered in the best interest of the patient and based on 
expertise of the investigator.  
C. Pre-infusion medication (Daratumumab) 
Administer pre-infusion medications to reduce the risk of infusion reactions 
to all patients approximately 1 hour prior to every infusion of daratumumab as 
follows: 
 intravenous corticosteroid (methylprednisolone 100 mg, or equivalent 
dose of an intermediate-acting or long-acting corticosteroid), plus 
 oral anti-pyretics (acetaminophen 650 to 1000 mg), plus 
 oral or intravenous antihistamine (diphenhydramine 25 to 50 mg or 
equivalent). 
 
Following the second infusion, the dose of corticosteroid may be reduced 
(methylprednisolone 60 mg intravenously). Please refer to Appendix B:  
Corticosteroid Comparison Chart for conversion of steroid dose. 
D. Post-infusion Medication (Daratumumab) 
For the prevention of delayed infusion-related reactions (IRR), all subjects will 
receive corticosteroid orally (20 mg methylprednisolone or equivalent in 

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accordance with local standards).  See Appendix B: Corticosteroid Comparison 
Chart on the 2 days following all daratumumab infusions (beginning the day after 
the infusion).  
 
For subjects with a higher risk of respiratory complications (e.g., subjects who 
have an FEV1 <80%), the following post-infusion medications should be 
considered: 
 H1-Antihistamine (diphenhydramine, cetirizine, or equivalent) on the first 
and second days after all infusions 
 Short-acting β2 adrenergic receptor agonist such as albuterol aerosol at 
any time as medically indicated. 
 Control medications for lung disease (e.g., inhaled corticosteroids ± long-
acting β2 adrenergic receptor agonists for subjects with asthma; long-
acting bronchodilators such as tiotropium or salmeterol ± inhaled 
corticosteroids for subjects with chronic obstructive pulmonary disease) as 
medically indicated.  In addition, these at-risk subjects may be hospitalized 
for monitoring for up to 2 nights after an infusion. If subjects are 
hospitalized, then their spirometry test (FEV1) should be measured before 
discharge. If these subjects are not hospitalized, then a follow up 
telephone call should be made to monitor their condition within 48 hours 
after all infusions. If the subject has not experienced a significant medical 
event but is hospitalized overnight only for observation, then the 
hospitalization should not be reported as a serious adverse event. 
Investigators may prescribe bronchodilators, H1-antihistamines, and 
corticosteroids that are deemed necessary to provide adequate supportive 
care in the event a bronchospasm occurs after subjects are released from 
the hospital/clinic. If an at-risk subject experiences no major infusion-
related reactions, then these post-infusion medications may be waived 
after 4 doses at the investigator’s discretion.  
 
Any post-infusion medication will be administered after the infusion has 
completed, per the timing noted above. 
 
E. Management of Infusion-related Reactions (Daratumumab) 
Subjects should be carefully observed during daratumumab infusions (Table 2 
for infusion rates). Trained study staff at the clinic should be prepared to 
intervene in case of any infusion reactions occurring, and resources necessary 
for resuscitation (e.g., agents such as epinephrine and aerosolized 
bronchodilator, also medical equipment such as oxygen tanks, tracheostomy 
equipment, and a defibrillator) must be available at bedside. Attention to staffing 
should be considered when multiple subjects will be dosed at the same time.  
If an infusion-related reaction develops, then the infusion should be paused.  In 
case of an infusion-related reaction, maintain the vital sign time points in relation 
to the initial start of the infusion. Additional vital sign time points are to be 
performed at the discretion of the investigator. Only clinically significant findings 

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need to be reported on unscheduled case report forms. Subjects who experience 
adverse events during the infusion must be treated according to the investigator’s 
judgment and best clinical practice. The following guidelines apply: 
 Subjects should be treated with acetaminophen, H1-antihistamine, or 
corticosteroids as needed. Intravenous saline may be indicated. For 
bronchospasm, urticaria, or dyspnea, subjects may require H1-
antihistamines, oxygen, corticosteroids, and/or bronchodilators. For 
hypotension, subjects may require vasopressors. 
 In the event of a life-threatening infusion-related reaction (which may include 
pulmonary or cardiac events) or anaphylactic reaction, daratumumab should 
be discontinued and after consultation with the supporter’s and/or IND office’s 
medical monitor, no additional daratumumab should be administered to the 
subject. Aggressive symptomatic treatment should be applied. If an infusion is 
paused, then a longer-than-anticipated infusion time may occur. Overnight 
stays at the hospital because of slow infusion times should not be reported as 
a serious adverse event.  
 
Infusion-Related Reactions of Grade 1 or Grade 2 
For infusion related adverse events that are Grade 1 or 2, the infusion should be 
paused. When the subject’s condition is stable, the infusion may be restarted at 
the investigator’s discretion. Upon restart, the infusion rate should be half of that 
employed before the interruption. Subsequently, the infusion rate may be 
increased at the investigator’s discretion. 
 
If the subject experiences a Grade 2 or higher event of laryngeal edema, or a 
Grade 2 or higher event of bronchospasm that does not respond to systemic 
therapy and does not resolve within 6 hours from onset, then the subject must be 
withdrawn from treatment.  
 
Infusion-Related Reactions of Grade 3 or Higher 
For infusion-related adverse events that are Grade 3 or higher, the infusion must 
be stopped and the subject must be observed carefully until resolution of the 
adverse event. If the intensity of any other adverse event remains at Grade 3 
after 2 hours, then the subject must be withdrawn from treatment. Any patient 
with grade 4 infusion related reaction will also be withdrawn from treatment. If the 
intensity of any other adverse event decreases to Grade 1 or 2 within 2 hours, 
then the infusion may be restarted at the investigator’s discretion. Upon restart, 
the infusion rate should be half of that employed before the interruption. 
Subsequently, the infusion rate may be increased at the investigator’s discretion. 
 
