Conditions: Acute Myeloid Leukemia With FLT3/ITD Mutation Recurrent Acute Myeloid Leukemia Refractory Acute Leukemia
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
This phase Ib/II trial studies the side effects and best dose of venetoclax in combination with quizartinib and how well they work in treating patients with acute myeloid leukemia that has come back or does not respond to treatment, and who are FLT3-mutation positive. Venetoclax and quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the combination of venetoclax with quizartinib in FLT3-internal tandem duplication (ITD) mutated patients with relapsed/refractory acute myeloid leukemia (AML). (Phase Ib) II. To determine the composite complete remission (CR) (CRc) rate including CR + CRp (complete remission with incomplete platelet recovery) + CRi (complete remission with incomplete count recovery) within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the composite CRc rate including CR + CRp + CRi within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/ refractory AML. (Phase Ib) II. To determine the overall response rate (ORR) including CRc + partial remission (PR) within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase Ib) III. To determine the duration of response (DOR), progression free survival, event-free survival (EFS), overall survival (OS), and number of patients bridged to hematopoietic stem cell transplant (HSCT) and median duration to HSCT from the initiation of the combination in FLT3-ITD mutated patients with relapsed/ refractory AML. (Phase Ib) IV. To characterize the pharmacokinetic (PK) profiles of combination therapy of venetoclax and quizartinib in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase Ib) V. To determine the ORR within 3 months of treatment initiation in FLT3-ITD mutated patients with relapsed/ refractory AML. (Phase II) VI. To determine the DOR, progression-free survival (PFS), EFS, OS, and number of patients bridged to HSCT and median duration to HSCT from the initiation of the combination in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase II) VII. To determine the safety and tolerability of the combination in FLT3-ITD mutated patients with relapsed/refractory AML. (Phase II)

EXPLORATORY OBJECTIVES:

I. To investigate possible relationships between baseline next generation gene sequencing and clinical response to the combination.

II. To investigate quantitative changes of FLT3-ITD allelic burden with time and the extent of pharmacodynamics biomarker (such as phosphorylated \[p\]-FLT3, p-ribosomal protein S6 kinase beta-1 \[p70S6K\], pERK, pSTAT) inhibition, and the induction of apoptosis in the bone marrow and peripheral blasts in patients treated with the combination.

III. To investigate possible relationships between baseline gene expression signatures, Bcl-2 family messenger ribonucleic acid (mRNA) and protein levels of AML blasts and/or stem cell sub-population, BH3 profiling of Bcl-2 family member dependency and ex vivo functional screen and clinical response to the combination.

IV. To analyze immune modulation including alterations in total and percent of CD3+ T-cells, total and percent of various T-cell subsets (CD4-effector, CD4-regs, CD8 cytotoxic T-cells), and total and percent of T-cell/T-cell subsets expressing specific checkpoint receptors/ligands with the combination.

V. To store and/or analyze surplus blood or tissue including bone marrow, if available, for potential future exploratory research into molecular and immune factors that may influence response to venetoclax and/or quizartinib (where response is defined broadly to include efficacy, tolerability or safety).

OUTLINE: This is a phase Ib dose-escalation study of quizartinib, followed by a phase II study.

Patients receive quizartinib orally (PO) once daily (QD) on days 1-28 and venetoclax PO QD beginning on day 8 of cycle 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment beyond 24 cycles at the discretion of the treating physician.

After completion of study treatment, patients are followed up at 30 days and then every 3-6 months for up to 5 years.

Arms:
arm 1: Dose finding: Patients receive quizartinib PO QD on days 1-28 and venetoclax PO QD beginning on day 8 of cycle 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment beyond 24 cycles at the discretion of the treating physician. arm 2: Patients will be treated at the established dose from the phase I portion of the study.

Patients receive quizartinib PO QD on days 1-28 and venetoclax PO QD beginning on day 8 of cycle 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment beyond 24 cycles at the discretion of the treating physician.

Interventions: intervention 1: Quizartinib intervention 2: Venetoclax
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO

Protocol document:
Prot_SAP_000.pdf: 
Venetoclax and quizartinib in AML 
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MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2018-0608 
Protocol Title 
A Phase Ib/II Study of Venetoclax in Combination with 
Quizartinib in FLT3-mutated Acute Myelogenous Leukemia 
(AML) 
Protocol Version 
14 
Version Date 
03/02/2020 
Protocol PI 
Naval Daver, MD 
Department 
Leukemia 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
141707 


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A Phase Ib/II Study of Venetoclax in Combination with 
Quizartinib in FLT3-mutated Acute Myelogenous 
Leukemia (AML) 
 
Principal Investigator: Naval Daver, M.D. 
Co-PI: Marina Konopleva 
Biostatistician: Jing Ning, Ph.D. 
Junsheng Ma, Ph.D. 
Sponsor: University of Texas, MD Anderson Cancer Center 
IND number: 141707 
 
 
University of Texas 
 
MD Anderson Cancer Center 
Leukemia Department, Unit 428, 
Houston, Texas, 77030. 
 
 
 
 
 
 
Contents 
1.0 OBJECTIVES ................................................................................................ 4 
2.0 BACKGROUND ............................................................................................ 5 
3.0 STUDY DESIGN… ...................................................................................... 17 


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4.0 PATIENT SELECTION ................................................................................ 20 
5.0 TREATMENT PLAN .................................................................................... 24 
6.0 CORRELATIVE/SPECIAL STUDIES........................................................... 38 
7.0 PATIENT EVALUATION ............................................................................ 39 
8.0 CRITERIA FOR RESPONSE ....................................................................... 43 
9.0 DISCONTINUATION OF TREATMENT ....................................................... 45 
10.0 ADVERSE EVENT REPORTING ............................................................... 46 
11.0 STATISTICAL CONSIDERATIONS ........................................................... 50 
12.0 REFERENCES .......................................................................................... 54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.0 OBJECTIVES 
 
1.1 Primary Objectives 


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Phase Ib 
1. To determine the maximum tolerated dose (MTD) and the recommended 
phase 2 dose (RP2D) of the combination of venetoclax with quizartinib in 
FLT3-ITD mutated patients with relapsed/refractory acute myeloid leukemia 
(AML). 
Phase II 
1. To determine the composite CR (CRc) rate including CR (complete 
remission) + CRp (complete remission with incomplete platelet recovery) + 
CRi (complete remission with incomplete count recovery) within 3 months of 
treatment initiation in FLT3-ITD mutated patients with relapsed/refractory 
AML. 
1.2 Secondary Objectives 
Phase Ib 
1. To determine the composite CRc rate including CR + CRp + CRi within 3 
months of treatment initiation in FLT3-ITD mutated patients with relapsed/ 
refractory AML. 
2. To determine the overall response rate (ORR) including CRc + partial 
remission (PR) within 3 months of treatment initiation in FLT3-ITD mutated 
patients with relapsed/ refractory AML. 
3. To determine the duration of response (DOR), progression free survival, 
event-free survival (EFS), overall survival (OS), and number of patients 
bridged to hematopoietic stem cell transplant (HSCT) and median duration to 
HSCT from the initiation of the combination in FLT3-ITD mutated patients 
with relapsed/ refractory AML. 
4. To characterize the pharmacokinetic (PK) profiles of combination therapy of 
venetoclax and quizartinib in FLT3-ITD mutated patients with 
relapsed/refractory AML.. 
 
Phase II 
1. To determine the ORR within 3 months of treatment initiation in FLT3-ITD 
mutated patients with relapsed/ refractory AML. 
2. To determine the DOR, PFS, EFS, OS, and number of patients bridged to 
HSCT and median duration to HSCT from the initiation of the combination in 
FLT3-ITD mutated patients with relapsed/ refractory AML. 
3. To determine the safety and tolerability of the combination in FLT3-ITD 
mutated patients with relapsed/ refractory AML. 
1.3 Exploratory Objectives 
 
1. To investigate possible relationships between baseline next generation gene 
sequencing and clinical response to the combination. 
2. To investigate quantitative changes of FLT3-ITD allelic burden with time and 
the extent of pharmacodynamics biomarker (such as p-FLT3, p-p70S6K, 
pERK, pSTAT) inhibition, and the induction of apoptosis in the bone marrow 
and peripheral blasts in patients treated with the combination. 


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3. To investigate possible relationships between baseline gene expression 
signatures, Bcl-2 family mRNA and protein levels of AML blasts and/or stem 
cell sub-population, BH3 profiling of Bcl-2 family member dependency and ex 
vivo functional screen and clinical response to the combination. 
4. To analyze immune modulation including alterations in total and percent of 
CD3+ T-cells, total and percent of various T-cell subsets (CD4-effector, CD4- 
regs, CD8 cytotoxic T-cells), and total and percent of T-cell/T-cell subsets 
expressing specific checkpoint receptors/ligands with the combination. 
5. To store and/or analyze surplus blood or tissue including bone marrow, if 
available, for potential future exploratory research into molecular and immune 
factors that may influence response to venetoclax and/or quizartinib (where 
response is defined broadly to include efficacy, tolerability or safety). 
2.0 BACKGROUND 
 
2.1 FLT3-mutated AML 
 
FLT3 (FMS-like tyrosine kinase III) belongs to the Class III family of receptor tyrosine 
kinases (RTKs; other members of this family include receptors for KIT, FMS, and 
PDGF) (1). Signaling via RTKs is frequently dysregulated in hematological 
malignancies (2). FLT3 is activated following binding of FLT3 ligand, which causes 
receptor dimerization leading to increased kinase activity and activation of 
downstream signaling pathways including Stat5, RAS, and PI3-kinase.(3-5) FLT3 
plays a role in the regulation of survival and proliferation of hematopoietic progenitor 
cells, in particular by synergy with other RTKs and cytokine receptors.(6-8) FLT3 is 
also expressed in acute myeloid leukemia cells from approximately 90-95% of 
patients and stimulates survival and proliferation of leukemic blasts.(9-11). 
Additionally, activating mutations in FLT3 are observed in 30% of adult AML patients 
(12). The two FLT3 mutations found in AML include internal tandem duplications in 
the juxta-membrane domain (ITD, 17–34%) and mutations in the tyrosine kinase 
domain (TKD) activation loop (7%) (13). FLT3-ITD mutations are associated with 
adverse prognosis. Patients with FLT3-ITD have significantly elevated peripheral 
blood white cell counts, increased bone marrow blasts, increased relapse risk, inferior 
event-free survival (EFS), and decreased overall survival (OS) (14-16). The FLT3- 
TKD mutations have unknown prognostic significance in AML (16). 
Several small-molecule FLT3 targeted tyrosine kinase inhibitors (TKIs) that are 
undergoing evaluation in phase I, II, and III trials have shown promising activity as 
single agents and in combination with hypomethylating agents or chemotherapy. 
These include quizartinib (AC220), sorafenib, midostaurin (PKC412), lestaurtinib, 
gilteritinib, and crenolanib(17). These TKIs act as direct inhibitors of FLT3 via 
competitive inhibition of the ATP-binding sites in the FLT3 receptor kinase domain 
(KD)(18, 19). 
 
Several multitargeted tyrosine kinase inhibitors (TKIs) such as lestaurtinib, sunitinib, 
sorafenib, and midostaurin had activity against FLT3 and have been investigated in 
FLT3-mutated AML. These agents have limited single-agent activity with marrow 
remission response rates of <10% with single-agent midostaurin(20) or sorafenib(21). 
On the other hand, second generation FLT3 inhibitors such as quizartinib and 
gilteritinib have demonstrated potent anti-leukemic activity and improved outcomes in 


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patients with relapsed/refractory AML and FLT3-ITD mutations(22). About 40-50% of 
such patients achieve marrow responses to the second generation FLT3 inhibitors 
such as quizartinib(23-25) and gilteritinib(26), with 20-30% bridged to allogeneic stem 
cell transplant. Although the response rates are high, the responses to both first and 
second generation FLT3 inhibitors are invariably transient, lasting 8-18 weeks (except 
among patients who undergo transplantation) due to the emergence of resistance(27, 
28). The primary cause of resistance is the acquisition of point mutations in the FLT3 
KD. Heidel et al first to identified point mutations in the FLT3-ITD KD as a mediator of 
resistance to the FLT3 inhibitor midostaurin. They reported a single amino acid 
substitution at position 676 (N676K) within the FLT3 KD as the sole cause of 
resistance to midostaurin in a patient with AML(29). Acquired point mutations in the 
KD may be preexisting or acquired after exposure to the FLT3 inhibitors as has been 
shown with midostaurin(29). Homology modeling has identified two main types of 
FLT3 mutations, namely TKD1 mutations involving the ATP-binding (hinge regions) 
and the TKD2 mutations involving the activation loop(30). Non-mutational 
mechanisms of resistance include up-regulation of compensatory pathways including 
the MAPK/ERK, PI3K/Akt/mTOR, FOXO3A, SYK, and STAT5/PIM pathways, up- 
regulation of the FLT3 ligand or receptor, mutations in other kinases (e.g. CBL), 
activation of anti-apoptotic proteins BCL2, MCL1 and BCL-x(L), and tumor 
microenvironment mediated resistance(31, 32). 
2.2 Quizartinib 
 
Quizartinib is a novel second-generation Class III RTK inhibitor with potent and highly 
efficacious FLT3 activity in vitro and in vivo. Activating gene mutations in the RTK 
FLT3 (FLT3 mutant) are present in approximately 30% of patients with AML. These 
patients with FLT3-mutants have a significantly worse prognosis than patients with 
FLT3 wild type (FLT3 WT), suggesting that the activated kinase is a driver of AML 
and a potential target for kinase inhibitor therapy. 
Toxicology studies with quizartinib in rats, dogs, and monkeys up to 90 days in 
duration have shown that the principle toxicological target organs were the bone 
marrow and lymphoid organs in rat, dog, and monkey. These findings are consistent 
with the presumed FLT-3 and c-KIT kinase inhibition mechanism of action of the drug. 
In addition, toxicological effects were observed in the kidney, the liver and the ovary, 
vagina, and testes. Target-organ toxicity appears to be dose-, and time-dependent, 
and most findings were reversible following a 28-day reversal period. Bioavailability 
and exposure were good across species, ranging from 15% in monkeys to 40% in 
dogs. Plasma protein binding with quizartinib was high (> 99%) in all 5 species 
examined (mouse, rat, dog, monkey, and human) and the compound has been 
shown to penetrate the brain poorly. In vitro CYP450 studies demonstrate that 
quizartinib is neither an inhibitor nor inducer of major human CYP isoforms. 
Quizartinib qualifies as P-gp substrate and has weak potential to inhibit P-gp. 
Evidence from rat toxicokinetic studies indicate that quizartinib does not accumulate 
nor does it induce its own metabolism. A major pharmacologically active metabolite, 
termed AC886, has been identified in the plasma of rat, dog, monkey, and humans. 
Quizartinib Clinical Pharmacology and Pharmacokinetics 


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Absorption: The time for quizartinib to reach maximum observed plasma 
concentration (Tmax) is approximately 4 hours in healthy volunteers and 2 hours in 
AML subjects. Food has minimal effect on the bioavailability of quizartinib: peak 
concentrations (Cmax) decreased by approximately 8% while area under the curve 
(AUC) values increased by approximately 5% to 8%. Food increased Tmax by 
approximately 2 hours. Quizartinib can be administered without any restriction on fed 
status. The proton pump inhibitor lansoprazole modestly decreased the absorption of 
quizartinib with Cmax decreased by 14% and AUC decreased by 5% to 6% 
Quizartinib can be coadministered with gastric acid reducing agents (i.e. proton pump 
inhibitors, H2 blockers, and antacids). 
At steady state in AML patients, the geometric mean (%CV) AUC0-24h for 30 mg QD 
and 60 mg QD were 3370 (72.5) and 8276 (95.7) ng·h/mL, respectively. The 
geometric mean (%CV) for Cmax at steady state for 30 mg QD and 60 mg QD were 
186 (66.0) and 487 (80.8) ng/mL, respectively. 
 
Distribution: Both quizartinib and its active metabolite, AC886, are highly plasma- 
protein bound with measured values >99% in all species tested. Both quizartinib and 
AC886 partition to red blood cells in a temperature-dependent manner. Blood 
samples must be processed at room temperature for accurate measurement of 
plasma quizartinib and AC886. 
Metabolism: Reaction phenotyping using human liver microsomes and recombinant 
human CYP enzymes revealed that both quizartinib and AC886 were substrates of 
CYP3A, with little or no contribution of CYP2D6, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, or CYP1A2. The in vitro studies showed that quizartinib is metabolized to 
AC886 by CYP3A. The metabolite AC886 is, in turn, metabolized by CYP3A. 
 
