Phase 1, Open-label, Study of Voruciclib in Subjects With Relapsed and/or Refractory B Cell Malignancies or AML After Failure of Prior Standard Therapies and Voruciclib in Combination With Venetoclax in Subjects With Relapsed/Refractory AML
Phase: PHASE1
Conditions: Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), Small Lymphocytic Lymphoma (SLL), Chronic Lymphocytic Leukemia (CLL), Diffuse Large B-cell Lymphoma (DLBCL), Acute Myeloid Leukemia (AML)
Sponsor: MEI Pharma, Inc.

CONFIDENTIAL 
This document is confidential and is the property of MEI Pharma, Inc. No part of this document may be transmitted, 
reproduced, published, or used by other persons without written authorization from MEI Pharma, Inc. 
CLINICAL STUDY PROTOCOL 
Protocol Number: ME-522-001  
A Phase 1, Open-Label, Study of Voruciclib in Subjects with Relapsed and/or 
Refractory B-Cell Malignancies or Acute Myeloid Leukemia After Failure of 
Prior Standard Therapies and Voruciclib in Combination with Venetoclax in 
Subjects with Relapsed and/or Refractory Acute Myeloid Leukemia 
Sponsor: 
MEI Pharma, Inc. 
11455 El Camino Real, Suite 250 
San Diego, CA 92130 
Phone: +1 (858) 792-6300 
Medical Monitor: 
Richard Ghalie, M.D. 
Chief Medical Officer 
MEI Pharma, Inc. 
Mobile: +1 (619) 990-1153 
rghalie@meipharma.com 
Study Chair: 
Yesid Alvarado-Valero, MD 
Associate Professor, Department of Leukemia 
Division of Cancer Medicine 
University of Texas MD Anderson Cancer Center 
yalvarad@mdanderson.org 
Investigational Drug: 
Voruciclib (ME-522, formerly P1446A-05) 
IND Number: 
121938, 159178  
Amendment 12: 
29 January 2024 

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SPONSOR’S PROTOCOL SIGNATURE PAGE 
By signing below, the Sponsor declares that this study will be conducted in accordance with 
current United States (US) Food and Drug Administration Code of Federal Regulations, 
Good Clinical Practice (GCP) standards, the Declaration of Helsinki (Scotland 2000, as 
clarified 2002), the Medical Research council’s “Code of Ethics for Research Involving Humans 
– May 1997,” and local ethical and legal requirements. 
 
 
 
 
Richard Ghalie, M.D. 
Chief Medical Officer 
 Date 
30-Jan-2024 | 14:09 PST

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INVESTIGATOR’S SIGNATURE PAGE 
By signing below, the Investigator agrees to adhere to the protocol as written and agrees that any 
changes to the protocol must be approved by MEI Pharma, Inc., before seeking approval from 
the Institutional Review Board (IRB)/Independent Ethics Committee (IEC). 
The study will be conducted in accordance with the current International Council on 
Harmonisation (ICH) Guidelines, the Guidelines for Good Clinical Practice (GCP), the 
Declaration of Helsinki, the Medical Research council’s “Code of Ethics for Research Involving 
Humans – May 1997,” and local ethical and regulatory requirements. 
The information contained in this protocol is proprietary and provided to me in confidence, and 
may not be disclosed to any other party, in any form, without prior authorization from MEI 
Pharma, Inc., except to the extent necessary for the conduct of the study at this study site. 
Principal Investigator: 
Signature 
Date 
Printed Name 
Institution 

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PROTOCOL SYNOPSIS 
TITLE 
A Phase 1, Open-label, Study of Voruciclib in Subjects with Relapsed and/or Refractory B-Cell 
Malignancies or Acute Myeloid Leukemia After Failure of Prior Standard Therapies and Voruciclib in 
Combination with Venetoclax in Subjects with Relapsed and/or Refractory Acute Myeloid Leukemia 
PROTOCOL NUMBER 
ME-522-001 
SUBJECT POPULATION 
Subjects with relapsed and/or refractory B-cell malignancies (Follicular lymphoma [FL], mantle cell 
lymphoma [MCL], marginal zone lymphoma [MZL], small lymphocytic lymphoma [SLL], chronic 
lymphocytic leukemia [CLL], and diffuse large B-cell lymphoma [DLBCL]) or relapsed and/or 
refractory acute myeloid leukemia (AML) 
INVESTIGATIONAL PRODUCT 
The active pharmaceutical ingredient, voruciclib, is (+)-trans-3-[2[(2-Chloro-4-trifluoromethyl-
phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one, and is available 
in 2 salt forms, hydrochloride and malonate. 
Voruciclib is a potent oral cyclin-dependent kinase (CDK) inhibitor that indirectly suppresses the 
function of the pro-survival Myeloid cell leukemia protein (Mcl-1).  
Voruciclib is provided as 50 and 100 mg capsules (hydrochloride salt) or tablets (malonate salt) for oral 
administration. The malonate salt tablet is the only formulation that will be used in the voruciclib and 
venetoclax (Venclexta®) combination portion of this study.  
Other co-administered drug (combination study cohorts in AML subjects only, per this amendment 
[Amendment 11]): 
Voruciclib will be administered, in some cohorts, in combination with the Bcl-2 inhibitor venetoclax. 
Venetoclax is approved by the US Food and Drug Administration for the treatment of adults with CLL 
or SLL, and in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of 
newly diagnosed AML in adults aged 75 years or older, or who have comorbidities that preclude use of 
intensive induction chemotherapy. 
Venetoclax is available commercially as 10 mg, 50 mg, and 100 mg tablets for oral administration. 
STUDY OBJECTIVES 
Primary Objectives 
• 
Determine the safety and tolerability of voruciclib and identify a safe and minimum biologically 
effective dose (mBED) of voruciclib monotherapy in subjects with relapsed or refractory B-cell 
malignancies and relapsed or refractory AML 
• 
Determine the safety and tolerability, and identify the safe and mBED of voruciclib in 
combination with venetoclax in subjects with relapsed or refractory AML  

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Secondary Objectives 
• 
Evaluate the potential efficacy of voruciclib monotherapy based on: 
o International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for 
CLL/SLL (Appendix 5) or the Lugano classification of response assessment for lymphoma 
(Appendix 6), as appropriate, for subjects with B-cell malignancies  
o The 2017 European LeukemiaNet (ELN) criteria for subjects with AML (Appendix 4) 
• 
Evaluate the potential efficacy of voruciclib in combination with venetoclax in subjects with 
AML based on the 2017 ELN criteria  
• 
Evaluate the pharmacokinetics (PK) of voruciclib administered as monotherapy, and the PK of 
voruciclib and venetoclax when administered in combination 
Exploratory Objectives 
• 
Determine the effect of voruciclib monotherapy and voruciclib in combination with venetoclax 
(AML only) on biomarkers and functional activities of proteins in the apoptotic pathway 
• 
Correlate anti-tumor activity with baseline tumor characteristics 
STUDY DESIGN 
This is a Phase 1, open-label, 3 + 3 dose escalation study to determine the safety and preliminary 
efficacy of voruciclib as monotherapy in subjects with relapsed or refractory B-cell malignancies or 
AML, and in combination with venetoclax in subjects with relapsed or refractory AML after treatment 
with standard therapy.  
Dose-Escalation Cohorts 
Voruciclib Monotherapy: Dose escalation with voruciclib monotherapy will be conducted separately 
for subjects with AML and B-cell malignancies, as tolerability, dose limiting toxicity (DLT), and safe 
and mBED may be different for these 2 disease groups.  
As of Amendment 7 (rationale provided below), voruciclib monotherapy is evaluated using an 
intermittent (IS) dosing schedule of 2 weeks on therapy and 2 weeks off therapy (IS IS2w,2w). If IS2w,2w 
is not tolerated, an intermittent schedule of 1 week on therapy followed by 3 weeks off therapy in a 
28-day cycle (IS1w,3w) may be evaluated.  
Subjects will be enrolled into separate but parallel dose cohorts, designated as ‘a’ for AML subjects 
and ‘b’ for B-cell malignancy subjects. The following voruciclib monotherapy dose/schedule cohorts 
will potentially be enrolled: 
• 
Cohort 6 a,b: 100 mg QD, administered IS2w,2w 
• 
Cohort 7 a,b: 150 mg QD, administered IS2w,2w 
• 
Cohort 8 a,b: 200 mg QD, administered IS2w,2w 
• 
Cohort 9 a,b: 100 mg QD, administered IS1w,3w 
• 
Cohort 10 a,b: 150 mg QD, administered IS1w,3w 
• 
Cohort 11 a,b: 200 mg QD, administered IS1w,3w 
Enrollment will proceed first on the IS2w,2w from Cohorts 6a to 8a (AML) and 6b to 8b (B-cell 
malignancies), with dose escalation based on DLT assessment in each disease group separately. 
If voruciclib monotherapy is deemed not tolerated in a Cohort 6 group (i.e., 6a or 6b), then dose 
escalation on the IS2w,2w schedule for that group will be closed and the IS1w,3w schedule for the same 

