Clinical trial NCT03634228
Conditions: Acute Myeloid Leukemia Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia
Sponsor: M.D. Anderson Cancer Center
Start date: 2018-12-17; Completion date: 2022-04-03
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase I/II trial studies the side effects and best dose of milademetan tosylate and to see how well it works with cytarabine with or without ventoclax in treating participants with acute myeloid leukemia that has come back (recurrent) or that does not respond to treatment (refractory). Milademetan tosylate and ventoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known if giving milademetan tosylate and low-dose cytarabine with or without ventoclax will work better in treating participants with recurrent or refractory acute myeloid leukemia.

Detailed description:
If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study.

If you are enrolled in Phase 1, the dose of DS-3032b you receive will depend on when you join this study.

If you are enrolled in Phase 2, you will receive DS-3032b at the highest dose that was tolerated in Phase 1.

All participants will receive LDAC at a fixed dose (meaning the dose will not change). If you are assigned to receive it, your dose of venetoclax will not change either. However, if needed because you have side effects, your dose may be adjusted.

Up to 58 participants will be enrolled in this study. All will take part at MD Anderson.

Arms: arm 1: Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive low dose cytarabine SC BID on days 1-10, milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17, and venetoclax PO QD on days 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Cytarabine intervention 2: Milademetan Tosylate intervention 3: Venetoclax
Intervention descriptions: intervention 1: Given SC intervention 2: Given PO intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2018-0333 August 3, 2020 
 
1 
 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2018-0333 
Protocol Title 
A Phase I/II study of the oral MDM2 inhibitor DS-3032b (Milademetan) in 
combination with low dose cytarabine (LDAC), in patients with newly diagnosed 
or relapsed/refractory acute myeloid leukemia (AML) 
Protocol Phase  
I/II 
Protocol Version 
03 
Version Date 
08/03/2020 
 
Protocol PI 
 Courtney DiNardo 
Department 
Leukemia 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
140658 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2018-0333 August 3, 2020 
 
2 
 
Study Title: A Phase I/II study of the oral MDM2 inhibitor DS-3032b (Milademetan) in combination with 
low dose cytarabine (LDAC), in patients with newly diagnosed or relapsed/refractory acute myeloid 
leukemia (AML) 
 
Institution Name: MD Anderson Cancer Center 
 
Protocol  
 
PI:  
 
 
 
 
 
 
PI: Courtney DiNardo, MD 
Unit 428 
1515 Holcolmbe Blvd 
Houston, TX 77030 
cdinardo@mdanderson.org 
O: 713-794-1141 
F: 713-745-4612 
 
Biostatistical Collaborator:  Wei Qiao and Graciela Nogueras-Gonzalez 
 
 


Protocol 2018-0333 August 3, 2020 
 
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TABLE OF CONTENTS 
 
 
Page 
1.  Objectives ................................................................................................................................................ 3 
 
2.  Background .............................................................................................................................................. 3 
 
3.  Subject Eligibility ..................................................................................................................................... 6 
 
4.  Treatment Plan ........................................................................................................................................ 8 
 
5.  Study Procedures ................................................................................................................................... 13 
 
6.  Response Definitions ............................................................................................................................. 18 
 
7.  Regulatory and Reporting Requirements ............................................................................................. 24 
 
8.  Statistical Considerations ...................................................................................................................... 26 
 
References ......................................................................................................................................................  
 
 
 


Protocol 2018-0333 August 3, 2020 
 
4 
 
1. OBJECTIVES 
 
1.1 Primary Objectives 
 
The primary objectives of this study are to evaluate the safety, tolerability and determine the 
recommended phase 2 dose  (Phase 1) and efficacy (by IWG criteria – Phase 2) of the MDM2 inhibitor, 
DS-3032b, in combination with LDAC, with or without the addition of venetoclax in both the frontline 
and relapsed/refractory (non-TP53 mutant) AML patient population.  
 
1.2 Secondary Objectives 
 
The secondary objectives of the study are:  
 
1.2.1. Evaluation of time to response variables including overall survival (OS), event-free survival (EFS) 
and duration of response (DOR) 
 
1.2.2. Determine biomarkers that may be predictive of DS-3032b activity.   
 
1.2.3. Molecular profiling at screening, on study, and at relapse to determine genomic predictors of 
response and resistance 
 
 
2.  BACKGROUND AND SCIENTIFIC RATIONALE 
 
2.1: Overview of AML: 
Outcomes for patients with AML remain poor.  Cytarabine has been the mainstay of AML therapy for 
nearly 40 years. In young patients, cytarabine is usually combined with an anthracycline. With this 
standard therapy the complete remission (CR) rates are 60-70% and the cure rates are 15-35%. Younger 
patients (age < 50 years) with diploid karyotype have CR rates of 70-80% and cure rates of 20-25%. Older 
patients and those with adverse karyotypes have CR rates of 35-50% with cure rates of 10% or less. This 
is due in part to the poor tolerance to therapy, and also the higher frequency of poor prognostic 
features, such as high-risk cytogenetic abnormalities and molecular mutations such as mutation of 
potent tumor suppressor gene - TP53 [1-3]. Low-dose cytarabine (LDAC) is better tolerated in this 


Protocol 2018-0333 August 3, 2020 
 
5 
 
patient population and has been shown to improve survival compared to supportive care ± hydroxyurea, 
and has therefore become a “de facto” standard therapy for older patients or patients not fit for 
intensive chemotherapy. However, the median survival is still only approximately 4 months. Thus, there 
is a need to improve the results obtained with standard chemotherapy. Efforts to improve both the 
remission rate and the durability of remission in AML patients of all ages are paramount.  The tumor 
suppressor gene TP53 plays a central role in the regulation of cell cycle, apoptosis, DNA repair and 
senescence [4]. Murine double minute 2 (MDM2) is an “oncoprotein” that functions by inhibiting wild-
type TP53 and thereby resulting in tumorigenesis [5]. Disruption of this MDM2-TP53 interaction is thus 
an important therapeutic target in cancers retaining wild-type TP53 [6-8]. Previously, MDM2 inhibitors 
(like Nutlin-3 and MI-63) have shown activity in hematological malignancies, including AML and CLL. DS-
3032b, a potent and small molecule inhibitor of MDM2 has demonstrated anti-tumor activity in 
preclinical studies and has also shown clinical benefit in solid tumors [9]. More recently in a phase 1 
study, DS-3032b demonstrated clinical activity as a single agent in relapsed/refractory AML and high-risk 
MDS in wild-type TP53 patients [10].  
 
Additionally, many hematologic malignancies are highly dependent upon the anti-apoptotic protein BCL-
2 for survival. Over-expression of BCL-2 is associated with tumor initiation, disease progression, and 
drug resistance, and is therefore a compelling target for antitumor therapy. Venetoclax is a potent, 
selective and orally bioavailable small-molecule inhibitor of BCL-2 that binds with > 1,000-fold higher 
affinity for BCL-2 (Ki < 0.010 nM) than for BCL-XL (Ki = 48 nm) or MCL-1 (Ki > 444 nM) [11]. In vitro, 
venetoclax has demonstrated cell killing activity against patient-derived chronic lymphocytic leukemia 
(CLL) cells and a variety of lymphoma and leukemia cell lines, including acute myeloid leukemia (AML) 
[11]. As a single agent for patients with R/R AML, venetoclax has demonstrated clinical activity although 
responses were relatively modest and short-lived . Synergistic activity against myeloid malignancies is 
seen in vitro and in vivo with venetoclax in combination with lower intensity antileukemia therapy, such 
as low-dose cytarabine (LDAC) or hypomethylatingagents (HMA) (i.e., azacitidine or decitabine) [13-
16].Clinical data are now also available demonstrating encouraging safety and efficacy in treatment-
naive elderly and/or unfit AML patients, with venetoclax in combination with either LDAC 
(NCT02287233), or the HMAs, azacitidine or decitabine (NCT02203773), leading to accelerated FDA 
approval of these treatment combinations [17-19]. 
 


Protocol 2018-0333 August 3, 2020 
 
6 
 
Recent studies conducted with MDM2 inhibitors (MDM2i) in combination with cytarabine have shown 
safety and activity in AML. In a phase I/Ib study of Idasanutlin (RG7388), a nutlin-class MDM2i, when 
given in combination with cytarabine, was noted to be safe and showed clinical activity in R/R AML, with 
6CRs out of 23 patients enrolled in the dose escalation phase and 4 CRs, 1 CRi, 1 PR, 1HI out of 34 
patients enrolled in the dose extension phase [11]. In a recent update of the study, the overall response 
rate was noted to be 33% with composite CR rate of 29% [12]. Currently a multi-center, double-blind, 
placebo controlled, phase III study of cytarabine with or without idasanutlin is ongoing (NCT02545283).  
 
In Xenograft models using MOLM-13 AML cell lines, no clear enhancement in activity was noted when 
DS-3032b was administered concomitantly with cytarabine, compared to DS-3032b alone. Since 
cytarabine causes cell cycle arrest in S phase and DS-3032b causes cell cycle arrest in G1 phase, one 
rationale is to use these drugs sequentially, cytarabine followed by DS-3032b. We therefore propose a 
trial of DS-3032b, in combination with LDACand venetoclax for induction and consolidation treatment of  
relapsed/refractory AML, followed by DS-3032b monotherapy maintenance in responding patients, in a 
two-arm phase 2 study. In this trial, cytarabine administration will be followed by DS-3032b. When 
added, venetoclax will be administered concurrently with LDAC and DS-3032b. Institutional standards 
will be followed for preparation and handling of cytarabine. 
 
2.2 Overview of investigational treatment, DS3032b – MDM2 inhibitor: 
The tumor suppressor p53 protein is a transcription factor that plays a central role in preventing tumor 
development and progression by inducing cell cycle arrest, apoptosis, or senescence. The gene encoding 
p53 (TP53) suffers disabling somatic mutations or deletions in about 50% of all malignant tumors; TP53 
mutations are less frequent in newly diagnosed leukemia, but are more common in an aberrant 
karyotype or in patients with relapsed or refractory disease. In tumors expressing wild-type protein, the 
tumor suppressor function of p53 may be attenuated by other mechanisms, such as over-expression of 
MDM2, a negative regulator of p53. MDM2 oncoprotein binds to p53 with high affinity and negatively 
modulates the transcriptional activity and stability of the tumor suppressor. In leukemia with functional 
p53, inhibition of the MDM2-p53 interaction can restore p53 activity and is expected to offer a novel 
strategy for therapy. DS-3032b is an orally available and highly selective inhibitor of the MDM2-p53 
interaction. It shows antitumor efficacy against tumors with wild-type p53 via activation of the tumor 
suppressor in a variety of cell culture and xenograft models. 
 