Steady state simulations of quizartinib coadministered with ketoconazole predicted 
that quizartinib Cmax and AUCtau increase by 86% and 96%, respectively, compared 
with quizartinib administered alone. Similarly, steady state simulations for quizartinib 
coadministered with fluconazole showed Cmax and AUCtau increases of only 20.1% 
and 20%, respectively. These results indicate that quizartinib should be dose 
reduced by approximately half when coadministered with a strong CYP3A inhibitor, 
but not a moderate or weak CYP3A inhibitor. 
The major circulating moeities are unchanged quizartinib and AC886 (> 10% of the 
total radioactivity exposure in plasma). AC886 has similar potency and selectivity to 
quizartinib and has been measured in all clinical studies with quizartinib PK 
assessments. The median Tmax for AC886 ranged from approximately 5 to 8 hours 
across studies in healthy volunteers. The ratio of AC886 to quizartinib (AUCinf) was 
approximately 0.5 at steady state. 
 
Elimination: The principal route of excretion was hepatobiliary, estimated as > 90%. 
Renal excretion was a minor route of elimination (< 2%). The terminal elimination 
half-lives for quizartinib and AC886 are approximately 100 hours. For quizartinib 60 
mg QD, the observed geometric mean accumulation ratios (AUC0-24h) for quizartinib 
and AC886 were 5.7 and 8.2, respectively. 
Safety 


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A cardiovascular safety pharmacology study in cynomolgus monkeys demonstrates 
that single oral doses of quizartinib result in prolonged QTc interval at ≥10 mg/kg 
doses and biologically significant increased systolic blood pressure at ≥100 mg/kg 
doses. It should be noted that increases in blood pressure were not observed in the 
Phase 1 dose-escalation study, Protocol AC220-CP0001; henceforth called Study 
CP0001(33). No QTc interval prolongation was evident in monkeys dosed with 3 
mg/kg quizartinib. It is suggested that quizartinib and AC886 induced blockade of 
human ether-à-go-go-related gene (hERG) current and IKs, and therefore caused QT 
prolongation by a decrease in the net repolarization currents. The effect on IKs was 
more dominant than that on hERG. There were no apparent electrocardiogram (ECG) 
abnormalities in the dog (28- and 90-day) or monkey (28- and 90-day) general 
toxicology studies. In addition, there were no apparent toxicologically relevant 
quizartinib-related heart microscopic changes in the rat, dog, or monkey general 
toxicology studies. 
Results from Study CP0001 have shown that quizartinib has been well tolerated in 
the 76 patients (23). The majority of adverse events (AEs) observed in the study were 
those associated with the underlying disease. In addition, the safety profile was 
similar between patients receiving continuous dosing (28 days continuous dosing as 
1 cycle) and those on the intermittent schedule (14 days dosing and 14 days rest as 1 
cycle). In spite of limitations of the Phase 1 design, e.g., limited evaluation of 
response and the potentially suboptimal intermittent dosing schedule, encouraging 
preliminary evidence of clinical activity has been observed in the first 76 patients 
treated with quizartinib. The overall response (complete remission [CR] + partial 
remission [PR]) observed in all quizartinib-treated patients was 32% (24/76). 
Responses were defined per modified Cheson criteria (34). Ten patients achieved a 
CR defined as a decrease of < 5% blast in bone marrow: 2 complete hematological 
recovery, 4 with incomplete platelet recovery (CRp), and 4 with incomplete platelet 
and neutrophil recovery (CRi). One of these patients also had complete resolution of 
leukemia cutis. Fourteen patients had PR, defined as a decrease of ≥ 50% blasts to 
levels of 5% to 25% in the bone marrow but with incomplete peripheral recovery of 
neutrophils and platelets. Most of the patients had best bone marrow responses 
(14/22, 64%) during the first 28 days of treatment (defined as Cycle 1). Median 
duration of response was 14.1 weeks (range, 4 to 61+ weeks). Consistent with the 
proposed mechanism of action, the response in the FLT3-ITD mutant population was 
the highest with an overall response rate of 61% (11/18) including 6 PR, 3 CRi, 1 
CRp, and 1 CR. 
The dose-limiting toxicity (DLT) as per protocol in Study CP0001 was National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3 
(v3) Grade 3 QTcF (corrected QTc by Fridericia’s correction factor) interval 
prolongation at the 300-mg dose of quizrtinib administered continuously, and 
considered to be possibly drug related. It should be noted that this study did not 
exclude high risk cardiac patients, including those with abnormal baseline QTcF 
prolongation, nor did it exclude the administration of QT/QTc-prolonging concomitant 
medications, and patients were sometimes in a state of electrolyte imbalance with low 
serum potassium and/or magnesium levels. These patients with Grade 3 QTcF 
interval prolongation have been asymptomatic, with no evidence of arrhythmias and 
have had reversal of QTcF prolongation when quizartinib dosing was interrupted. The 
ECGs were originally analyzed by the sites, however they were subsequently re-read 


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using a centralized digital analysis system employed by a central ECG laboratory 
(EResearch Technology in Philadelphia, PA) and a formal analysis was performed. 
This determined that the ECG data in Study CP0001 did not demonstrate any clear 
signal of any clinically important effect on heart rate, PR (atrioventricular conduction), 
or QRS interval duration (depolarization) or morphology. The primary finding in this 
first-in-human study with limited cardiac safety data was that quizartinib appears to 
have a marked effect on cardiac repolarization, which is best defined by the 
Fridericia’s corrected QT data (QTcF). The time-averaged mean change from 
baseline for QTcF duration for the intermittent dose groups showed no QTcF effect 
for the 12- to 60-mg dose groups. Starting with the 90-mg dose, however, the QTcF 
interval change from baseline was > 20 ms and tended to increase with dose, up to 
30 to 38 ms for the 300- to 450-mg doses. For the continuous treatment dose groups, 
the QTcF interval change from baseline for 200 mg was 26 ms and for 300 mg was 
54 ms. During the first 14 days of dosing, the intermittent and continuous treatment 
dose groups at 200 mg and 300 mg experienced the same exposure to quizartinib, 
and therefore, the data over this time period may be considered together. Taken 
together, the QTcF interval change from baseline for the 200-mg dose was 22 ms to 
26 ms, and for the 300-mg dose was 38 ms to 54 ms, and the incidence of new cases 
(not seen at baseline) of Grade 3 QTcF interval prolongation (> 500 ms) was 9.5% 
(2/21 patients) at 200 mg and 30% (3/10 patients) at 300 mg. This demonstrates a 
clear dose-related and marked QTcF interval change at the ≥200-mg dose level. The 
QTcB (Bazett’s correction factor) results were comparable. The onset of increase to > 
500 ms QTcF occurred as early as 2 hours after the first dose and by Cycle 1 Day 8 
of dosing in the cases that were observed. Additional observations were made in 
women and patients of > 62 years, as is usual in these settings. The 
pharmacokinetic-pharmacodynamic (PK-PD) relationship for parent and metabolite 
was also indicative that quizartinib caused a positive QTc response of a magnitude 
that was observed by the ECG data. 
The results of a randomized phase 2 trial comparing two lower doses of quizartinib 
have been reported (35, 36). In this trial, patients with relapsed or refractory AML with 
FLT3 mutation were randomized to receive quizartinib 30 mg or 60 mg orally, daily. A 
total of 76 patients were enrolled (38 to each arm). The overall composite response 
rate (CRc, which was the primary endpoint) was identical for the two arms (47%). The 
overall response rate was slightly higher with 60 mg daily (71%) than with 30 mg daily 
(61%) because of a higher rate of partial responses in the 60mg arm (24%) compared 
to the 30 mg arm (13%). QTc prolongation to >500 msec (the dose limiting toxicity for 
quizartinib) occurred in 3% with 60 mg and 5% with 30 mg. When comparing these 
results with a prior study (37) exploring higher doses (90 mg, 135 mg, and 200 mg) it 
is clear that the rate of CRc is identical at all dose levels with some increase in PR 
with progressively higher doses. However, QTc prolongation is clearly dose 
dependent and prolongations >60 msec from baseline occur in 40% or more of the 
patients treated at doses of 90mg or above, exceeding the threshold of acceptable 
grade 3 toxicity for the standard definition of MTD. 
 
2689-CL-2004 
AC220-002 (Cohort 2) 


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30 mg/day 
(N = 38) 
60 
mg/day 
(N = 38) 
90 mg/day 
(N=57) 
135 mg/day 
(N=67) 
200 mg/day 
(N=12) 
Best Response 
CRc Rate 
47% 
47% 
47% 
45% 
42% 
PR Rate 
13% 
24% 
25% 
28% 
50% 
Maximum change in QTcF from baseline (msec) 
≤ 30 
50% 
44% 
9% 
9% 
0% 
> 30 to ≤ 60 
47% 
36% 
46% 
51% 
8% 
> 60 
3% 
19% 
46% 
39% 
92% 
 
In a recently reported phase I/II study, quizartinib and low intensity chemotherapy 
combination was shown to be safe and effective in patients with FLT3+ AML(38). In the 
phase I, patients with relapsed/refractory high-risk MDS, chronic myelomonocytic 
leukemia (CMML), or AML were eligible irrespective of FLT3 mutation and salvage 
status. The phase II enrolled patients age >60 years with untreated MDS/CMML/AML or 
patients of any age receiving first salvage treatment for AML with FLT3-ITD were 
eligible. Other requisites: performance status ≤2, adequate organ function and normal 
electrolytes (potassium, calcium and magnesium). Exclusions include: QTcF>450 msec, 
administration of drugs that prolong QT/QTc or strong CYP3A4 inhibitors or inducers. 
Each treatment cycle was 28 days and comprised azacytidine (AZA) 75 mg/m2 
subcutaneously (SQ) or intravenously for 7 days per cycle, or low-dose cytarabine 
(LDAC) 20 mg SQ twice daily for 10 days per cycle along with quizartinib at 2 planned 
dose levels: 60 mg (dose level 1) or 90 mg orally daily (dose level 2), uninterrupted. 
Patients were assigned to AZA or LDAC arm by physician choice. 
 
Sixty-one (Phase I=12, phase II=49) patients were enrolled: 38 to AZA arm and 23 to 
LDAC arm, and 59 were evaluable for response (2 too early). Median age was 68 years 
(range, 23-84), 27 (44%) were female. Forty-three patients [14 in LDAC arm (67%) and 
29 in AZA arm (76%)] of the 59 evaluable had responded with an ORR of 73 % (CR=10, 
CRp=6, CRi=20, PR=2); 5/43 (12%) patients were negative for minimal residual disease 
(MRD). Twelve patients were previously untreated, and 11 responded (ORR 92%) 
(CR-6, CRi-1, CRn-1, CRp-2, HI-P-1). The median overall survival (OS) for 
previously untreated patients was 18.6 months (range, 3.91-43.5). ORR among the 
47 previously treated was 68% (CR-4, CRi-19, CRp-4, HI-2, HI-E-1, PR-2), and the 
median OS was 11.25 months (range, 1.15 – 38.93). ORR was 75% among all patients 
(frontline and salvage 1) harboring a FLT3-ITD mutation (N=55), and 5 (9%) had no 
MRD detectable (4 AZA, 1 LDAC)(38). 
For additional details please see the quizartinib Investigator's Brochure (IB) (Appendix) 
for additional details on nonclinical and clinical studies. 
 
2.3 Overview of BCL-2 and venetoclax in AML 


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2.3.1 Venetoclax 
See the Venetoclax Investigator's Brochure (IB) (Appendix) for additional details on 
nonclinical and clinical studies. 
Bcl-2 overexpression has been implicated in maintaining the survival of AML cells and 
has been associated with resistance to chemotherapy and inferior overall survival (39). 
Venetoclax (VEN) is a potent and selective small-molecule inhibitor of Bcl-2 that has 
demonstrated cell-killing activity against a variety of leukemia cell lines, primary patient 
samples and leukemia stem/progenitor cells (40, 41). VEN also has been found to 
synergize with agents known to down-regulate Mcl-1, including azacytidine. (42) 
Based on the mechanism of action and nonclinical and clinical data available to date, the 
safety profile of venetoclax is well described. The most common adverse drug reactions 
across all indications are nausea, diarrhea, hematological effects, and serious and/or 
opportunistic infections. Hematologic effects include neutropenia/febrile neutropenia, 
thrombocytopenia, anemia, and lymphopenia. Upper respiratory tract infections are 
among the most common infections. TLS is an important identified risk and is 
predominantly seen in the CLL population with high tumor burden. Based on pre-clinical 
data, decreased spermatogenesis has been identified as a potential risk for venetoclax. 
 
2.3.2 Summary of Venetoclax Nonclinical Pharmacology 
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 (dissociation constant [Ki] < 0.010 
nM) than for Bcl-XL (Ki - 48 nM or Mcl-1 (Ki > 444 nM).(40) 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(40). Venetoclax has 
demonstrated potent killing of AML cell lines, primary patient samples, and leukemic 
stem/progenitor cells ex vivo, and has also exhibited anti-tumor efficacy in vivo, inhibiting 
the growth of AML cells systemically engrafted into immunocompromised mice. 
2.5.3 Summary of Venetoclax Nonclinical Pharmacokinetics 
The pharmacokinetics of venetoclax was evaluated in mice, rats, monkeys, and dogs. 
Venetoclax pharmacokinetic (PK) profile was characterized by low plasma clearance 
and low to moderate volumes of distribution. Half-lives ranged from 2.2 hours in 
monkeys to 12 hours in dogs. 
Venetoclax demonstrated high protein binding to human, rat, dog, and monkey plasma 
proteins (> 99.9%). Blood to plasma ratios showed that venetoclax does not partition 
preferentially into the red blood cells. Following oral administration of venetoclax to 
nonclinical species and humans, parent compound and metabolites were mainly cleared 
via biliary excretion and fecal elimination, with minimal renal clearance. 
 
Venetoclax is predominantly metabolized by cytochrome P450 (CYP) 3A4 (CYP3A4) in 
vitro; UDP-glucuronosyltransferases (UGTs) are not involved in the metabolism of 
venetoclax. In addition, venetoclax is also a substrate for P-gp and BCRP. Active 
uptake of venetoclax was not observed in cells overexpressing OATP1B1, OATP1B3 or 
OCT1. In vitro studies indicated that venetoclax is not an inhibitor or inducer of 
CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 at clinically relevant concentrations. 
Venetoclax is a weak inhibitor of CYP2C8, CYP2C9, and UGT1A1 in vitro, but it is not 
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Venetoclax is a P-gp and BCRP inhibitor and weak OATP1B1 inhibitor in vitro. In vitro, 
venetoclax is metabolized by CYP3A4 and is a moderate inhibitor of CYP2C8. Definitive 
in vitro experiments showed that venetoclax is not predicted to be an inducer or inhibitor 
of the metabolism of CYP2C9 substrate compounds. Venetoclax is not a reversible 
inhibitor of CYP1A2, CYP2B6, CYP2D6, CYP2C19 or CYP3A4 (IC50 > 30 µM) in vitro 
and does not induce CYP3A4 or CYP1A2 at concentrations up to 10 µM. 
2.5.4 Summary of Nonclinical Toxicology 
Venetoclax has been assessed in repeated-dose general toxicology studies and in 
genetic, developmental/reproductive, and safety pharmacology studies. The primary 
toxicities associated with venetoclax administration included effects on the hematologic 
system (decreased lymphocytes and erythrocytes) in mice and dogs, the male dog 
reproductive system (testicular germ cell depletion), and embryo-fetal toxicity in mice. 
2.5.5 Summary of Venetoclax Clinical Data 
Clinical Efficacy Data for Venetoclax: Preliminary efficacy results are available for 
subjects with a variety of hematological neoplasms; venetoclax is approved for the 
treatment of CLL patients whose cells have a 17p chromosomal deletion and venetoclax 
in combination with rituximab is approved for the treatment of CLL or small lymphocytic 
lymphoma (SLL) patients, with or without 17p deletion, who have received at least one 
prior therapy. 
. Preliminary data indicate that venetoclax shows promising efficacy in AML. 
• 
In Study M14-212 the ORR for subjects treated with venetoclax monotherapy was 
19%.(43) 
• 
In Study M14-358 the ORR for AML subjects (given venetoclax plus azacitidine or 
decitabine) was 68%.(44) 
• 
In Study M14-387 the ORR for AML subjects (given venetoclax plus low dose ara-C) 
was 75%.(45) 
 
Venetoclax Clinical Pharmacology and Pharmacokinetics: Venetoclax clinical 
pharmacology is being evaluated in several Phase I to III clinical trials, and data are 
available from three Phase I studies (M12-175, M13-367, M12-630), four Phase Ib 
studies (M13-365, M12-901, GO29440, GP28331), one Phase II study (M14-212) and 
five dedicated clinical pharmacology studies (Study M13-364, M14-497, M13-363, M14- 
253 and M15-101). 
 