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disease group will be evaluated, with enrollment proceeding from Cohorts 9 to 11 (a, and/or b, as 
appropriate). 
Dose escalation to the next ‘a’ or ‘b’ cohort will be allowed after 3 subjects have completed Cycle 1 
with no reported DLTs or after 6 subjects have completed Cycle 1 with no more than 1 DLT in the 
respective ‘a’ or ‘b’ cohort (DLT criteria defined below). Escalation to the next dose level or moving to 
the less intensive dosing schedule will depend on demonstrated safety and tolerability within a cohort 
and with the approval of the Study Review Committee (SRC), composed of clinical investigators and 
sponsor representatives (including the Medical Monitor). 
If the next dose level in the AML or B-cell malignancies monotherapy cohorts has been declared safe 
by the SRC, subjects with the same disease type (AML or B-cell malignancies) enrolled in the 
monotherapy cohorts at a lower dose level may have their dose escalated to the next dose level after 
completing Cycle 1 without a DLT (intra-subject dose escalation). For example, a subject with B-cell 
malignancies enrolled in Cohort 6b (100 mg IS2w,2w) may have the dose increased to 150 mg IS2w,2w in 
Cycle 2 if the dose of 150 mg IS2w,2w was deemed safe in the B-cell malignancies cohort by the SRC. 
Voruciclib + Venetoclax Combination Therapy (AML Only)  
In Amendment 11, subsequent to determination of the safe and mBED of voruciclib monotherapy in 
AML subjects, the combination of voruciclib with venetoclax will be evaluated in subjects with 
relapsed and/or refractory AML (see rationale provided below). 
The combination cohorts, beginning at Cohort 12 dose level of voruciclib in combination with 
venetoclax on an IS2w,2w dosing schedule, will be enrolled as follows: 
• 
Cohort 12: 50 mg once every other day (QOD), administered IS2w,2w + venetoclax administered 
QD × 28 days 
• 
Cohort 13: 50 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
• 
Cohort 14: 100 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
• 
Cohort 15: 150 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
• 
Cohort 16: 200 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
• 
Cohort 17: 250 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
• 
Cohort 18: 300 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
• 
Cohort 19: 350 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
Dose escalation to the next cohort will be reviewed by the SRC after 3 subjects have completed 1 cycle 
with no reported DLTs, or after 6 subjects have completed 1 cycle with no more than 1 DLT. (DLT 
criteria defined below.) Escalation to a subsequent cohort will depend on demonstrated safety and 
tolerability within a cohort and with the approval of the SRC.  
If the next dose level in the AML combination cohort has been declared safe by the SRC, subjects 
enrolled at a lower dose level may have their dose escalated to the next dose level after completing 
Cycle 1 without a DLT (intra-subject dose escalation). For example, a subject with AML enrolled in 
Cohort 13 (50 mg IS2w,2w) may have the dose increased to 100 mg in Cycle 2 if the dose of 100 mg 
IS2w,2w was deemed safe in Cohort 14 by the SRC. 
Dose escalation proceeds until a real-time assessment of clinical and PK parameters by the SRC 
establishes the safe and mBED for voruciclib in combination with venetoclax. More specifically, a 
voruciclib dose in combination with venetoclax that meets the following criteria:  
• 
DLT not to exceed 1 in 6 subjects, overall response rate (ORR) ≥30%, as compared to historical 
ORR of 19% with 400-800 mg venetoclax alone in relapsed/refractory AML (Konopleva 2016), 
and  

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•
Trough plasma concentration of 1 to 1.5 µM, concentrations shown to be synergistic in
combination with venetoclax in preclinical models.
In Amendment 12, the combination of voruciclib with venetoclax will be evaluated in subjects with 
relapsed and/or refractory AML using a voruciclib intermittent schedule of daily dosing on Days 1–21 
in a 28-day cycle, with no voruciclib dosing on Days 22–28 of the cycle, designated as IS3w,1w. (see 
rationale below). In Cycle 1, voruciclib dosing begins on Day 3 after completion of venetoclax dose 
ramp-up.  The starting voruciclib dose level on IS3w,1w will be 150 mg (i.e., 2 dose levels lower than the 
dose of 250 mg that was shown to have no DLTs in the IS2w,2w schedule). The venetoclax dose will be 
200 mg on Days 1–21 and 400 mg on Days 22–28 in a 28-day cycle. In Cycle 1, venetoclax dose ramp-
up will consist of venetoclax 100 mg on Day 1, then 200 mg on Days 2–21, then 400 mg on Days 22–
28, with voruciclib beginning on Day 3. Dose escalation will follow the same 3+3 design as in the 
IS2w,2w cohorts, and uses the same definition for DLT, MTD, and mBED. 
In the IS2w,2w dose escalation cohorts, no DLTs have been reported at doses ranging from 50 mg QOD 
to 250 mg QD, and enrollment was ongoing at the 300 mg dose level at the time of issuance of protocol 
Amendment 12. 
The combination cohorts on IS3w,1w will be numbered as listed below: 
•
Cohort 21: 150 mg QD, administered IS3w,1w + venetoclax administered QD × 28 days
•
Cohort 22: 200 mg QD, administered IS3w,1w + venetoclax administered QD × 28 days
•
Cohort 23: 250 mg QD, administered IS3w,1w + venetoclax administered QD × 28 days
•
Cohort 24: 300 mg QD, administered IS3w,1w + venetoclax administered QD × 28 days
•
Cohort 25: 350 mg QD, administered IS3w,1w + venetoclax administered QD × 28 days
Expansion Cohorts 
For AML subjects only, after review of safety and clinical activity data, the SRC may select a 
recommended dose level for expansion cohorts of voruciclib monotherapy (6 subjects) and/or 
voruciclib + venetoclax combination therapy (up to an additional 12 subjects each for IS2w,2w and 
IS3w,1w) in order to obtain additional safety, efficacy, PK, and pharmacodynamic/biomarker data. 
Formal stopping rules for excess toxicity in the AML combination therapy expansion cohort are 
provided in the protocol (Section 4.5). 
Rationale for Dose Schedule Changes in Amendment 7 
In the earlier dose-escalation phase of this study, in which voruciclib was administered QD for 28 days 
per 28-day cycle, there were no DLTs in the 50 mg QD dose cohorts in either B-cell or AML subjects. 
However, at 100 mg QD dose level, 2 subjects with AML had DLTs of pneumonitis (n = 1) and 
interstitial lung disease (n = 1), prompting a Sponsor decision to no longer pursue a QD dosing 
schedule in either disease group. Because there were no objective responses reported at the dose of 
50 mg QD, intermittent dosing schedules (IS2w,2w and IS1w,3w) were started with voruciclib 100 mg to 
determine whether doses of 100 mg or greater can be administered safely. These doses are projected to 
achieve plasma concentrations consistent with concentrations shown to demonstrate anti-proliferative 
effects in in vitro models.  
(Note: Amendments 8, 9, and 10 were not implemented) 
Rationale for the Addition of Voruciclib + Venetoclax Combination Therapy in Amendment 11 
For the treatment of AML subjects, it is hypothesized that use of a CDK9 inhibitor (such as voruciclib) 
with its corollary effect on Mcl-1 inhibition when given in combination with a Bcl-2 inhibitor (such as 
venetoclax) could synergistically bring about disruption of the cell cycle and inhibition of pro-survival 
cell cycle pathways. Based on preliminary safety and tolerability data with voruciclib monotherapy, the 
IS2w,2w dosing schedule will be used for the combination of voruciclib and venetoclax in AML patients. 

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Rationale for an Additional Voruciclib Schedule in Amendment 12 
The rationale for the IS3w,1w is to decrease the number of days without voruciclib from 14 to 7 days in a 
treatment cycle, thereby reducing the potential risk of AML regrowth during the 2-week treatment 
break in the IS2w,2w schedule. 
STUDY TREATMENT 
Study Drug Administration 
For monotherapy cohorts, voruciclib will be administered once daily on dosing days of IS2w,2w or 
IS1w,3w cohorts in 28-day cycles, with the first day of treatment designated as Day 1. 
For combination cohorts, see Administration Schedule of Voruciclib IS2w,2w and Venetoclax per 28-day 
Cycle, below. 
Administration Schedule of Voruciclib IS2w,2w and Venetoclax per 28-day Cycle 
Cycle 1 
Day 1 
Day 2 
Days 3 to 14 
Days 15 to 21 
Days 22 to 28 
Venetoclax 
100 mg 
200 mg 
200 mg 
200 mg 
400 mg 
Voruciclib QD 
- 
- 
Cohort dose 
None 
None 
Voruciclib QODa 
- 
- 
50 mga 
None 
None 
Cycle 2 and beyond  
Days 1 to 14 
Days 15 to 21 
Days 22 to 28 
Venetoclax 
200 mg 
200 mg 
400 mg 
Voruciclib QD 
Cohort dose 
None 
None 
Voruciclib QODa 
50 mga 
None 
None 
Abbreviation: QOD = once every other day 
a For Cohort 12, the dose of voruciclib will be 50 mg once every other day (QOD) on Days 3, 5, 7, 9, 11, and 13 of Cycle 1, 
and on Days 1, 3, 5, 7, 9, 11, and 13 of Cycle 2 and beyond 
 
For combination cohorts, see Administration Schedule of Voruciclib IS3w,1w, and Venetoclax per 
28-day Cycle below. 
Administration Schedule of Voruciclib IS3w,1w and Venetoclax per 28-day Cycle 
Cycle 1 
Day 1 
Day 2 
Days 3 to 21 
Days 22 to 28 
Venetoclax 
100 mg 
200 mg 
200 mg 
400 mg 
Voruciclib QD 
- 
- 
Cohort dose 
None 
Cycle 2 and beyond  
Days 1 to 21 
Days 22 to 28 
Venetoclax 
200 mg 
400 mg 
Voruciclib QD 
Cohort dose 
None 
Abbreviation: QD = once per day. 
Dosing Instructions 
For subjects in the monotherapy cohorts, voruciclib is to be taken orally on an empty stomach, at least 
1 hour prior to food or 2 hours after food, at approximately the same time each day on dosing days. It is 
recommended that voruciclib be taken in the morning. A missed dose may be taken up to 12 hours after 
the usual time; after 12 hours the dose should be omitted. 
For subjects in the combination voruciclib + venetoclax cohorts, venetoclax is to be taken first (with a 
meal) followed by voruciclib taken at least 2 hours later (e.g., meal completed at 8 a.m. with 
venetoclax, dose voruciclib after 10:00 a.m.), with the exception of C2D1 when voruciclib is to be 
dosed 6 hours after venetoclax administration, after completion of the 6-hour PK sample collection. 
Voruciclib tablets must not be chewed, crushed, or broken.  