If the intensity of the adverse event returns to Grade 3 or 4 after restart of the 
infusion, then the procedure described in this section may be repeated at the 
investigator’s discretion. Should the intensity of the adverse event increase to 
Grade 3 for a third time, then the subject must be withdrawn from treatment. Any 
patient with grade 4 infusion related reaction at any time will be withdrawn from 
treatment. 

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F. Permitted Therapies 
Use of hydroxyurea to control proliferative disease will be allowed prior to starting 
therapy on study and for up to 7 days (per cycle) during Cycles 1-3 (maximum 
daily dose of 7gm). Use of growth factors (G-CSF, GM-CSF and erythrpoietic 
growth factors) will be permitted if considered to be in the best interest of the 
patient.  Use of prophylactic/therapeutic antiemetics, antibiotics, antivirals and 
antifungals are permitted as per the decision of the treating physician. 
Prophylactic antiviral prophylaxis is recommended for all patients unless 
contraindicated. 
G. Prohibited Therapies 
Concomitant administration of investigational agents, including medications that 
target CD38, with the intention of treating AML/MDS are prohibited. 
Administration of commercially available agents with activity against or under 
investigation for AML/MDS/T-ALL (except hydroxyurea) should be avoided.  
 
Concurrent use of corticosteroids is prohibited, unless used for prevention or 
treatment of infusion reactions (as above) or patients are on chronic steroids 
(maximum dose 20 mg/day prednisone equivalent) if they are being given for 
disorders other than treatment of AML/MDS, i.e., adrenal insufficiency, 
rheumatoid arthritis, etc. 
H. Duration of Therapy 
If a patient continues to respond or receive clinical benefit, he/she can continue 
treatment.   
 
In the absence of treatment delays due to adverse event(s), treatment may 
continue once every four weeks (28 days) until one of the following criteria 
applies: disease progression or 1 year of treatment whichever is earlier. 
8. Study Procedures 
All study procedures are presented in Table 7. Schedule of Study Events.  Results 
of all assessments will be recorded on the appropriate CRF. Study treatment should 
be initiated within 72 hours after registration. One cycle is 4 weeks (28 days) in 
duration. The start of each cycle may occur +/- 3 days of the scheduled day in order 
to accommodate the schedule of the site or subject. 
 
Beyond day 1, safety laboratory evaluations can be done according to the time 
window provided for subsequent dosing. 
i. Screening Procedures 
The investigator will inform each prospective subject of the nature of the study, 
explain the potential risks, and obtain written informed consent from the subject 

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prior to performing any study-related procedures and prior to the administration 
of study drug. 
 
The results of the screening evaluation must meet the inclusion/exclusion criteria 
for the subject to be entered into the study. Thus the investigator must review the 
results of diagnostic testing (bone marrow biopsy/aspirate and serum pregnancy 
test [if applicable], and clinical laboratory tests), and the results of that screening 
testing must meet the inclusion/exclusion criteria for the subject to be enrolled 
into the study. 
 
ii. Daratumumab Interference with Indirect Antiglobulin 
Test (IAT) results  
Daratumumab interferes with the Indirect Antiglobulin Test (IAT), which is a 
routine pre-transfusion  test  performed  to identify a patient’s antibodies to minor 
antigens so that suitable donor blood can be given for transfusion. Daratumumab 
does not interfere with ABO/RhD typing.  CD38 is expressed at very low levels 
on erythrocytes.  Daratumumab binds to the CD38 on erythrocytes, which results 
in a positive IAT (Indirect Coombs Test).  This positive result masks the detection 
of antibodies to minor antigens and may prevent or delay blood banks from 
issuing donor blood for transfusion.  This effect occurs during daratumumab 
treatment and for up to 6 months after treatment ends.  Subjects will receive a 
patient information card for the study that includes the blood profile (ABO, Rh, 
and IAT) determined before the first infusion of daratumumab along with 
information on the IAT interference for healthcare providers/blood banks.  
Subjects are to carry this card throughout the treatment period and for at least 6 
months after treatment ends.  MDACC Blood bank will also be alerted when a 
subject is enrolled on study. Blood banks can eliminate the daratumumab IAT 
interference by treating reagent RBCs with dithiothreitol (DTT).[25] 
 
Possible methods for blood banks to provide safe RBCs for transfusion to 
subjects receiving daratumumab include: 
 Providing ABO/RhD compatible, phenotypically or genotypically matched 
units 
 Providing ABO/RhD compatible, K-negative units after ruling out or 
identifying alloantibodies using DTT-treated reagent RBCs 
 
Uncrossmatched, ABO/RhD compatible RBC units should be administered if 
transfusion is needed emergently as per local blood bank practice. 
 
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically 
significant hemolysis has been observed in daratumumab studies. For additional 
details, refer to the Daratumumab IB. 
 

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iii. Clinic Visits 
The procedures for each visit are listed in Table 7 Schedule of Study Events. 
  
A bone marrow aspirate and/or biopsy with differential and estimate of cellularity 
at baseline, on Day 1 (+/- 2 days) of each cycle after Cycle 1 until response is 
achieved. Subsequent bone marrow examinations will be performed at treating 
physician’s discretion (suggested every 2-3 months).  
D. Follow-up Period 
Follow-Up procedures will occur after End of Treatment (EoT). The subject will 
be contacted regularly by telephone, approximately 1 time each month for the 
first year after the EoT visit, then every 6 months during the second year, and 
then 1 time each year after that to determine survival status. Any adverse events 
ongoing when subject stops the study will be followed by the Investigator until the 
event resolves, stabilizes, or returns to baseline status. 
 
For the subject with response, the Follow-Up procedures include blood draw for 
CBC/Chemistry once per month for first 2 years after the EoT visit. Patients with 
continued response will be moved from this study to be followed under Leukemia 
Department umbrella protocols.  
  