In the Phase 1 Study M14-358, preliminary pharmacokinetic results in 31 treatment- 
naïve AML subjects were available for venetoclax doses ranging from 400 mg to 800 mg 
when given in combination with decitabine (Arm A) or azacitidine (Arm B) and with or 
without posaconazole (Arm C). For Arm A and Arm B, venetoclax steady-state mean 
Cmax and AUC24 (Cycle 2 Day 5) ranged from 1.77 – 3.36 μg/mL and 24.7 – 59.5 
μg/mL, respectively. Based on the limited preliminary pharmacokinetic data, there was 
no evidence to suggest a marked effect of the co-administration of decitabine and 
azacitidine on the pharmacokinetics of venetoclax. In Arm C of this study, preliminary 
pharmacokinetic results from 6 subjects were available on Cycle 1 Day 20 (venetoclax 
400 mg alone QD until Day 20) and Cycle 1 Day 28 (venetoclax 100 mg QD with 
posaconazole given from Day 21 to Day 28). Venetoclax Cmax and AUC following co- 
administration of venetoclax 100 mg with posaconazole were 2.1- and 2.7-fold higher 
respectively, compared to venetoclax 400 mg alone. 


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Preliminary pharmacokinetic results of venetoclax are available from 12 treatment-naïve 
subjects with AML in Cohorts 1 (600 mg) and 2 (800 mg) from the ongoing Phase 1 
combination study of venetoclax and low dose cytarabine (Study M14-387). On Cycle 1 
Day 10 (with cytarabine), venetoclax mean Cmax and AUC24 values ranged from 2.25 – 
2.56 μg/mL and 34.7 – 44.6 μg•hr/mL, respectively. On Cycle 1 Day 18 (venetoclax 
alone), mean Cmax and AUC values of venetoclax ranged from 2.38 – 2.89 μg/mL and 
37.9 – 45.3 μg•hr /mL. Dose-normalized Cmax and AUC24 of venetoclax on Cycle 1 
Day 10 (with cytarabine) were comparable to dose normalized Cmax and AUC24 on 
Cycle 1 Day 18 (venetoclax alone), suggesting that co-administration of cytarabine did 
not markedly affect venetoclax exposures. 
Clinical Safety Data for Venetoclax: As of 05 June 2017, three Phase 1/2 studies have 
been conducted in the AML indication as described below. 
Overview of Phase 2 Study M14-212: Venetoclax Monotherapy in AML 
This is a completed study with single agent venetoclax in subjects with R/R AML and 
those unfit for intensive therapy. A total of 32 subjects were dosed. Exposure, safety, 
and efficacy data are available for this study.(43) The most common adverse events 
observed in ≥ 30% of the subjects in Study M14-212 were nausea (59.4%); diarrhea 
(56.3%); hypokalemia, vomiting (40.6% each); fatigue, headache (34.4% each); 
hypomagnesemia (37.5%); febrile neutropenia (31.3%); abdominal pain, cough, 
hypophosphatemia (28.1% each); epistaxis, hyperphosphatemia, hypocalcemia, 
malignant neoplasm progression (25.0% each); dyspnea, hypotension, peripheral 
edema, pyrexia, and pneumonia (21.9% each). Serious adverse events were reported 
in 27 subjects (84.4%), the most common being febrile neutropenia (28.1%), malignant 
neoplasm progression (25.0%), and pneumonia (15.6%). Three serious adverse events 
were considered to have a reasonable possibility of being related to venetoclax (i.e., 1 
event each of diarrhea, febrile neutropenia, and pseudomonal bacteremia). No cases of 
TLS occurred during venetoclax treatment. 
In this phase II multicenter trial single agent VEN produced an overall response in 5/32 
relapsed/refractory AML patients (CR in 1 patient, CRi in 4 patients) (46). Of the 5 
patients with CR/CRi, 3 had IDH mutations suggesting that patients with IDH mutations 
may be particularly sensitive to VEN. 
Two ongoing trials are evaluating VEN combination regimens in treatment naïve patients 
with AML who are ≥65 years of age and who are not eligible for standard induction: (a) 
to evaluate the efficacy and tolerability of the combination of VEN with a 
methyltransferase inhibitor (azacytidine or decitabine) (ClinicalTrials.gov Identifier: 
NCT02203773); (b) to evaluate VEN with low-dose cytarabine (ClinicalTrials.gov 
Identifier: NCT02287233). 
 
Overview of Ongoing Phase 1b Study (M14-358): Venetoclax in Combination with 
HMA in Treatment Naïve AML 
As of 09 March 2016, a total of 45 subjects ≥ 65 years of age with treatment naïve AML 
ineligible to receive standard induction therapy were enrolled into the escalation stage at 
3 dose levels of venetoclax at 400 mg, 800 mg, and 1200 mg. Venetoclax was 
administered daily during the 28-day cycles in combination with decitabine (20 mg/m2 
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or subcutaneously on Days 1 – 7 once every 28 days). Preliminary safety and efficacy 
data are available from the ongoing dose escalation stage of this trial.(45, 47) 
The most common adverse events for all subjects in Study M14-358 were nausea 
(53.3%), diarrhea (44.4%), febrile neutropenia (40.0%), neutrophil count decreased 
(31.1%), platelet count decreased, cough, and fatigue (28.9% each), edema peripheral 
and hypokalemia (26.7% each). Events grade 3 and above were reported for the 
majority (91.1%) of subjects; the most common event was febrile neutropenia (40.0%). 
Serious adverse events were reported for 27 (60.0%) subjects, including febrile 
neutropenia (11 subjects), malignant neoplasm progression (3 subjects) atrial fibrillation, 
abdominal pain, non-cardiac chest pain, pyrexia, pneumonia, sepsis, bone pain (2 
subjects each). All other events occurred in 1 subject each. The combination of 
venetoclax with decitabine and azacitidine demonstrates a tolerable safety profile. 
As of 09 March 2016, the ORR, as assessed by the investigators for the subjects 
enrolled into the 3 dose levels, was 62.2% (28 of 45), with CR in 12 (26.7%), CRi in 15 
(33.3%), and PR in 1 (2.2%). Four subjects (8.9%) were reported to have morphologic 
leukemia-free state (less than 5% blasts in bone marrow aspirate sample with at least 
200 nucleated cells) after completion of Cycle 1. Eight patients (17.8%) had resistant 
disease. However, all of the patients with resistant disease had evidence of blast 
reduction at completion of Cycle 1. The patients enrolled into the 1200 mg dose level 
had a shorter follow-up at the time of this analysis. 
 
The maximum tolerated dose has not been reached in either arm and dose escalation 
stage has completed enrollment. Enrollment into safety expansion at 400 mg and 800 
mg dose of venetoclax in combination with both HMAs is ongoing. 
 
Study M14-387: Study M14-387 titled, "A Phase 1/2 study of venetoclax in combination 
with low-dose cytarabine in treatment naïve subjects with acute myeloid leukemia who 
are ≥ 65 years of age and who are not eligible for standard anthracycline-based 
induction therapy," is an ongoing, open-label, multicenter safety and pharmacokinetics 
study. The primary objectives of the Phase 1 portion are to assess the safety profile, 
characterize pharmacokinetics, and determine the dose schedule, the MTD, and the 
RPTD of venetoclax in combination with low-dose cytarabine (LCD) in treatment-naïve 
AML subjects. The primary objectives of the Phase 2 portion of the study are to evaluate 
preliminary estimates of efficacy (including ORR and TTP) and to characterize the 
toxicities of the combination at RPTD. Secondary objectives of the Phase 2 portion 
include evaluating leukemia response (rates of CR, CRi, PR, RD, and HR including 
transfusion support needs) and DOR. An additional exploratory objective includes the 
evaluation of biomarkers that may serve as surrogate or predictors for clinical outcomes 
for future studies. 
Of the 25 subjects in Study M14-387, 24 (96.0%) experienced at least 1 treatment- 
emergent adverse event. The most common adverse events for all subjects in Study 
M14-387 were: nausea (54%), febrile neutropenia (41%), diarrhea (44%), decreased 
appetite (33%), and peripheral edema (31%). Adverse events leading to study drug 
discontinuation occurred in 4 (16.0%) subjects, including 1 event each of disease 
progression, acute hepatic failure, Candida pneumonia, and subdural hemorrhage. Fatal 
adverse events occurred in 5 (20.0%) subjects: 2 events of malignant neoplasm 
progression and 1 event each of acute hepatic failure, Candida pneumonia, and lung 
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For further details of venetoclax preclinical studies, clinical studies, toxicities, 
pharmacokinetics, and adverse events please see the venetoclax Investigator Brochure 
(attached). 
 
Experience with Venetoclax in combination therapy in relapsed and refractory 
myeloid malignancies 
Efficacy of venetoclax combinations in the salvage setting will be presented at ASH 
2017. Twenty-seven patients treated at our institution with relapsed/refractory AML 
(n=24), MDS (n=2) or BPDCN (n=1) received combinations including with decitabine 
(n=16) or azacitidine (n=5). Objective responses were achieved in 22% (n=6) of patients 
after a median of 1 cycle (range 1-4), including 11% with CRi and 11% with MFLS. 4 of 
the 6 responding patients received decitabine + venetoclax combinations, including 2 
patients treated on the 5-day schedule and 2 patients treated on the 10-day schedule. 
2.4 RATIONALE FOR STUDY 
 
Second generation FLT3 inhibitors such as quizartinib and gilteritinib demonstrate potent 
anti-leukemic activity and improve outcomes in patients with relapsed/refractory AML 
with FLT3-ITD mutations(22). About 40-55% of FLT3-mutated patients not previously 
exposed to FLT3-inhibitors achieved marrow responses (CRc) to the second generation 
FLT3 inhibitors quizartinib(23-25) and gilteritinib(26), with 20-30% bridged to allogeneic 
stem cell transplant. Of note, recent FDA approval of midostaurin in combination with 
7+3 induction chemotherapy in newly diagnosed FLT3-mutant AML signifies that 
essentially all relapsed FLT3-mutated AML patient will likely been exposed to at least 
one FLT3 targeting TKI. In this setting, the marrow response (CRc) rates with second 
generation FLT3 inhibitors such as crenolanib, gilteritinib and quizartinib have been 
reported to be lower than in prior FLT3 TKI naïve patients and are in the range of 20- 
25% (26, 48, 49) and Daiichi Sankyo unpublished communication). 
Although response rates are high, the responses to single agent second generation 
FLT3 inhibitors are almost invariably transient, maintained for 14-17 weeks, except 
among patients who undergo transplantation, due to the emergence of resistance(27, 
28). The causes of resistance include the acquisition of point mutations in the FLT3 KD 
(in 30-40% of resistant cases) and non-mutational mechanisms of resistance (in 50-60% 
of resistant cases) including up-regulation of compensatory pathways including the 
activation of anti-apoptotic proteins BCL2, MCL1 and BCL-x(L), PI3K/Akt/mTOR, 
FOXO3A, SYK, RAS and STAT5/PIM pathways, up-regulation of the FLT3 ligand or 
receptor, mutations in other kinases (e.g. CBL), and tumor microenvironment mediated 
resistance(31). 
MCL-1 was reported as an essential effector of FLT3-ITD-mediated drug resistance (50) 
and a number of FLT3 inhibitors down-regulate MCL1 thereby reducing the propensity to 
resistance to BCL2 inhibitors. Combination of ABT-737 and FLT3 inhibitors was 
synergistic in FLT3-ITD-mutated AML(51). 
Furthermore, our recent data shows that FLT3-ITD activation/mutations may play a 
major role in primary and secondary resistance to ABT-199 (Popovic R, Daver N et al, 
manuscript accepted to American Journal of Hematology May 2018). A phase 2 trial 
evaluated the efficacy and safety of venetoclax monotherapy in 32 patients with 


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relapsed/refractory acute myeloid leukemia (AML) or those unfit for intensive 
therapy(46). Venetoclax demonstrated activity and a tolerable safety profile in these 
patients with a CR/CRi in 6/32 (19%) of patients and biological activity defined as any 
measurable reduction in bone marrow blast counts after initiation of venetoclax therapy 
observed in 17/32 (53%) of patients. Occurrence of genetic mutations known to be 
associated with myeloid malignancies was investigated by next generation sequencing 
on blood and bone marrow specimens collected at baseline (32 patients) and relapse 
(20 patients). Eleven of 17 (65%) patients with biological activity had blasts containing 
mutations in the splicing factor genes SRSF2/ZRSR2, among them 6 patients also had 
blasts with mutations in IDH1/IDH2. Of the remaining 6 patients with biological activity, 1 
patient had an IDH2 mutation and the remaining 5 patients were wild-type for 
SRSF2/ZRSR2/IDH1/IDH2. Four of 15 patients (27%) without biological response to 
venetoclax had blasts with FLT3-ITD mutation prior to therapy. Four of the 17 patients 
(24%) with initial biological response to venetoclax acquired a new FLT3-ITD or PTPN11 
mutation at loss of response. Previous studies have shown that both these genetic 
alterations affect the expression of BCL-2 family members, suggesting that FLT3-ITD 
mutations may be responsible for primary and acquired resistance to venetoclax in AML 
patients by deregulating anti-apoptotic proteins. Furthermore, pretreatment and/or 
acquisition of FLT3 mutations correlated with decreased time on study. 
Based on our sequencing findings, we assessed the combination of venetoclax with the 
small-molecule FLT3 inhibitor quizartinib in the FLT3-ITD+ mutant xenograft model MV- 
4-11. In vitro, the MV-4-11 cells were sensitive to BCL-2 inhibition by venetoclax.3 
However, similar to our clinical observations, venetoclax did not inhibit the growth of 
these tumors when implanted in vivo. Although daily dosing of quizartinib induced tumor 
regressions in this model, the tumors eventually regrew. Strikingly, co-treatment with 
venetoclax and quizartinib induced similar tumor regressions as quizartinib alone but 
with significantly increased durability, preventing tumor re-emergence for up to 3 months 
post-cessation of treatment (Figure 1). These data suggested that combining venetoclax 
with FLT3 inhibitors such as quizartinib could be highly effective for the treatment of 
FLT3-mutated AML (and potentially in non FLT3-mutated AML as well) and may also 
prevent the emergence of FLT3-mutated, venetoclax-resistant sub-clones in patients 
who do not have an already detectable FLT3 mutation. 
Figure 1: Tumor growth inhibition by venetoclax plus quizartinib in mice 
xenografted with FLT3-ITD+ MV-4-11 cells. 


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2200  
V e h ic le  
V en eto clax ( 5 0 m g / k g , p . o . Q D x 21 ) 
Q u iz a r t in ib ( 1 0 m g / k g , p .o . Q D x 1 4 ) 
V en eto c lax ( 50 m g / kg ) + Q u iz ar t in ib ( 10 m g / kg ) 
 
2000  
 
1800  
 
1600  
 
1400  
 
1200  
 
1000  
 
800  
 
600  
 
400  
 
200  
 
0 
0 
25 
50 
75 
100 
125  
D ays sin ce in o cu la tio n 
BCL-2 over-expression has also been implicated in maintaining the survival of 
FLT3-mutated AML cells. BCL-2 inhibition pre-clinically has been shown to 
potentiate the effects of FLT3-inhibitors, especially quizartinib (see attached prelim 
data from our lab) (Figure 2). 
 
 
Figure 2: Venetoclax with FLT3-inhbiitor in cell lines 
T um or v olum e (m m 3 ) 


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Our collaborator Jeff Tyner (Drug sensitivity testing for individualized therapies in 
hematologic malignancies. Jeffrey W. Tyner, OHSU Knight Cancer Institute, Portland, 
OR. AACR major symposium, 2016) has performed functional ex vivo screening of 
primary patient samples to identify effective small molecule drug combination 
strategies based on IC50 evaluation. In his study the combination of quizartinib with 
venetoclax revealed a higher percentage of sensitive samples than to venetoclax 
alone or quizartinib alone. This was one of the most potent small molecule 
combinations of multiple evaluated TKI combinations 
3.0 STUDY DESIGN: 
 
3.1 General 
The study will be a phase Ib/II, single-institution, open label, non-randomized, 
single arm, clinical trial. All patients will be registered through CORe/PDMS. 
 
• 
Phase Ib 
o This will include FLT3-ITD mutated patients with 
relapsed/refractory AML (up to four prior therapeutic regimens for 
AML i.e. up to salvage 4 status), including patients who may have 
been previously exposed to one prior FLT3-inhibitor other than 
quizartinib. Relapsed/ refractory status defined by the failure of at 
least one prior cycle of therapy for active AML (including but not 
limited to cytotoxic chemotherapy, hypomethylator therapy, 
immune-based therapy, stem cell transplant or stem cell therapy, 


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one prior FLT3-inhibitor therapy exposure allowed, investigational 
therapy, and others). 
o The DLT assessment period will be only during Cycle 1 of the 
Phase Ib (DLT assessment period = 28 days). 
 
3.2 Study Design 
• 
The phase Ib portion is aimed at finding the MTD and RP2D of the 
two drugs in this combination. The target dose is dose level +1, 
and the starting dose will be dose level 0. The first 6 patients on 
study will receive dose level 0. 
 