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Dose Modifications 
For subjects enrolled on voruciclib monotherapy cohorts, criteria for interrupting study drug treatment 
and requirements for re-treatment or discontinuation of study drug are provided in Table 10 of the 
protocol. 
For subjects enrolled on voruciclib + venetoclax combination cohorts, dose modifications for toxicities 
attributed to venetoclax or for the combined effect of voruciclib and venetoclax will be based on the 
Venclexta US Prescribing Information and are provided in protocol Table 11.  
Duration of Therapy 
Subjects may continue to receive voruciclib monotherapy or voruciclib + venetoclax while there is 
evidence of clinical benefit (partial remission [PR] or better) in subjects with B-cell malignancies or 
AML by the end of Cycle 6 and acceptable toxicity as judged by the Investigator.  
SAFETY PLAN 
Dose-Limiting Toxicity (DLT)  
A DLT will be defined as any of the following treatment-emergent adverse events (TEAEs) occurring 
in Cycle 1 (first 28 days) of voruciclib monotherapy or voruciclib + venetoclax combination therapy 
that are clearly unrelated to the underlying disease or extraneous causes: 
• 
Symptomatic nonhematological Grade ≥3 laboratory abnormalities or asymptomatic 
nonhematological Grade ≥3 laboratory abnormalities that fail to improve to Grade ≤2 within 
72 hours 
• 
Grade 3 vomiting lasting >48 hours despite recommended antiemetic support or any occurrence 
of Grade ≥4 vomiting 
• 
Grade 3 diarrhea lasting >48 hours despite recommended antidiarrheal support or any occurrence 
of Grade ≥4 diarrhea 
• 
All other Grade ≥3 nonhematological adverse event (AE) not listed above 
• 
Grade 3 or higher tumor lysis syndrome (TLS) regardless of prophylaxis 
• 
Hy’s law cases 
• 
Febrile neutropenia of any duration (not applicable to AML subjects) 
• 
Grade 4 neutropenia lasting ≥7 days; or in AML subjects only lasting ≥42 days and not due to 
progressive disease 
• 
Grade ≥3 thrombocytopenia with Grade ≥2 bleeding or Grade 4 thrombocytopenia of any 
duration (not applicable to AML subjects) 
• 
Grade 4 thrombocytopenia lasting ≥42 days (AML subjects only) 
• 
Grade 4 anemia unexplained by underlying disease  
Additionally, discontinuation of study drug in Cycle 1 due to an AE that is clearly unrelated to the 
underlying disease, or an extraneous cause will be considered a DLT. 
For subjects receiving combination voruciclib + venetoclax, the DLT assessment period will begin with 
the initial dose of venetoclax in Cycle 1. 

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STUDY ASSESSMENTS 
Assessments for safety, efficacy/antitumor activity, PK, and biological/correlative activity will be 
performed according to the schedules outlined in Appendix 1, Appendix 2 or Appendix 3, as 
appropriate for disease type and cohort enrollment. 
Safety Assessments 
Safety will be assessed by AEs graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v5.0, laboratory safety tests including hematology 
(complete blood count [CBC]), serum chemistry, physical examination, vital signs, and 12-lead 
electrocardiogram (ECG). 
ESTIMATED NUMBER OF SUBJECTS 
At the start of Amendment 12, a total of 40 subjects have been enrolled in the now completed 
monotherapy dose escalation/expansion cohorts. Assuming an average enrollment of 4 subjects per 
dose level for DLT evaluation, up to 12 subjects to be enrolled in the 2 combination AML expansion 
cohorts, and an additional 10% for early drop-outs due to non-evaluability after failure to complete 
Cycle 1 treatment for reasons other than AEs related to voruciclib, the total enrollment for the 
voruciclib plus venetoclax combination group is estimated to be approximately 68 subjects, for a total 
of approximately 108 subjects to be enrolled in the study.  
ESTIMATED NUMBER OF SITES 
Approximately 10 to 16 sites in the United States (US) 
SUBJECT ELIGIBILITY 
Inclusion Criteria 
To be eligible for study participation, subjects must meet all of the following inclusion criteria: 
1. Signed, informed consent 
2. Age ≥18 years 
3. Histologically confirmed diagnosis of FL, MCL, marginal zone lymphoma (MZL), SLL, CLL, or 
DLBCL, and: 
a. 
Subjects must have disease that has relapsed or is refractory to 2 or more prior regimens and 
in need of treatment due to progressive disease (PD) 
b. 
Subjects must have received appropriate standard therapy for the subject’s malignancy and 
have developed disease progression or are intolerant to appropriate standard therapy 
c. 
The clinical investigator must have discussed all alternative treatment options with the 
potential study subject prior to study enrollment 
4. Histologically confirmed diagnosis of primary AML or secondary AML (e.g., following 
myelodysplastic syndrome or myeloproliferative disease) as defined by World Health Organization 
(WHO) criteria (Arber 2016) 
a. 
Relapsed or primary refractory disease having received 2 or more lines of therapy (voruciclib 
monotherapy cohorts) or 1 or more lines of therapy (voruciclib plus venetoclax combination 
cohorts) 

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b. 
Subjects must not be eligible for, or have failed, other therapies known to be effective for 
treatment of their AML 
NOTE: a subject must meet inclusion criterion 3 or 4, but not both  
5. Presence of measurable disease defined per the 2008 International Workshop on CLL guidelines 
(see Appendix 5) or by 2014 Lugano criteria for non-Hodgkin lymphoma (see Appendix 6); these 
criteria do not apply to subjects with AML 
6. Life expectancy of ≥3 months 
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 
8. For subjects with B-cell malignancies, adequate hematologic parameters unless clearly due to the 
disease under study: 
a. Absolute neutrophil count (ANC) ≥0.5 × 109/L 
b. Platelet count >50 × 109/L  
c. Hemoglobin ≥8.0 g/dL  
9. Adequate coagulation parameters:  
a. Prothrombin time (PT) ≤1.5 × ULN (i.e., Grade ≤1) 
b. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN (i.e., Grade ≤1) 
10. Adequate renal and hepatic function, per laboratory reference range at screening: 
a. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine 
aminotransferase (ALT)/ serum glutamate-pyruvate transaminase (SGPT) ≤2.5 × ULN 
b. Total bilirubin ≤1.5 × ULN (if secondary to Gilbert’s syndrome, ≤3 × ULN is permitted) 
c. Creatinine clearance ≥60 mL/minute 
11. Subjects with B-cell malignancies must have completed:  
a. Previous anti-cancer medication a minimum of 5 elimination half-lives (t½) or 2 weeks 
(whichever is less) prior to Day 1 (a course of corticosteroids ≤7 days in duration prior to 
Day 1 is allowed) 
b. Radiation therapy or surgery ≥2 weeks before Day 1 
12. Subjects with AML must have completed: 
a. Previous anti-cancer medication for a minimum of 5 elimination half-lives (t½) or 2 weeks 
(whichever is less) prior to start of voruciclib (monotherapy) or venetoclax (combination 
therapy) administration 
b. Radiation therapy ≥2 weeks or major surgery ≥4 weeks before start of voruciclib 
(monotherapy) or venetoclax (combination therapy) administration 
Note: Hydroxyurea and other therapy to control leukocytosis is allowed up to the end of Cycle 1 
13. All clinically significant treatment-related toxicity from prior therapy (other than alopecia) must 
have resolved to Grade ≤1, or to a new stable baseline at time of enrollment 
14. Females of childbearing potential must have a negative serum pregnancy test within 14 days prior 
to Day 1 
15. For subjects capable of procreation, agree to use medically effective contraception during the 
study (which must, at the minimum, include a barrier method), and for 90 days after 