End of Treatment 
At the time of discontinuation of treatment for any reason, subjects will report to 
the study site. EoT assessments may be performed at the discretion of the 
investigator. This assessment is to be completed 28-35 days after last dose 
administered. 
9. Criteria for Response for Acute Leukemias and MDS 
International Working Group Criteria[23, 24] will be used to define response. In 
general responses will include 
 
1. Complete remission (CR):  The patient must be free of all symptoms related 
to leukemia and have an absolute neutrophil count >/= 1.0 x 109/L, platelet 
count >/- 100 x 109/L, and normal bone marrow differential (</= 5% blasts). 
2. Complete remission without platelet recovery (CRp): As per CR but platelet 
count  < 100 x 109/L. 
3. Partial remission (PR): CR with 6 to 25% abnormal cells in the marrow or 
50% decrease in bone marrow blasts.   
4. Marrow CR:  Bone marrow:  </= 5% myeloblasts and decrease by >/= 50% 
over pre-treatment (MDS only) 
5. Morphologic leukemia-free state:  Normal marrow differential (<5% blasts); 
absolute neutrophil count and platelet counts are not considered.  (AML only) 

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6. Hematologic Improvement (HI):  HI should be described by the number of 
individual, positively affected cell lines (e.g. HI-E; HI-E + HI-N; HI-E + HI-P 
+HI-N) 
a) Erythroid response (HI-E):   
 Major response:  For patients with pretreatment hemoglobin less than 
11 g/dL, greater than 2 g/dL increase in hemoglobin; for RBC 
transfusion-dependent subjects, transfusion independence. 
 Minor response:  For patients with pretreatment hemoglobin less than 
11 g/dL, 1 to 2 g/dL increase in hemoglobin; for RBC transfusion-
dependent patients, 50% decrease in transfusion requirements.  
b) Platelet response (HI-P): 
 Major response:  For patients with a pretreatment platelet count less 
than 100 x 109/L, an absolute increase of 30 x 109/L or more; for 
platelet transfusion-dependent patients, stabilization of platelet 
transfusion independence. 
 Minor response:  For patients with a pretreatment platelet count less 
than 100 x 109/L, a 50% or more increase in platelet count with a net 
increase greater than 10 x 109/L but less than 30 x 109/L. 
c) Neutrophil response (HI-N): 
 Major response:  For absolute neutrophil count less than 1.5 x 109/L 
before therapy, at least a 100% increase, or an absolute increase of 
more than 0.5 x 109/L, whichever is greater. 
 Minor response:  For ANC less than 1.5 x 109/L before therapy, ANC 
increase of at least 100%, but absolute increase less than 0.5 x 109/L. 
10. 
Exploratory Studies 
The baseline expression of CD38 in leukemic blasts will be assessed by flow cytometry. 
Expression of other marker of leukemia blasts will be available as part of routine clinical flow 
cytometry. This will include but not limited to CD33, 34 etc. 
 
The mutation profile of leukemia relevant genes also will be available as part of routine work up 
done through Molecular Diagnostic Laboratory at MDACC. 
11. 
Statistical Considerations 
This is a Phase II study of daratumumab and venetoclax in patients with 
relapsed/refractory AML,  high risk MDS and T-ALL/T-LBL. Subjects will enrolled in a 
cohort size of 6 with up to 36 to receive daratumumab and Venetoclax. The intent will 
be to enroll at least 10 patients with T-ALL. Daratumumab will be administered at a 
starting dose of 16mg/kg every week for 8 weeks (2 cycles), followed by 16mg/kg every 
2 weeks for 16 weeks (4 cycles), and then every 4 weeks until progression or up to 1 
year of treatment, whichever comes earlier. Venetoclax administration will follow its 
package insert dosing guidelines for AML. The primary endpoint of this study is overall 
response (OR), defined as achievement of complete remission (CR), CR with 
incomplete platelet recovery (CRp), partial remission (PR), morphologic leukemia-free 

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state or marrow CR within 12 weeks of treatment.  The method of Thall, Simon and 
Estey[26] will be used to monitor efficacy and safety. The design software Multc Lean 
Desktop (version 2.1) developed by the Department of Biostatistics at M. D. Anderson 
Cancer Center (MDACC) was used to generate the stopping boundaries and the 
operating characteristics table for futility and toxicity monitoring. 
 
Futility  
We assume a target response rate of 25% and a response rate of 15% or lower will be 
considered not desirable. The study will be stopped early if the data suggest that: 
Pr(PE > PH + 0.10 | data)<0.025 
where PE and PH are the response rates for daratumumab in combination with 
venetoclax and historical treatment, respectively. That is, if at any time during the study 
we determine that there is less than 2.5% chance that the response rate improves over 
historical rate by more than 10%, the trial will be stopped due to futility. PE and PH are 
assumed to follow a prior of Beta (0.3, 1.7) and Beta (150, 850), respectively. The 
stopping boundaries for efficacy based on these assumptions and monitoring conditions 
are provided in Table 4. We will apply these stopping boundaries in cohort sizes of 6.  
 
Table 4.  Stopping boundaries for futility monitoring 
# of patients 
evaluated for 
response 
Stop the trial if # of patients 
with response is less than or 
equal to: 
6-12 
0 
18 
0-1 
24 
0-2 
30 
0-3 
36 
0-4 
 
Toxicity 
Unacceptable toxicities are defined as any treatment-related grade 3 or higher non-
hematologic  toxicities that occur within the first 12 weeks of treatment. Denote the 
probability of toxicity by PT. We assume as a priori, PT ~ beta (0.6, 1.4). Our stopping 
rule is given by the following probability statement:  
Pr(PT > 0.30 | data)>0.975. 
 