• 
 The Investigator is responsible for completing the cohort 
summary template and submitting to the IND office Medical 
Monitor for review and approval prior to advancing subjects to 
the next protocol specified cohort/dose level. A copy of the cohort 
summary should be placed in the Investigator’s Regulatory 
Binder under “sponsor correspondence”. This should be submitted 
after the first six patients. 
• 
The dosing schema is shown in Table 1 below. 
Table 1: Dosing schema 
Dose level 
Quizartinib 
Venetoclax 
+1 (Target dose) 
60 mg daily 
400 mg daily 
0 (Starting dose, n=6) 
30 mg daily 
400 mg daily 
-1 
20 mg daily 
400 mg daily 
 
3.3 Dosing algorithm 
The goal of the lead-in phase Ib is to determine the MTD and 
RP2D. We will first treat 6 patients at dose level 0 in the phase 
Ib. If DLT occurs in >/=2/6 patients, this dose level would exceed 
the MTD, and 6 patients will be treated at the next lower dose 
level (i.e. dose level -1). If DLT occurs in <2/6 patients at dose 
level 0, the next cohort of 6 patients will be treated at the next 
higher dose level (i.e. dose level +1). The dose escalation or 
de-escalation (Table 1) will continue in cohorts of 6 until we 
reach the highest dose level at which <2/6 patients experience a 
DLT in the first 28 days. The highest dose level at which 0-1/6 
patients experience a DLT in the first 28 days of treatment will be 
the MTD. The RP2D will be selected from among the doses 
evaluated after reviewing the efficacy, safety, 
pharmacodynamics data. The RP2D selected may be lower than 
the MTD. The RP2D will be used to treat an additional 20 
patients in the phase II expansion portion of the study. 
If >/=2/6 patients experience DLT at dose level -1, the study may 
be revised to consider additional lower dose levels. 


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Patients that are removed from study before day 28 for any 
reason other than toxicity and have not experienced DLT will be 
replaced. 
*With up to1 potential dose escalation level (+1) to be studied and 
up to 6 patients to be treated at a given dose, the target maximum 
number of patients projected to be enrolled in the phase Ib part of 
the trial will be 12. 
 
3.4 Definition of dose-limiting toxicity (DLT) 
DLT is defined as a grade 3 or higher, clinically significant non- 
hematologic adverse event or abnormal laboratory value 
assessed as unrelated to disease progression, intercurrent illness, 
or concomitant medications and occurring during the first cycle on 
study, with the following exceptions: 
• 
Grade 3 or 4 nausea, vomiting, or diarrhea that can be managed to 
≤ grade 2 with standard antiemetic or antidiarrheal medications 
used at prescribed dose within 7 days of onset. 
• 
Electrolyte abnormalities of Grade 3 or higher which can be corrected to 
grade 2 or less within 48 hours will not be considered as DLT only if the 
abnormalities are asymptomatic and corrected by optimal replacement 
therapy within 48 hours. Symptomatic grade 3 or higher electrolyte 
abnormalities will be considered DLT even if correctable within 48 
hours. 
• 
Grade 3 or 4 biochemical abnormalities of amylase or lipase without 
evidence of clinical pancreatitis. 
• 
Grade 3 or 4 anorexia or fatigue. 
• 
Grade 3 QTc prolongation will constitute DLT as follows: The QTc 
interval will be calculated by Fridericia’s correction factor (QTcF). If 
the QTcF is > 500 msec the EKG must be evaluated within 4 hours 
in triplicate and if persistent ≥ grade 3 QTc prolongation is 
confirmed this will be considered a DLT. Note: Grade 4 QTc 
prolongation will be considered a DLT. 
• 
All other clinically significant non-hematological adverse event that 
is Grade 3 according to the NCI CTCAE version 5.0 will be DLTs. 
• 
Myelosuppression and cytopenias are expected outcomes of 
leukemia treatment and per se will not constitute DLT. Only 
prolonged myelosuppression, as defined by the NCI criteria specific 
for leukemia, i.e. marrow cellularity < 5% with grade 4 neutropenia 
or thrombocytopenia on Day 42 or later from start of therapy without 
any evidence of leukemia, will be considered in defining DLT. In 
case of a normocellular bone marrow with no evidence of leukemia, 
8 weeks with grade 4 neutropenia or thrombocytopenia will be 
considered a DLT. Anemia will not be considered for the definition 
of DLT. 
Any patients who stop treatment prior to completing evaluation for 
the DLT observation period (first 28 days) due to disease 
progression or refusal for further participation for reasons other than 


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toxicity during the DLT defining phase Ib portion of the study will be 
replaced for DLT evaluation. Patients who come off study earlier 
than 28 days during the DLT evaluation period may continue 
therapy off protocol if they are having clinical benefit, after 
discussion with the PI. The rationale for continuing therapy must be 
clearly documented in the patients chart. 
Patients must receive at least 75% of the scheduled doses of 
quizartinib and at least 75% of the scheduled doses of venetoclax, 
respectively, in any given cohort to be eligible for DLT evaluation. 
Patients who receive <75% of the scheduled dose of either 
quizartinib or venetoclax will not be eligible for DLT evaluation and 
must be replaced. However, subjects who are unable to complete 
at least 75% of the prescribed dose of venetoclax and quizartinib in 
Cycle 1 (28 days) due to clinically significant non-hematologic 
adverse event or abnormal laboratory values that meet the 
definition of DLT in section 3.4 will be considered to have a DLT. 
Such patients may continue to receive protocol therapy if they are 
having clinical benefit, after discussion with the PI. The rationale for 
continuing therapy must be clearly documented in the patient’s 
chart. 
 
3.5 Phase II expansion 
Once MTD is defined, the RP2D will be selected based on 
efficacy, safety, and pharmacodynamics data evaluation from the 
phase Ib in discussion with the PI, Co-PI, sponsor and supporting 
companies (Daiichi-Sankyo, Abbvie and Genentech). The PI is 
responsible for completing the cohort summary template prior to 
advancing subjects to the phase II portion. The phase II portion 
will have 20 patients. Any patients still on study from the phase I 
portion at a dose lower than RP2D can be dose escalated up to 
RP2D in accordance with the dose escalation guidelines in section 
5.2.3. 
However, the dose for any patient may never exceed the RP2D. 
4.0 PATIENT SELECTION 
Patients must have baseline evaluations performed prior to the first dose of study 
drug and must meet all inclusion and exclusion criteria. Results of all baseline 
evaluations, which assure that all inclusion and exclusion criteria have been 
satisfied, must be reviewed by the Principal Investigator or his/her designee prior 
to enrollment of that patient. In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent. The written 
informed consent must be obtained from the patient prior to initiating treatment or 
any study-specific procedures. The following criteria apply to all patients enrolled 
onto the study unless otherwise specified. 


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4.1 Inclusion Criteria: 
A subject will be eligible for study participation if he/she meets the following 
criteria within 14 days prior to the first day of therapy. 
 
1. FLT3-ITD mutated patients with relapsed/refractory AML (up to four prior 
therapeutic regimens for AML i.e. up to salvage 4 AML), including patients who 
may have been previously exposed to prior FLT3-inhibitor/s other than quizartinib 
(SCT or stem cell therapy for patients who previously underwent SCT/stem cell 
therapy in remission will not be considered a salvage regimen). 
 
2. Patients must be ≥18. 
 
3. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2. 
 
4. Potassium, magnesium, and calcium (normalized for albumin) levels should be 
within institutional normal limits. 
 
5. Adequate hepatic (serum direct bilirubin </= 1.5 x upper limit normal (ULN) (or 
</= 3.0 x ULN if deemed to be elevated due to leukemia), alanine 
aminotransferase and/or aspartate transaminase </= 2.5 x ULN (or </= 5.0 x ULN 
if deemed elevated due to leukemia). Note: Subjects with documented Gilbert's 
Syndrome may have a total bilirubin > 1.5 × ULN. 
 
6. Adequate renal function as demonstrated by a serum creatinine </=1.8 
 
7. Patients must provide written informed consent. 
8.  With the exception of patients with rapidly proliferative disease, the interval from 
prior treatment to time of initiation of venetoclax and quizartinib administration will 
be at least 14 days or at least 5 half-lives (whichever is shorter) for 
cytotoxic/noncytotoxic agents. Patients with rapidly proliferative disease will not 
be required to wait for a washout and can start therapy at any time. The half-life 
for the therapy in question will be based on published pharmacokinetic literature 
(abstracts, manuscripts, investigator brochure’s, or drug-administration manuals) 
and will be documented in the protocol eligibility document. The use of 
chemotherapeutic or anti-leukemic agents is not permitted during the study with 
the following exceptions: (1) intrathecal (IT) therapy for patients with controlled 
CNS leukemia at the discretion of the PI. Controlled CNS leukemia is defined by 
the absence of active clinical signs of CNS disease and no evidence of CNS 
leukemia on the most recent 2 simultaneous CSF evaluations. (2) Use of one 
dose of cytarabine (up to 2 g/m2) or hydroxyurea for patients with rapidly 
proliferative disease is allowed before the start of study therapy and on therapy. 
These medications will be recorded in the case-report form. 
9. Baseline ejection fraction by ECHO or MUGA must be ≥ 50%. 
 
10.  Women of non-childbearing potential are those who are postmenopausal greater 
than 1 year or who have had a bilateral tubal ligation or hysterectory.. 


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11.  Women of childbearing potential must agree to have a negative serum or beta 
human chorionic gonadotropin ( Beta-hCG) pregnancy test result within 7 days 
prior to the first dose of study drugs and must agree to use an effective 
contraception method during the study and for 90 days following the last dose of 
the study. Men who have partners of childbearing potential must agree to use an 
effective contraceptive method during the study and for 90 days following the last 
dose of study drug. 
4.2 Exclusion Criteria 
1. Subject has t(8;21) or inv(16) karyotype abnormalities. 
 
2. Subject has acute promyelocytic leukemia (French-American-British Class M3 
AML). 
3. Prior exposure to quizartinib at any time in the past. 
 
4. Serum potassium < 3.5 mEq/L despite supplementation, or > 5.5 mEq/L. 
Serum magnesium above or below the institutional normal limit despite 
adequate management. Serum calcium (corrected for albumin levels) 
above or below institutional normal limit despite adequate management. 
5. Patients with known allergy or hypersensitivity to quizartinib, venetoclax or any of 
their components. 
6. Subject with a known history of being HIV positive (due to potential drug-drug 
interactions between antiretroviral medications and venetoclax, as well as 
anticipated venetoclax mechanism-based lymphopenia that may potentially 
increase the risk of opportunistic infections). Note: HIV testing is not required. 
 
7. Subject has consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or Star fruit within 3 days prior to the 
initiation of study treatment. 
 
8. Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, 
metabolic, immunologic, hepatic, cardiovascular disease, or any other medical 
condition that in the opinion of the investigator and/or the PI would adversely 
affect his/her participating in this study. Patients who have had any major 
surgical procedure within 14 days of Day 1. 
9. Subject has a malabsorption syndrome or other condition that precludes enteral 
route of administration. 
10. Subject exhibits evidence of other clinically significant uncontrolled condition(s) 
including, but not limited to: 
a. Uncontrolled systemic infection requiring IV therapy (viral, bacterial or fungal). 
Infections controlled on concurrent anti-microbial agents are acceptable, and 
anti-microbial prophylaxis per institutional guidelines is acceptable. Patients with 
neutropenic fever considered infection related should be afebrile for at least 72 
hours prior to first dose. 


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11. Subject has a history of other malignancies within 1 year prior to study entry, with 
the exception of: 
a. Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of 
breast; 
b. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the 
skin; 
c. Previous malignancy confined and surgically resected (or treated with other 
modalities) with curative intent. 
d. Patients on active antineoplastic or radiation therapy for a concurrent 
malignancy, with curative or palliative intent, at the time of screening. 
Maintenance therapy, hormonal therapy, or steroid therapy for well-controlled 
malignancy is allowed. 
12.  Patients with a known positive hepatitis B or C infection by serology, with the 
exception of those with an undetectable viral load within 3 months (hepatitis B or 
C testing is not required prior to study entry). Subjects with serologic evidence of 
prior vaccination to HBV [i.e., HBs Ag-, and anti-HBs+] may participate. 
 
13. Female subjects who are pregnant or breastfeeding. 
 
14. Impaired cardiac function including any of the following: 
 
-Screening ECG with a QTc >450 msec. The QTc interval will be calculated by 
Fridericia’s correction factor (QTcF) at Screening and on Day 1 prior to the first 
dose of quizartinib. The QTcF will be derived from the average QTcF in triplicate. 
If QTcF >450 msec on Day 1, quizartinib will not be given. 
-Patients with congenital long QT syndrome 
 
-History or presence of sustained ventricular tachycardia requiring medical 
intervention within 3 months prior to starting study drug 
-Any history of clinically significant ventricular fibrillation or torsades de pointes 
 
-Known history of second or third degree heart block (may be eligible if the patient 
currently has a pacemaker) within 3 months prior to starting study drug 
-Sustained heart rate of <50/minute on screening or Day 1 ECG 
 
-Right bundle branch block + left anterior hemiblock (i.e. bifascicular block). 
Isolated RBBB will not be an exclusion criterion. 
-Complete left bundle branch block 
 
-Patients with myocardial infarction or unstable angina within 6 months prior to 
starting study drug 
 
-CHF NY Heart Association class III or IV within 3 months prior to starting study 
drug 


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-Atrial fibrillation documented within 2 weeks prior to first dose of study drug. 
 
-Patients who are actively taking CYP3A inducers. CYP3A4 inducers should be 
stopped at least 3 days prior to the first dose of quizartinib and are prohibited at 
any time on study 
 
-Patients who are actively taking a strong CYP3A inhibitors medication [see 
section 5.5.2 for the list of moderate and strong CYP3A4 inhibitors]. Strong 
CYP3A4 inhibitors should be stopped at least 3 days prior to the first dose of 
quizartinib and are prohibited anytime during study. Moderate (but not strong) 
CYP3A4 inhibitors may be used with the below dose reductions of venetoclax. 
Patients may receive weak CYP3A4 inhibitors at any time on study. The 
venetoclax and quizartinib doses do not need to be adjusted for weak CYP3A4 
inhibitors. 
 
Assigned Venetoclax Dose 
Venetoclax Dose if Co-Administered with a 
Moderate CYP3A Inhibitor/Inducer 
100mg 
50mg 
200mg 
100mg 
400mg 
200mg 
 
-Patients who require treatment with concomitant drugs that prolong QT/QTc 
interval [see section 5.5.2 for the list of strong drugs that prolong QT/QTc]. QT/QTc 
prolonging drugs should be stopped at least 3 days prior to the first dose of 
quizartinib and are prohibited at any time on study. 
 
-Known family history of congenital long QT syndrome 
 
5.0 TREATMENT PLAN: 
 
5.1 Schedule 
 
All patients will be registered through CORe. 
 
The Phase Ib dose escalation stage of the study will evaluate the safety, 
tolerability, PD and PK of venetoclax in combination with quizartinib, with 
the objectives of identifying the MTD and RP2D for each combination. 
Quizartinib will be administered orally daily continuously staring on cycle 
1 day 1. Patients will self-administer quizartinib tablets orally QD. If a 
dose is missed or vomited, the next dose should not be increased to 
account for missing a dose. The subject should take the next regular dose 
at the regularly scheduled time. Patients will receive one cycle of therapy 
every 28 days (+/- 7 days). Cycle 1 Day 1 of each cycle will be counted 
from the start of the quizartinib dosing. Quizartinib dose escalation criteria 
will be maintained as suggested in quizartinib Investigational Brochure 
(IB) as follows: 
Daver,Naval 
2020-02-25 21:44:00 
-------------------------------------------- 
Rationale: Moderate CYP3A4 inhibitors have 
been safely administered with venetoclax 
with appropriate dose reduction as per US 
label. Moderate CYP3A4 inhibitors have 
been safely administered with Quizartinib. 
Based on this we are allowing moderate 
CYP3A4 inhibitors on protocol


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1. If the target dose for the given patient in the phase IB or phase II 
portion is quizartinib 30mg the patient will start the dosing on C1D1 at 
quizartinib 30mg per day 
2. If the target dose for the given patient in the phase IB or phase II 
portion is quizartinib 60mg the patient will start the dosing on C1D1 at 
quizartinib 30mg per day and can increase to quizartinib 60mg per 
day on C1D12 only if QTcF on triplicate ECG is <450 msec on the 
Day 12 post-dose EKG 
The initiation of venetoclax will be deferred for 7 days in cycle 1 to allow 
clinical and correlative evaluation of quizartinib single agent activity, and 
to debulk tumor burden thereby reducing the risk of tumor lysis syndrome 
(TLS). The intent is to initiate venetoclax on cycle 1 day 8. Blood samples 
will be collected at pre-dose, 2 (+/- 30 minutes) , 4 (+/- 30 minutes) , 6(+/- 
30 minutes) , 8 (+/- 30 minutes) and 24 (+/- 30 minutes) hours post-dose 
on cycle 1 day 14 to measure venetoclax, quizartinib and AC886 
concentrations in patients enrolled in the dose-escalation period (n=12). 
The WBC count must be <10K prior to the initiation of venetoclax dosing. 
Note: Hydroxyurea can be used if needed during these initial 7 days to 
control WBC count, if needed. 
It is suggested that each dose of venetoclax be taken with approximately 
240 mL of water within 30 minutes after the completion of a low-fat 
breakfast. Examples of a low-fat breakfast include 2 slices of white toast 
with 1 tablespoon of low-fat margarine and 1 tablespoon of jam, and 
8 ounces/240 mL of skim milk (319 calories and 8.2 g fat) or 1 cup/30 g of 
cereal, 8 ounces/240 mL of skim milk, 1 slice of toast with jam, 
1 cup/240 mL of apple juice, and 1 cup/240 mL of coffee or tea 
(520 calories and 2 g fat). If vomiting occurs within 15 minutes after taking 
venetoclax and all expelled tablets are still intact, another dose may be 
taken. Otherwise, no replacement dose is to be taken. In cases where a 
dose of venetoclax is missed or forgotten, the patient should take the 
dose as soon as possible, ensuring that the dose is taken with food within 
8 hours after the missed dose. Otherwise, the dose should not be taken. 
Patient compliance with the assigned daily dose of venetoclax will be 
assessed by standard pill counts. Bottles containing venetoclax tablets 
will be given to patients at regular scheduled visits. Previously distributed 
bottles will be returned to the clinic and tablets counted and returned 
study drug destroyed per institutional policy. Any discrepancy will be 
resolved with the patient at each clinic visit and documented in the patient 
record. 
 