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discontinuation of study drug. Females of childbearing potential should use 2 forms of 
contraception, one of which should be a barrier contraceptive 
16. Agree to not donate sperm or oocytes during the entire study treatment period and for 90 days 
after study drug discontinuation 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. History of pneumonitis due to any cause 
2. For AML subjects only 
a. Acute promyelocytic leukemia (APL with promyelocytic leukemia/retinoic acid receptor alpha 
[PML-RARA]) 
b. Peripheral blast count >25 × 109/L (hydroxyurea or other treatment to lower white blood cell 
[WBC] count to avoid this exclusion is allowed) 
3. Known central nervous system involvement  
4. History of another malignancy, except for the following: 
a. Adequately treated local basal cell or squamous cell carcinoma of the skin 
b. Adequately treated carcinoma in situ without evidence of disease 
c. Adequately treated papillary, noninvasive bladder cancer 
d. Other cancer that has been in complete remission for ≥ 2 years (subjects with low-grade 
prostate cancer on active surveillance and not expected to clinically progress over 2 years are 
allowed) 
5. Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, 
cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina 
requiring therapy; symptomatic peripheral vascular disease; New York Heart Association Class 3 
or 4 congestive heart failure; or uncontrolled Grade ≥ 3 hypertension (diastolic blood pressure 
≥100 mmHg or systolic blood pressure ≥ 160 mmHg) despite antihypertensive therapy  
6. Significant screening electrocardiogram (ECG) abnormalities, including unstable cardiac 
arrhythmia requiring medication, atrial fibrillation/flutter, left bundle branch block, 2nd-degree 
atrioventricular (AV) block type II, 3rd-degree AV block, Grade ≥ 2 bradycardia, or corrected QT 
by Fridericia formula (QTcF average of triplicate ECG) >450 msec 
7. Subjects who are receiving: 
a. Warfarin 
b. Other anti-cancer therapy (treatment to reduce leukocyte count in AML subjects is allowed) 
c. Strong or moderate CYP3A inhibitors (including grapefruit, Seville oranges, and star fruit) are 
to be avoided. Other CYP inhibitors (see Appendix 7) should be avoided and used only if 
essential for patient care. Strong or moderate CYP3A inhibitors and P-gp inhibitors must be 
discontinued 3 or more days before initiating venetoclax (subjects enrolled on combination 
voruciclib + venetoclax cohorts) 
d. Strong or moderate CYP3A inducers should be discontinued at least 7 days prior to venetoclax 
administration (subjects enrolled on combination voruciclib + venetoclax cohorts)  
e. Calcineurin inhibitors within 28 days prior to start of study drug 

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f. Any other investigational agent 
8. Gastrointestinal (GI) diseases that may interfere with drug absorption or that will affect 
interpretation of GI AEs (including but not limited to gastric or intestinal bypass surgery, 
pancreatic enzyme insufficiency, malabsorption syndrome, symptomatic inflammatory bowel 
disease, chronic diarrheal illness, bowel obstruction). The Medical Monitor should be contacted if 
there is any question of eligibility in this regard  
9. Ongoing risk for bleeding due to active peptic ulcer disease, bleeding diathesis, or other condition 
10. Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upper respiratory 
tract infections) at the time of start of voruciclib therapy, including: 
a. Positive hepatitis B surface antigen and/or hepatitis B core antibody test plus a positive 
hepatitis B polymerase chain reaction (PCR) assay (subjects with a negative PCR assay are 
permitted with appropriate anti-viral prophylaxis) 
b. Positive hepatitis C virus antibody (HCV Ab) test; subjects with positive HCV Ab test are 
eligible if they are negative for hepatitis C virus by PCR 
c. Symptomatic/uncontrolled HIV infection/AIDS, or currently taking contraindicated 
medications for HIV control  
11. Receipt of an allogeneic transplant at any time prior to enrollment or an autologous transplant 
within the preceding 3 months at time of enrollment in the monotherapy cohorts 
Note: Prior allogenic transplant is permitted for AML subjects enrolled in voruciclib + venetoclax 
combination cohorts 
12. Pregnant or breastfeeding or planning to become pregnant 
13. Prior solid organ transplantation 
14. Prior therapy with a CDK9 inhibitor 
15. Ongoing immunosuppressive treatment (including calcineurin inhibitors as noted in Exclusion 7) 
at the time of the start of study treatment (Cycle 1, Day 1), including systemic or enteric 
corticosteroids except as follows:  
a. Prior to the start of study treatment, subjects may be using systemic corticosteroids 
(≤20 mg/day of prednisone or equivalent), topical, or inhaled corticosteroids 
b. During study treatment, subjects may use systemic, topical, or enteric corticosteroids, if needed 
16. Concurrent participation in another therapeutic clinical trial 
17. Any illness, medical condition, organ system dysfunction, medication use, or social situation 
(including mental illness or substance abuse) deemed by the Investigator to be likely to interfere 
with a subject’s ability to sign informed consent, adversely affect the subject’s ability to cooperate 
and participate in the study, or otherwise compromise the interpretation of study results 
STUDY TREATMENT CONSIDERATIONS  
In vitro studies have shown that voruciclib has the potential to inhibit CYP2C9, CYP2C19, CYP2D6, 
and CYP3A4, therefore, drugs with a narrow therapeutic window that are metabolized by these 
enzymes should be avoided or used with caution (see Appendix 7).  
Subjects receiving warfarin treatment are excluded, since voruciclib is highly protein bound and a 
competitive inhibitor of CYP2C9 at higher concentrations, and may, therefore, potentiate the action of 
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Tumor lysis syndrome (TLS) includes electrolyte abnormalities (hyperkalemia, hypocalcemia, 
hyperuricemia, and hyperphosphatemia), cardiac dysrhythmias, and renal failure. Guidance on 
categorizing AML and CLL subjects for risk of TLS (Appendix 9), as well as a monitoring plan based 
on the Venclexta [US Prescribing Information] Rev 2022, is provided in Table 24.  
Differentiation syndrome (DS) was considered a contributing factor in the pneumonitis cases and was 
reported as a DLT in 2 subjects with AML enrolled in Cohort 2. Therefore, tumor cytoreduction with 
hydroxyurea should be considered in subjects with AML and high peripheral counts, and 
corticosteroids administered per institutional standards if DS is suspected.  
STATISTICAL ANALYSIS 
Subjects completing the first cycle of treatment or experiencing a DLT during the first cycle (28 days) 
of treatment, will be considered evaluable for the occurrence of DLTs. The 3 + 3 design targets a DLT 
rate for the MTD of approximately 20 to 25%. 
Summary statistics for continuous variables will include the mean, standard deviation, median, and 
range (minimum/maximum). Categorical variables will be presented as frequency counts and 
percentages. 
Response to treatment will be tabulated with 95% exact binominal confidence intervals (CI)s, 
analyzing all subjects who complete the first scheduled post-baseline efficacy evaluation (scheduled on 
C3D1 for B-cell lymphoma subjects and C2D1 for AML subjects) or who experienced disease 
progression prior to completing the first scheduled post baseline disease assessment. The Kaplan-Meier 
method will be used to estimate PFS within subjects of the same tumor type. For PFS, subjects without 
documented progression will be censored at the date of last disease assessment.  
Associations between PK findings, efficacy findings, and biomarker results will be explored by tests of 
association for binary endpoints (e.g., Fisher’s exact test) and by T-tests (or appropriate non-parametric 
alternatives) for continuous variables. 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
SPONSOR’S PROTOCOL SIGNATURE PAGE ...........................................................................2 
INVESTIGATOR’S SIGNATURE PAGE......................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
ABBREVIATIONS .......................................................................................................................21 
1. 
BACKGROUND AND RATIONALE .......................................................................24 
2. 
STUDY OBJECTIVES ..............................................................................................27 
2.1. 
Primary Objectives .....................................................................................................27 
2.2. 
Secondary Objectives .................................................................................................27 
2.3. 
Exploratory Objectives ...............................................................................................27 
3. 
SUBJECT ELIGIBILITY ...........................................................................................28 
3.1. 
Inclusion Criteria ........................................................................................................28 
3.2. 
Exclusion Criteria .......................................................................................................29 
4. 
STUDY DESIGN .......................................................................................................31 
4.1. 
Overall Study Design ..................................................................................................31 
4.2. 
Starting Dose and Dose Levels ...................................................................................32 
4.2.1. 
Voruciclib Monotherapy .............................................................................................32 
4.2.1.1. 
Rationale for Dose and Schedule Changes in Amendment 7 – Voruciclib 
Monotherapy ...............................................................................................................32 
4.2.2. 
Voruciclib + Venetoclax Combination Therapy in Subjects with AML ....................33 
4.2.2.1. 
Rationale for Voruciclib + Venetoclax Combination Therapy in 
Amendment 11 ............................................................................................................33 
4.2.2.2. 
Rationale for an Additional Voruciclib Schedule in Amendment 12 .........................34 
4.3. 
Dose Escalation Scheme .............................................................................................34 
4.3.1. 
Voruciclib Monotherapy .............................................................................................34 
4.3.1.1. 
Dose Cohort Escalation Prior to Amendment 7 .........................................................34 
4.3.1.2. 
Dose Cohort Escalation as of Amendment 7 ..............................................................35 
4.3.2. 
Dose Cohort Evaluation of Voruciclib + Venetoclax Combination Therapy 
in AML .......................................................................................................................38 
4.3.2.1. 
Administration Schedules and Doses of Voruciclib + Venetoclax ............................40 
4.3.2.2. 
Justification of Dose and Administration Sequence of Voruciclib + 
Venetoclax ..................................................................................................................42 
4.4. 
Dose-Limiting Toxicity (DLT) ...................................................................................44 