That is, we will stop the trial for new patient enrollment if at any time during the study, 
we determine that there is more than 97.5% chance that the unacceptable toxicity rate 
is more than 30%. This toxicity monitoring rule will be applied after the first 6 patients 
have been enrolled and evaluated, and then in cohort size of 6. Stopping boundaries 
corresponding to this stopping rule are listed in Table 5. The operating characteristics 
for efficacy and toxicity monitoring are summarized in Table 6.  
 
Table 5.  Early stopping boundaries for toxicity monitoring 

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# of patients  
(in cohort size of 6, 
starting from the 
6th  patient) 
Stop the trial if there 
are this many 
patients with 
toxicities: 
6 
5-6 
12 
8-12 
18 
10-18 
24 
13-24 
30 
15-30 
36 
17-36 
 
Table 6. Operating characteristics for efficacy and toxicity monitoring  
True response 
rate 
True toxicity 
rate 
Prob 
(stop the trial 
early) 
Average number 
of patients 
treated 
0.15 
0.10 
0.5752 
25.3 
 
0.30 
0.5959 
24.7 
 
0.40 
0.7049 
22.3 
 
0.50 
0.8895 
17.3 
0.25 
0.10 
0.2119 
35.0 
 
0.30 
0.2504 
34.1 
 
0.40 
0.4526 
30.2 
 
0.50 
0.7950 
22.3 
0.30 
0.10 
0.1282 
37.6 
 
0.30 
0.1708 
36.6 
 
0.40 
0.3945 
32.3 
 
0.50 
0.7732 
23.6 
 
Analysis Plan 
Summary statistics will be provided for continuous variables and frequency tables will 
be used to summarize categorical variables. We will estimate the overall response rate, 
along with the Bayesian 95% credible interval. Kaplan-Meier method will be used to 
estimate overall survival, time to treatment and progression-free survival. The two-sided 
log-rank tests will be used to assess the differences of time-to-event outcomes between 
subgroups of patients. Logistic regression analyses will be used to explore the 
association between biomarker and response or resistance to therapy.  
 
Data from all subjects who receive any study drug will be included in the safety 
analyses. Subjects who entered the study but did not take any of the study drug and 
had this confirmed will not be evaluated for safety. The severity of the toxicities will be 
graded according to the NCI CTCAE v4.03 whenever possible. We will follow standard 
reporting guidelines for adverse events. Safety data will be summarized by category, 
severity and frequency.   

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12. Adverse Events and Reporting Requirements 
Adverse event reporting will be as per the current NCI criteria and the Leukemia-specific 
Adverse Event Recording and Reporting Guidelines (Appendix D) . The descriptions 
and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
http://ctep.cancer.gov/reporting/ctc.html 
A.  Adverse Events 
Adverse event is any untoward medical occurrence that may present during 
treatment with a pharmaceutical product but which does not necessarily have a 
causal relationship with this treatment. Adverse drug reaction is a response to a 
drug which is noxious and unintended and which occurs at doses normally used 
in man for prophylaxis, diagnosis, or therapy of disease or for the modification of 
physiologic function. The Investigator or physician designee is responsible for 
verifying and providing source documentation for all adverse events, and 
assigning attribution for each event on all subjects enrolled on this study. 
 
For this protocol, adverse events and protocol specific data will be entered into 
PDMS/CORe.  PDMS/CORe will be used as the electronic case report form for 
this protocol. 
 
Only unexpected AEs related to the study drug will be recorded in the Case 
Report Form (CRF).  Expected events during leukemia therapy are: 
 
1. Myelosuppression related events (due to disease or leukemia therapy) 
a) febrile or infection episodes not requiring management in the intensive 
care unit 
b) epistaxis or bleeding except for catastrophic CNS or pulmonary 
hemorrhage 
c) anemia, neutropenia, lymphopenia, thrombocytopenia, leukopenia, 
leukocytosis 
 
2. Disease related events 
a) symptoms associated with anemia 
i. 
fatigue 
ii. 
weakness 
iii. 
shortness of breath 
b) electrolyte abnormalities (sodium, potassium, bicarbonate, CO2, 
magnesium) 
c) chemistry abnormalities (LDH, phosphorus, calcium, BUN, protein, 
albumin, uric acid, alkaline phosphatase, glucose) 
d) coagulation abnormalities 
e) disease specific therapy (induction, maintenance, salvage, or stem cell 
therapy) 
f) alopecia 

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g) bone,  joint, or muscle pain 
h) liver function test abnormalities associated with infection or disease     
progression 
i) disease progression 
 
3. General therapy related events 
a) catheter related events 
b) renal failure related to tumor lysis syndrome or antibiotic/antifungal 
therapy 
c) rash related to antibiotic use 
d) abnormal hematologic values will not be recorded on the CRF. For 
abnormal chemical values grade 3 or 4, the apogee will be reported per 
course in the CRF. 
 
B. Serious Adverse Event (SAE) Reporting 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the supporter, it results in any of the following 
outcomes: 
 Death 
 A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of death 
from the adverse experience as it occurred. It does not include an adverse 
experience that, had it occurred in a more severe form, might have caused 
death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 A congenital anomaly/birth defect. 
 A suspected transmission of an infectious agent via a medicinal product 
 Is medically important* 
 
*Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
 Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be 

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reported as an SAE if deemed appropriate by the Principal Investigator or 
the IND Supporter, IND Office. 
 
 All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas MD Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”.  Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
 
 All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next working 
day) of knowledge of the event to the Safety Project Manager in the IND Office. 
 
 Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB.  
 
 Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last study 
treatment/intervention, unless the participant withdraws consent. Serious 
adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has 
stabilized, or there has been acceptable resolution of the event. 
 
 Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS ADVERSE EVENT. 
 
C. Reporting to FDA 
 Serious adverse events will be forwarded to FDA by the IND Supporter 
(Safety Project Manager IND Office) according to 21 CFR 312.32. 
 It is the responsibility of the PI and the research team to ensure that serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the supporter’s guidelines, 
and Institutional Review Board policy. 