Any overdose or incorrect administration of Venetoclax and Quizartinib 
should be noted within Prometheus. Adverse events associated with an 
overdose or incorrect administration of study drug should be recorded as 
an Adverse Event within Prometheus. 
 
5.1.1.1  Cycles may be started early (but not earlier than day 21) for 
patients with active disease if judged in the best interest of 
the patient. 


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*For the phase Ib, DLT defining period is 28 days. As such, 
cycle 2 should not be started before 28 days for the patients 
being treated on the phase Ib cohort to allow for adequate 
evaluation of DLTs. 
5.1.1.2  Subsequent cycles may be delayed for recovery of toxicity 
or other medical conditions. Delays in start of subsequent 
cycles greater than 8 weeks will be acceptable only for 
patients who are deriving clinical benefit and after 
discussion with the principal investigator and the sponsor of 
potential risk/benefit ratio and complete documentation of 
the degree of clinical benefit and reason for continuation on 
this regimen. 
5.1.1.3  In instances where one drug has to be discontinued 
transiently because of safety, the administration of the other 
drug may continue as scheduled. If the drug that is held can 
resume at a later time, no doses will be made up and the 
administration will follow the originally defined schedule 
calendar according to the drug that was continued. 
 
5.1.1.4  For patients who discontinue therapy, the reason for 
treatment discontinuation will be documented. 
5.2 Dose Adjustments 
 
5.2.1  Venetoclax and quizartinib dose adjustments for drug-related 
hematological adverse events (AEs) (all dose adjustments to 
follow guidelines in section 5.2.2) 
 
Dose reduction/interruption/discontinuation decisions should be 
based on the CTCAE version 5.0 of the toxicity and the guidelines 
provided below. 
 
• Patients with acute 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 cycles and/or in the presence of residual leukemia. After 
that, treatment interruptions and dose adjustments may be 
considered according to the following guidelines only when there 
is no evidence of residual leukemia. 
 Patients with a response (no marrow evidence of 
leukemia) and pre-cycle counts of neutrophils >1.0 x 
109/L and platelets >50 x 109/L who have sustained low 
counts of neutrophils <0.5 x 109/L or a platelet count <20 
x 109/L for more than 2 consecutive weeks in the current 
cycle, are recommended to have the treatment with 


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venetoclax and/or quizartinib interrupted or dose- 
reduced by one dose level after discussing with the PI 
until neutrophils recover to ≥0.5 x109/L and platelets to 
≥20 x 109/L. If prolonged myelosuppression defined as 
ANC < 0.5 x 109/L and platelets <20 x109/L (more than 
8 weeks) with evidence of a hypocellular marrow 
(marrow cellularity less than 5% without evidence of 
leukemia) is observed in these patients, both venetoclax 
and quizartinib will be discontinued. Delays in start of 
subsequent cycles greater than 8 weeks will be 
acceptable only for patients who are deriving clinical 
benefit and after discussion with the principal 
investigator of potential risk/benefit ratio and complete 
documentation of the degree of clinical benefit and 
reason for continuation on this regimen. 
 If there are persistent peripheral blood blasts, or the 
bone marrow shows >5% blasts or evidence of leukemia 
by other assays, treatment may be continued regardless 
of neutrophil and platelet count with supportive care as 
needed. 
Dose-interruptions 
of 
venetoclax and/or 
quizartinib in these patients should be considered on an 
individual case and discussed with the PI and the 
sponsor. 
 
 Patients with a response (no marrow evidence of 
leukemia) and pre-cycle counts of neutrophils <1x109/L 
and platelets <50 x109/L may be continued regardless 
of neutrophil and platelet count with supportive care as 
needed. Dose-interruptions in these patients should be 
considered on an individual case and discussed with the 
PI. 
 
 Investigators should, whenever possible, determine 
which medication is causing the toxicity and interrupt or 
dose 
reduce 
venetoclax 
and/or 
quizartinib, 
as 
applicable. 
 
5.2.2 Venetoclax and quizartinib dose adjustments for non- 
hematologic drug-related AEs 
Investigators should, whenever possible, determine which 
medication is causing the toxicity and interrupt or dose reduce 
venetoclax and/or interrupt quizartinib, as applicable. Thus, if 
dose level +1 is established as the MTD (Table 1), one dose 
level reductions of quizartinib will be quizartinib 30 mg daily, two 
dose level reductions of quizartinib will be 20 mg daily, three 
dose reductions of quizartinib will be 15 mg daily, respectively. If 
the RP2D is lower than dose level +1 (Table 1) further dose 
reduction levels of quizartinib will be defined before moving to 
the phase II portion of the study. 


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Dose reductions of venetoclax for non-hematologic drug-related 
AEs will be as follows: assuming the starting dose = venetoclax 
400 mg daily: one dose level reduction = 200 mg daily, two dose 
level reductions= 100 mg daily, three dose level reductions = 50 
mg daily. The venetoclax dose will not be reduced beyond 50 
mg daily. Reductions in the number of days of venetoclax, i.e. 
going from 28 day continuous dosing per cycle to 21-days on/7- 
days off schedule or a 14-days on/14-days off schedule will be 
allowed if this is felt to be in the best interest of the patient only 
after discussion and approval from the PI and clearly 
documenting the reason for the change in the schedule in the 
medical records of the patient. 
During the dose escalation phase 1B dose-reductions will be 
allowed and will follow the schema outlined above. 
Table 2 Dose adjustments for non-hematologic drug-related AEs, clinically 
significant in the opinion of the investigator (all dose adjustments 
to follow guidelines in section 5.2.2) 
(The list of QTc prolonging medications is not comprehensive) 
 
Grade 
Occurrence 
Dose modification 
1 or 2 
Any time 
No dose reduction. 
3 
(Persistent 
grade 2: 
Consider 
similar dose 
adjustments 
if persistent 
and not 
responding 
to optimal 
management 
in the 
opinion of PI 
and treating 
physician) 
1st time 
Hold venetoclax and/or quizartinib. 
Resume venetoclax and/or quizartinib at prior dose if 
recovery to ≤ Grade 1 or baseline occurs within 14 
days. 
If toxicity persists for 15-28 days, hold therapy and 
resume at ONE dose level below current dose for 
venetoclax OR quizartinib OR both based on which 
medication is likely causing the toxicity ONLY after 
recovery of toxicity to ≤ Grade 2. 
Dose re-escalation to prior dose of venetoclax OR 
quizartinib OR both is permitted if tolerated and no 
recurrent Grade 3 or 4 toxicities occur over 4 weeks 
while on the lower dose level. 
2nd time 
Hold venetoclax and/or quizartinib. 
Follow until toxicity ≤ Grade 2. 
Resume at TWO dose level below current dose for 
venetoclax OR quizartinib OR both based on which 
medication is likely causing the toxicity ONLY after 
recovery of toxicity to ≤ Grade 2. 
Dose re-escalation by one dose level every 4 weeks 
of venetoclax OR quizartinib OR both is permitted if 
tolerated and no recurrent Grade 3 or 4 toxicities 
occur over the 4 weeks while on the lower dose level. 


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3rd time 
Stop venetoclax and quizartinib and discontinue 
patient. 
(For patients with clinical benefit/response from the 
combination we will consider continuation if toxicities 
resolve to ≤ grade 1 within 28 days and with proper 
dose adjustments after consultation with the PI and 
the sponsor.) 
4 
1st time 
Hold venetoclax and/or quizartinib. 
Resume venetoclax and/or quizartinib at prior dose if 
recovery to ≤ Grade 1 or baseline occurs within 14 
days. 
If toxicity persists for 15-28 days, hold therapy and 
resume at ONE dose level below current dose for 
venetoclax OR quizartinib OR both based on which 
medication is likely causing the toxicity ONLY after 
recovery of toxicity to ≤ Grade 2. 
Dose re-escalation to prior dose of venetoclax OR 
quizartinib OR both is permitted if tolerated and no 
recurrent Grade 3 or 4 toxicities occur over 4 weeks 
while on the lower dose level. 
2nd time 
Stop venetoclax and quizartinib and discontinue 
patient. 
(For patients with clinical benefit/response from the 
combination we will consider continuation if toxicities 
resolve to ≤ grade 1 within 28 days and with proper 
dose adjustments after consultation with the PI and 
the sponsor.) 
Cardiac 
Toxicity 
Grade 1 
QTc ≥ 450 and 
≤ 480 msec 
Check magnesium and potassium levels and correct 
any abnormalities. If possible, stop any medications 
that may prolong the QTc interval. Continue 
quizartinib at the same dose. 
Cardiac 
Toxicity 
Grade 2 
QTc> 480 and 
≤ 500 msec 
Check magnesium and potassium levels and correct 
any abnormalities. If possible, stop any medications 
that may prolong the QTc interval. The dose of 
quizartinib will be reduced one level without 
interruption of dosing. Following dose reduction, the 
quizartinib dose may be resumed at the previous level 
in the next cycle if the QTc has decreased to within 30 
msec of baseline or <450 msec but subject must be 
monitored closely for QT prolongation for the first 
cycle at the increased dose. Subjects who experience 
>480 msec QTc prolongation and undergo dose 
interruption and/or reduction must be monitored 
closely with ECGs, performed twice weekly for the 
first week of the QTc prolongation and then weekly 
thereafter until the QTc prolongation is resolved. 


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Cardiac 
Toxicity 
Grade 3 
QTc interval 
>500 msec (at 
least on two 
separate EKGs) 
or >60 ms 
change from 
baseline 
Check magnesium and potassium levels and correct 
any abnormalities. Interrupt quizartinib and if possible 
any medications that may prolong the QTc interval. 
Quizartinib dosing will be interrupted for up to 14 
days. If QTcF returns to within 30 msec of baseline or 
<450 msec within 14 days, quizartinib administration 
may be resumed at a reduced dose (reduce by one 
level). Subjects who experience >500 msec QTcF 
prolongation and undergo dose interruption and/or 
reduction must be monitored closely with ECGs, 
performed twice weekly for the first week of the QTcF 
prolongation and then weekly thereafter until the QTc 
prolongation is resolved. 
Cardiac 
Toxicity 
Grade 4 
, and Torsade 
de pointes or 
polymorphic 
ventricular 
tachycardia or 
signs/symptoms 
of serious 
arrhythmia (i.e., 
grade 4) 
Quizartinib dosing will be permanently discontinued 
 
• 
If the criteria to resume treatment are met, the subject should restart 
treatment at the next scheduled time point per protocol. However, 
if the treatment is delayed past the next scheduled time point per 
protocol, the next scheduled time point will be delayed until dosing 
resumes. 
• 
Patients in whom the toxicity occurs or persists beyond the planned 
completion of drug administration for the cycle will have the dose 
reductions for either venetoclax or quizartinib or both agents (based 
on attribution of the specific toxicity to venetoclax or quizartinib or 
both) implemented in subsequent cycles provided the toxicity has 
resolved as specified in Table 2 above. 
 
• 
These general guidelines constitute guidance to the Investigator 
and may be supplemented by discussions with the PI in specific 
cases. 
 
• 
Guidelines for dose adjustment for toxicities that are may be 
reasonably related to venetoclax are given below. 
 
5.2.3 
Intra-patient dose escalation 
Intra-patient dose escalation of venetoclax and quizartinib (in 
accordance with the dosing schema in Table 1) will be permitted 
provided: 


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 Patient has completed ≥1 cycle at their current dose level 
 Patient has not experienced any grade 3 or higher non- 
hematologic drug-related toxicity (including Grade 3 QTcF 
prolongation), and 
 
 Patient has not experienced hematologic DLT, and 
 
 At least 6 patients have been treated at the next higher dose 
level and followed for at least 28 days without experiencing 
DLT and this dose level has been deemed safe and does 
not exceed the RP2D. 
 
 The dose may be escalated by one dose level per cycle (per 
Table 1) provided such dose level does not exceed RP2D. 
 Dose escalation of only one of the two agents is allowed if 
judged in the best interest of the patient (e.g., in patients 
with neutropenia this would be likely secondary to 
venetoclax, in patients with QTc changes this would be likely 
secondary to quizartinib). 
 
 However, the dose of any agent cannot be escalated 
beyond the established RP2D for the combination. 
5.2.4 Modifications of dose schedules other than the above will be allowed within 
the following guidelines: 
 
5.2.4.1 Further dose reductions can be made to keep clinically significant 
toxicities grade < 2. 
5.2.4.2 Dose adjustments by more than 1 dose level at a time (e.g., from 
quizartinib 60 mg daily to 20 mg daily) can be considered when judged 
in the best interest of the patient (e.g. severe myelosuppression or other 
toxicity attributable to one of the agents) when toxicity has resolved. 
The reason for this reduction will be discussed with the PI or Co-PI and 
documented in the medical record. 
 
5.2.4.3 A patient who has had a dose reduction because of any of the reasons 
mentioned above may have their dose escalated provided the patient 
has remained free of toxicity requiring dose adjustments as defined 
above for at least 1 month. Escalation will be made by 1 dose-level 
increment only, and not more frequent than every month. 
 
5.2.4.4 Treatment interruptions and dose modifications other than the ones 
mentioned above can be considered after discussion with the PI and 
proper documentation of the rationale. Dose adjustment/delay of only 
one of the agents is permissible if the toxicity is most likely judged to be 
related to one of the agents by the investigator (e.g., in patients with 


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prolonged neutropenia this would be likely secondary to venetoclax, in 
patients with QT changes this would be likely secondary to quizartinib). 
5.3 Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment 
may continue until one of the following criteria applies: 
1. Clinically significant progressive disease, or 
 
2. Grade 4 QTc prolongation (based on average of triplicate). 
 
3. Intercurrent illness that prevents further administration of treatment, or 
 
4. Patient request, or 
 
5. General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator, or 
6. Unacceptable toxicity that in the opinion of the investigator makes it unsafe 
to continue therapy. This includes patients with grade 4 non-hematological 
toxicity unless it reverses to grade ≤ 1 on or before 8 weeks of interrupting 
quizartinib and/or venetoclax. 
5.3.1 
 It is planned that up to a total of 24 cycles of therapy will be 
administered for patients deriving benefit from this regimen. 
Continuation of therapy for patients completing 24 cycles of 
therapy may be considered on a case-by-case basis after 
discussion with the principal investigator. 
5.3.2.  All patients receiving at least one dose of either of the two drugs 
will be considered evaluable for toxicity. 
 
5.4 Drug administration 
5.4.1 Venetoclax administration 
a. Dosage Form 
Venetoclax (GDC-0199/ABT-0199) is manufactured by AbbVie, 
Inc. and will be supplied by Abbvie as oral film-coated tablets of 
10-mg, 50-mg, and 100-mg strength. Venetoclax tablets will be 
packaged in high-density polyethylene (PE) plastic bottles to 
accommodate the study design. 
 
Venetoclax is an investigational agent supplied to investigators of 
this study by Abbvie Inc at no cost. 
Each bottle of venetoclax tablets will be labelled in accordance 
with current International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP), FDA and specific national 
requirements. 