Protocol 2018-0333 August 3, 2020 
 
7 
 
Recently, a phase 1 dose escalation study of DS-3032b as a single agent was conducted in patients with 
hematological malignancies (NCT02319369) [10]. A total of 38 patients with relapsed/refractory AML or 
high-risk MDS were enrolled in the study in 5 dose levels: 60mg (7 patients), 90mg (6 patients), 120mg 
(12 patients), 160 mg (8 patients) and 210 mg (5 patients). Median age was 68.5 years (range 30-88) 
with approximately 2/3rd patients were >65 years. Maximum tolerated dose (MTD) of DS-3032b was 
determined to be 160 mg daily in 21/28 day cycle. 93% of the subjects experienced a grade >=3 
treatment emergent adverse event (TEAE).  
The most common (≥20%) TEAEs of any grade regardless of attribution were nausea (73%), diarrhea 
(57%) vomiting (33%), fatigue (37%), anemia (33%), thrombocytopenia (33%), neutropenia (20%) 
hypotension (30%), hypokalemia (23%) and hypomagnesemia (20%). A total of 5 subjects experienced 
dose limiting toxicities; two subjects in the 160 mg cohort due to grade 3 hypokalemia and grade 3 
diarrhea, and three subjects in the 210 mg cohort due to grade 3 nausea and vomiting, grade 2 
creatinine elevation/ renal insufficiency, and grade 3 anorexia and fatigue. Preliminary PK results 
showed plasma exposure (Cmax and AUClast) increased with dose; and approximately 2-fold drug 
accumulation was observed on Day 15 following the daily oral dosing. Increase in the serum levels of 
macrophage inhibitory cytokine (MIC-1) as a p53 target gene was used as a circulating 
pharmacodynamic biomarker, where magnitude of MIC-1 serum level increase corresponded with 
DS3032 plasma exposure. 
Clinical activity of single agent DS-3032b was observed from the reduction in bone marrow blasts by the 
end of cycle 1 (4 weeks) in 15 of 38 patients. Complete remission was observed in 2 subjects with AML; 1 
subject each at 120 mg and at 160 mg, with a remission duration of >4 and >10 months, respectively. 
One subject with MDS achieved marrow CR with platelet improvement, of 4 months duration, at the 120 
mg dose level. Of note, each of these three subjects developed a TP53 mutation while on treatment, 
identifying a key resistance pathway with MDM2 inhibition as a single agent. Preliminary efficacy and 
safety results of DS-3032b monotherapy in AML is favorable and supports further evaluation of DS-
3032b in combination approaches. 
 
,  
 DS-3032B (Milademetan) is a substrate for CYP3A and P-gp. A phase I study in healthy subjects was 
conducted to evaluate the effect of co-administration of the strong CYP3A4 inhibitors (itraconazole and 


Protocol 2018-0333 August 3, 2020 
 
8 
 
posaconazole) on milademetan PK (Study U107). Co-administration of milademetan 100 mg with 
itraconazole 200 mg at steady state increased milademetan mean Cmax and AUCinf by 8% and 115%. 
Similarly, posaconazole 200 mg at steady state increased milademetan mean Cmax by approximately 
19% and AUCinf by approximately 149%. Therefore, dose of milademetan is recommended to be 
reduced to half when it is concomitantly administered with strong CYP3A4 inhibitors. The regularly 
scheduled dose of miladematan  can be resumed after a 3-day washout period following discontinuation 
of the strong CYP3A inhibitor.  
 
3.  STUDY ELIGIBILITY 
 
3.1 Inclusion Criteria 
 
1) Diagnosis of AML by WHO 2016 criteria. Patients will be divided into 2 arms during the Phase 2 
portion:   
Arm A: Subjects must have newly diagnosed AML, who are otherwise ineligible for intensive 
chemotherapy. 
 
 
Arm B: Subjects must have refractory or relapsed AML  
 
2) TP53 wild-type status on molecular testing performed within the last 3 months. 
 
3) Patient should be >/= 18 years old.  
 
4) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3.  
 
5) Adequate renal function, defined as:  creatinine clearance >/= 30 mL/min, as calculated using the 
modified Cockcroft-Gault equation, ([{140 - age in years} × {actual weight in kg}] divided by [{72 × serum 
creatinine in mg/dL} multiply by 0.85 if female]), OR creatinine </= 1.5 x ULN., unless related to leukemic 
involvement. 
 
6) Adequate hepatic function, defined as:  AST/ALT≤3 × ULN; Bilirubin ≤ 1.5 × ULN, unless resulting from 
hemolysis, Gilbert’s disease or considered to be due to leukemic involvement.  
 
7) No gastrointestinal issues to interfere with oral medication absorption.  
 


Protocol 2018-0333 August 3, 2020 
 
9 
 
8) No active uncontrolled infection or comorbidity that would interfere with therapy or place patient at 
increased risk. 
 
9) Subject (male and female) of childbearing/ reproductive potential must agree to use double-barrier 
contraceptive measures or avoid intercourse during the study and for 90 days after the last dose of 
study drug. 
 
10) Subject must sign and date an Institutional Review Board-approved informed consent form 
(including Health Insurance Portability and Accountability Act authorization, if applicable) before 
performance of any study-specific procedures or tests. 
 
11) Able and willing to provide bone marrow biopsies/aspirates as requested by the protocol. 
 
12) Willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion at screening. 
 
13. Use of hydroxyurea is allowed prior to and during the first cycle of study treatment. 1-2 doses of 
cytarabine are also permitted if needed for cytoreduction prior to initiating study treatment.  
 
 
3.2 Exclusion: 
 
1) Patient with t(15;17) karyotypic abnormality or a diagnosis of acute promyelocytic leukemia. 
 
2) Patients who are suitable for and willing to receive intensive chemotherapy. 
 
3) Patient with other malignancy that contains a non-synonymous mutation, insertion, or deletion in the 
TP53 gene determined previously or at screening. 
 
4) Prior treatment with MDM2 inhibitor. 
 
5) Presence of central nervous system involvement of leukemia.  History of prior leptomeningeal 
leukemia / disease that has fully resolved is eligible.  
 
6) A second concurrent primary malignancy that has required systemic anti-neoplastic treatment within 
the previous 6 months, except for localized cancers that have apparently been cured, for example non-
melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast. 
 
7) Any condition that would preclude adequate absorption of DS-3032b, including refractory vomiting, 
malabsorption, biliary shunt, significant bowel resection, and/or graft-versus-host disease 
(GVHD) affecting the gut. 
 
 


Protocol 2018-0333 August 3, 2020 
 
10 
 
 
8) Any active uncontrolled infection, known human immunodeficiency virus infection, or active hepatitis 
B or C infection. 
 
9) Any concomitant medical condition that would in the opinion of the Investigator increase the risk of 
toxicity. 
 
10) Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) 
not yet resolved to NCI-CTCAE v5, Grade </=1 or baseline. Subjects with chronic Grade 2 toxicities may 
be eligible per discretion of the Investigator and Sponsor (eg, Grade 2 chemotherapy-induced 
neuropathy). 
 
11) Patient having received Hematopoietic Stem Cell Transplantation (HSCT) within 60 days of the first 
dose of DS-3032b, is on immunosuppressive therapy post-HSCT at the time of screening, or has clinically 
significant GVHD (use of topical steroids for ongoing skin GVHD will be permitted).  
 
12) Prolongation of corrected QT interval using Fridericia’s method (QTcF) at rest, where the mean QTcF 
interval is > 450 ms for males or > 470 ms for females based on electrocardiograms (ECGs). Patients with 
RRBB will be eligible after discussion with PI.  
 
13) Pregnant or breastfeeding. 
 
14) Substance abuse or medical, psychological, or social conditions that, in the opinion of the 
investigator, may interfere with the subject’s participation in the clinical study or evaluation of the 
clinical study results. 
 
Pregnancy related risks: 
Pregnant and lactating women will not be eligible; women of childbearing potential should have a 
negative pregnancy test prior to entering on the study and be willing to practice methods of 
contraception throughout the study period. Women do not have childbearing potential if they have had 
a hysterectomy or are postmenopausal without menses for 12 months. In addition, men enrolled on this 
study should understand the risks to any sexual partner of childbearing potential and should practice an 
effective method of birth control. Appropriate birth control will be determined by the treating physician. 
 
 
4. TREATMENT PLAN 
4.1 Study design: 
 
- 
This is a phase I/II single center, open-label study designed to assess the safety and efficacy of 
DS-3032b, oral MDM2 inhibitor in combination with LDAC, with or without the addition of 
venetoclax in patients with newly diagnosed and relapsed/refractory AML. 


Protocol 2018-0333 August 3, 2020 
 
11 
 
- 
The Phase I portion will use a 3+3 study design to identify the recommended phase 2 
combination doses. 18 patients will enroll in the phase 1 portion of the study.  
- 
 40 patients will be enrolled in Phase II portion; 20 patients in each Arm A and B respectively. 
 
4.2 Dose regimen: 
- 
Cytarabine will be administered SQ twice daily for 10 days of a 28 day cycle (Days 1-10). 
Cytarabine can be self-administered by the patient as per institutional standard.   
 
- 
DS-3032b will be administered orally, with at least 8 ounces of water once daily depending on 
the cohort: D8-14, D8-21, or D5-7 and D15-17 of a 28 day cycle. An alternative drug 
administration schedule for dose escalation may be considered based on safety and 
pharmacodynamics response data collected during dose escalation and upon review by the 
principal investigators and sponsor. If the patient vomits after taking the dose or misses a dose, 
they should not make up or double dose the next day. 
 
- 
Venetoclax will be administered orally daily on D1-14 of a 28 day cycle.  
               Each daily dose of venetoclax should be taken together with approximately 240 mL of water  
               and  within  30 minutes after the completion of a meal, preferably a low or moderate-fat    
               breakfast. Subjects should not consume grapefruit or grapefruit products, Seville oranges,  
               or Star fruit within the 3-day period prior to the first venetoclax administration and until the  
               last day of venetoclax is completed due to possible CYP3A mediated metabolic interaction. 
 
 
4.3 Phase 1 – dose escalation/determination of RP2D: 
In this phase, the 3+3 algorithm will be applied for dose escalation. Four dose levels of DS-3032b in 
combination with LDAC, with or without venetoclax will be tested.  Based on safety and tolerability data 
from Phase I dose escalation study of DS-3032b in patients with hematological malignancies, the starting 
dose of DS-3032b will be 120mg (dose level 0), in combination with cytarabine.   
 
Initially 3 patients will be treated at dose level 0. The following is a description of the dose escalation 
rule: 
If none of the initial 3 patients in the cohort experience a DLT, then a new cohort of 3 patients will be 
treated at the next dose level  (i.e. Dose Level 1), ie cytarabine plus 200 mg DS-3032b plus venetoclax at 
600mg orally daily as shown in Table 1., Further escalations of DS-3032b and venetoclax will follow as in 
Table 1 based on the overall safety and DLT rates. The dose escalations to MTD and the stopping rules 
are the following: 
- 
If 1 of the 3 initial patients experiences a DLT, then treat 3 additional patients at the same dose 
(i.e. Dose Level 0).  Escalation will only continue if no more than 1 of the 6 patients experiences 
a DLT. 
- 
If ≥2/3 or ≥2/6 patients experience DLTs in the first treatment cycle, the MTD has been 
exceeded. No additional patients will be treated at that dose and no further dose escalation 


Protocol 2018-0333 August 3, 2020 
 
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above that dose either will occur.  A new cohort of three patients will be enrolled at the next 
lower dose of DS-3032b(120mg or 90mg depending on dose level at which MTD was exceeded) 
if at that dose only three patients were treated. 
- 
If dose level ‐1 is too toxic (i.e. ≥2/3 or ≥2/6 patients experience DLTs in the first cycle), the study 
will be stopped.  
- 
MTD is defined as the highest dose at which no more than one patient out of 6 patients 
experience DLTs in the first cycle.   
 