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4.5. 
Expansion Cohort and Early Stopping Boundaries for Toxicity ................................44 
4.6. 
Maximum Tolerated Dose (MTD) ..............................................................................45 
4.7. 
Recommended Phase 2 Dose (RP2D) for Voruciclib Monotherapy ..........................45 
4.8. 
Dose Modifications .....................................................................................................45 
4.8.1. 
Dose Modifications for Cohorts 1 to 5 - Voruciclib Monotherapy Continuous 
Dosing .........................................................................................................................45 
4.8.2. 
Re-treatment Following Adverse Events in Cohorts 6 to 11 with Intermittent 
Schedules of Voruciclib Monotherapy .......................................................................48 
4.8.3. 
Dose Modifications for Cohorts 12–19 and 21–25 - Voruciclib + Venetoclax 
Combination Dosing in AML .....................................................................................48 
4.9. 
Tumor Lysis Syndrome (TLS) ....................................................................................50 
4.10. 
Differentiation Syndrome ...........................................................................................50 
4.11. 
Interstitial Lung Disease/Pneumonitis ........................................................................51 
4.12. 
Subject Replacement ..................................................................................................52 
4.13. 
Discontinuation of Voruciclib Administration ...........................................................52 
4.14. 
Prohibited Treatments and Concomitant Medications – Cautions and 
Prohibitions .................................................................................................................52 
4.14.1. 
Concomitant Medications with Voruciclib – Cautions and Prohibitions ...................52 
4.14.2. 
Procedures and Surgery ..............................................................................................56 
4.14.3. 
Concomitant Medications with Venetoclax – Cautions and Prohibitions ..................56 
4.15. 
CYP3A4 and P-gp Inhibition Potential of Voruciclib ................................................57 
4.16. 
Impact of COVID-19 on Study Procedures/Visits .....................................................58 
4.17. 
Removal of Subjects from Study ................................................................................58 
5. 
VORUCICLIB ADMINISTRATION ........................................................................58 
5.1. 
Preparation and Administration of Voruciclib ...........................................................58 
5.2. 
Voruciclib Accountability and Compliance ...............................................................59 
5.3. 
Storage of Voruciclib ..................................................................................................59 
5.4. 
Storage of Venetoclax .................................................................................................59 
6. 
ADVERSE EVENTS..................................................................................................59 
6.1. 
Adverse Event (AE) Definition Using CTCAE V5.0 .................................................59 
6.2. 
Assessment of AEs .....................................................................................................59 
6.3. 
Serious Adverse Event (SAE) Definition ...................................................................60 
6.4. 
Serious Adverse Event (SAE) Reporting ...................................................................60 
6.5. 
Pregnancies .................................................................................................................61 

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6.6. 
Relationship of Adverse Events to Study Treatment ..................................................61 
7. 
RESPONSE ASSESSMENT ......................................................................................62 
7.1. 
Response Assessment for Subjects with CLL/SLL ....................................................62 
7.2. 
Response Assessment for Subjects with FL and Other B-Cell Lymphomas ..............62 
7.3. 
Response Assessment for Subjects with AML ...........................................................62 
8. 
STUDY PROCEDURES ............................................................................................62 
8.1. 
Informed Consent .......................................................................................................62 
8.2. 
Subject Enrollment .....................................................................................................63 
8.3. 
Screening Period .........................................................................................................63 
8.4. 
Enrollment and Randomization ..................................................................................63 
8.5. 
Cycle 1 Day 1 Tests and Administration of Voruciclib or Venetoclax ......................63 
8.6. 
Treatment ....................................................................................................................64 
8.7. 
End of Study Visit ......................................................................................................64 
8.8. 
End of Study ...............................................................................................................64 
9. 
STUDY ASSESSMENTS ..........................................................................................64 
9.1. 
Medical History and Prior Anti-Cancer Treatment ....................................................64 
9.2. 
Demographics .............................................................................................................64 
9.3. 
Concomitant Medication ............................................................................................64 
9.4. 
Physical Examination and Vital Signs ........................................................................65 
9.5. 
Adverse Events ...........................................................................................................65 
9.6. 
Electrocardiograms .....................................................................................................65 
9.7. 
Laboratory Tests .........................................................................................................65 
9.8. 
Disease Assessment ....................................................................................................67 
9.9. 
ECOG .........................................................................................................................67 
9.10. 
Pregnancy Test ............................................................................................................67 
9.11. 
Virology ......................................................................................................................67 
9.12. 
Compliance Diary .......................................................................................................67 
9.13. 
Dispensation, Administration, and Accountability of Voruciclib and 
Venetoclax ..................................................................................................................67 
9.14. 
Pharmacokinetics ........................................................................................................68 
9.14.1. 
Voruciclib Monotherapy .............................................................................................68 
9.14.2. 
Voruciclib + Venetoclax Combination Therapy .........................................................68 
9.15. 
Pharmacodynamics of Voruciclib and Voruciclib + Venetoclax ...............................71 

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10. 
STATISTICS ..............................................................................................................71 
10.1. 
Number of Subjects ....................................................................................................71 
10.2. 
Study Endpoints ..........................................................................................................72 
10.3. 
Analysis Methods .......................................................................................................72 
10.3.1. 
Handling of Missing Data ...........................................................................................73 
10.3.2. 
Analysis Populations ..................................................................................................73 
10.4. 
Safety Analyses ..........................................................................................................73 
10.4.1. 
Adverse Events ...........................................................................................................73 
10.4.2. 
Clinical Safety Laboratory Results .............................................................................73 
10.4.3. 
Vital Signs ..................................................................................................................74 
10.4.4. 
Electrocardiogram .......................................................................................................74 
10.5. 
Pharmacokinetic Analyses ..........................................................................................74 
10.6. 
Efficacy Analyses .......................................................................................................74 
11. 
REGULATORY AND REPORTING REQUIREMENTS ........................................74 
11.1. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................74 
11.2. 
Public Clinical Trial Registry .....................................................................................75 
11.3. 
Confidentiality ............................................................................................................75 
11.4. 
Financial Disclosure ...................................................................................................75 
11.5. 
Data Quality Assurance ..............................................................................................75 
12. 
DATA MANAGEMENT ...........................................................................................76 
12.1. 
Use of Electronic Case Report Forms ........................................................................76 
12.2. 
Study Site Monitoring.................................................................................................76 
12.3. 
Record Retention ........................................................................................................76 
13. 
AMENDMENTS TO THE PROTOCOL ...................................................................77 
14. 
PUBLICATION POLICY ..........................................................................................77 
15. 
REFERENCES ...........................................................................................................78 
APPENDIX 1. SCHEDULE OF ASSESSMENTS – CLL/SLL, FL, MCL, MZL, 
DLBCL, AND HIGH-GRADE B-CELL LYMPHOMAS .........................................80 
APPENDIX 2. SCHEDULE OF ASSESSMENTS - AML SUBJECTS ONLY - 
MONOTHERAPY ......................................................................................................83 
APPENDIX 3. SCHEDULE OF ASSESSMENTS - AML SUBJECTS ONLY – 
COMBINATION THERAPY ....................................................................................86 
APPENDIX 4. AML RESPONSE CRITERIA ..........................................................................91 

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APPENDIX 5. CLL/SLL RESPONSE CRITERIA: IWCLL .....................................................93 
APPENDIX 6. FOLLICULAR LYMPHOMA RESPONSE CRITERIA: LUGANO 
CLASSIFICATION ....................................................................................................96 
APPENDIX 7. LIST OF SENSITIVE CYTOCHROME P450 SUBSTRATES: 
CYP2C9, CYP2C19, CYP2D6, AND CYP3A4 ......................................................101 
APPENDIX 8. LIST OF DRUGS KNOWN TO PROLONG QT/QTC INTERVAL ..............102 
APPENDIX 9. MANAGEMENT OF TUMOR LYSIS SYNDROME ....................................107 
APPENDIX 10. CAIRO-BISHOP CRITERIA FOR DIAGNOSIS OF TUMOR LYSIS 
SYNDROME ............................................................................................................110 
 
LIST OF TABLES 
Table 1: 
Voruciclib Dose Escalation (Prior to Amendment 7) .................................................34 
Table 2: 
Voruciclib Dose Levels in Amendment 7 ..................................................................36 
Table 3: 
Dose Cohorts with Combination Voruciclib + Venetoclax (Amendment 11) ...........39 
Table 4: 
Dose Cohorts with Combination Voruciclib + Venetoclax (Amendment 12) ...........40 
Table 5: 
Administration Schedules of Voruciclib given in Combination with 
Venetoclax (IS2w,2w) ....................................................................................................41 
Table 6: 
Administration Schedules of Voruciclib given in Combination with 
Venetoclax (IS3w,1w) ....................................................................................................42 
Table 7: 
Early Stopping Boundaries for Toxicity – Expansion Cohort ....................................45 
Table 8 
Dose Modification Schedule Cohorts 1 to 5 ...............................................................46 
Table 9: 
Dose Modification Cohorts 1 to 5 ..............................................................................47 
Table 10: Re-treatment Following a Grade 3-4 Adverse Event in Cycles ≥2 in the 
Intermittent Schedules ................................................................................................48 
Table 11: Venetoclax Schedule Modification and Voruciclib Dose Modification for 
Toxicity .......................................................................................................................49 
Table 12: Monitoring and Management of Interstitial Lung Disease/Pneumonitis ....................51 
Table 13: Management of Potential Venetoclax Interactions with CYP3A and P-gp 
Inhibitors .....................................................................................................................56 
Table 14: PK Sample Collection for Voruciclib, Cohort 12 (QOD Dosing) ..............................69 
Table 15: PK Sample Collection for Voruciclib, Cohorts 13–19 and 21–25 (QD 
Dosing) .......................................................................................................................69 
Table 16: PK Sample Collection for Venetoclax, Cohort 12 (QOD Dosing) .............................70 
Table 17: PK Sample Collection for Venetoclax, Cohorts 13–19 and 21–25 (QD 
Dosing) .......................................................................................................................70 