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13. Reporting SAE to Janssen Scientific Affairs, LLC 
A. Management of Safety Data 
This Study has been designated as an interventional study.  As such, all adverse 
events for Janssen Medicinal Products regardless of causality and special situations 
excluding those from subjects not exposed to a Janssen Medicinal Product and 
product quality complaints with or without an adverse event as described in this 
Exhibit will be reported from the time a subject has signed and dated an Informed 
Consent Form (ICF) until completion of the subject’s last study-related procedure 
(which may include contact for follow-up safety).  Serious adverse events will be 
reported for 30 days after the last dose of study drug. 
 
For the purposes of this study, the Janssen medicinal product is: DARZALEX™ 
(daratumumab)  
B. Adverse Events of Special Interest  
Adverse events of special interest are events that Janssen Scientific Affairs, LLC is 
actively monitoring as a result of a previously identified signal (even if non-serious).  
 
These adverse events are: 
 Infusion reactions ≥ Grade 3 
 Infections ≥ Grade 4 
 Cytopenias ≥ Grade 4 (Only related to Daratumumab) 
 Tumor Lysis Syndrome 
 Other Malignancies  
 Intravascular Hemolysis – All Grades 
 
Any Adverse Event of Special Interest that is to be reported to the COMPANY should be 
recorded on a Serious Adverse Event Report Form and be reported to the COMPANY 
within 24 hours of knowledge of the event. 
 
 
Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory 
reporting requirements. 
 an identifiable subject (but not disclosing personal information such as the 
subject’s name, initials or address) 
 an identifiable reporter (investigational site) 
 a Janssen medicinal product 
 an adverse event, outcome, or certain special situations  
 
The minimum information required is: 
 suspected Janssen medicinal product (doses, indication) 
 date of therapy (start and end date, if available) 

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 batch or lot number, if available 
 subject details (subject ID and country) 
 gender 
 age at AE onset 
 reporter ID 
 adverse event detail (AE verbatim in English), onset date, relatedness, causality, 
action taken, outcome, (if available) 
 Janssen protocol ID 
 
Product Quality Complaint (PQC) 
A product quality compliant is defined as any suspicion of a product defect related to 
a potential quality issue during manufacturing, packaging, release testing, stability 
monitoring, dose preparation, storage or distribution of the product, or delivery 
system.  Not all PQCs involve a subject.  Lot and batch numbers are of high 
significance and need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
 Functional Problem: e.g., altered delivery rate in a controlled release product 
 Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
 Potential Dosing Device Malfunction: e.g., autoinjector button not working, needle 
detaching from syringe 
 Suspected Contamination 
 Suspected Counterfeit 
 
C. Unlisted (Unexpected) Adverse Event/Reference Safety 
Information 
An adverse event is considered unlisted if the nature or severity is not consistent 
with the applicable product reference safety information. For a medicinal product(s) 
with a marketing authorization, the expectedness of an adverse event will be 
determined by whether or not it is listed in the applicable product information.  
 
http://www.darzalex.com/shared/product/darzalex/darzalex-prescribing-
information.pdf 
 
For DARZALEX™ (daratumumab), the expectedness of an adverse event will be 
determined by whether or not it is listed in the Investigator's Brochure. 
 
D. Special Reporting Situations  
Safety events of interest for a Janssen medicinal product that require expediting 
reporting and/or safety evaluation include, but are not limited to: 
 Drug exposure during pregnancy (maternal and paternal) 
 Overdose of a Janssen medicinal product  

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 Exposure to a Janssen medicinal product from breastfeeding  
 Suspected abuse/misuse of a Janssen medicinal product 
 Inadvertent or accidental exposure to a Janssen medicinal product  
 Any failure of expected pharmacological action (i.e., lack of effect) of a Janssen 
medicinal product 
 Medication error involving a Janssen medicinal product (with or without patient 
exposure to the Janssen medicinal product, e.g., name confusion) 
 Suspected transmission of any infectious agent via administration of a medicinal 
product 
 Unexpected therapeutic or clinical benefit from use of a Janssen medicinal 
product 
 
These safety events may not meet the definition of an adverse event; however, from 
a Janssen Scientific Affairs, LLC perspective, they are treated in the same manner 
as adverse events. Special situations should be recorded on the Adverse Event 
page of the CRF. 
 
Any special situation that meets the criteria of a serious adverse event should be 
recorded on a Serious Adverse Event Report Form and be reported to Janssen 
Scientific Affairs, LLC within 24 hours of becoming aware of the event. 
 
E. Pregnancy  
Females who choose to participate should not become pregnant during the study.  
Likewise, males participating in the study should not cause their partner to become 
pregnant while participating.  
 
The effects of daratumumab and venetoclax on fertility, the human embryo, the 
fetus, or the breast-fed infant are unknown.  Subjects must agree not to become 
pregnant while on this study.  Subjects cannot take part in this study if they are 
pregnant or breastfeeding a child.   
 
Women of childbearing potential will be required to undergo pregnancy tests prior to 
taking daratumumab and venetoclax.  Males must not get anyone pregnant during 
the course of the study and for 3 months after stopping daratumumab and 
venetoclax.   
 
Women must not donate eggs during the study and for 3 months after the last dose 
of study drugs.   
 
Males must not donate sperm during the study and for 3 months after the last dose 
of study drugs.  
 
Both male and female patients must use effective methods of birth control during the 
course of the study and for 3 months after stopping daratumumab and venetoclax.  

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The type of birth control used must be discussed with, and approved by, the study 
doctor before beginning the study.  Approved birth control must be in the form of 
oral, injected or implanted methods (e.g., placement of an intrauterine device or 
intrauterine system, condom with spermicidal foam/gel/film/cream/suppository, 
diaphragm, cervical/vault caps with spermicidal foam/gel/film/cream/suppository, 
male partner sterilization, or abstinence).   
 