Table 1:Phase 1 dose reduction and escalation for DS-3032b + LDAC + venetoclax  
Dose Level 
Cytarabine (mg BID), 
SubQ 
Venetoclax 
(mg/daily), oral 
DS-3032b (mg/daily) , 
oral 
+2 
20mg BID x 10 days 
(D1-10) 
600mg daily x 14 
days (D1-14) 
260mg daily x D5-7 
and D15-17 
+1 
20mg BID x 10 days 
(D1-10) 
600mg daily x 14 
days (D1-14) 
200mg daily x 7 days 
(D8-14) 
0 (starting dose) 
20mg BID x 7 days 
(D1-7) 
---- 
120mg daily  x 14 
days (D8-21) 
-1 
20mg BID x 10 days 
(D1-7) 
---- 
120mg daily x 7 days 
(D8-14) 
Dose reductions beyond those mentioned in this table or different to the doses specified should 
be discussed with the PI and documentation of the justification recorded in the chart. 
 
 
4.4 Dose escalation using alternative drug administration schedule: 
Based on the safety and pharmacodynamics response data collected during dose escalation using dose 
schedule/duration (LDAC D1-7 followed by DS-3032b D8-21, venetoclax D1-14), an alternative drug 
administration schedule for dose escalation may be considered following review by the principal 
investigators and study supporter. This will be submitted as a separate protocol amendment.  
 
4.5 Phase 2-Dose expansion: 
Upon completion of the Phase 1 portion, the dose expansion phase will begin at the recommended 
phase 2 dose and drug administration schedule with the intention of confirming safety, tolerability and 
determining the efficacy of DS-3032b in combination with LDAC, with or without addition of venetoclax 
in patients with newly diagnosed and relapsed/refractory AML.  An additional 40 patients will be 
enrolled in the Phase 2 portion, 20 patients in each Arm A and B respectively. 
 
4.7 Disease assessment:  
Bone marrow biopsies/aspirates and blood samples for disease assessment will be performed according 
to the study schedule at baseline and on Cycle 2 Day 1 while the subject remains on study. If aplasia is 
observed on Cycle 2 Day 1, study drugs will be withheld and a confirmation bone marrow assessment 
will be performed in 2 weeks. For subjects who achieve a complete remission (CR), a follow-up bone 
marrow evaluation is only required as clinically indicated. All subjects with less than a CR must have a 


Protocol 2018-0333 August 3, 2020 
 
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monthly bone marrow evaluation unless blasts are present in the peripheral blood, in which case bone 
marrow sampling is only required as clinically indicated (See Table of Events). 
 
4.8 Study duration: 
Ongoing study treatment will continue until discontinuation due to relapse, unacceptable toxicity, lack 
of response, or progressive disease.  This is no finite number of cycles received; patients may continue 
on study so long as they derive clinical benefit from study treatment.  This includes: 
1. clinically significant progressive disease at any time, or 
2. a lack of clinical benefit after 2 induction cycles of treatment, or  
3. possibility of undergoing allogeneic stem cell transplantation, or  
4. intercurrent illness that prevents further administration of treatment, or  
5. unacceptable adverse event(s), or  
6. patient decision for study withdrawal, or  
7. general or specific changes in the patient’s condition that render the patient unacceptable for    
further treatment in the judgment of the investigator                                                          
In addition, if TP53 genotyping performed during screening shows that a subject’s malignancy contains a 
non-synonymous mutation, insertion, or deletion in the TP53 gene after DS-3032b administration has 
begun, the subject will discontinue from the study unless a clinical response is noted upon completion of 
Cycle 1. 
4.9 Dosing delays/dose modifications: 
4.9.1 Toxicity Directly Attributable to Study Drug  
Patients experiencing unacceptable toxicity directly attributable to the study drugs should temporarily 
stop treatment according to the guidelines in the dose adjustment schema.  
4.9.2 Toxicity Grading 
Toxicity grading will be according to the NCI CTCAE, v5. To prevent unnecessary morbidity, the following 
guidelines for dose adjustment for drug-related toxicities are recommended. 
4.9.3 Dose reductions 
Table 2: Dose adjustments of Cytarabine, DS-3032b and venetoclax for hematological drug-related 
adverse events 
Dose Level 
 
Cytarabine (mg BID), 
SubQ 
Venetoclax 
(mg/daily), oral 
DS-3032b (mg/daily), 
oral 
+2 
20mg BID x 10 days (D1-
10) 
600mg daily x 14 
days (D1-14) 
260mg/daily D5-7 and 
D15-17 
+1 
20mg BID x 10 days 
(D1-10) 
600mg daily x 14 
days (D1-14) 
200mg/daily x 7 days 
(D8-14) 


Protocol 2018-0333 August 3, 2020 
 
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0 (starting dose) 
20mg BID x 7 days (D1-
7) 
-- 
120mg/daily x 14 days 
(D8-21) 
-1 
20mg BID x 7 days (D1-
7) 
-- 
120mg/daily x 7 days 
(D8-14) 
Dose reductions beyond those mentioned in this table or different to the doses specified should 
be discussed with the PI and documentation of the justification recorded in the chart. 
 
4.9.4  Dose modifications and interruptions are permitted as necessary for the clinical benefit of the 
patient.  Dose modification and/or discontinuation of either LDAC, DS-3032b and/or venetoclax for 
patients receiving combination therapy are allowed.  If side effects or toxicity are related to one study 
drug only; patients may discontinue that agent and continue treatment with the alternate study drug 
(i.e. DS-3032b or venetoclax as monotherapy), if in the investigator’s assessment the patient continues 
to demonstrate clinical benefit and all protocol-specified criteria for continuation of study treatment are 
met.  All dose modifications should be discussed with the PI and clearly documented in the medical 
record.  Treatment may be held as long as clinically necessary for resolution, after discussion with the PI.   
 
4.9.5 Myelosuppression: 
Patients with leukemias usually present with abnormal peripheral blood counts at the time therapy is 
started and myelosuppression is an expected event during the course of therapy for acute leukemias. 
Thus, no dose adjustments or treatment interruptions for myelosuppression will be planned for the first 
4 weeks of therapy. After this time, treatment interruptions and dose adjustments may be considered 
on an individual basis. The following guidelines can be used to consider treatment: 
4.9.5.1 Patients with neutropenia or thrombocytopenia as a consequence of the disease do not require 
treatment interruptions for myelosuppression. Dose reductions in these patients should be considered 
in an individual case discussed with the PI. The following guidelines can be used for these patients: 
4.9.5.1.1 Patients with a response and pre-cycle counts of neutrophils >1 x109 /L and platelets >50 x109 
/L who have sustained low counts of neutrophils <0.5 x109/L or a platelet count <20 x109/L for more 
than 2 consecutive weeks in the current cycle, may receive a subsequent course at 1 dose level 
reduction. A reduction of 2 dose levels may be considered if the myelosuppression was deemed severe 
and life threatening by the treating physician, and if it is in the patient's best interest. 
4.9.5.1.2 If there are persistent peripheral blood blasts, or the bone marrow shows >5% blasts, may 
continue treatment regardless of neutrophil and platelet count and give supportive care as needed. 
4.9.5.1.3 If no marrow evidence of leukemia, may hold therapy until recovery of granulocytes to ≥1 x109 
/L and platelets ≥ 60 x109 /L, then resume at same or 1 lower dose level according to guidelines 
mentioned above. 
4.9.5.1.4 Based on clinical observations with BCL-2 inhibition, patients treated with venetoclax may 
experience neutropenia.   


Protocol 2018-0333 August 3, 2020 
 
15 
 
If a patient achieves a clinical response including CR, CRi, or MLFS while on study and they have not 
recovered ANC > 500/uL within 14 days of venetoclax drug interruption, unless it is thought to be due to 
the underlying disease, venetoclax dosing may be further interrupted until ANC recovery to > 500/uL.  
Venetoclax may be reinitiated at a lower dose or reduced duration per cycle  (7 days) per discussion with 
the PI.   GCSF may be administered if in the best interest of the patient. 
 
4.9.5 Dose reductions for non-hematologic toxicity possibly related to study drugs should be performed 
according to the following table: 
Toxicity  
Grade 
Actions 
Non-hematological (excludes 
myalgia/ arthralgia responding to 
treatment, inadequately treated 
nausea, vomiting and diarrhea, or 
electrolyte abnormalities unless 
not responding to optimal 
supplementation) 
>=3 
Hold therapy until recovery to 
Grade ≤ 1, then re-start and 
reduce to the next lower dose 
level. If toxicity recurs again, hold 
therapy until recovery to grade 
≤1, then re-start and reduce one 
additional dose level. Dose 
reductions below dose level -1 
will be considered on an 
individual basis after discussion 
with the principal investigator. 
Non-hematological, study-drug 
related 
4 
Remove from study. An exception 
can be made if grade 4 toxicity 
reverses to Grade ≤ 1 on or 
before 14 days of interrupting 
study drug and re-dosing with 
MDM2i is considered safe and in 
the best interest of the patient. In 
those instances treatment may be 
resumed with a 1 dose-level 
reduction after discussion with PI 
and Sponsor. 
Non-hematological (excludes 
myalgia/ arthralgia responding to 
treatment, inadequately treated 
vomiting and diarrhea, or 
electrolyte abnormalities unless 
not responding to optimal 
supplementation) 
Persistent 2 considered clinically 
significant or upon patient’s 
request 
Hold therapy until recovery to 
Grade ≤ 1, then re-start and 
reduce to the next lower dose 
level. If toxicity recurs again, hold 
therapy until recovery to grade 
≤1, then re-start and reduce one 
additional dose level. Dose 
reductions below dose level -1 
will be considered on an 
individual basis after discussion 
with the principal investigator. 
 
4.9.5.1 Patients in whom the toxicity occurs or persists beyond the planned completion of drug 
administration for the cycle will have the dose reductions implemented in subsequent cycles provided 
the toxicity has resolved as specified in the table above.  


Protocol 2018-0333 August 3, 2020 
 
16 
 
4.9.5.2 If adverse events are clearly associated with one of the drugs, dose adjustments to only that 
agent may be performed.  
4.9.5.3 Dose modifications different than those described above (e.g., dose reductions by 2 dose levels, 
decreased number of days of administration of either drug, continuation of only DS-3032b) may be 
implemented if judged in the best interest of the patient after discussion with the PI and documentation 
of the rationale for this action.  
4.9.5.4 Dose adjustments for only one of the drugs may be considered when the adverse event may be 
clearly associated with only one drug. 
 