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Table 18: European LeukemiaNet (ELN) Response Criteria in AML .......................................91 
Table 19: Schedule of Response Assessments for Subjects with CLL/SLL ..............................93 
Table 20: Response Criteria for CLL/SLL per IWCLL (Hallek et al) .......................................94 
Table 21: Schedule of Response Assessments for Subjects with Follicular Lymphoma 
and Other B-Cell Lymphomas ....................................................................................96 
Table 22: Revised Criteria for Response Assessment from Cheson et al 2014 ..........................98 
Table 23: Sensitive Substrates of CYP2C9, CYP2C19, CYP2D6, and CYP3A4 ....................101 
Table 24: Guidelines for Prophylaxis and Monitoring for Patients with CLL/SLL and 
other B-cell Malignancies at Risk of TLS ................................................................108 
Table 25: Definitions of Laboratory and Clinical Tumor Lysis Syndrome ..............................110 
 
LIST OF FIGURES 
Figure 1: 
Dose Escalation Scheme .............................................................................................35 
Figure 2: 
Dose Level/Schedule Scheme for IS ..........................................................................37 
Figure 3: 
TLS Risk Assessment for AML ...............................................................................109 
 

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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
Alkaline phosphatase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
APL 
acute promyelocytic leukemia 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
area under the concentration versus time curve 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CDK 
cyclin-dependent kinase 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
CR 
complete response/remission 
CRi 
complete remission with incomplete marrow recovery 
CRh 
complete remission with partial hematologic recovery 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP  
cytochrome 
DDI 
drug-drug interaction 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity  
DOR 
duration of response 
DS 
differentiation syndrome 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ELN 
European LeukemiaNet 
FDA 
Food and Drug Administration 

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Abbreviation 
Definition 
FDG 
fluorodeoxyglucose 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
FL 
follicular lymphoma 
GI 
gastrointestinal 
h 
hour 
HCV Ab 
Hepatitis C virus antibody 
ICF 
informed consent form 
IDH 
isocitrate dehydrogenase 
IEC 
Independent Ethics Committee 
IgHV 
immunoglobulin g heavy chain variable region 
ILD 
interstitial lung disease 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IS 
intermittent dosing schedule 
IS1w,3w 
intermittent dosing schedule of 1 week on therapy and 3 weeks off therapy 
IS2w,2w 
intermittent dosing schedule of 2 weeks on therapy and 2 weeks off therapy 
IS3w,1w 
intermittent dosing schedule of 3 weeks on therapy and 1 week off therapy 
IVIG 
intravenous immune globulin 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
LDH 
lactate dehydrogenase 
LDi 
longest diameter 
mBED 
minimum Biologically Effective Dose  
MCL 
mantle cell lymphoma 
Mcl-1 
myeloid cell leukemia protein 1 
MRD 
minimal residual disease 
MTD 
maximum tolerated dose 
MZL 
marginal zone lymphoma 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
overall response rate 
OTC 
over-the-counter 
PCR 
polymerase chain reaction  

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Abbreviation 
Definition 
PFS 
progression-free survival 
PI 
prescribing information 
PK 
pharmacokinetic(s) 
PML-RARA 
promyelocytic leukemia/retinoic acid receptor alpha 
PPI 
proton pump inhibitor 
PR 
partial response 
PT 
prothrombin time 
QD 
quaque die (once per day) 
QOD 
once every other day 
QTc 
QT corrected (corrected QT interval) 
QTcF 
QT-interval corrected according to Fridericia’s formula 
RBC 
red blood cell 
RP2D 
recommended Phase 2 dose 
RU 
ramp-up 
SAE 
serious adverse event 
SD 
stable disease 
SDi 
shortest diameter 
SLL 
small lymphocytic lymphoma 
SRC 
Study Review Committee 
TEAE 
treatment-emergent adverse event 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
uMRD 
undetectable minimal residual disease 
US 
United States 
WBC 
white blood cell 
WHO 
World Health Organization  
 

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1. 
BACKGROUND AND RATIONALE 
B-cell lymphoid malignancies arise from the accumulation of monoclonal, neoplastic 
B lymphocytes in lymph nodes and often in organs such as blood, bone marrow, spleen, and 
liver. Among the variants of B-cell lymphoid cancers is chronic lymphocytic leukemia/small 
lymphocytic lymphoma (CLL/SLL). As it progresses, this disorder is characterized by disabling 
constitutional symptoms: lymphadenopathy and organomegaly that can induce life-threatening 
organ dysfunction, as well as myelosuppression and immunocompromise that can result in 
susceptibility to infection and bleeding. Front-line use of multiagent chemoimmunotherapy or a 
Bruton tyrosine kinase inhibitor (e.g., ibrutinib) is commonly successful in suppressing disease 
manifestations for prolonged periods. However, CLL/SLL is incurable, and patients require 
further therapy to maintain disease control. 
Acute myeloid leukemia (AML) has a similar pathogenesis. Most adult patients will achieve a 
complete remission with initial chemotherapy and more than 45% of patients in complete 
response/remission (CR) will survive more than 3 years. The proportion of patients achieving a 
CR and the duration of remission is inversely related to age with a markedly worse prognosis for 
older patients. Patients who have failed to respond to initial treatment or relapsed after remission 
also have a poor prognosis, and allogeneic stem cell transplantation after achieving a remission 
to salvage chemotherapy offers the best option for long-term survival.  
Among the agents that have been approved for the therapy of CLL/SLL and AML is the oral 
drug, venetoclax, which is an inhibitor of the antiapoptotic protein B-cell leukemia/lymphoma-2 
(Bcl-2). Venetoclax is approved by the Food and Drug Administration (FDA) for the treatment 
of adults with CLL or SLL and in combination with azacytidine, or decitabine, or low-dose 
cytarabine for the treatment of newly diagnosed AML in adults 75 years or older, or who have 
comorbidities that preclude use of intensive induction chemotherapy (Venclexta® 
[US Prescribing Information] Rev 2022). 
Venetoclax has also been studied in other B-cell malignancies. A Phase 1 study which enrolled 
patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell 
lymphoma (MCL), Waldenström macroglobulinemia, and marginal zone lymphoma, showed 
evidence of efficacy with a 44% ORR. Adverse events (AEs) observed were similar to those 
reported in CLL except for a lower incidence of tumor lysis syndrome (TLS) with no clinical 
cases and laboratory findings only (Davids 2017). 
Approval of venetoclax in AML was based on data from a randomized, double-blind, 
placebo-controlled multicenter trial (VIALE-A) and 2 open-label studies. (Venclexta 
[US Prescribing Information] Rev 2022). In VIALE-A, patients were randomized to either 
venetoclax + azacitidine (n = 286) or placebo + azacitidine (n = 145). Median overall survival 
with venetoclax + azacitidine was 14.7 months versus 9.6 months with placebo + azacitidine 
(Hazard ratio = 0.66 [95% CI 0.52, 0.85]; p < 0.001). The CR rate was 37% with venetoclax + 
azacitidine versus 18% for placebo + azacitidine (p < 0.001), while the combined CR + CR with 
partial hematologic recovery (CRh) rate was 65% with venetoclax + azacitidine versus 23% for 
placebo + azacitidine (p < 0.001).  
In one of the open-label studies, venetoclax was evaluated in combination with azacitidine 
(n = 67) or decitabine (n = 13) and achieved CR and CRh rates of 43% and 18%, respectively, 
when administered with azacitidine and CR and CRh rates of 54% and 7.7%, respectively, when 