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Sites must request study drug by submitting an order form directly 
to the drug depot in order for the study drug to be shipped to the 
site pharmacy. The Investigator (or designee) will verify and 
acknowledge receipt of all study drug shipments by signing and 
returning all required forms. 
The Investigational medicinal product should not be used for any 
purpose outside the scope of this protocol, nor can Investigational 
medicinal product be transferred or licensed to any party not 
participating in the clinical study. Venetoclax’s data for 
Investigational medicinal product are confidential and proprietary 
and shall be maintained as such by the Investigators. 
 
b. Drug Storage 
Venetoclax must be stored at 15°C − 25°C (59°F − 77°F) in a 
locked and secured area with restricted access. The tablets should 
not be stored at freezer temperatures or allowed to freeze. All 
medication must be stored in a secure area under the proper 
storage requirements with access restricted to the site staff 
pharmacist or designee(s). 
c. Accountability and Destruction of Investigational Medicinal 
Product 
The Principal Investigator (or an authorized designee) at each 
participating institution must maintain a careful record of the 
inventory of the Investigational medicinal product received using 
the Drug Accountability Form. The study drug will be destroyed as 
per the institutions destruction policies and documentation of 
study drug destruction will be provided to Abbvie Inc. Both used 
and unused study drug may be returned to Abbvie Inc if 
requested. 
For information on the formulation and handling of venetoclax, see 
the Venetoclax IB. 
5.4.2 Quizartinib administration 
a. Description 
The chemical name of the investigational product, quizartinib, is N- 
(5-tert-Butyl-isoxazol-3-yl)-N′-[4-[7-(2-morpholin-4-yl- 
ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl] 
urea 
dihydrochloride salt. 
Quizartinib is supplied as tablets each containing 15 mg, 20 mg or 
30 mg quizartinib. The tablets also contain microcrystalline 
cellulose, magnesium stearate, and Opadry® II 85F18422 white 
film coating. They are packaged in high density polyethylene 
bottles, each containing 30 tablets, with child-resistant caps. 
 
 
c. Potential Indications and Usage 


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Quizartinib + Chemotherapy: Ongoing Clinical Trial 
(ClinicalTrials.gov 10/26/17) 
 
 
ID 
Setting 
Phase 
Clinical Trials 
Identifier 
AC220-A- 
U302 
Frontline 
Phase 
3 
Quizartinib + standard chemotherapy (Quantum- 
First) 
NCT02668653 
AC220-A- 
J102 
Frontline 
Phase 
1 
Quizartinib + 7 + 3 (in Japan) 
NCT02834390 
2012-1047 
Both 
Phase 
1/2 
Quizartinib + LDAC or AZA 
NCT01892371 
AML005 
Both 
Phase 
2 
Quizartinib and Omacetaxine 
NCT03135054 
AC220-007 
Relapsed Phase 
3 
Quizartinib versus LDAC, or MEC or FLAG-IDA 
(Quantum-R) 
NCT02039726 
 
d. Dosing 
Each patient will receive or be instructed to take quizartinib oral 
tablets at the assigned dose once a day on in the morning for 28 
consecutive days as 1 cycle of treatment. 
e. Selection and Timing of Dose 
Each treatment cycle consists of 28 consecutive days. Quizartinib 
will be taken orally once a day in the morning. 
f. Packaging and Labeling 
Please refer to the Investigational Brochure for packaging and 
labeling information. 
 
 
5.4.3 Disposition of unused drug 
All unused drug will be disposed of per institutional guidelines and procedures. 
5.5 Concomitant medication 
 
5.5.1  In general, the use of any concomitant medication/therapies 
deemed necessary for patient supportive care and safety are 
permitted. Since the effect of both venetoclax and quizartinib may 
be delayed for up to 4 weeks, patients with high WBC counts may 
receive hydroxyurea and up to 1 dose of cytarabine (up to 2 g/m2) 
prior to study entry, and while on therapy. Hydroxyurea and 
cytarabine use would be recorded in the CRF. Concurrent therapy 
for CNS prophylaxis or continuation of therapy for controlled CNS 
disease is permitted as defined in inclusion criteria. With the 
exception of these agents, concomitant systemic chemotherapy is 
not permitted. 
 
5.5.2  Concomitant medications are recommended as prophylaxis for 
nausea, vomiting, and infections, and are allowed for managing 
myelosuppression as shown in Table 3. 


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The administration of drugs known to prolong QTc interval is strictly 
prohibited on this protocol. QT/QTc prolonging drugs should be 
stopped at least 3 days prior to the first dose of quizartinib and are 
prohibited at any time on study. 
See Section 5.2.2 (Table 2) for guidelines on monitoring and 
managing QTc prolongation. 
 
Category 
Drug Name 
QT prolonging drugs 
with a known risk to 
induce Torsades de 
Pointes (TdP) 
amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, bepridil, 
chloroquine, chlorpromazine, cilostazol, ciprofloxacin, cisaprideC, citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidoneI, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
gatifloxacin, grepafloxacin, halofantrine, haloperidol, ibogaine, ibutilide, 
levofloxacin, levomepromazineI, levomethadyl, levosulpiride, mesoridazine, 
methadone, moxifloxacin, ondansetron, oxaliplatin, papaverine HCl, 
pentamidine,pimozide, probucol, procainamide, quinidine, roxithromycin, sev 
ofluran, sotalol, sparfloxacin, sulpiride, terfenadine, 
thioridazine, vandetanib 
 
Propofol is allowed on this study. 
 
Strong CYP3A4 inhibitors should be stopped at least 3 days prior to 
the first dose of quizartinib and are prohibited anytime during the 
study. Moderate (but not strong) CYP3A4 inhibitors may be used 
with the below dose reductions of venetoclax. Patients may receive 
weak CYP3A4 inhibitors at any time on study. The venetoclax and 
quizartinib doses do not need to be adjusted for weak CYP3A4 
inhibitors. 
 
Assigned Venetoclax Dose 
Venetoclax Dose if Co-Administered with a 
Moderate CYP3A Inhibitor/Inducer 
100mg 
50mg 
200mg 
100mg 
400mg 
200mg 
Strong CYP3A inducers – avasimibe, carbamazepine (Tegretol®), 
enzalutamine, mitotane, phenytoin (Dilantin®), rifampin (Rifadin®), 
St. john's wort 
 
Moderate CYP3A inducers – bosentan, efavirenz, etravirine, 
modafinil, nafcillin 
Strong CYP3A inhibitors – Boceprevir, clarithromycin, cobicistat, 
conivaptan, danoprevir/ritonavir, elvitegravir/ritonavir, idelalisib,* 
indinavir, itraconazole, ketoconazole, mibefradil, lopinavir/ritonavir, 
nefazodone, nelfinavir, paritaprevir/ritonavir combinations, ritonavir, 
Daver,Naval 
2020-02-25 21:42:00 
-------------------------------------------- 
Rationale: Moderate CYP3A4 inhibitors have 
been safely administered with venetoclax 
with appropriate dose reduction as per US 
label. Moderate CYP3A4 inhibitors have 
been safely administered with Quizartinib. 
Based on this we are allowing moderate 
CYP3A4 inhibitors on protocol


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posaconazole, saquinavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycin, voriconazole 
Moderate CYP3A inhibitors – Amprenavir, aprepitant, atazanavir, 
cimetidine, ciprofloxacin, 
clotrimazole, crizotinib,* cyclosporine,* darunavir/ritonavir, 
diltiazem†, dronedarone, erythromycin, fluconazole, fluvoxamine, 
fosamprenavir, imatinib,* isavuconazole, tofisopam, verapamil 
* These are anticancer agents; excluded on study as per protocol. 
† Moderate CYP3A inhibitor per venetoclax FDA USPI. 
 
Note: This is not an exhaustive list. For an updated list, see the 
following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Developm 
entResources/DrugInteractionsLabeling/ucm093664.htm 
 
Table 3: Instructions for the use of concomitant medications and therapies 
Category of Use 
Medication 
Comment on Use 
Restriction on Use 
Recommended 
Prophylactic 
antibiotics, 
antifungal agents, 
and antiviral agents 
Strongly 
encouraged 
None 
Antiemetic agents 
According to 
standard of care at 
MDACC 
None 
Allowed 
Oral allopurinol or 
rasburicase 
At investigators 
discretion 
None 
Leukapheresis 
According to 
standard of care at 
MDACC 
Before induction 1 
day 1 only 
Red blood cell 
transfusion 
None 
None 
Platelet transfusion 
None 
None 
White blood cell 
transfusion 
At investigators 
discretion 
according to 
standard of care at 
MDACC 
None 
Myeloid growth 
factors or 
At investigators 
discretion 
according to 
standard of care at 
MDACC 
None 


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At investigators 
None 
discretion 
according to 
standard of care at 
MDACC 
Any other 
At investigators 
None 
medication for 
discretion 
supportive care 
according to 
standard of care at 
MDACC 
 
5.5.3 Use of Blood Products 
During the administration of venetoclax, patients may receive red blood 
cell (RBC) or platelet transfusions, if clinically indicated, per institutional 
guidelines. 
Myelosuppression is expected in patients with AML due to underlying 
disease, as well as due to therapies (such as venetoclax and sorafenib), 
or both. Most patients have neutropenia, thrombocytopenia, or both at 
study entry. Significant or life-threatening myelosuppression may be 
managed with growth factor support including G-CSF, GM-CSF and 
erythropoietin/darbepoetin/blood transfusion according to institutional 
standard of care, American Society of Clinical Oncology (ASCO) 
Practice Guidelines, and/or NCCN Practice Guidelines. 
5.5.4 Tumor Lysis Prophylaxis 
There is a potential for TLS in patients treated with venetoclax, 
especially in those with elevated pretreatment LDH levels, elevated 
leukocyte count, renal dysfunction, and dehydration. To mitigate the 
potential risk of TLS, patients will be required to have WBC count <10K 
prior to initiating venetoclax on C1D8 and will receive TLS prophylaxis 
prior to venetoclax initiation on C1D8 and prior to venetoclax dose 
escalation. Patients will be hospitalized on Day -1 (C1D7) of venetoclax 
through at least 24 hours post target cohort dose. Thus it is projected 
that if WBC is <10K on C1D7, patients will be hospitalized C1D7 (day -1 
venetoclax) through C1D12 (24 hours post venetoclax dose escalation 
completed). 
Venetoclax will be administered at a dose of 50 mg on day 8, 100 mg on 
day 9, 200 mg on day 10, and 400mg on days 11-28 of the first cycle. All 
subsequent cycles, Venetoclax will begin on Day 1. For toxicities that 
could be attributed to either drug, Venetoclax or Quizartinib or both could 
be held or modified, based on perceived contribution (as per treating 
physician, in discussion with PI) of respective drug to the toxicity. This 
schedule may need to be adjusted if we see any signs of TLS. If this 
occurs it should be discussed with the PI and the new schedule 
documented in the patients chart. 
To mitigate the risk for TLS, subjects must be receiving tumor lysis 
prophylaxis, including hydration (oral, intravenous) and treatment with a 


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uric acid reducing agent (allopurinol, rasburicase) at least 24 hours prior 
to the first dose of venetoclax and during the venetoclax ramp up period 
of Cycle 1. 
TLS chemistry tests (potassium, uric acid, creatinine, calcium and 
phosphorus) will be obtained prior to dosing and 6-8 hours after each 
day of a new venetoclax dose. TLS chemistry test results will be 
reviewed by the investigator in real time and prior to the subject’s next 
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. 
5.5.5 Prohibited Food 
Use of the following foods is prohibited during the study and for at least 7 
days prior to initiation of study treatment: 
Grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or starfruit within 3 days prior to the initiation 
of study treatment 
Patients who consume any of these foods will be discontinued from 
study treatment and followed for safety outcomes for 4 weeks after the 
last dose of study treatment or until initiation of another subsequent anti- 
cancer therapy, whichever comes first. 
5.5.6 P-glycoprotein substrates 
There is a narrow therapeutic index for interactions between venetoclax 
and P-glycoprotein substrates. A list of p-glycoprotein substrates is 
provided via link below. Patients who are taking a p-glycoprotein 
substrate and venetoclax should take the p-glycoprotein substrate 6 
hours before the venetoclax. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentR 
esources/DrugInteractionsLabeling/ucm080499.htm 
 
Note: Every effort will be made to adhere to the quizartinib and 
venetoclax dose reduction. Variations in schedule of events such as 
late/missed interventions that do not affect the rights and safety of the 
patient will not be considered as deviations. 
 
5.5.7 DRUG DRUG INTERACTION ASSESSMENT 
Both quizartinib and venetoclax are CYP3A and Pgp substrates. Both 
quizartinib and ventoclax are Pgp inhibitors, and the latter also inhibits 
BCRP. Therefore, the potential for a two way drug drug interaction will 
be assessed in a substudy of the first 12 subjects enrolled in the Phase 
1b. Specifically this substudy will assess the effect of venetoclax on 
quizartinib PK (i.e. Cmax and AUC0-24h) and the effect of quizartinib on 
venetoclax PK (i.e. Cmax and AUC0-24h) as summarized in section 5.1. 


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6.0 CORRELATIVE/SPECIAL STUDIES (Optional) 
Biomarker assessments may include: 
6.1 81-gene 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 81-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 28-gene panel will be performed on the screening BM aspirate and 
the progression BM aspirate. 
6.2 Minimal Residual Disease assessment by flow-cytometry 
As a standard of care all BM aspirates including but not limited to the screening 
BM, end of cycle 1 BM, end of cycle 3 BM, will be evaluated for MRD by 
validated 17-color multiplanar flow-cytometry at MDACC. 
6.3 Gene expression signatures by RNA sequencing and/or RT-PCR 
This will be performed on the pretreatment BM aspirate and when available, the 
progression/relapse BM aspirate. 
6.4 Cytof analysis 
We will analyze BCL-2 family expression, stem cell surface markers and 
intracellular signaling markers in AML cells by CyTOF (mass cytometry) assay 
established in Dr Konopleva’s laboratory. This will be done on mononuclear cells 
obtained from BM aspirate and when available from PB at all time points 
specified in 7.1.8 and 7.2.9. 
 
6.5 Immune assays 
To analyze immune modulation including alterations in total and percent of CD3+ 
T-cells, total and percent of various T-cell subsets (Cd4-effector, CD4-regs, CD8 
cytotoxic T-cells), and total and percent of T-cell/T-cell subsets expressing 
specific checkpoint receptors/ligands with single-agent quizartinib and with the 
combination. This will be done on peripheral blood and BM aspirate at all time 
points specified in 7.1.8 and 7.2.9. 
 
6.6 BH3 profiling of BCL-2 family member dependency 
BH3 profiling will be performed on PB samples at pre-treatment, pre venetoclax 
dose 1 (cycle 1 day 7), and at progression. 
 
6.7 Single Cell Genotyping 
To precisely monitor mutant clones and address clonal heterogeneity on a single 
cell level, we will utilize a high-throughput single-cell genomics platform for 
targeted sequencing, in collaboration with Catherine Smith (UCSF) on PB at all 
time-points in 7.1.8 and 7.2.9 
7.0 PATIENT EVALUATION 


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Every effort will be made to adhere to the schedule of events and all protocol 
requirements. Variations in schedule of events and other protocol requirements 
that do not affect the rights and safety of the patient will not be considered as 
deviations. Such variations may include laboratory assessments completed 
outside of schedule, occasional missed required research samples such 
correlative assays. 
7.1 Pre-Treatment Evaluation 
 
All pretreatment studies should be obtained within 14 days from time of first 
dose of the study drug administration, unless otherwise specified: 
 
7.1.1 A complete history and physical, concomitant medications and 
performance status. 
7.1.2 CBC, platelet count, hemoglobin, differential (differential can be 
omitted if WBC is ≤0.5 x109/L). 
 
7.1.3 Creatinine, total bilirubin, ALT, potassium, magnesium, calcium, 
sodium, chloride, CO2 (HCO3), uric acid, phosphorus, and BUN. 
7.1.4 Serum or urine pregnancy test in females of childbearing potential, 
should be performed within 72 hours before the initiation of therapy. 
7.1.5 Bone marrow aspirate with or without biopsy within the last 21 days 
preceding study initiation. 
 
7.1.6 Evaluation of FLT3, NPM1, IDH1 & 2 should have been done within 
60 days preceding study initiation. 
7.1.7 12-lead EKG (in triplicate) and ECHO and/or MUGA. 
 
7.1.8 Pretreatment optional correlative studies (see section 6.0) 
Peripheral blood (up to 40 cc) – (1) Cytof and gene expression 
signatures by RNA sequencing and/or RT-PCR, (2) BH3 profiling, (3) 
immune panel in the blood prior to first dose of quizartinib at baseline 
(Cycle 1 Day 1) 
 
• 
Bone marrow samples (up to 15 cc): (1) Mutation analysis of leukemia 
associated genes by deep sequencing; (2) Cytof (3) immune panel 
prior to first dose of quizartinib at baseline (Cycle 1 Day 1) 
 
7.2 Evaluation During Treatment 
7.2.1 During Cycle 1 Day 7-12 patients will be admitted to the inpatient 
service and have labs done at least daily to monitor closely for TLS, 
proliferative disease, and electrolyte changes. Patient can be treated 
as an outpatient if WBC <10,000 with approval from the PI. 


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7.2.2 Physical exam on day 1 of each cycle (± 1 days) for the first 4 cycles. 
 