5. STUDY PROCEDURES (see Table of Events) 
5.1 Screening:  
5.1.1 Screening (Pre-cycle) 
The screening (pre-cycle) period occurs within 14 days prior to starting study therapy.  
The following procedures will be performed during the screening period:  
• Obtain written (ie, signed and dated) informed consent.  
• Perform a complete physical examination and record weight and height.  
• Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, and body 
temperature).  
• Assess functional status using the ECOG Performance Status Scale. 
• Obtain blood samples including CBC/diff, chemistry (including LFTs), uric acid and coagulation profile 
(PTT; INR/PT) 
• Obtain a blood sample for biomarkers.  
• Obtain a serum or urine sample for pregnancy testing in women of childbearing potential.  
• 
Obtain urine analysis. 
• Perform a 12-lead ECG.  
• Record concomitant medications.  
• 
Concomitant medication will be captured in subjects medical record only 
• Assess subjects for adverse events.  


Protocol 2018-0333 August 3, 2020 
 
17 
 
• Obtain bone marrow biopsies/aspirates for marrow assessment and biomarker test. A bone marrow 
evaluation is required for all subjects at screening. 
 
5.2 Treatment Period 
5.2.1 Cycle 1/Day -1 (for dose level +1 and beyond) 
The patient will be admitted to the hospital for the venetoclax ramp-up period during Cycle 1.  
Hospitalization will begin by study day -1, until at least 24 hours after reaching the designated dose of 
venetoclax.  To mitigate the risk for TLS, subjects must be receiving tumor lysis prophylaxis, including 
hydration (oral, intravenous) and treatment with a uric acid reducing agent (allopurinol, rasburicase) per 
institutional guidelines prior to and during the venetoclax ramp-up period of Cycle 1.  
 
5.2.2 Cycle 1/Day 1( +/- 2 days) 
• Perform a complete physical examination and record weight.  
• Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, and body 
temperature). 
• Obtain blood samples including CBC/diff,chemistry and uric acid.  
• Obtain a blood sample for biomarkers. 
• Record concomitant medications.  
• Assess subjects for adverse events.  
• Administer LDAC twice daily Day 1-7/28 (dose level 0); Day 1-10 (dose level +1 and beyond) per 
protocol. 
• Administer venetoclax daily Day 1-14/28 per protocol (for dose level +1 and beyond) 
 Venetoclax Ramp-Up: 
At dose level  +1 and +2, venetoclax will be administered at a dose of 100 mg on day 1, 200 mg on day 2, 
and 400 mg on day 3, and 600mg on day 4-14 of the first cycle.  
 
During cycle 1 venetoclax dosing ramp up, TLS lab monitoring (K+, uric acid, Phosphorus, Calcium and 
Creatinine) should occur at pre- dose and 24 hours post dose (inpatient AM labs may substitute for the 
24 hour post-dose labs).  Patients will be admitted to the hospital for the venetoclax ramp-up period of 
cycle 1.   
 


Protocol 2018-0333 August 3, 2020 
 
18 
 
5.2.3 Cycle 1/Day 8 (dose level 0 and +1) (+/- 2 days) 
The following procedures will be completed during Cycle 1/Day 8 visit. 
• Perform a complete physical examination and record weight.  
• Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, and body 
temperature).  
• Obtain blood samples including CBC/diff,chemistry and uric acid. 
• Obtain a blood sample for biomarkers.  
• Record concomitant medications.  
• Assess subjects for adverse events.  
• Administer LDAC twice daily Day 1-10 (dose level +1 and beyond) per protocol. 
• Administer venetoclax daily Day 1-14/28 per protocol. 
• Administer DS-3032b for QD Day 8-21/28 (dose level  0);  day 8-14/28 (dose level +1) per protocol. 
• 
For dose level +2, there will be a cycle1/Day 5 visit and DS3032b will be administered Day 5-7 
and Day 15-17/28 days per protocol. There will not be a cycle 1/Day 8 visit for dose level +2. 
 
5.2.4 Cycle 1/Day 15 (+/- 2 days) 
The following procedures will be performed during Cycle 1/Day 15 visit  
• Perform a complete physical examination and record weight.  
• Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, and body 
temperature).  
• Obtain blood samples including CBC/diff,chemistry and uric acid. 
• Record concomitant medications.  
• Assess subjects for adverse events. • Administer DS-3032b for QD Day 8-21/28 (dose level 0); Day 15-
17 (dose level +2) per protocol.  
 
5.2.5 Cycle 1/Day 22 (+/- 2 days) 
The following procedures will be completed during Cycle 1/Day 22 visit:  


Protocol 2018-0333 August 3, 2020 
 
19 
 
• Perform a complete physical examination and record weight.  
• Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, and body 
temperature).  
• Obtain blood samples including CBC/diff,chemistry and uric acid. 
• Record concomitant medications.  
• Assess subjects for adverse events.  
5.2.6 Cycle 2/Day 1 (± 3 days) 
• Perform a complete physical examination and record weight.  
• Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, and body 
temperature).  
• Obtain blood samples including CBC/diff and chemistry 
• Obtain a blood sample for biomarkers.  
• Record concomitant medications.  
• Assess subjects for adverse events.  
• Obtain bone marrow biopsies/aspirates for marrow assessment and/or biomarker tests. 
• Administer LDAC twice daily Day 1-7/28 per protocol. 
 
5.2.7 Cycle 3 and all subsequent cycles, Day 1 (± 7 days) 
The following procedures will be performed at Cycle 3/Day 1 visit 
• Perform a complete physical examination and record weight. 
• Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, respiratory rate, and 
body temperature).  
• Obtain blood samples including CBC/diff and chemistry (including LFTs) 
• Obtain a blood sample for biomarkers.  
• Record concomitant medications.  
• Assess subjects for adverse events.  


Protocol 2018-0333 August 3, 2020 
 
20 
 
• Obtain bone marrow biopsies/aspirates for marrow assessment and/or biomarker tests after C3 
(C4D1) and then after every odd cycle till CR. Once in CR, additional bone marrow exams per clinical 
discretion. Bone marrow biomarkers will be obtained with each bone marrow performed.  
5.2.8 End-of-Treatment (Post-cycle)  
This End-of-Treatment Visit should occur at the earliest day possible within 30 days after the last 
administration of DS-3032b, but before beginning any other form of anticancer therapy. The following 
assessments will be performed at this visit:  
• Perform a complete physical examination and record weight and height.  
• Obtain vital sign measurements (systolic and diastolic blood pressure, pulse rate, and body 
temperature).  
• Obtain blood samples including CBC/diff and chemistry 
• Obtain a serum or urine sample for pregnancy testing in women of childbearing potential.  
• Obtain a blood sample for biomarkers.  
• Record concomitant medications.  
• Assess subjects for adverse events.  
• Record reason for treatment discontinuation.  
• Bone marrow re-biopsy for subjects who achieved an initial CR/PR to DS-3032b but later developed 
progressive disease while on therapy. 
 
5.3 Identification of Investigational Product: 
International Non‐proprietary name: DS-3032b                 
Manufacturer: Daiichi Sankyo Pharma Development  
Dose:  120 – 260 mg 
Route of Administration: oral  
Formulation:  30mg and 100mg DS-3032b capsules which are individually packaged in desiccant-
embedded aluminum blisters 
DS-3032b will be provided by Daiichi Sankyo Pharma Development. All expired/unused study drug 
will be destroyed per the institution policy. 


Protocol 2018-0333 August 3, 2020 
 
21 
 
 
LDAC and venetoclax will be obtained commercially.   
 
5.4 Supportive care: 
Supportive measures including blood and platelet transfusions, prophylactic and therapeutic 
antimicrobials, and analgesics are permitted.  Growth factor use is permitted on study at the discretion 
of the treating physician if in the best interest of the patient. Electrolyte abnormalities will be addressed 
prior to starting therapy.  
Tumor Lysis Prophylaxis: 
The venetoclax dose titration scheme utilized in AML studies to date to mitigate the risk of tumor lysis 
syndrome (TLS) will be employed.  All patients will be hospitalized for the entirety of the venetoclax 
dose escalation ramp up starting at least on day -1 of treatment initiation and until 24 hours after the 
completion of venetoclax dose escalation.  
 
To mitigate the risk for TLS, subjects must be receiving tumor lysis prophylaxis, including hydration (oral, 
intravenous) and treatment with a uric acid reducing agent (allopurinol, rasburicase) as per institutional 
standards prior to and during the venetoclax ramp up period of Cycle 1.  Patients with reduced renal 
clearance and/or splenomegaly are at increased risk to develop TLS.   
 
TLS chemistry tests (potassium, uric acid, creatinine, calcium and phosphorus) will be obtained prior to 
dosing and 24 hours after dosing each day of a new venetoclax dose.  TLS chemistry test results will be 
reviewed by the investigator and prior to the subject’s next venetoclax dose to ensure appropriate 
management.  If a subject meets criteria for clinically significant laboratory or clinical TLS, no additional 
venetoclax should be administered until resolution.   
 
Venetoclax interruption for up to 72 hours following transient (< 48 hours) chemical changes and 
laboratory TLS will be allowed and will not require a dose reduction and is not considered a DLT.   
 
CYP3 Inducers and Inhibitors: 
Moderate and strong CYP3A inhibitors including isavuconazole and posaconazole are allowed.  If a 
moderate CYP3A inhibitor is prescribed on study, a 50% dose reduction of VEN will be required (i.e. 300 
mg instead of 600 mg, etc).  If a strong CYP3A inhibitor is prescribed on study, a 75% dose reduction of 
VEN will be required (i.e. 150 mg instead of 600 mg, etc).  With concomitant posaconazole use, the dose 
of VEN should be reduced to 70mg. For DS3032b, no dose reduction is required for moderate CYP3A 
inhibitors. For strong CYP3A inhibitors, a 50% dose reduction of DS3032b will be required (i.e. 60mg 
instead of 120mg, etc). The regularly scheduled dose of DS-3032b (miladematan)  can be resumed after a 
3-day washout period following discontinuation of the strong CYP3A inhibitor. 


Protocol 2018-0333 August 3, 2020 
 
22 
 
 
 
 
 


Protocol 2018-0333 August 3, 2020 
 
23 
 
Table of Events 
Cycle  
Pre-cycle 
1(+/- 2 days) 
  
 
2 (± 3 
days) 
3 and 
beyond 
(±7 days) 
End of study 
(within 30 days of 
last dose of DS-
3032b) 
Cycle Day (s) 
-14 to 0 
-1 
(dose 
level 
+1 
and 
above
) 
1 
8d 
15 
22 
1 
 
1 
 
Informed 
consent 
x 
 
 
 
 
 
 
 
 
 
Pregnancy test 
x 
 
 
 
 
 
 
 
 
 
Adverse events 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
Prior/concomit
ant 
medications 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
Tumor lysis 
syndrome 
prophylaxisa  
 
x 
x 
x 
x 
x 
 
 
 
 
ECOG 
x 
 
 
 
 
 
 
 
Physical 
examination, 
including vitals, 
height and 
weight 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
CBC/diffb 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
Chemistries 
and uric acidb 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
Coagulation 
panel 
x 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
EKG 
x 
 
 
 
 
 
 
 
 
 
Peripheral 
Blood 
Biomarkers 
x 
 
x 
x 
 
 
x 
 
x 
x 
Bone marrow 
assessment c 
x 
 
 
 
 
 
x 
 
x 
x 
End of study 
bone marrow 
assessment 
 
 
 
 
 
 
 
 
 
x 
a.   All subjects must receive tumor lysis prophylaxis prior to and during treatment.  For details 
on tumor lysis prophylaxis and management, refer to Section on Management of Tumor 
Lysis Syndrome and index A.  