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administered with decitabine. In the other open-label study, venetoclax was evaluated in 
combination with low dose cytarabine (n = 61) and achieved a CR and CRh rate of 21% and 
21%, respectively.  
A Phase 2 study of venetoclax monotherapy in 32 patients with AML (30 with relapsed and/or 
refractory; 2 newly diagnosed), demonstrated a 19% response rate (2 CR and 4 complete 
remissions with incomplete hematologic recovery [CRi]) with a median duration of response 
(DOR) of 48 days. Venetoclax was generally tolerated up to doses of 1200 mg daily 
(Konopleva 2016). In another study, venetoclax in combination with azacitidine or decitabine in 
57 previously untreated elderly AML patients was administered at doses up to 1200 mg. No 
dose-limiting toxicities (DLTs) were observed, but subjects at the 1200 mg dose had frequent 
dose reductions due to gastrointestinal (GI) events. Overall, a 61% remission rate was obtained 
with 14/57 CR and 21/57 CRi (DiNardo 2018).  
These data demonstrate that targeted therapy specific for the apoptotic pathway can have 
significant clinical benefit for patients with both B-cell malignancies and AML. However, 
despite high response rates, patients are not cured by currently approved therapy and will 
generally experience disease progression, indicating the need for development of new agents 
with a complementary mechanism of action that either alone or in combination with venetoclax 
or other agents enhance disease clearance and circumvent disease resistance.  
Myeloid cell leukemia protein 1 (Mcl-1) is a member of the Bcl-2 anti-apoptotic, pro-survival 
family of molecules that are commonly over-expressed in B-cell malignancies and AML. 
Overexpression of Mcl-1 is associated with poor prognosis and resistance to therapy. Mcl-1 is 
not inhibited by venetoclax, which is specific for Bcl-2, and increased expression of Mcl-1 can 
be a mechanism of resistance for venetoclax therapy. Acquired resistance of lymphoma cell lines 
to Bcl-2 inhibition in vitro has been shown to involve transcriptional upregulation of Mcl-1 
(Yecies 2010). Additionally, non-clinical studies have also demonstrated the ability of Mcl-1 to 
render AML cells resistant to Bcl-2 targeted agents, and have demonstrated synergy in AML 
models between agents targeting Bcl-2 with those targeting Mcl-1 expression including 
cyclin-dependent kinase 9 (CDK9) inhibitors (Pan 2015, Bogenberger 2017, Luedtke 2017). 
Voruciclib is a potent oral cyclin-dependent kinase (CDK) inhibitor that indirectly suppresses the 
function of the pro-survival Mcl-1. Voruciclib inhibits Mcl-1 activity via 2 primary mechanisms: 
transcriptional repression through CDK9 inhibition and upregulation of the endogenous Mcl-1 
antagonist, NOXA. Exposure to voruciclib at concentrations of 1.5 µM and above leads to near 
complete apoptosis of CLL cells in vitro. This effect was independent of prognostic 
characteristics of the CLL cells (such as immunoglobulin heavy-chain variable-region [IgHV] 
mutation status, ZAP-70, or expression of CD38), although CLL cells with P53 mutations 
showed slightly decreased susceptibility. This effect was specific for CLL cells and not donor 
B cells (Paiva 2015). Voruciclib has also been demonstrated to induce apoptosis in AML cell 
lines in vitro and shows synergy with venetoclax (Luedtke 2018).  
The safety profile of voruciclib has been established in two Phase 1 single-agent studies in 
subjects with solid tumors (India study Protocol P1446A-05/19/08 and Canada study 
Protocol P1446A-05/20/08, total subjects n = 77) and in one Phase 1 study in advanced or 
inoperable malignant melanoma in combination with the BRAF inhibitor, vemurafenib, 
(Protocol P1446A-05/72/12); this study was terminated early by Piramal, the original voruciclib 
Sponsor, due to business reasons after 9 subjects were enrolled. In the first single-agent study 

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(Protocol P1446A-05/19/08), conducted in India, voruciclib was administered for 14 days in 
21-day cycles. Dose levels of 75 to 850 mg/day were evaluated, and a total of 29 subjects were 
enrolled. Common AEs (occurring in ≥25% subjects) were vomiting, nausea, diarrhea, decreased 
appetite, pyrexia, asthenia, constipation, abdominal pain, headache, and back pain. One subject 
in the 600 mg cohort experienced DLTs of Grade 3 diarrhea and Grade 3 intestinal obstruction. 
Two DLTs (Grade 3 abdominal pain and Grade 2 acute renal failure) leading to discontinuation 
from the study were reported in the 850 mg/day cohort. The dose level of 600 mg/day was 
declared the maximum tolerated dose (MTD). Six serious adverse events (SAEs) related to 
voruciclib were reported during this study, including gastroenteritis, hematuria, diarrhea, 
elevated creatinine, death not otherwise specified, and acute renal failure. Stable disease (SD) 
was reported in 8 subjects for at least 2 cycles, with 4 of 6 subjects achieving SD for 4 cycles, 
and 1 of the 6 achieving SD for 6 cycles. 
The second single-agent study (Protocol P1446A-05/20/08), conducted in Canada, evaluated 
dose levels of 75 to 500 mg/day administered daily continuously, with a total of 39 subjects 
enrolled. Common AEs (occurring in ≥25% subjects) were diarrhea, nausea, fatigue, decreased 
appetite, vomiting and dyspnea. Three DLTs (including an increase in International Normalized 
Ratio [INR], hypokalemia, and diarrhea) were reported at 500 mg/day cohort. One DLT of 
diarrhea was reported in the expanded MTD cohort of 350 mg/day. Three SAEs related to 
voruciclib were reported in this study, including increased INR (500 mg dose cohort), sudden 
death (500 mg dose cohort), and diarrhea leading to death (350 mg dose cohort). Overall, SD 
lasting for at least 2 cycles was reported in 12 subjects. One subject with small cell lung cancer 
remained on treatment with SD for 6 cycles, while another with alveolar soft tissue sarcoma, 
whose disease was progressing at the time of enrollment, achieved SD as a best response and 
remained on treatment for 12 cycles. 
Based on PK data from Phase 1 studies P1446A-05/19/08 and P1446A-05/20/08 the average 
accumulation ratios of 2.06 and 2.77, voruciclib effective half-life value was estimated to be 
24 hours to 36 hours (for further justifications of voruciclib dosing rationale in combination with 
venetoclax see Section 4.2.2.1). There was modest accumulation with steady state being reached 
by 14 days. Doses of ≥200 mg daily achieved through levels above 1.5 µM at 14 days. Further 
details on the PK are presented in the current Investigator’s Brochure.  
Prior to this ongoing study, voruciclib has not been studied in patients with B-cell malignancies 
or AML, although the intravenous CDK inhibitors (flavopiridol and dinaciclib) have been 
studied in both. In CLL activity has been seen with partial remission rates in the 25–40% range. 
Tumor lysis syndrome (TLS) was observed with these agents and was the DLT for flavopiridol 
(Lanasa 2015, Ghia 2017). The safety and efficacy of flavopiridol has also been examined in a 
Phase 1 study in non-Hodgkin lymphoma, with a 14% partial response (PR) rate observed with 
responses in MCL, FL, DLBCL, and SLL. The rate of TLS was lower in lymphoma patients 
compared to CLL, with 2 of 46 enrolled subjects showing biochemical evidence of TLS 
(Jones 2014). In AML, both have shown limited activity as single agents with transient reduction 
in peripheral leukocyte counts but no true complete remissions (Blum 2010, Gojo 2013). This 
level of activity may be due to the intravenous (IV) route of administration, the intermittent 
administration schedule and/or the short half-life of less than 4 hours for each compound. 
Voruciclib is administered orally, once daily and has a half-life of 24 to 48 hours, and therefore 
has the potential for continuous inhibition of CDK9. The ability to continuously suppress the 

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target has the potential for significantly greater efficacy than that seen with other CDK9 
inhibitors. 
Collectively, these data provide context for the clinical development of voruciclib for the 
treatment of B-cell malignancies and AML. This clinical protocol will further characterize the 
safety, pharmacology, and activity of voruciclib in these hematologic malignancies. In addition, 
the combination of voruciclib and venetoclax will be investigated since these agents target 
distinct proteins (Mcl-1 and Bcl-2) involved in regulating apoptosis. It is hypothesized that 
co-administration of venetoclax and voruciclib will result in a higher proportion of patients 
achieving CR and improved progression-free survival (PFS).  
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
• Determine the safety and tolerability of voruciclib and identify a safe and minimum 
biologically effective dose (mBED) of voruciclib monotherapy in subjects with relapsed or 
refractory B-cell malignancies and relapsed or refractory AML 
• Determine the safety and tolerability and identify the safe and mBED of voruciclib in 
combination with venetoclax in subjects with relapsed or refractory AML  
2.2. 
Secondary Objectives 
• Evaluate the potential efficacy of voruciclib monotherapy based on: 
a. International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for 
CLL/SLL (Appendix 5) or the Lugano classification of response assessment for 
lymphoma (Appendix 6), as appropriate, for subjects with B-cell malignancies  
b. The 2017 European LeukemiaNet (ELN) criteria for subjects with AML 
(Appendix 4) 
• Evaluate the potential efficacy of voruciclib in combination with venetoclax in subjects 
with AML based on the 2017 ELN criteria  
• Evaluate the PK of voruciclib administered as monotherapy, and the PK of voruciclib and 
venetoclax when administered in combination 
2.3. 
Exploratory Objectives 
• Determine the effect of voruciclib monotherapy and voruciclib in combination with 
venetoclax (AML only) on biomarkers and functional activities of proteins in the apoptotic 
pathway  
• Correlate anti-tumor activity with baseline tumor characteristics 

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3. 
SUBJECT ELIGIBILITY 
3.1. 
Inclusion Criteria  
To be eligible for study participation, subjects must meet all of the following inclusion criteria: 
1. 
Signed, informed consent 
2. 
Age ≥18 years 
3. 
Histologically confirmed diagnosis of FL, MCL, marginal zone lymphoma (MZL), SLL, 
CLL, or DLBCL, and: 
a. Subjects must have disease that has relapsed or is refractory to 2 or more prior regimens 
and in need of treatment due to progressive disease (PD) 
b. Subjects must have received appropriate standard therapy for the subject’s malignancy 
and have developed disease progression or are intolerant to appropriate standard therapy 
c. The clinical investigator must have discussed all alternate treatment options with the 
potential study subject prior to study enrollment 
4. 
Histologically confirmed diagnosis of primary AML or secondary AML (e.g., following 
myelodysplastic syndrome or myeloproliferative disease) as defined by World Health 
Organization (WHO) criteria (Arber 2016) 
a. Relapsed or primary refractory disease having received 2 or more lines of therapy 
(voruciclib monotherapy cohorts) or 1 or more lines of therapy (voruciclib plus 
venetoclax combination cohorts) 
b. Subjects must not be eligible for, or have failed, other therapies known to be effective 
for treatment of their AML 
NOTE: A subject must meet inclusion criterion 3 or 4, but not both 
5. 
Presence of measurable disease defined per the 2008 International Workshop on CLL 
guidelines (see Appendix 5) or by 2014 Lugano criteria for non-Hodgkin lymphoma 
(see Appendix 6); these criteria do not apply to subjects with AML 
6. 
Life expectancy of ≥3 months 
7. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤1 
8. 
For subjects with B-cell malignancies, adequate hematologic parameters unless clearly due 
to the disease under study: 
a. Absolute neutrophil count (ANC) ≥0.5 × 109/L 
b. Platelet count >50 × 109/L  
c. Hemoglobin ≥8.0 g/dL 
9. 
Adequate coagulation parameters: 
a. Prothrombin time (PT) ≤1.5 × ULN (i.e., Grade ≤1) 
b. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN (i.e., Grade ≤1) 