All initial reports of pregnancy must be reported to Janssen Scientific Affairs, LLC by 
the PRINCIPAL INVESTIGATOR within 24 hours of becoming aware of the 
event using the Serious Adverse Event Form. Abnormal pregnancy outcomes (e.g. 
spontaneous abortion, fetal death, stillbirth, congenital anomaly, ectopic pregnancy) 
are considered serious adverse events and must be reported using the Serious 
Adverse Event Form.  
 
Any subject who becomes pregnant during the study must be promptly withdrawn 
from the study and discontinue further study treatment. 
Because the effect of the Janssen medicinal product on sperm is unknown, 
pregnancies in partners of male subjects exposed to a Janssen medicinal product 
will be reported by the PRINCIPAL INVESTIGATOR within 24 hours of their 
knowledge of the event using the Serious Adverse Event Form.  Depending on 
local legislation this may require prior consent of the partner. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
F. Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. 
The PRINCIPAL INVESTIGATOR shall provide all adverse events, both serious and 
non-serious, in report format. However, in certain circumstances more frequent 
provision of safety data may be necessary, e.g. to fulfill a regulatory request, and as 
such the data shall be made available within a reasonable timeframe at Janssen 
Scientific Affairs, LLC request. 
G. Procedures for Reporting Safety Data and Product Quality 
Complaints (PQCs) for Janssen Medicinal Products to Janssen 
Scientific Affairs, LLC 
All adverse events and special situations, whether serious or non-serious, related or 
not related, following exposure to a Janssen medicinal product are to be 
documented by the investigator and recorded in the CRF and in the subject’s source 
records. Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to a Janssen medicinal product.  
 
All (serious and non-serious) adverse events reported for a Janssen medicinal 
product should be followed-up in accordance with clinical practice. 
 

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H. SAEs, Adverse Events of Special Interest and Special Reporting 
Situations 
All serious adverse events that have not resolved by the end of the study, or that 
have not resolved upon discontinuation of the subject's participation in the study, 
must be followed until any of the following occurs: 
 The event resolves 
 The event stabilizes 
 The event returns to baseline, if a baseline value/status is available 
 The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct 
 It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts) 
 
The PRINCIPAL INVESTIGATOR will transmit all SAEs, Adverse Events of Special 
Interest and special situations following exposure to a Janssen product under study 
in a form provided by Janssen Scientific Affairs, LLC in accordance with Section 
11,Transmission Methods, in English within 24-hours of becoming aware of the 
event(s). 
 
In the event the study is blinded, the PRINCIPAL INVESTIGATOR will submit an 
unblinded SAE or pregnancy exposure report to Janssen Scientific Affairs, LLC. 
All follow-up information for serious adverse events that are not resolved at the end 
of the study or by the time of patient withdrawal must be reported directly by the 
PRINCIPAL INVESTIGATOR, within 24 hours becoming aware, to Janssen 
Scientific Affairs, LLC using the Janssen Scientific Affairs, LLC Serious Adverse 
Event Report  
 
All available clinical information relevant to the evaluation of a related SAE, Adverse 
Events of Special Interest, serious ADR or special situation is required. 
 
The PRINCIPAL INVESTIGATOR is responsible for ensuring that these cases are 
complete and if not are promptly followed-up. A safety report is not considered 
complete until all clinical details needed to interpret the case are received. Reporting 
of follow-up information should follow the same timeline as initial reports. 
 
Copies of any and all relevant correspondences with regulatory authorities and 
ethics committees regarding any and all serious adverse events, irrespective of 
association with the Janssen Product under study, are to be provided to Janssen 
Scientific Affairs, LLC using a transmission method in Section 13L within 24 hours 
of such report or correspondence being sent to applicable health authorities. 
 

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I. 
Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC 
according to the timeframe outlined in the Research Funding Agreement section 
entitled Reporting of Data. 
 
J. PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, 
accurate, and complete reporting and analysis of PQC information from studies are 
crucial for the protection of patients, investigators, and Janssen Scientific Affairs, 
LLC, and are mandated by regulatory agencies worldwide. Janssen Scientific 
Affairs, LLC has established procedures in conformity with regulatory requirements 
worldwide to ensure appropriate reporting of PQC information. Lot and/or Batch #s 
shall be collected or any reports failure of expected pharmacological action (i.e., lack 
of effect). The product should be quarantined immediately and if possible, take a 
picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be reported 
to Janssen Scientific Affairs, LLC by the PRINCIPAL INVESTIGATOR within 24 
hours after being made aware of the event. The Janssen contact will provide 
additional information/form to be completed. 
 
If the defect for a Janssen medicinal product under study is combined with either a 
serious adverse event or non-serious adverse event, the PRINCIPAL 
INVESTIGATOR must report the PQC to Janssen Scientific Affairs, LLC according 
to the serious adverse event reporting timelines.  A sample of the suspected product 
should be maintained for further investigation if requested by Janssen Scientific 
Affairs, LLC. 
 
K. Reporting Procedures for Reporting Safety Data and Product 
Quality Complaints (PQCs) for Non-Janssen Medicinal Products  
For SAEs, special reporting situations and PQCs following exposure to a non-
Janssen medicinal product under study, the PRINCIPAL INVESTIGATOR should 
notify the appropriate regulatory/competent authority or the manufacturer of that 
medicinal product (in the absence of appropriate local legislation) as soon as 
possible. 
 
L. Transmission Methods 
The following methods are acceptable for transmission of safety information to 
Janssen Scientific Affairs, LLC: 
 Electronically via Janssen SECURE Email service (preferred) 
 For business continuity purposes, if SECURE Email is non-functional: 

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o Facsimile (fax), receipt of which is evidenced in a successful fax 
transmission report 
 Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen 
Scientific Affairs, LLC.  
 