Protocol 2018-0333 August 3, 2020 
 
24 
 
b.   CBC differential may be omitted if WBC < 0.5 x 10^9/L.  During cycle 1 venetoclax dosing 
ramp up, TLS lab monitoring (K+, uric acid, Phosphorus, Calcium and Creatinine) should 
occur at pre- dose and 24 hours post dose (inpatient AM labs may substitute for the 24 hour 
post-dose labs).   
c. Obtain bone marrow biopsies/aspirates for marrow assessment and/or biomarker tests 
after C1 (C2D1), after C3 (C4D1) and then after every odd cycle till achieving CR. Once in CR, 
additional bone marrow exams per clinical discretion. Bone marrow biomarkers will be 
obtained with each bone marrow performed.  
d. At dose level +2, there will be a Cycle 1 Day 5 visit instead of a Day 8 visit.  
 
 


Protocol 2018-0333 August 3, 2020 
 
25 
 
 
6. RESPONSE DEFINITIONS 
6.1 Study endpoints: 
6.1.2 Primary Efficacy Analysis: 
Clinical activity of LDAC in combination with DS-3032b, with or without the addition of venetoclax will be 
assessed based on the 2017 ELN recommendations for AML, with an overall response rate (ORR) defined 
as CR + CRi +PR+MLFS.   
 
Additional analyses of response including CR/CRi rate and MLFS rate will be performed for enrolled 
subjects.   The depth of remission such as with exploratory analyses of MRD negativity by flow 
cytometry and/or molecular analysis will also be performed.     
For each subject, response to therapy, duration of response, event‐free survival, and overall survival will 
be calculated. The duration of response is defined as the number of days from the date of initial 


Protocol 2018-0333 August 3, 2020 
 
26 
 
response (PR or better) to the date of first documented disease progression/relapse or death, whichever 
occurs first. Event‐free survival is defined as the number of days from the date of treatment initiation 
(i.e., C1D1) to the date of documented treatment failure, relapses from CR, or death from any cause, 
whichever occurs first, and will be calculated for all patients. In the event that neither disease 
progression nor death is documented prior to study termination, analysis cutoff, or the start of 
confounding anticancer therapy, these endpoints will be censored at the date of last tumor assessment 
date.  
In addition, relationships between anti‐leukemia activity / efficacy, pharmacodynamic markers, 
exploratory biomarkers, and drug exposure levels will be explored. 
6.1.3 Primary Safety Endpoint: 
The primary safety endpoint will include serious adverse events (SAEs), TEAEs, DLTs, physical 
examination findings (including ECOG performance status), vital sign measurements, clinical laboratory 
parameters (serum chemistry, hematology, and urinalysis), and electrocardiogram (ECG) parameters, 
particularly the QTcF. Adverse events will be categorized using the Medical Dictionary for Regulatory 
Activities (MedDRA). Adverse events and laboratory test results will be graded using the NCI-CTCAE 
version 5.0. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related to 
study drug. Medical conditions/diseases present before starting study drug are only considered adverse 
events if they worsen after starting study drug. Abnormal laboratory values or test results, even when 
they do not induce clinical signs or symptoms, or require therapy, are considered clinically significant. 
.Adverse events (AEs) will be collected using the Leukemia‐Specific Adverse Event Recording and 
Reporting Guidelines. 
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.  
All “suspected adverse reactions” (as defined in 21 CFR 312.32(a)) will be captured in the case report 
forms (CORe and PDMS).  For abnormal chemical values grade 3 or 4, the apogee will be reported per 
course in the CRF.  
Assessing causal connections between agents and disease is fundamental to the understanding of 
adverse drug reactions. In general, a drug may be considered a contributory cause of an adverse event 
if, had the drug not been administered, 1) the event would not have happened at all, 2) the event would 
have occurred later than it actually did, or 3) the event would have been less severe.  
The Investigator or physician designee is responsible for verifying and providing source documentation 
for all adverse events and assigning the attribution for each event for all subjects enrolled on the trial.  
   


Protocol 2018-0333 August 3, 2020 
 
27 
 
6.1.4 Monitoring, recording and reporting adverse events 
All subjects will be monitored for AEs during the study. Assessments may include monitoring of any or 
all of the following parameters: the subject’s clinical symptoms, laboratory, pathological, radiological or 
surgical findings, physical examination findings, or findings from other tests and/or procedures.  
AEs will be recorded in the subject’s source documents by the Investigator from the first dose through 
30 days after the last dose. Serious Adverse Events (SAEs) will be captured starting from the first 
protocol intervention. The Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for each event for all subjects 
enrolled on the trial.  
The Principal Investigator will sign and date the adverse event logs per patient at the completion of each 
course.  Following signature, the adverse event logs will be used as source documentation for the 
adverse events for attribution. 
The Leukemia-specific Adverse Event Recording and Reporting Guidelines will be followed for the 
recording and reporting of adverse and serious adverse events. 
1. Baseline events will be recorded in the medical history section of the case report form and will 
include the terminology event name, grade, and start date of the event.  The medical history section 
of the case report form will serve as the source document for baseline events once signed and dated 
by the principal investigator.   
Baseline events are any medical condition, symptom, or clinically significant lab abnormality present 
before the informed consent is signed 
 
i. Hematologic laboratory abnormalities will not be recorded as baseline events for patients with 
acute leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, or chronic myeloid 
leukemia in blast phase. 
ii. If exact start date is unknown, month and year or year may be used as the start date of the 
baseline event. 
2. The maximum grade of the adverse event will be captured per course or protocol defined visit date. 
3. These adverse events will be recorded in the case report form: 
a. Any grade adverse event that is possibly, probably, or definitely related to the study 
drug(s). 
b. All serious adverse events regardless of attribution to the study drug(s). 
c. Any grade adverse event regardless of attribution to the study drug(s) that results in 
any dose modification. 
4. Hematologic adverse events will not be recorded or reported for studies in patients with acute 
leukemia,  myelodysplastic syndrome, chronic lymphocytic leukemia, or chronic myeloid leukemia in 
blast phase except for: 
a. Prolonged myelosuppression as defined by the NCI-CTCAE criteria specific for 
leukemia, e.g. marrow hypocellularity on day 42 or later (6 weeks) from start of 
therapy without evidence of leukemia (< 5% blasts), or that results in dose 
modifications, interruptions or meets the protocol definition of DLT or SAE. 
5. Serious adverse events will be reported according to institutional policy. 
6. Protocol specific language regarding the recording and reporting of adverse and serious adverse 
events will be followed in the event of discordance between the protocol and Leukemia-specific 


Protocol 2018-0333 August 3, 2020 
 
28 
 
adverse event recording and reporting guidelines.  
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).   
 
6.1.5 Definition of Dose-Limiting Toxicity  
A dose-limiting toxicity (DLT) is defined as any clinically significant non-hematologic treatment-emergent 
adverse event (TEAE) or abnormal laboratory value that is Grade 3 or higher according to National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 occurring during 
the first cycle on study that cannot be attributed by the investigator to a clearly identifiable cause such 
as disease progression, underlying illness, concurrent illness, or concomitant medication, with the 
following exceptions: 
For elevations in hepatic function enzymes, a DLT is defined as follows:  
1. Grade 4 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels  
2. AST/ALT > 5 × the upper limit of normal (ULN) lasting > 3 days  
3. AST/ALT > 5 × ULN if accompanied by ≥ Grade 2 elevation in bilirubin  
 
The following events are classified as DLTs:  
1. Subjects who are unable to complete at least 75% of the prescribed dose (ie, 10 days) of DS-
3032b in the first cycle as a result of non-disease related Grade ≥ 2 events will be considered to 
have a DLT.  
2. Failure to recover a peripheral absolute neutrophil count ≥ 500/mm3 and platelets ≥ 20 × 109 /L 
in the setting of a hypocellular bone marrow without evidence of residual leukemia, resulting in 
a > 2-week delay in initiating Cycle 2.  
3.  Any grade 3 nausea, vomiting  or diarrhea that requires TPN or tube feeding. 
 
The following adverse events are NOT considered DLTs:  
1. Grade 3 fatigue lasting < 3 days  
2. Grade 3 nausea or vomiting that has resolved to ≤Grade 2 within 48 hours following 
administration of preventive, as well as additional therapeutic antiemetic agents for managing 
established nausea or vomiting (eg droperidol, aprepitant, etc.)Grade 3 diarrhea that has 
resolved to Grade ≤ 2 within 48 hours after standard antidiarrheal therapies  
3. Isolated laboratory findings not associated with signs or symptoms including Grade 3 or4 
alkaline phosphatase, uric acid, amylase, and lipase elevations, and Grade 3 hyponatremia 
lasting < 72 hours developed from Grade 1 at baseline. 
Venetoclax interruption for up to 72 hours following transient (< 48 hours) chemical changes 
and laboratory TLS may be allowed and may not be considered a DLT. 


Protocol 2018-0333 August 3, 2020 
 
29 
 
4. Grade ≥3 electrolyte abnormalities should only be considered as exceptions to the DLT 
criteria if they are both correctable within a fixed time period of no more than 72 hours and are 
clinically asymptomatic.  
 
Hematologic DLT is defined as Grade > 3 neutropenia and/or thrombocytopenia, with a hypocellular 
bone marrow and no greater than 5% marrow blasts lasting for 6 weeks or more after the start of a 
course in the absence of underlying MDS.  Anemia will not be considered for the definition of DLT.   
Patients with neutropenia or thrombocytopenia as a consequence of the disease prior to the start of 
therapy do not require treatment interruptions for myelosuppression.  Dose reductions of the study 
treatment in these patients should be considered on an individual case basis and discussed with the PI.   
 
6.1.6 Definition of Serious Adverse Events (SAEs) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, 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 
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 reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, 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 M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”.  Unless 


Protocol 2018-0333 August 3, 2020 
 
30 
 
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 dose of drug, 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. 
 
Reporting to FDA: 
- 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager IND 
Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
  
6.1.7 Biomarker Endpoints (non-optional): 
Peripheral blood and bone marrow aspirate samples will be obtained at study specified time points.  
Unused cells will be frozen and stored.   
 
NGS molecular sequencing in all patients 
As a standard of care all AML patients at MDACC are evaluated for karyotype and molecular mutation 
profile using a CLIA-certified next-generation gene panel sequencing platform. The effects of the 
combination will be compared not only to historical outcomes in matched groups of patients, but also at 
the molecular and cellular level by correlating with karyotype and molecular mutation profile. The NGS 
gene panel will be performed on the screening BM aspirate and the progression/relapse BM aspirate. An 
aliquot of DNA will be stored for additional analysis of DNA mutations in responding patients. 
TP53 genotyping: 
TP53 genotyping will be performed on whole sample or on enriched leukemic cells from peripheral 
blood and/or bone marrow samples from all enrolled subjects. Confirmation of TP53 wild-type status 
from the screening analysis is NOT required prior to DS-3032b dosing, but the Investigator and subject 
will be informed about the genotyping result as soon as it is available. If the testing result shows that a 


Protocol 2018-0333 August 3, 2020 
 
31 
 
subject’s malignancy contains a non-synonymous mutation, insertion, or deletion in the TP53 gene after 
DS-3032b administration has begun, the subject will discontinue from the study unless a clinical 
response is noted upon completion of Cycle 1. If the TP53 testing result returns as indeterminate, the 
subject can still continue the study if clinical benefit is noted. TP53 re-testing can be considered.  
 