7.2.3 CBC, platelet count, hemoglobin, differential at least twice weekly for 
the first 3 cycles, then at least once a week (differential can be 
omitted if WBC is ≤0.5 x109/L). Outside labs may be used, but the 
PI/Treating physician must review all protocol specific outside lab 
results and determine the clinical significance of abnormal values then 
sign/date the results or dictate this process in the medical record. 
 
7.2.4 Creatinine, total bilirubin, ALT, K, Mg, Ca, sodium, chloride, and CO2 
(HCO3) on day 1 prior to start of quizartinib, at least twice weekly for 
the first 3 cycles, then at least once a week. For initial labs and initial 
management of electrolyte imbalances and prevention of tumor lysis 
syndrome patients will be admitted and monitored inpatient for cycle 1 
Days 7-12 (section 5.5.4). 
 
7.2.5 Laboratory tests can be ordered more frequently if mandated by 
development of peripheral blast/blood counts or electrolyte/liver 
function test abnormalities. 
7.2.6 Bone marrow aspiration for differential and PCR for FLT3 on day 28 
(±7 days) of cycle 1, day 28 of cycle 3 (±7 days), then every 2 cycles. 
Bone marrow tests can be ordered more frequently if mandated by 
development of peripheral blood counts. No repeat bone marrow is 
necessary if nonresponse or progressive disease can be 
unequivocally diagnosed from peripheral blood tests or, in patients 
with a WBC < 0.3 if the bone marrow test is considered 
noncontributory by the investigator at any time point. 
 
7.2.7 Concomitant medication data will not be collected or entered into the 
case report form (Prometheus is the case report form for this study). 
Concomitant medication data will not be collected or entered into the 
case report form except for concomitant hydroxyurea if administered 
during the first cycle; however, the subject’s medication record will 
contain a list of concomitant medications. 
 
7.2.8 EKG will be performed on day 1, day 5, day 8, and day 12 of the first 
cycle (all ±2 days) Day 1 and day 8 ECG are collected pre-dose; day 
5 are collected pre-dose and 4 hrs (+/- 2 hrs) post-dose; day 12 are 
collected 4 hrs (+/- 2 hrs) post-dose. Then ECG to be done on day 1 
of each cycle for cycles 2, 3, 4 and 5 before initiation of quizartinib 
and 4 hr (+/-2 hrs) post dose, then pre-dose every 2 subsequent 
cycles. EKG may be omitted if patient has not received study drug 
(quizartinib) in the 48 hrs preceding the time when EKG is done. EKG 
at screening and for the first 3 cycles will be done in triplicate. 
Subjects should rest in the supine position or semi-recumbent, 
with the same position used for an individual subject for the 
duration of the study, for at least 5 minutes before each 12-lead 
ECG recording is started. The ECGs should be reviewed, signed, 


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and dated by a qualified physician (or qualified physician’s 
assistant or nurse practitioner) and any clinically important 
finding recorded on the appropriate eCRF. The results will 
include heart rate, PR interval, QRS interval, QT interval, and 
QTcF interval. QTcF is calculated using the formula, (QT)/3√ 
(RR). All screening and on study ECGs should be obtained in 
triplicate (10 seconds for each ECG over the 5-minute period). 
A. On patients who increase the dose of Quizartinib or start 
therapy with a drug that is a moderate CYP3A4 inhibitor, 
an EKG will be required 24 hrs (±6 hrs), 7 days (±2 days) 
and 14 days (±2 days) after the dose increase or after the 
start of the moderate CYP3A4 inhibitor. 
 
B. Patients who had their dose reduced because of QTc 
prolongation and have their dose re-escalated as 
described in section 5.2.3 will have an EKG repeated 24 
hrs (±6 hrs) and 7 days (± 2 days) after re-escalation. 
C. The QTc interval will be calculated by Fridericia’s 
correction factor (QTcF). The 12–lead EKG evaluation will 
consist of 3 separate EKGs obtained at least 5 minutes 
apart. 
7.2.9 Peripheral blood (up to 40 cc each time) and bone marrow (up to 15 
cc each time) for pharmacodynamic studies (Optional) as defined in 
section 6.0 on 
 
Peripheral blood: 
• 
Prior to first dose of quizartinib at baseline (Cycle 1 Day 1). 
• 
Cycle 1 Day 8: prior to the first dose of venetoclax 
• 
Cycle 1 Day 15: prior to the dose of quizartinib and venetoclax 
(steady state) 
• 
Cycle 1 Day 28 (+/- 4 days): prior to the dose of quizartinib 
and venetoclax 
• 
At progression/relapse (if sample available) 
Bone marrow samples: 
• 
At screening (within 14 days preceding study initiation) as per 
section 7.1.8 – This BM will be done after the patient is 
consented to the study 
• 
Cycle 1 day 8 (prior to the first dose of venetoclax) 
• 
At the time of disease assessment on day 28 (+/- 4 days) 
• 
At response assessment pre-cycle 4 (EOC 3) 
• 
At progression/relapse (if sample available) 
 
• 
Missed samples or cycles outside the provided time windows 
for correlative studies and/or for PK analysis will not constitute 


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protocol deviations. These studies are optional on this 
protocol. 
7.2.10 All treatment prescriptions for quizartinib and venetoclax must be 
written by the patient’s attending physician at MDACC or the PI of 
the study. We do not intend for the subjects to receive prescriptions 
for quizartinib or venetoclax at an outside physician’s office. During 
the first cycle all the protocol required laboratory evaluations will be 
done at MDACC. Subsequently, the patient may have the laboratory 
work done at a local clinic and the results reported to the research 
nurse for the study. The laboratory work done at the local clinic will 
be forwarded to the patient’s attending physician at MDACC or PI of 
the study, who will sign off on the labs to verify that the results have 
been reviewed. 
 
Outside Physician Participation During Treatment 
 
1. MDACC Physician communications with the outside physician 
is required prior to the patient returning to the local physician. 
This will be documented in the patient record. 
2. A letter to the local physician outlining the patient's participation 
in a clinical trial will request local physician agreement to 
supervise the patient's care. 
 
3. Protocol required evaluations outside MDACC will be 
documented by telephone, fax or e-mail. The PI/treating physician 
must review the labs, determine clinical significance and sign and 
date the report. 
4. A copy of the informed consent, protocol abstract, treatment 
schema and evaluation during treatment will be provided to the 
local physician. 
5. Documentation to be provided by the local physician will include 
progress notes, reports of protocol required laboratory and 
diagnostic studies and documentation of any hospitalizations. 
 
6. The home physician will be requested to report to the MDACC 
physician investigator all life threatening events within 24 hours of 
documented occurrence. 
 
7. All follow-up visits that correspond with drug dispensation will be 
performed at MDACC. 
8. 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. 


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7.2.11 For patients that remain on study with no significant toxicity for 
more than 6 months, subsequent evaluations during study may be 
modified after discussion with the PI. These include a decrease in 
frequency of bone marrow aspirations to every 6-12 months (or as 
clinically indicated) and other laboratory tests to once every cycle. 
7.2.12 Pregnancy test (urine or serum) in females of childbearing 
potential every 3 months (±2 weeks). 
 
7.2.13 Patients will be followed for survival at MD Anderson Cancer 
Center (MDACC) every 3 to 6 months after the end of treatment 
visit for up to 5 years after completion of active treatment. If the 
patient is unable to return to MDACC the follow-up visits may be 
conducted via telephone. 
 
8.0 CRITERIA FOR RESPONSE 
Response criteria will be modified from the International Working Group for AML(52). 
Responders are patients who obtain a Composite Complete Remission Rate (CRc) with 
or without cytogenetic response, hematologic improvements, and morphologic leukemia- 
free state. CRc rate is defined as the confirmed remission rate of all complete and 
incomplete CRs (i.e., CR+ CRp + CRi). 
 
8.1 Complete Remission (CR) 
For patients to be classified as being in CR, they must have bone marrow 
regenerating normal hematopoietic cells and achieve a morphologic leukemia-free 
state and must have an ANC > 1 × 109/L and platelet count ≥ 100 × 109/L, and 
normal marrow differential with < 5% blasts, and patients will be red blood cell (RBC) 
and platelet transfusion independent (defined as 4 weeks without RBC transfusion 
and 1 week without platelet transfusion). There should be no evidence of 
extramedullary leukemia. 
 
8.2 Complete Remission with Incomplete Platelet Recovery (CRp) 
For patients to be classified as being in CRp, they must achieve CR except for 
incomplete platelet recovery (< 100 × 109/L). 
 
8.3 Complete Remission with Incomplete Hematological Recovery (CRi) 
For patients to be classified as being in CRi, they must fulfill the criteria for CR 
except for incomplete hematological recovery with residual neutropenia (ANC ≤ 1 × 
109/L) with or without thrombocytopenia (platelet count < 100 × 109/L). In addition, 
patients do not need to be RBC or platelet transfusion independent (modification to 
Cheson criteria). 
 
8.4 Partial Remission (PR) 
For patients to be classified as being in PR, they must have bone marrow 
regenerating normal hematopoietic cells with evidence of peripheral recovery with no 
(or only a few regenerating) circulating blasts and with a decrease of at least 50% in 
the percentage of blasts in the bone marrow aspirate with the total marrow blasts 
between 5% and 25% and meet the criteria for CR. 
 
8.5 Morphologic leukemia-free state: 


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8.6 Hematologic Improvement (HI): Hematologic response must be described by 
the number of positively affected cell lines. 
 
♦ Erythroid response (E) (pretreatment Hgb <11 g/dL) 
Hgb increase by 1.5 g/dL 
 
♦ Platelet response (P) (pretreatment platelets <100 x109/L) 
Absolute increase of 30 x 109/L for patients starting with > 20 x 109/L platelets 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100% 
♦ Neutrophil response (N) (pretreatment ANC <1.0 x109/L) 
At least 100% increase and an absolute increase > 0.5 x 109/L 
♦ Blast response (B) 
≥50% reduction in bone marrow blasts but still >5% 
 
8.7 Recurrence of Disease 
Relapse after CR is defined as a reappearance of leukemic blasts in the peripheral 
blood or ≥ 5% blasts in the bone marrow aspirate not attributable to any other cause 
or reappearance or new appearance of extramedullary leukemia. Relapse after PR is 
similarly defined with reappearance of significant numbers of peripheral blasts and 
an increase in the percentage of blasts in the bone marrow aspirate to > 25% not 
attributable to any other cause or reappearance or new appearance 
of extramedullary leukemia. 
 
8.8 Best Response measurement 
Response will be measured and defined for primary endpoints as the best response 
achieved during the first 3 cycles of therapy, or at time off study, for those patients 
discontinuing treatment before the completion of 3 cycles of therapy. Best response 
is defined to be the best-measured response (CRc=CR+CRp+CRi, PR, or marrow 
clearance) post-treatment up to that time. Best response will also be evaluated for 
the full treatment period using all assessments up to and including treatment 
discontinuation. 
 
9 .0 DISCONTINUATION OF TREATMENT: 
9.1 Discontinuation Criteria for Individual Patients 
 
9.1.1 Patient Withdrawal 
Patients may voluntarily withdraw consent to participate in the clinical study at any 
time and without giving any reason. Their withdrawal will not jeopardize their 
relationship with their healthcare providers or affect their future care. Patients may 
also choose to withdraw from study treatment, but agree to remain in the study for 
follow-up procedures. 
9.1.2 Investigator Discontinuation of Patient 


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The investigator may exercise medical judgment to discontinue study treatment if 
clinically significant changes in clinical status or laboratory values are noted. 
9.1.3 Criteria for Protocol-Defined Required Discontinuation of Treatment 
The protocol requires discontinuation of study treatment for the following reasons: 
1. Patient requests discontinuation. 
2. Unacceptable toxicity that in the opinion of the investigator makes it unsafe to 
continue therapy. 
3. Clinically significant progressive disease. 
4. Investigator discretion. 
 
9.1.4 Follow-Up at Treatment Discontinuation or Early Withdrawal 
Patients who discontinue treatment for any reason should complete end-of-treatment 
procedures when possible. End of treatment procedures will include a physical 
examination, CBC with differential and platelets and a limited chemistry profile (total 
bilirubin, serum creatinine, SGPT or SGOT). A bone marrow aspiration may be 
recommended only if non-response or progressive disease cannot be unequivocally 
diagnosed from peripheral blood. Although treatment will be discontinued at that 
time, all patients who do not withdraw consent for follow-up, die, or become lost to 
follow-up, will remain on study for follow-up evaluations. Subject will be followed for 
toxicity for at least 30 days after the last protocol treatment. The 30-day (+/-7 days) 
follow-up visit will be scheduled as a clinic visits for clinical evaluation and physical 
examinations. If the patient cannot make it to the MDACC clinic for this visit, the 
required follow up treatment procedures may be done with a local physician and the 
records forwarded to MDACC. The research nurse will contact the patient by 
telephone and get a verbal assessment of the patient’s condition. The phone 
conversation will then be documented in the patient’s charts. 
9.2 Study Stopping Rules 
The principal investigator, the MDACC IND office (Sponsor) and the supporting 
companies (Daiichi-Sankyo and Abbvie) have the right to terminate this clinical study 
at any time. The principal investigator and MDACC IND office, as appropriate, will be 
involved in any decisions regarding terminating the study, temporarily suspending 
enrollment, or stopping ongoing treatment with study treatment. 
Reasons for terminating the clinical study or a study site’s participation include, but 
are not limited to, the following: 
• 
The incidence or severity of an adverse reaction related to treatment in this study 
or other studies indicates a potential health hazard to patients 
• 
Data recording is significantly inaccurate or incomplete 
• 
Study site personnel are noncompliant with study procedures 
• 
Pattern of noncompliance is observed 
9.3 Protocol Violations and Deviations 
Protocol violations are defined as significant departures from protocol-required 
processes or procedures that affect patient safety or benefit potential, or confound 
assessments of safety or clinical activity. A protocol deviation is a departure from the 
protocol that does not meet the above criteria. Protocol violations or deviations may 
be grouped into the following classes: 
• 
Enrollment criteria 


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• 
Study activities (missed evaluations or visits) except for those allowed per 
protocol 
• 
Noncompliance with dose or schedule, including dose calculation, administration, 
interruption, reduction, or delay; or discontinuation criteria 
• 
Investigational product handling, including storage and accountability 
• 
Informed consent and ethical issues 
10.0 ADVERSE EVENT REPORTING 
 
10.1 
 Adverse event is any untoward medical occurrence that may present during 
treatment with a pharmaceutical product but which does not necessarily have a 
causal relationship with this treatment. 
 
Adverse drug reaction is a response to a drug which is noxious and unintended 
and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for the modification of physiologic function. 
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 providing source 
documentation and assigning attribution for all AEs. 
10.2 
 Adverse Events (AEs) will be evaluated against the most current version of the 
venetoclax and quizartinib IBs for expectedness. Adverse Events (AEs) will be 
evaluated according to the latest CTCAE version 5.0 and documented in 
medical record. AEs will be recorded in the Case Report Form (CRF). The 
Leukemia-specific Adverse Event Recording and Reporting Guidelines (Appendix 
G) will be used for reporting. 
 
10.3 
 Abnormal hematologic values will not be recorded on the case report form. 
For abnormal chemical values, the apogee or nadir (whichever is 
appropriate) will be reported per course on the case report form, unless the 
event is considered a DLT as listed in section 3.4. 
10.4 
Serious Adverse Event Reporting (SAE) 
An adverse event (AE) or suspected adverse event 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 might have caused death if it had 
occurred in a more severe form. 


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• Inpatient hospitalization or prolongation of existing hospitalization, not 
to include planned hospitalization for ramp-up portion of the therapy 
• 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 that meet the 
definition of a SAE must be reported to the IRB in accordance with 
the timeframes and procedures outlined in “University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs 
and Devices.” Unless stated otherwise in the protocol, all SAEs, 
expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the 
event). 
• 
All life-threatening or fatal events, that are unexpected, and 
related to the study drug, must have a written report submitted within 
24 hours (next working day) of knowledge of the event to the Safety 
Project Manager in the IND Office. 
 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will 
be utilized for safety reporting to the IND Office and MDACC IRB. 
 