The Investigator is obligated under applicable law and regulations to report any 
serious and related adverse event, if any that occurs during study treatment to the 
Institution’s IRB/Ethics Committee and to the governing Regulatory Authority in 
accordance with applicable filing timelines promptly after any such event occurs.  
Prior to or at the time of filing any such report with the governing Regulatory 
Authority, the Investigator will also transmit an information copy of the report as sent 
to the authorities to Janssen. The Investigator shall make available to Janssen 
promptly such records as may be necessary and pertinent to investigate any such 
adverse event, if specifically requested by Janssen. 
 
14.  Drug Destruction Policy 
Unused drug will be destroyed per Investigational Pharmacy “Return and Disposal of 
Investigational Medications.” 
15. References 
1. 
Estey, E.H., Acute myeloid leukemia: 2012 update on diagnosis, risk stratification, and 
management. Am J Hematol, 2012. 87(1): p. 89-99. 
2. 
Roboz, G.J., Current treatment of acute myeloid leukemia. Curr Opin Oncol, 2012. 24(6): 
p. 711-9. 
3. 
Price, S.L., et al., Salvage chemotherapy regimens for acute myeloid leukemia: Is one 
better? Efficacy comparison between CLAG and MEC regimens. Leuk Res, 2011. 35(3): 
p. 301-4. 
4. 
Samudio, I., et al., Pharmacologic inhibition of fatty acid oxidation sensitizes human 
leukemia cells to apoptosis induction. The Journal of clinical investigation, 2010. 120(1): 
p. 142-56. 
5. 
Faderl, S., et al., Clofarabine plus cytarabine compared with cytarabine alone in older 
patients with relapsed or refractory acute myelogenous leukemia: results from the 
CLASSIC I Trial. J Clin Oncol, 2012. 30(20): p. 2492-9. 
6. 
Wierzbowska, A., et al., Cladribine combined with high doses of arabinoside cytosine, 
mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients 
with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the 
Polish Adult Leukemia Group. Eur J Haematol, 2008. 80(2): p. 115-26. 
7. 
Fenaux, P., et al., Efficacy of azacitidine compared with that of conventional care 
regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, 
open-label, phase III study. Lancet Oncol, 2009. 10(3): p. 223-32. 

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8. 
Jabbour, E., et al., Acute myeloid leukemia after myelodysplastic syndrome and failure 
of therapy with hypomethylating agents: an emerging entity with a poor prognosis. Clin 
Lymphoma Myeloma Leuk, 2014. 14(2): p. 93-7. 
9. 
Riva, L., L. Luzi, and P.G. Pelicci, Genomics of acute myeloid leukemia: the next 
generation. Front Oncol, 2012. 2: p. 40. 
10. 
Cortes, J.E., et al., Phase I study of quizartinib administered daily to patients with 
relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-
internal tandem duplication status. J Clin Oncol, 2013. 31(29): p. 3681-7. 
11. 
Taussig, D.C., et al., Leukemia-initiating cells from some acute myeloid leukemia 
patients with mutated nucleophosmin reside in the CD34(-) fraction. Blood, 2010. 
115(10): p. 1976-84. 
12. 
Sun, Q., et al., Functional alterations of Lin-CD34+CD38+ cells in chronic 
myelomonocytic leukemia and on progression to acute leukemia. Leuk Res, 2008. 32(9): 
p. 1374-81. 
13. 
Gokbuget, N. and D. Hoelzer, Treatment of adult acute lymphoblastic leukemia. Semin 
Hematol, 2009. 46(1): p. 64-75. 
14. 
Armstrong, S.A. and A.T. Look, Molecular genetics of acute lymphoblastic leukemia. J 
Clin Oncol, 2005. 23(26): p. 6306-15. 
15. 
Hoelzer, D. and N. Gokbuget, T-cell lymphoblastic lymphoma and T-cell acute 
lymphoblastic leukemia: a separate entity? Clin Lymphoma Myeloma, 2009. 9(3): p. 015. 
16. 
Marks, D.I., et al., T-cell acute lymphoblastic leukemia in adults: clinical features, 
immunophenotype, cytogenetics, and outcome from the large randomized prospective 
trial (UKALL XII/ECOG 2993). Blood, 2009. 114(25): p. 5136-45. 
17. 
Goldberg, J.M., et al., Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber 
Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol, 
2003. 21(19): p. 3616-22. 
18. 
Bride, K.L., et al., Targetting CD38 in T Cell Acute Lymphoblastic Leukemia. Blood 
(proceedings from ASH 2017), 2017. 130: p. Abstr 3888. 
19. 
de Weers, M., et al., Daratumumab, a novel therapeutic human CD38 monoclonal 
antibody, induces killing of multiple myeloma and other hematological tumors. J 
Immunol, 2011. 186(3): p. 1840-8. 
20. 
Del Gaizo Moore, V., et al., BCL-2 dependence and ABT-737 sensitivity in acute 
lymphoblastic leukemia. Blood, 2008. 111(4): p. 2300-9. 
21. 
Chonghaile, T.N., et al., Maturation stage of T-cell acute lymphoblastic leukemia 
determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer 
Discov, 2014. 4(9): p. 1074-87. 
22. 
Numan, Y., et al., Case Report:  First Report of Clinical Response to Venetoclax in Early 
T-cell Precursor Acute Lymphoblastic Leukemia. JCO Precison Oncology, 2018. 2: p. 1-
6. 
23. 
Cheson, B.D., et al., Revised recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol, 2003. 21(24): 
p. 4642-9. 
24. 
Cheson, B.D., et al., Clinical application and proposal for modification of the International 
Working Group (IWG) response criteria in myelodysplasia. Blood, 2006. 108(2): p. 419-
25. 
25. 
Chapuy, C.I., et al., Resolving the daratumumab interference with blood compatibility 
testing. Transfusion, 2015. 55(6 Pt 2): p. 1545-54. 
26. 
Thall, P.F., R.M. Simon, and E.H. Estey, Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Stat Med, 1995. 14(4): p. 357-79. 