Genomic DNA (gDNA) is extracted from fresh bone marrow (BM) aspirate or peripheral blood (PB) using 
ReliaPrep™ Large Volume HT gDNA Isolation System and quantified using a Qubit dsDNA Broad Range 
Assay Kit (Thermo Fisher Scientific). Either entire coding sequences or limited exons/hotspots for 81-
gene target genes, including TP53 TP53 with the following codons (exons) covered, 2 (1-25), 4-11 (80-
394) is captured using the hybridization-based HaloPlex HS target enrichment system by Agilent 
Technologies. 250 ng gDNA is fragmented using restriction enzymes. A probe library is added to guide 
the targeted fragments to form circular DNA molecules. The probes are complementary to the 5’- and 
3’- ends of a targeted DNA restriction fragment, and contain sequencing-specific motifs. The circular 
DNA molecules are annealed and amplified by polymerase chain reaction (PCR). PCR amplification 
generates linear barcoded fragments, which are subject to sequencing. Bidirectional paired-end 
sequencing is performed using the Illumina MiSeq platform. A minimum of 250x coverage depth is 
required for any target region for the interpretation. 
TP53 gene coding sequences (exons) are captured using the hybridization-based HaloPlex HS target 
enrichment system (Agilent Technologies). A total of 250 ng gDNA is fragmented using restriction 
enzymes. A probe library is added to guide the targeted fragments to form circular DNA molecules. The 
probes are complementary to the 5’- and 3’- ends of a targeted DNA restriction fragment, and contain 
sequencing-specific motifs. The circular DNA molecules are annealed and amplified by polymerase chain 
reaction (PCR). PCR amplification generates linear barcoded fragments, which are subject to sequencing. 
Bidirectional paired-end sequencing is performed using the Illumina MiSeq platform. A minimum of 250x 
coverage depth is required for any target region for the interpretation. Overall, the assay covers 98% of 
TP53 coding sequence (exons 2 and, 4 to 11) and >99.5% of all reported TP53 mutations (COSMIC 
database v86) at the desired coverage of 250x or better. 
 
Analytical validity: A total of 65 patient samples with known TP53 mutation status as tested by an 
alternative test platform were included in validation. This cohort included 22 samples with TP53 
mutations and 43 samples that were wild-type for TP53. The known variants were successfully detected 
at the level as low as 5% VAF (one mutant allele in the background of nineteen wild type alleles) in all 22 
samples.  Overall, all 65 samples showed expected TP53 genotype (wild-type or mutant) showing a 100% 
concordance with the alternative test method (NGS, Sanger sequencing, and/or Pyro-Sequencing) at 
analytical sensitivity of 5%.   
Since the assay is utilized for AML patients with elevated blast count, the combination of elevated blasts 
and 5% analytical sensitivity will prevent any false-negative results. In addition, based on the clinical 
experience with this assay which utilizes unique molecular identifiers (UMI) for error correction, 
mutations in VAF range of 2% to 5% are routinely detected and reported with a comment about low 


Protocol 2018-0333 August 3, 2020 
 
32 
 
(<5%) VAF after manual review and confirmation by a MD pathologist to prevent false negative calls in 
cases with low tumor burden.   
The limit of detection (LOD) of this panel was assessed by sequencing 2 cell lines and one patient 
sample. The cell lines were diluted in a negative control sample (human female DNA, Promega) at 5 
different dilutions factors of 100%, 50%, 20%, 10% and 5%. The positive patient sample was diluted into 
negative patient sample at 6 different dilution factors of 100%, 50%, 20%, 10%, 5% and 2.5%.  A total of 
151 different single nucleotide variations (SNVs) or indels in 5 different genes at various variant allelic 
frequencies were known in the cell lines and the patient sample consisting of 65 samples. The known 
variants were successfully detected at the level of 5% VAF (one mutant allele in the background of 
nineteen wild type alleles) taking into consideration the depth of coverage at a given base, establishing 
an analytical sensitivity of 99.3%. Out of the 151 variants, 150 were concordant to the calls made by an 
alternate chemistry, TruSeq, HaloPlex, Sanger, and Pyro-Sequencing.  The variants include 135 single 
nucleotide polymorphisms (SNPs), and 16 insertion/deletions (INDELS).  The missed call was due to low 
variant allelic frequency, below that assay sensitivity establishing an overall accuracy of 99.3%. 
All reagents obtained by the CAP-accredited/CLIA-certified lab are stored and handled as recommended 
by the manufacturer and records of refrigerator, freezer, and room temperature monitoring is routinely 
kept. All reagents and chemicals are used within their indicated expiration date. New reagent lots and 
shipments are checked against old reagent lots using reference material such as a positive control, 
previously performed patient samples or concurrently prior to placing the reagents in service. For non-
critical reagents a concurrent lot validation is performed. The process involves documenting the last run 
using the old lot and the first run using the new lot. Parallel validation is performed for critical reagents. 
This involves running two patient samples that have previously been sequenced for the panel within the 
first run of the new lot. The raw data from the two previously sequenced patient samples performed on 
both the old and new lot are reviewed by a supervisor and must passed all performance QC metrics as 
defined by the validation study. Records of the acceptability studies for the new reagents lot and 
shipments are maintained within the laboratory. 
 
Minimal Residual Disease assessment by flow-cytometry 
As a standard of care all BM aspirates will be evaluated for MRD by validated (to a level of at least 0.1%) 
17-color multiplanar flow-cytometry. 
 
Gene expression and methylation signatures by RNA sequencing and/or gene expression arrays  
This will be performed on PB and/or BM aspirates at screening, end of cycle 1, end of cycle 3, and at time 
of progression / end of study.  
 
CyTOF analysis (MDACC) 


Protocol 2018-0333 August 3, 2020 
 
33 
 
We will analyze MDM2 family expression, stem cell surface markers, differentiation markers, and 
intracellular signaling markers in AML cells by CyTOF (mass cytometry) assay established in Dr Andreeff 
laboratory, on PB and/or BM at screening, end of cycle 1, end of cycle 3 and at the time of progression / 
end of study.  
Additional relationships between anti-leukemia activity / efficacy, PDn markers and exploratory 
biomarkers will be explored.   
 
7. Regulatory and Reporting Requirements  
7.1. Informed Consent 
Before a subject’s participation in the clinical study, the investigator is responsible for obtaining written 
informed consent from the subject or legally acceptable representative after adequate explanation of 
the aims, methods, anticipated benefits, and potential hazards of the study and before any protocol‐ 
specific screening procedures or any investigational products are administered.  A legally acceptable 
representative is an individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study.  
The acquisition of informed consent should be documented in the subject’s medical records, and the 
informed consent form should be signed and personally dated by the subject or a legally acceptable 
representative and by the person who conducted the informed consent discussion.  The original signed 
informed consent form should be retained in accordance with institutional policy, and a copy of the 
signed consent form should be provided to the subject or legally acceptable representative.  
 
7.2. Independent Ethics Committee/Institutional Review Board  
A copy of the protocol, proposed informed consent form, other written subject information, and any 
proposed advertising material must be submitted to the IEC/IRB for written approval. A copy of the 
written approval of the protocol and informed consent form must be received by Daiichi Sankyo before 
recruitment of subjects into the study and shipment of investigational product.  
The investigator must submit and, where necessary, obtain approval from the IEC/IRB for all subsequent 
protocol amendments and changes to the informed consent form. The investigator should notify the 
IEC/IRB of deviations from the protocol or serious adverse events occurring at the site and other adverse 
event reports received from Daiichi Sankyo, in accordance with local procedures.  
The investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout the 
duration of the study. Copies of the investigator’s reports and the IEC/IRB’s continuance of approval 
must be sent to Daiichi Sankyo. 
7.3 Subject Confidentiality  


Protocol 2018-0333 August 3, 2020 
 
34 
 
The investigator must ensure that the subject’s confidentiality is maintained. On documents submitted 
to Daiichi Sankyo, subjects should be identified by their study number only. Documents that are not for 
submission to Daiichi Sankyo (eg, signed informed consent forms) should be kept in strict confidence by 
the investigator.  
In compliance with ICH GCP Guidelines, it is required that the investigator and institution permit 
authorized representatives of the company, of the regulatory agency(s), and the IEC/IRB direct access to 
review the subject’s original medical records for verification of study‐related procedures and data. 
Direct access includes examining, analyzing, verifying, and reproducing any records and reports that are 
important to the evaluation of the study. The investigator is obligated to inform and obtain the consent 
of the subject to permit named representatives to have access to his/her study‐related records without 
violating the confidentiality of the subject. 
7.4. Study Termination 
Both Daiichi Sankyo and the investigator reserve the right to terminate the study according to the study 
contract. The investigator should notify the IEC/IRB in writing of the study’s completion or early 
termination and send a copy of the notification to Daiichi Sankyo.  
Subjects may be eligible for continued treatment with investigational product by extension protocol or 
as provided for by the local country’s regulatory mechanism. However, Daiichi Sankyo reserves the 
unilateral right to determine whether to supply the investigational product, and by what mechanism, 
after termination of the trial and before it is available commercially.  
 
7.5. Study Documentation and Archival  
The investigator should maintain a list of appropriately qualified persons to whom he/she has delegated 
study duties. All persons authorized to make entries and/or corrections on case report forms will be 
included on the Delegation of Authority Form.  
Source documents are original documents, data, and records from which the subject’s case report form 
data are obtained. These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. Case report 
form entries may be considered source data if the CRF is the site of the original recording (ie, there is no 
other written or electronic record of data). In this study, case report forms calculating IPSS may be used 
as source documents for IPSS risk category assignment.  
The investigator and study staff are responsible for maintaining a comprehensive and centralized filing 
system of all study‐related (essential) documentation, suitable for inspection at any time by 
representatives from Daiichi Sankyo and/or applicable regulatory authorities. Elements should include:  
- Subject files containing completed case report forms, informed consent forms, and subject 
identification list  


Protocol 2018-0333 August 3, 2020 
 
35 
 
- Study files containing the protocol with all amendments, investigator’s brochure, copies of 
prestudy documentation and all correspondence to and from the IEC/IRB and Daiichi Sankyo. 
 - Proof of receipt, Investigational Product Accountability Record, Return of Investigational Product for 
Destruction, Final Investigational Product Reconciliation Statement, and all drug‐related correspondence. 
*. All expired/unused study drug will be destroyed per the institution policy.In addition, all original source 
documents supporting entries in the case report forms must be maintained and be readily available.  No 
study document should be destroyed without prior written agreement between Daiichi Sankyo and the 
investigator. Should the investigator wish to assign the study records to another party or move them to 
another location, he/she must notify Daiichi Sankyo in writing of the new responsible person and/or the 
new location. 
 