• 
Serious adverse events will be captured from the time of the first 
protocol-specific intervention, until 30 days after the last 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 is related to the study treatment must be reported to 


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the IND Office, Abbvie Inc and Daiichi-Sankyo. This may include the 
development of a secondary malignancy. 
• 
All cases of venetoclax or quizartinib overdose (defined as accidental 
or intentional ingestion of any dose of the product that is considered 
excessive and medically important) must be reported as an SAE to 
the Sponsor (MDACC IND office) and to the supporting company on 
the SAE Form. 
• 
Pregnancy alone is not considered an AE. However, if a patient 
becomes pregnant or causes a pregnancy during treatment or within 
6 months of ending treatment, even if the subject is withdrawn from 
the study, the pregnancy must be reported immediately to the 
sponsor (MDACC IND office) on the MD Anderson SAE Form and to 
the supporting company within 1 days of the Investigator’s 
knowledge of the pregnancy. The investigator should abide by 
necessary regulation for medical release from a female partner of a 
male subject prior to obtaining follow up. The investigator will follow 
the pregnancy to term or termination, will collect data on both the 
maternal and fetal outcome and will report all outcomes as a follow- 
up report to the initial pregnancy notification to the supporting 
company, Daiichi-Sankyo and Abbvie Inc. 
Notwithstanding, all pregnancy outcomes that meet the regulatory 
definition of serious (i.e. spontaneous abortion, neonatal death, 
congenital anomaly in an aborted fetus or neonate) will be reported 
on the MD Anderson SAE Form to the sponsor (MDACC IND office) 
and the supporting companies within 24 hours of Investigator 
knowledge of the outcome. 
10.4.1 Adverse Events of Special interest (AESI): 
a. QTc Prolongation, TdP, and Other Ventricular 
ArrhythmiasSubjects who experience >480 msec QTcF 
prolongation and undergo dose interruption and/or reduction 
must be monitored closely with ECGs, performed twice weekly 
for the first week of the QTcF prolongation and then weekly 
thereafter until the QTcF prolongation is resolved, as described in 
Section 5.2.2.( dose modification section). 
a. QTcF prolongation ≥ Grade 3, either serious or non- 
serious and whether or not causally related, must be 
recorded as AE or SAE in the [Electronic Data Capture 
(EDC)], with the Investigator’s assessment of 
seriousness, causality, and a detailed narrative. 
- Electrolytes (potassium, calcium, and magnesium) 
should be checked and supplementation given to correct 
any values outside the normal range; 
- Concomitant medications should be reviewed to identify 
and, if appropriate, discontinue any medication with 
known QT prolonging effects (section 5.5.2); 
- Subjects who experience >480 msec QTcF prolongation 
and undergo dose interruption and/or reduction must be 


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monitored closely with ECGs, performed twice weekly for 
the first week of the QTcF prolongation and then weekly 
thereafter until the QTcF prolongation is resolved.b. 
.Combined Elevations of ATs and Bili 
Combined elevations of aminotransferases and bilirubin, 
either serious or non-serious and whether or not causally 
related, meeting the laboratory criteria of a potential Hy’s 
Law case [ALT or AST ≥3 x ULN with simultaneous TBL 
≥2 x ULN] should always be recorded as an AE or SAE 
within 24 hours of awareness, with the Investigator’s 
assessment of seriousness, causality, and a detailed 
narrative. Subjects will be monitored as described below: 
 
Evaluation may include the following depending on the 
clinical situation: 
• Medical history and physical exam, including focus on 
medications and substances used: alcohol, 
acetaminophen, azole antifungals, change in 
medication dosages, new medications added, over the 
counter medication use and recreational drug use. Check 
for change in diet or use of dietary 
supplements; 
• Abdominal ultrasound; 
• Hepatitis A, B, C, and E screening (anti-hepatitis A virus 
immunoglobulin M, hepatitis B surface antigen, anti- 
hepatitis C virus plus viral titer, and 
evaluation for Hepatitis E), antinuclear antibody and anti- 
Smith antibody, cytomegalovirus, Epstein Barr virus; 
• Additional evaluations as deemed appropriate by the 
Investigator to exclude other causes of liver enzyme and 
bilirubin elevations; 
• All laboratory results, including local laboratory reference 
ranges are to be recorded. 
10.5 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. 
 
10.6 Serious Adverse Event Reporting to Abbvie Inc and Daiichi-Sankyo. 
All SAEs, whether related or unrelated to venetoclax and/or quizartinib, 
Quizartinib , pregnancies and reports of overdose regardless of 
suspected causality and expectedness will be reported immediately but 
not later than 24 hours of the PI becoming aware of the SAE to Abbvie’s 
and Daiichi-Sankyo’s SAE Management team who will ensure data is 


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captured in Abbvie’s and Daiichi Sankyo Pharmacovigilance systems. 
The PI will forward completed SAE and pregnancy forms by fax to 617- 
224-9420 (Abbvie) and 732-906-9621 (Daiichi-Sankyo). 
Address and phone number of person responsible for SAE management 
at Abbvie: 
PPDINDPharmacovigilance@abbvie.com 
 
The Alliance Pharmacovigilance Agreement executed on February 2018 
between Daiichi Sankyo, Plexxikon and MDACC describes all Safety 
Information-related exchange obligations and will govern all ICSR case 
report exchanges between MDACC and Daiichi Sankyo. Any serious 
suspected unexpected adverse reaction (where SAE is not reported in the 
Investigator Brochure and is considered to be related to study drug) will 
be reported by the Investigator via email immediately to CSPV- 
Clinical@dsi.com. 
 
Information not available at the time of the initial report (e.g., an end date 
for the adverse event or laboratory values received after the report) must 
be documented on a follow-up report. A final report to document 
resolution of the SAE is required. For any event of TLS, serious or non- 
serious, additional details maybe requested. 
11.0 STATISTICAL CONSIDERATIONS 
 
The primary objectives of the study are to evaluate safety and efficacy of venetoclax in 
combination with quizartinib in patients with FLT3-ITD mutated AML. The total accrual is 
32 patients (Phase Ib: 12 patients and Phase II: 20 patients). 
11.1 Phase Ib (Lead-in Phase) 
The phase Ib portion is aimed at finding the MTD and RP2D of the two drugs in this 
combination. We plan to select a RP2D based on efficacy, toxicity, and PD data from the 
phase 1b dose-escalation. 3 patients at each dose level may not be sufficient to get a 
good estimate of efficacy and PD changes, and thus 6 patient dose escalation schema is 
proposed. 
Patients will be enrolled in cohorts of 6 patients in the phase Ib portion of the study. The 
target dose is dose level +1, and the starting dose will be dose level 0. The first 6 
patients on study will receive dose level 0. 
The MTD is defined as the highest dose level with </= 1 out of 6 patients experience a 
DLT during the first 28 days of treatment. DLT is defined in section 3.4. The planned 
dosing algorithm is presented in section 3.3 and the dosing schema for the combination 
treatment is shown in Table 1. The RP2D will be selected at the end of the phase I 
portion based on reviewing the safety, efficacy, and PD data of quizartinib and 
venetoclax after discussion between the PI/Co-PI, the sponsor (MDACC IND office), and 
the supporting companies (Daiichi-Sankyo and Abbvie Inc). The Investigator is 
responsible for completing the cohort summary template prior to advancing subjects to 
the phase II part. Once RP2D has been established, any patients still on study at a dose 
lower than RP2D can be dose escalated up to RP2D in accordance with the dose- 
escalation guidelines in section 5.2.3. 


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The PK of quizartinib will be summarized statistically as n, geometric mean, %CV, 
median, minimum and maximum as Cmax and AUC0-24h of quizartinib and AC886 
collected on Cycle 1 Day 7 (quizartinib alone) and Cycle 1 Day 8 (quizartinib + 
venetoclax) for the first 12 subjects. PK parameters will be dose normalized. 
The PK of venetoclax will be summarized statistically as n, geometric mean, %CV, 
median, minimum and maximum for Cmax and AUC0-24h of venetoclax and M27 
collected on Cycle 1 Day 8 (venetoclax + quizartinib) for the first 12 subjects. PK 
parameters will be dose normalized. 
11.2 Phase II 
The primary objective of the phase II is to evaluate the efficacy of the combination in 
patients with FLT3-ITD mutated AML (n=20). The primary endpoint is the rate of CRc 
(CRc=CR/CRp/CRi) at any time during the first three cycles of therapy. The CRc will be 
monitored with a time window of 3 months, and toxicity will be monitored as DLT within 1 
cycle of the treatment. CRc and toxicity will be monitored simultaneously using the 
Bayesian approach of Thall, Simon, Estey (1995, 1996) as extended by Thall and Sung 
(1998). 
Of note, recent FDA approval of midostaurin in combination with 7+3 induction 
chemotherapy in newly diagnosed FLT3-mutant AML signifies that essentially all 
relapsed FLT3-mutated AML patient will likely have been exposed to at least one FLT3 
targeting TKI. In this setting, the marrow response (CRc) rates with second generation 
FLT3 inhibitors such as crenolanib, gilteritinib and quizartinib have been reported to be 
lower than in prior FLT3 TKI naïve patients and are in the range of 20-25% (26, 48, 49) 
and Daiichi Sankyo unpublished communication). 
 
Thus, the historical data suggested a CRc rate of 25% for this population with quizartinib 
alone and the target CRc with the quizartinib and venetoclax combination is 50%. The 
treatment will be considered worthy of further investigation if it elicits an increase in CRc 
to 50% or higher with acceptable toxicity. A >30% DLT rate is considered unacceptable. 
Given this, we will stop enrollment into this cohort if the observed patients’ data suggest 
that: 
1) Pr (CRcE> CRcH +0.25|data) < 0.025 or 
2) Pr (TOXE> 0.30|data) > 0.90 
Here CRcE and CRcH are the CRc rate for quizartinib in combination with venetoclax and 
the historical treatment, respectively. TOXE is the toxicity rate for quizartinib in 
combination with venetoclax, where the toxicity is defined as the DLTs. That is, if at any 
time during the study we determine that there is a less than 2.5% chance that the 
average CRc rate improves over historical CRc rate by more than 25% we will stop 
enrollment to this cohort. The second condition will stop the study early if there is more 
than 90% chance that the toxicity rate is more than 30%. The CRcE and CRcH are 
assumed to follow a prior of Beta (0.5, 1.5) and a constant of 25%, respectively. The 
stopping boundaries for CRc, based on these assumptions and monitoring conditions 
are found in Table 4. We will apply these stopping boundaries continuously starting from 
the tenth patient in a cohort size of 5 patients. For example, accrual will cease if less 
than or equal to 2 patients experience CRc among the first 10 patients treated. 


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Table 4. Stopping boundaries for CRc rate. 
Stop accrual if the number patients with CRc among the number of patients 
evaluated 
Number of patients evaluated for 
CRc 
10 
15 
20 
Number of patients with CRc 
(i.e., CR, CRp, or CRi) 
is less than or equal to 
0-2 
0-4 
Always stop with 
this many 
patients 
 
Similarly, for monitoring the toxicity, a beta (0.6, 1.4) prior and a constant 30% toxicity 
rate were assumed for the historical treatment and the experimental combination, 
respectively. Based on these assumptions and monitoring conditions, the stopping 
boundaries for toxicity were generated and summarized in Table 5. For toxicity 
monitoring, 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 4 or more 
patients experience toxicities among the first 5 patients. 
For accrual between cohorts, if there are enough evidence indicating that the number of 
patients with CRc will be greater than that of the stopping boundaries (i.e., 2/10 or 4/15), 
it will continue; while will be held for evaluations of all patients if this cannot yet be 
determined with currently available data. Same strategy will be also applied to the 
toxicity monitoring. 
Table 5. Stopping boundaries for Toxicity 
Stop accrual if the number of patients with DLTs among the number of patients 
evaluated 
# patients evaluated 
5 
10 
15 
20 
# patients with toxicities 
4-5 
6-10 
8-15 
Always stop with this many patients 
 
The operating characteristics are summarized in Table 6. The probability of stopping the 
study early if the true CRc of the combination treatment was 50% and the true toxicity 
rate was 30% was 16.1%. Probabilities of stopping early for high true toxicity rates (i.e., 
50%) were 59.5% when the true CRc was 50% and 56.2% when true CRc rate was 
65%. 
 
Table 6. Operating characteristics for simultaneous monitoring response and 
toxicity rates for patients treated with combination treatment 
True Toxicity Rate 
True CRc 
Prob(stop the trial early) 
0.10 
0.25 
0.7188 
0.35 
0.3976 
0.50 
0.0837 
0.60 
0.0177 
0.65 
0.0069 
0.20 
0.25 
0.7223 
0.35 
0.4052 
0.50 
0.0952 
0.60 
0.0301 


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Table 6. Operating characteristics for simultaneous monitoring response and 
toxicity rates for patients treated with combination treatment 
True Toxicity Rate 
True CRc 
Prob(stop the trial early) 
0.65 
0.0194 
0.30 
0.25 
0.7424 
0.35 
0.4481 
0.50 
0.1605 
0.60 
0.1001 
0.65 
0.0902 
0.40 
0.25 
0.7956 
0.35 
0.5621 
0.50 
0.3340 
0.60 
0.2860 
0.65 
0.2782 
0.50 
0.25 
0.8758 
0.35 
0.7340 
0.50 
0.5955 
0.60 
0.5663 
0.65 
0.5616 
 
If the study is not stopped early and 20 patients have been treated and evaluated in the 
study, a 95% credible interval around the CRc under the combination treatment will be 
no wider than 41%. The in-house Multc Lean Desktop (version 2.1.0) was used to 
generate the toxicity and futility stopping boundaries, and the Parameter Solver (version 
3.0.0) was used to construct the credible intervals. 
11.3 Statistical Analysis Plan 
All patients who receive any dose of the study agent will be included in the analysis for 
efficacy and safety. We will follow standard reporting guidelines for adverse events, and 
summarize safety data by category, severity and frequency. For the primary efficacy 
analysis, we will estimate the CRc rate for the combination treatment, along with the 
95% credible interval. Patients who drop out of the study before completing all the 
cycles will be treated as “failures” for the primary analysis. 
Patients’ demographic and clinical characteristics will be summarized using descriptive 
statistics. Specifically, categorical covariates will be summarized by frequencies and 
percentages and their associations with responses will be assessed using Fisher’s exact 
test or its generalization. Continuous covariates will be summarized by means, standard 
deviations, medians and ranges, and the difference between responses groups will be 
assessed using the Wilcoxon rank sum test. Paired t-tests or Wilcoxon signed-rank 
tests will be used to determine the immunological and molecular changes in the 
peripheral blood and bone marrow from baseline to the time of response, and to the time 
of disease progression. 
We will estimate the rates of partial response and bone marrow blast reduction ≥ 50% 
within 3 months, along with 95% confidence intervals. For each subject, duration of 
response (DOR), event-free survival time and overall survival time will be calculated. 
DOR is defined as the time period from the first documentation of CRc to disease 


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recurrence, disease progression, or death whichever occurs first. Event-free survival 
time is defined as the time period from the date of treatment initiation to the date of 
documented treatment failure, relapses from CRc, or death from any cause, whichever 
occurs first. The observed DOR/EFS will be censored at the last follow-up if the patient 
is alive and no events observed. The overall survival time is defined as the time duration 
from treatment start till death or last follow-up if the patient is alive. The distributions of 
time-to-event endpoints including OS and DOR will be estimated using the Kaplan-Meier 
method. Comparisons of time-to-event endpoints by important covariate subgroups will 
be made using the log-rank tests. Progressive disease will be determined using ELN 
(2017) recommendations and is defined as any one or more of the following: 
• 
50% increase in marrow blasts over baseline (a minimum 15% point 
increase is required in cases with < 30% blasts at baseline; or 
persistent marrow blast percentage of > 70% over at least 3 months; 
without at least a 100% improvement in ANC to an absolute level (> 
0.5 × 109/L [500/mL], and/or platelet count to > 50 × 109/L [50 
000/mL] non-transfused); 
• 
50% increase in peripheral blasts (WBC × % blasts) to > 25 × 109/L 
(> 25 000/µL); 
• 
New extramedullary disease 
 
The Investigator is responsible for completing Safety/Efficacy summary reports and 
submitting them to the IND office Medical Monitor for review, as follows: 
 
Phase Ib Portion: 
Submit a Toxicity Summary after the first six evaluable patients complete the first 28 
days of study treatment, and every 6 patients thereafter, and before any dose 
modification or dose expansion. 
 
Phase 2 Portion: 
Submit an Efficacy/Toxicity Summary after the first five evaluable patients, per cohort, 
complete the first 28 days of study treatment and every 5 evaluable patients per cohort, 
thereafter. On every report submission, the information from previous reported patients 
will need to be updated to include toxicity assessment by the end of the first 28 days of 
treatment, and efficacy assessment by the end of cycle 3. 
 
 
12.0 REFERENCES 
1. 
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acute myeloid leukaemia patients with normal cytogenetics is affected by molecular 
genetic alterations: a concise review. British journal of haematology. 2007;137(5):387- 
400. 
2. 
Grundler R, Miething C, Thiede C, Peschel C, Duyster J. FLT3-ITD and tyrosine 
kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow 
transplantation model. Blood. 2005;105(12):4792-9. 
3. 
Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito H, et al. 
Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces 
autonomous cell growth in IL-3-dependent cell lines. Oncogene. 2000;19(5):624-31. 


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4. 
Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C, et al. Flt3 
mutations from patients with acute myeloid leukemia induce transformation of 32D cells 
mediated by the Ras and STAT5 pathways. Blood. 2000;96(12):3907-14. 
5. 
Zhang S, Broxmeyer HE. p85 subunit of PI3 kinase does not bind to human Flt3 
receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa 
protein in Flt3 ligand-stimulated hematopoietic cells. Biochemical and biophysical 
research communications. 1999;254(2):440-5. 
6. 
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