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Table 7: Schedule of Study Events 
 
 
Notes 
Screening  
Phase 
Treatment  
(Cycles 1-2) 
Treatment  
(Cycles 3-6) 
Treatment  
(Cycles 7+) 
EoT 
Follow-up 
w/Response 
within 14 days  
D1, D8, D15, 
D22 
D1, D15 
D1 
(28-35 
days  
after last 
dose) 
(after EoT) 
Procedures 
 
Informed consent 
ICF must be signed before any study-
related procedures are performed. 
X 
 
 
 
 
 
Eligibility criteria 
 
X 
 
 
 
 
 
Demography/ 
Medical History 
 
X 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
Weight 
Dose of study medication does not need 
to be recalculated for weight changes 
<10% 
X 
D1 of each cyclec 
 
Spirometry / FEV1 
test 
For subjects with COPD or asthma, 
FEV1 should be measureda 
X 
 
 
 
 
 
ECOG 
See Appendix C 
X 
D1 of each cyclec 
 
12-lead ECG 
Screening 12-lead ECG showing a 
baseline QT interval as corrected by 
Fridericia’s formula (QTcF) ≤470 msec 
X 
 
C3D1 
C7D1 
X 
 
Physical exam 
Including neurological exam 
X 
Symptom and disease directed exam as clinically indicated 
 
Vital signs 
 
Vital signs (blood pressure, heart rate, 
temperature) measured in sitting position. 
On C1D1: immediately before the start of 
daratumumab infusion; at 0.5, 1, 1.5, 2, 
3.5 hr after start of infusion; at end of 
infusion; 0.5,1 hr after end of infusion.  
X 
X 
X 
X 
 
 

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Notes 
Screening  
Phase 
Treatment  
(Cycles 1-2) 
Treatment  
(Cycles 3-6) 
Treatment  
(Cycles 7+) 
EoT 
Follow-up 
w/Response 
within 14 days  
D1, D8, D15, 
D22 
D1, D15 
D1 
(28-35 
days  
after last 
dose) 
(after EoT) 
For all other infusions, vital signs 
measured immediately before start and 
at end of daratumumab infusion. 
Laboratory Assessments 
Serum Pregnancy 
testb 
For women of childbearing potential only, 
within 14 days of first dose and again 
within 24 hrs of first dose. 
X 
X 
Q4 Weeks 
 
Hematology 
Includes WBC with differential, 
hemoglobin, platelet 
X 
X 
X 
X 
X 
X* 
Serum Chemistry 
Includes Na, K, Bicarbonate, BUN, 
creatinine, AST and/or ALT, Ca, 
Phosphorus, total bilirubin 
X 
D1, D15 
D1 
X 
X 
X 
Bone Marrow  
aspirate and/or 
biopsy  
 
Morphology, immunohistochemistry/ 
immuno fluorescence/flow cytometry as 
appropriate.  With differential and 
estimate of cellularity. 
X 
C2, D1 
(+/- 2 days) 
C3, D1 every cycle until response 
(+/- 2 days) 
After that, according to investigator’s 
discretion 
 
Blood type 
assessment and 
wallet card 
 
X 
 
 
 
CMV screening 
 
X 
Every 2 weeks 
Every 4 weeks 
Every 4-12 
weeks 
HBV, HCV, HIV 
testing 
 
Xe 
 
 
 
HBV DNA testing 
 
 
Xf 
 
 
Ongoing Subject Review 
Adverse Events 
See Section 12 for detailed instructions 
 
Continuous from the time of signing of ICF until 30 days after last dose of last 
study drug.  Any adverse event ongoing at EoT will be followed until the event 
resolves, stabilizes or returns to baseline status. 
Concomitant 
Medicationsd 
 
 
Continuous from the time of signing the ICF until 30 days after last dose of study 
drug. 

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Notes 
Screening  
Phase 
Treatment  
(Cycles 1-2) 
Treatment  
(Cycles 3-6) 
Treatment  
(Cycles 7+) 
EoT 
Follow-up 
w/Response 
within 14 days  
D1, D8, D15, 
D22 
D1, D15 
D1 
(28-35 
days  
after last 
dose) 
(after EoT) 
Survival Status 
(no response) 
Telephone interview lasting 
approximately 5 minutes:  Following 
EoT:  one time each month for the first 
year; every six months during the second 
year; one time per year thereafter 
 
 
 
 
 
 
Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; C=cycle; Ca: calcium; CMV: PCR; COPD=chronic obstructive 
pulmonary disease; ECOG=Eastern Cooperative Oncology Group; D=day; ECG=electrocardiogram; EoT= End of Treatment; FEV1= Forced Expiratory Volume (in 1 
second); HBV=surface antigen and core antibody; HCV:  surface antigen and core antibody; HIV: 1/2; hrs: hours; ICF=informed consent form; K: potassium; Na:  sodium; 
wbc:  white blood cells 
*Monthly for the first two years;   
 aSee Appendix A.  Classification of Asthma Severity 
bSerum pregnancy test will occur at Screening (within 14 days) and Day 1 of each cycle prior to dosing.  If screening pregnancy test occurs within 24 hours of first dose, it 
will not be repeated. 
cCan be performed one day prior to D1 treatment 
dConcomitant medications will be captured in the medical records except for hydroxyurea.  Hydroxyurea will be captured in the medical record and case report form. 
e Within 3 months from enrollment 
f HBV DNA (Q12W during treatment, at EOT, and Q12W for up to 6 months last dose of study treatment), for subjects with serologic evidence of resolved HBV infection (i.e. 
positive Anti-HBs or positive Anti-HBc) at screening