7.6. Investigator Communication with Supporting Company: 
 
The Alliance Pharmacovigilance Agreement (Section VIII. Safety Information Management) executed in 
February 2018 describes all Safety Information-related exchange obligations and will govern all ICSR case 
report exchanges.  ICSR case reports as defined in this section will be exchanged as per the timelines 
stated and sent to CSPV-Clincial@dsi.com via secure e-mail. Additional information secured after the 
initial exchange will be sent as follow-up report. A final report to document resolution of the SAE is also 
required.  
 
7.7. Product Complaints 
In addition to compliance with all FDA requirements pursuant to 21 CFR 211 and 21 CFR 820, Principal 
Investigator will report to Daiichi Sankyo within 24 hours any suspected quality defect in an Daiichi 
Sankyo Product or its Daiichi Sankyo‐provided packaging, labeling, or medical device component 
(collectively, “Product Complaint”.  Principal Investigator will report Product Complaints that involve a 
Daiichi Sankyo Product, whether Daiichi Sankyo has supplied the Daiichi Sankyo Product used in the 
Study or not.  Daiichi Sankyo’s contact for reporting Product Complaints shall be handled according to 
the Quality Agreement included in the study binder by contacting Daichi Sankyo, INC., office 211 Mt. 
Airy Road, Basking Ridge, NJ 07920-2311. (908) 992-7072 or email: mreeves@dsi.com. 
8. STATISTICAL CONSIDERATIONS  
8.1 Statistical Design  
This is a phase 1/2 study of DS-3032b with LDAC, with or without addition of venetoclax in patients with 
AML.  The primary objective of the study in phase I is to evaluate the safety and tolerability of the 
combination therapy and determine the maximum tolerated dose (MTD).   The primary objective of the 
phase II part is to evaluate the efficacy of this combination treatment in newly diagnosed and 
relapsed/refractory AML patients, respectively.  An estimated 58 patients will be enrolled. 
8.1.1: Phase I 
In this phase, the 3+3 algorithm will be applied for dose escalation or dose de-escalation.  There are 3 
doses involved (Table 8.1). The starting dose tested will be dose level 0, and escalate to planned dose 


Protocol 2018-0333 August 3, 2020 
 
36 
 
level +2 if dose level 0, +1, are determined safe. Initially three patients will be treated at dose 
level 0.    Up to 18 patients will be enrolled in the phase I part.  
 
Table 8.1 Phase 1 dose reduction and escalation for DS-3032b + LDAC + venetoclax  
Dose Level 
Cytarabine (mg BID), 
SubQ 
Venetoclax 
(mg/daily), oral 
DS-3032b (mg/daily), 
oral 
+2 
20mg BID x 7 days (D1-
10) 
600 mg daily x 14 
days (D1-14) 
260mg daily x D5-7 and 
D15-17 
+1 
2020mg BID x 7 days 
(D1-10) 
600mg daily x 14 
days (D1-14) 
200mg daily x 7 days 
(D8-14) 
0 (starting dose) 
20mg BID x 7 days (D1-7) 
---- 
120mg daily x 14 days 
(D8-21) 
-1 
20mg BID x 7 days (D1-7) 
---- 
120mg daily x 7 days 
(D8-14) 
 
The following is a description of dose escalation rule.  
- 
If none of the initial 3 patients in the cohort experience a DLT, then a new cohort of 3 patients will 
be treated at the next higher dose level (i.e. Dose Level 1). 
- 
 If 1 of the 3 initial patients experiences a DLT, then treat 3 additional patients at the same dose 
(i.e. Dose Level 0).  Escalation will only continue if 1 of the 6 patients experiences a DLT. 
- 
If ≥2/3 or ≥2/6 patients experience DLTs in the first treatment cycle, the MTD has been exceeded. 
No additional patients will be treated at that dose and no further dose escalation above that dose 
either will occur.  A new cohort of three patients will be enrolled at the next lower dose  if at that 
dose only three patients were treated. 
- 
If dose level ‐1 is too toxic (i.e. ≥2/3 or ≥2/6 patients experience DLTs in the first cycle), the study 
will be stopped. MTD is defined the highest dose at which no more than one patient out of 6 
patients experience DLTs in the first cycle.   Table 8.2 lists the probabilities of dose escalation 
based on different DLT rate for the 3+3 design. 
 
- 
Table 8.2 below gives the probabilities of dose escalation based on true DLT risk in the 3+3 design. 
                                                                                         True DLT rate 
 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of 
escalation 
 
0.91 
 
0.71 
 
0.49 
 
0.31 
 
0.17 
 
0.08 
 
0.03 
 
0.01 
 
0.001 
- 
 
- 
8.1.2. Phase II:  
- 
The Phase II portion is designed to determine the response rate of the combination of DS-3032b 
and LDAC, with or without the addition of venetoclax (if the dose level 0 is identified as MTD, 


Protocol 2018-0333 August 3, 2020 
 
37 
 
then the phase II patients will be treated only with combined DS-3032b and LDAC  without 
venetoclax) in two populations of 20 patients each: 
- 
(Arm A): Newly diagnosed patients with AML;  
- 
(Arm B): Relapsed/refractory AML patients. 
- 
 
- 
The primary endpoint for the phase II part is overall response rate (ORR) which will be evaluated 
within the first 2 cycles of the treatment.  
- 
 
- 
Arm A: The historical data suggests an ORR rate of 25% for this population and the target ORR 
with DS-3032b and LDAC will be > 40%.  This treatment combination will be considered worthy 
of further investigation if it elicits an increase in ORR to 40%, with acceptable toxicity.   
 
- 
Given this, we will stop enrollment if the observed patients’ data suggest that: 
- 
Pr (ORRE> ORRH +0.15|data) < 0.02 or 
- 
Pr (TOXE> 0.30|data) > 0.88 
 
Here ORRE and ORRH are the ORR rate for new experimental therapy and the historical treatment, 
respectively. TOXE is the toxicity rate which is defined as therapy related non-hematological grade 3/4 
toxicity within the 1st cycle of treatment. That is, if at any time during the study we determine that there 
is a less than 2% chance that the average ORR rate improves over historical ORR rate by more than 15% 
we will stop enrollment to this cohort. The second condition will stop the study early if excessive therapy-
related non-hematological grade 3/4 toxicity (>30%) is highly probable (i.e., probability >88%).  The ORRE 
and ORRH are assumed to follow a prior of Beta (0.5, 1.5) and a constant of 25%, respectively. The stopping 
boundaries for ORR, based on these assumptions and monitoring conditions are found in Table 8.3. We 
will apply these stopping boundaries continuously starting from the fifth patient in a cohort size of 5 
patients.  For example, accrual will cease if 1 patient experiences ORR among the first 10 patients treated.  
 
Table 8.3. Stopping boundaries for ORR rate for the cohort with Newly diagnosed patients with AML 
# of patients 
Stop the trial if there are this many  ORR totals 
5 
0 
10 
0-1 
15 
0-2 
20 
Always stop with this many patients 
The monitoring rule for the toxicity rate, based on these assumptions and monitoring conditions above 
is found in Table 8.4. For example, accrual will cease if 4 or more patients experience toxicities among 
the first 5 patients. 
 
Table 8.4. Stopping boundaries for Toxicity for the cohort with Newly diagnosed patients with AML 


Protocol 2018-0333 August 3, 2020 
 
38 
 
# of patients 
Stop the cohort if there are this many therapy-
related non-hematological grade 3/4 toxicities 
total 
5 
4-5 
10 
6-10 
15 
7-15 
20 
Always stop with this many patients 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility stopping boundaries 
and the OC table (Table 8.5).  A 30% toxicity constant rate and beta (0.6, 1.4) priors were assumed for 
the standard treatment toxicity constant rate and experimental treatment toxicity prior distribution, 
respectively. 
 
The probability of stopping the study early if the true ORR of the combination treatment was 40% and 
the true toxicity rate was 30% was 24%.  Probabilities of stopping early for high true toxicity rates (i.e., 
50%) were 74% when the true ORR was 40% and 72% when true ORR rate was 50%. 
 
Table 8.5.  Operating characteristics for simultaneous monitoring response and toxicity rates for 
patients treated with combination treatment  for the cohort with Newly diagnosed patients with AML 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.20 
0.15 
0.72 
 
0.25 
0.40 
 
0.4 
0.13 
 
0.5 
0.06 
0.30 
0.15 
0.75 
 
0.25 
0.47 
 
0.4 
0.24 
 
0.5 
0.18 
0.50 
0.15 
0.92 
 
0.25 
0.82 


Protocol 2018-0333 August 3, 2020 
 
39 
 
Table 8.5.  Operating characteristics for simultaneous monitoring response and toxicity rates for 
patients treated with combination treatment  for the cohort with Newly diagnosed patients with AML 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
 
0.4 
0.74 
 
0.5 
0.72 
 
If the study is not stopped early and 20 patients have been treated and evaluated in the study, assuming 
8 of the 20 patients achieve ORR under the combination treatment and without using any non-informative 
prior distribution, then the 95% credible interval for ORR rate will be (0.20 -0.62). 
 
Arm B: The historical data suggests an ORR rate of 15% for this population and the target ORR with DS-
3032b and LDAC will be > 30%.  This treatment combination will be considered worthy of further 
investigation if it elicits an increase in ORR to 30%, with acceptable toxicity.   
 
Given this, we will stop enrollment if the observed patients’ data suggest that: 
 
1) Pr (ORRE> ORRH +0.15|data) < 0.02 or 
2) Pr (TOXE> 0.30|data) > 0.88 
 
Here ORRE and ORRH are the ORR rate for new experimental therapy and the historical treatment, 
respectively. TOXE is the toxicity rate which is defined as therapy related non-hematological grade 3 or 
higher toxicity within the 1st cycle of treatment. That is, if at any time during the study we determine that 
there is a less than 2% chance that the average ORR rate improves over historical ORR rate by more than 
15% we will stop enrollment to this cohort. The second condition will stop the study early if excessive 
therapy-related non-hematological grade 3/4 toxicity (>30%) is highly probable (i.e., probability >88%).  
The ORRE and ORRH are assumed to follow a prior of Beta (0.3, 1.7) and a constant of 15%, respectively. 
The stopping boundaries for ORR, based on these assumptions and monitoring conditions are found in 
Table 8.6. We will apply these stopping boundaries continuously starting from the fifth patient in a cohort 
size of 5 patients.  For example, accrual will cease if 0 patient experiences ORR among the first 10 patients 
treated.  
 
 
Table 8.6. Stopping boundaries for ORR rate  
# of patients 
Stop the trial if there are this many  ORR totals 
5-10 
0 
15 
0-1 


Protocol 2018-0333 August 3, 2020 
 
40 
 
20 
Always stop with this many patients 
The monitoring rule for the toxicity rate, based on these assumptions and monitoring conditions above 
is found in Table 8.7. For example, accrual will cease if 4 or more patients experience toxicities among 
the first 5 patients. 
Table 8.7. Stopping boundaries for Toxicity  
# of patients 
Stop the cohort if there are this many therapy-
related non-hematological grade 3/4 toxicities 
total 
5 
4-5 
10 
6-10 
15 
7-15 
20 
Always stop with this many patients 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility stopping boundaries 
and the OC table (Table 8.8). A 30% toxicity constant rate and beta (0.6, 1.4) priors were assumed for 
the standard treatment toxicity constant rate and experimental treatment toxicity prior distribution, 
respectively. 
 
The probability of stopping the study early if the true ORR of the combination treatment was 30% and 
the true toxicity rate was 30% was 30%.  Probabilities of stopping early for high true toxicity rates (i.e., 
50%) were 76% when the true ORR was 30% and 72% when true ORR rate was 50%. 
Table 8.8.  Operating characteristics for simultaneous monitoring response and toxicity rates  
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.20 
0.15 
0.53 
 
0.25 
0.28 
 
0.3 
0.20 
 
0.5 
0.05 
0.30 
0.15 
0.59 
 
0.25 
0.37 
 
0.3 
0.30 
 
0.5 
0.17 


Protocol 2018-0333 August 3, 2020 
 
41 
 
Table 8.8.  Operating characteristics for simultaneous monitoring response and toxicity rates  
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.50 
0.15 
0.86 
 
0.25 
0.79 
 
0.3 
0.76 
 
0.5 
0.72 
 
 
If the study is not stopped early and 20 patients have been treated and evaluated in the study, assuming 
6 of the 20 patients achieve ORR under the combination treatment and without using any non-informative 
prior distribution, then the 95% credible interval for ORR rate will be (0.13 -0.51). 
 
 
 
8.2 Sample Size 
Up to 58 patients may be entered in this trial.  The phase I portion is anticipated to enroll 18 patients, 
unless the lowest dose is too toxic.  The phase II portion will evaluate 40 patients.  
 
8.3 Analysis Populations:   
8.3.1 Safety Population: 
All patients who receive at least 1 dose of study treatment will be included in the analysis of safety 
regardless of the duration of treatment. Patients who experience adverse events during the Screening 
period but who do not start on study treatment due to reasons that include, but are not limited to 
ineligibility/screen failure, death or withdrawal of consent, will not be included in the safety population. 
8.3.2 DLT-evaluable Population (Phase I portion only): 
Unless doses are missed in Cycle 1 due to DLT(s), a patient must receive at least 85% of the planned 
doses of DS-3032b to be considered evaluable for DLTs.  If a patient received fewer doses/days of 
treatment in the first cycle of treatment for reasons other than a DLT, the patient will be considered 
non-evaluable for DLT and replaced. 


Pr ot oc ol 2 0 1 8 -0 3 3 3 A u g ust 3, 2 0 2 0  
 
4 2  
 
8. 4   St atistic al A n al ysis Pl a n:  
T h e r at es of r es p o ns e t o t h er a py ( O R R) will b e esti m at e d al o n g wit h t h e 9 5 % cr e di bl e i nt erv al. Fis h er’s 
ex act t est a n d Wilc ox o n r a nk t est will b e us e d i n t h e d at a a n al ys es of c at e g oric al a n d c o nti n u o us v ari a bl es, 
r es p ectiv ely. T h e K a pl a n -M ei er m et h o d will b e us e d t o esti m at e t h e pr o b a biliti es of e v e nt fr e e s urvi v al 
( E F S), D O R, a n d ov er all s urvi v al (O S) wit h a p pr o pri at e l e v els of err or as i n dic at e d, s uc h as 9 5 % c o nfi d e nc e 
i nt erv als f or t h e m e di a ns or st a n d ar d err ors f or t h e pr o p orti o ns s ur vivi n g at a s p ecific ti m e. T h e d ur ati o n 
of r es p o ns e is d efi n e d as t h e n u m b er of d a ys fr o m t h e d at e of i niti al r es p o ns e t o t h e d at e of first 
d oc u m e nt e d dis e as e pr o gr essi o n/r el a ps e or d e at h, w hic h e v er occ urs first. E v e nt -fr e e s ur viv al is d efi n e d 
as t h e n u m b er of d ays fr o m t h e d at e of tr e at m e nt i niti ati o n t o t h e d at e of d oc u m e nt e d tr e at m e nt f ail ur e, 
r el a ps es fr o m C R, or d e at h fr o m a ny c a us e, w hic h e v er occ urs first, a n d will b e c alc ul at e d f or all p ati e nts. 
T h e o v er all s ur viv al is d efi n e d as t h e ti m e fr o m tr e at m e nt st art till d e at h or l ast f oll o w -u p.  L o g-r a n k t ests 
will b e us e d t o c o m p ar e a m o n g s u b gr o u ps of p ati e nts i n t er ms of E F S  or O S  if a ny s u b gr o u ps ar e l ar g e 
e n o u g h wit h e n o u g h e v e nts t o w arr a nt a c o m p aris o n.  A nti -t u m or activity, P D m ark ers, ex pl or at or y 
bi o m ark ers a n d dr u g ex p os ur e l e v els will b e s u m m ariz e d gr a p hic all y a n d wit h d escri pti v e st atistics. Ex act 
lo gistic  r egr essi o n a n al ysis will b e us e d t o e v al u at e t h e ass oci ati o n of P D/ P K p ar a m et ers wit h r es p o ns e.  
S af et y d at a will b e s u m m ariz e d usi n g fr e q u e nc y a n d p erc e nt a g e, by c at e g ory a n d s e v erity.   Ex pl or at or y 
m e as ur es of M R D a n d g e n etic ex pr essi o n will b e pr es e nt e d gr a p hic all y wit h d escri pti v e st atistics t o 
i d e ntif y p ot e nti al pr o g n ostic m ark ers f or i ncl usi o n i n f ut ur e tri als. 
 
T h e I nv esti g at or is r es p o nsi bl e f or c o m pl eti n g t oxicity / effic ac y s u m m ary r e p orts a n d s u b mitti n g t h e m t o 
t h e I N D offic e M e dic al Aff airs a n d S af ety Gr o u p f or r evi e w a n d a p pr ov al.   T h es e s h o ul d b e s u b mitt e d as 
f oll o ws:  
 
•  
P h as e I:  
Aft er t h e first 3 e v al u a bl e p ati e nts c o m pl et e cycl e 1  of st u dy tr e at m e nt, a n d ev ery 3 ev al u a bl e p ati e nts 
t h er e aft er, pri or t o a dv a nci n g/c h a n gi n g d os e l e v els. 
 
•  
P h as e II:  
Aft er t h e first 5 e v al u a bl e p ati e nts  c o m pl et e cycl e 1 of st u dy tr e at m e nt, a n d ev ery 5 p ati e nts t h er e aft er, 
u ntil e nr oll m e nt is c o m pl et e.  
 
A c o py of t h e c o h ort s u m m ar y s h o ul d b e pl ac e d i n t h e I nv esti g at or’s R e g ul at ory Bi n d er u n d er “s p o ns or 
c orr es p o n d e nc e”. 
9. 0 Pr ot oc ol L a n g u a g e T e m pl at e O utsi d e P h ysici a n P artici p ati o n D uri n g Tr e at m e nt  
1. M D A C C P hysici a n c o m m u nic ati o n wit h t h e o utsi d e p hysici a n i s r e q uir e d pri or t o t h e p ati e nt r et ur ni n g 
t o t h e l oc al p hysici a n. T his will b e d oc u m e nt e d i n t h e p ati e nt r ec or d . 
2. A l ett er t o t h e l oc al p hysici a n o utli ni n g t h e p ati e nt's p artici p ati o n i n a cli nic al tri al will  r e q u est l oc al 
p hysici a n a gr e e m e nt t o s u p er vis e t h e p ati e nt’s c ar e.  


Protocol 2018-0333 August 3, 2020 
 
43 
 
3. Protocol required evaluations outside MDACC will be documented by telephone, fax or e-mail.  Fax 
and/or e-mail will be dated and signed by the MDACC physician, indicating that they have reviewed it. 
4. Changes in drug dose and/or schedule must be discussed with and approved by the MDACC physician 
investigator, or their representative prior to initiation, and will be documented in the patient record. 
5. A copy of the informed consent, protocol abstract, treatment schema and evaluation during 
treatment will be provided to the local physician. 
6. Documentation to be provided by the local physician will include drug administration records, 
progress notes, reports of protocol required laboratory and diagnostic studies and documentation of 
any hospitalizations.  
7. The home physician will be requested to report to the MDACC physician investigator all life threatening events 
within 24 hours of documented occurrence. 
8. Patients will return to MDACC every month for evaluation. 
 
 


Protocol 2018-0333 August 3, 2020 
 
44 
 
Appendix A:  Recommendations for initial management of electrolyte imbalances and prevention of 
tumor lysis syndrome (TLS)_ 
Abnormality 
Management Recommendations 
Hyperkalemia (including rapidly rising potassium) 
Potassium > upper limit 
of normal 
• 
Perform STAT ECG and commence telemetry. 
• 
Nephrology (or other acute dialysis service) notification with 
consideration of initiating dialysis. 
• 
Administer Kayexalate 60 g (or Resonium A 60 g). 
• 
Administer furosemide 20 mg IV × 1. 
• 
Administer calcium gluconate 100 – 200 mg/kg IV slowly if there is 
ECG/telemetry evidence of life-threatening arrhythmias. 
• 
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT. 
Hyperuricemia 
Uric acid ≥ 10 mg/dL (595 
µmol/L)  
OR  
Uric acid ≥ 8.0 mg/dL 
(476 µmol/L) with 25% 
increase and creatinine 
increase ≥ 0.3 mg/dL 
(≥ 0.027 mmol/L) from 
pre-dose level 
• 
Administer rasburicase (dose per institutional guidelines). 
• 
If rasburicase is used, sodium bicarbonate should not be used as this 
may exacerbate calcium phosphate precipitation. 
• 
Notify nephrology (or other acute dialysis service). 
• 
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT. 
• 
If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium and creatinine 2 and 4 hours later, if no other 
evidence of tumor lysis. 
Hypocalcemia 
Calcium ≤ 7.0 mg/dL 
(1.75 mmol/L)  
AND  
Patient symptomatic 
e.g., muscle cramps, 
hypotension, tetany, 
cardiac arrhythmias) 
• 
Administer calcium gluconate 50 – 100 mg/kg IV slowly with ECG 
monitoring. 
• 
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT. 
• 
If calcium normalized 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium and creatinine 2 and 4 hours later, if no other 
evidence of tumor lysis. 
• 
Calculate corrected calcium and check ionized calcium if albumin low. 
Hyperphosphatemia 
Phosphorus ≥ 6.0 mg/dL 
with ≥ 0.5 mg/dL increase 
• 
Administer a phosphate binder (e.g., aluminum hydroxide, calcium 
carbonate, sevelamer hydroxide, or lanthanum carbonate). 
• 
Nephrology (or other acute dialysis service) notification (dialysis 
required for phosphorus ≥ 10 mg/dL). 
• 
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT. 
Creatinine 
Increase ≥ 25% from 
baseline 
Start or increase rate of IV fluids. 
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 – 
2 hours STAT. 
 


Protocol 2018-0333 August 3, 2020 
 
45 
 
 
 
 
 


Protocol 2018-0333 August 3, 2020 
 
46 
 
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