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10. Adequate renal and hepatic function, per laboratory reference range at screening: 
a. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), 
alanine aminotransferase (ALT)/serum glutamate-pyruvate transaminase (SGPT) 
≤2.5 × ULN 
b. Total bilirubin ≤1.5 × ULN (if secondary to Gilbert’s syndrome, ≤3 × ULN is permitted) 
c. Creatinine clearance ≥60 mL/minute 
11. Subjects with B-cell malignancies must have completed:  
a. Previous anti-cancer medication a minimum of 5 elimination half-lives (t½) or 2 weeks 
(whichever is less) prior to Day 1 (a course of corticosteroids ≤7 days in duration prior 
to Day 1 is allowed) 
b. Radiation therapy or surgery ≥2 weeks before Day 1 
12. Subjects with AML must have completed: 
a. Previous anti-cancer medication for a minimum of 5 elimination half-lives (t½) or 
2 weeks (whichever is less) prior to start of voruciclib (monotherapy) or venetoclax 
(combination therapy) administration 
b. Radiation therapy ≥2 weeks or major surgery ≥4 weeks before start of voruciclib 
(monotherapy) or venetoclax (combination therapy) administration  
Note: Hydroxyurea and other therapy to control leukocytosis is allowed up to the end of 
Cycle 1 
13. All clinically significant treatment-related toxicity from prior therapy (other than alopecia) 
must have resolved to Grade ≤1, or to a new stable baseline at time of enrollment 
14. Females of childbearing potential must have a negative serum pregnancy test within 14 days 
prior to Day 1 
15. For subjects capable of procreation, agree to use medically effective contraception during 
the study (which must, at the minimum, include a barrier method), and for 90 days after 
discontinuation of study drug. Females of childbearing potential should use 2 forms of 
contraception, one of which should be a barrier contraceptive 
16. Agree to not donate sperm or oocytes during the entire study treatment period, and for 
90 days after study drug discontinuation 
3.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. 
History of pneumonitis due to any cause 
2. 
For AML subjects only 
a. Acute promyelocytic leukemia (APL with promyelocytic leukemia/retinoic acid 
receptor alpha [PML-RARA]) 
b. Peripheral blast count >25 × 109/L (hydroxyurea or other treatment to lower WBC 
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3. 
Known central nervous system involvement  
4. 
History of another malignancy, except for the following: 
a. Adequately treated local basal cell or squamous cell carcinoma of the skin 
b. Adequately treated carcinoma in situ without evidence of disease 
c. Adequately treated papillary, noninvasive bladder cancer 
d. Other cancer that has been in complete remission for ≥2 years (subjects with low-grade 
prostate cancer on active surveillance and not expected to clinically progress over 
2 years are allowed) 
5. 
Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, 
cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina 
requiring therapy; symptomatic peripheral vascular disease; New York Heart Association 
Class 3 or 4 congestive heart failure; or uncontrolled Grade ≥3 hypertension (diastolic 
blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) despite 
antihypertensive therapy  
6. 
Significant screening electrocardiogram (ECG) abnormalities, including unstable cardiac 
arrhythmia requiring medication, atrial fibrillation/flutter, left bundle branch block, 
2nd-degree atrioventricular (AV) block type II, 3rd-degree AV block, Grade ≥2 bradycardia, 
or corrected QT by Fridericia formula (QTcF average of triplicate ECG) >450 msec 
7. 
Subjects who are receiving:  
a. Warfarin 
b. Other anti-cancer therapy (treatment to reduce leukocyte count in AML subjects is 
allowed) 
c. Strong or moderate CYP3A inhibitors (including grapefruit, Seville oranges, and star 
fruit) are to be avoided. Other CYP inhibitors (see Appendix 7) should be avoided and 
used only if essential for patient care. Strong or moderate CYP3A inhibitors and P-gp 
inhibitors must be discontinued 3 or more days before initiating venetoclax (subjects 
enrolled on combination voruciclib + venetoclax cohorts) 
d. Strong or moderate CYP3A inducers should be discontinued at least 7 days prior to 
venetoclax administration (subjects enrolled on combination voruciclib + venetoclax 
cohorts)  
e. Calcineurin inhibitors within 28 days prior to start of study drug 
f. Any other investigational agent 
8. 
GI diseases that may interfere with drug absorption or that will affect interpretation of GI 
AEs (including but not limited to gastric or intestinal bypass surgery, pancreatic enzyme 
insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronic 
diarrheal illness, bowel obstruction). The Medical Monitor should be contacted if there is 
any question of eligibility in this regard 
9. 
Ongoing risk for bleeding due to active peptic ulcer disease, bleeding diathesis, or other 
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10. Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upper 
respiratory tract infections) at the time of start of voruciclib therapy, including: 
a. Positive hepatitis B surface antigen and/or hepatitis B core antibody test plus a positive 
hepatitis B polymerase chain reaction (PCR) assay (subjects with a negative PCR 
assay are permitted with appropriate anti-viral prophylaxis) 
b. Positive hepatitis C virus antibody (HCV Ab) test; subjects with positive HCV Ab test 
are eligible if they are negative for hepatitis C virus by PCR 
c. Symptomatic/uncontrolled HIV infection/AIDS, or currently taking contraindicated 
medications for HIV control  
11. Receipt of an allogeneic transplant at any time prior to enrollment or an autologous 
transplant within the preceding 3 months at time of enrollment in the monotherapy cohorts 
Note: Prior allogenic transplant is permitted for AML subjects enrolled in voruciclib + 
venetoclax combination cohorts 
12. Pregnant or breastfeeding or planning to become pregnant 
13. Prior solid organ transplantation 
14. Prior therapy with a CDK9 inhibitor 
15. Ongoing immunosuppressive treatment (including calcineurin inhibitors as noted in 
Exclusion 7) at the time of the start of study treatment (Cycle 1, Day 1), including systemic 
or enteric corticosteroids except as follows:  
a. Prior to the start of study treatment, subjects may be using systemic corticosteroids 
(≤20 mg/day of prednisone or equivalent), topical, or inhaled corticosteroids 
b. During study treatment, subjects may use systemic, topical, or enteric corticosteroids, 
if needed 
16. Concurrent participation in another therapeutic clinical trial 
17. Any illness, medical condition, organ system dysfunction, medication use, or social 
situation (including mental illness or substance abuse) deemed by the Investigator to be 
likely to interfere with a subject’s ability to sign informed consent, adversely affect the 
subject’s ability to cooperate and participate in the study, or otherwise compromise the 
interpretation of study results 
4. 
STUDY DESIGN 
4.1. 
Overall Study Design 
This is a Phase 1, open-label, 3 + 3 dose escalation study to determine the safety and preliminary 
efficacy of voruciclib as monotherapy in subjects with relapsed and/or refractory B-cell 
malignancies or AML and in combination with venetoclax in subjects with relapsed and/or 
refractory AML after treatment with standard therapy.  
Initially 3 subjects will be enrolled into a dose cohort and followed for 28 days. Due to the 
likelihood of subjects with advanced malignancy discontinuing between the start of the informed 

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consent process and before completion of the first 28-day cycle for reasons unrelated to 
voruciclib toxicity, a fourth subject may be enrolled. This will mitigate the risk of delay in 
assessing each dose level. If a fourth subject is enrolled, the DLT period will close when 
3 subjects have completed 28 days without DLT. If one DLT occurs in any of the four subjects 
during the DLT assessment period, an additional 2 subjects will be enrolled to a total of 
6 subjects.  
As of Amendment 7, intermittent schedule (IS) dosing regimens were implemented in order to 
mitigate toxicities observed with continuous voruciclib dosing (see rationale provided in 
Section 4.2.1.1).  
Amendments 8, 9 and 10 were not implemented. 
Starting with Amendment 11, the safety and tolerability of voruciclib administered in 
combination with venetoclax will be evaluated in subjects with relapsed and/or refractory AML 
(see rationale provided in Section 4.2.2.1). 
In Amendment 12, an additional intermittent dosing schedule of 3 weeks on/1 week off (IS3w,1w) 
of voruciclib administered in combination with venetoclax will be evaluated in subjects with 
relapsed and/or refractory AML (see rationale provided in Section 4.2.2.2). 
4.2. 
Starting Dose and Dose Levels 
4.2.1. 
Voruciclib Monotherapy 
Voruciclib has been studied in two previous single-agent Phase 1 studies in advanced refractory 
malignancies (India study Protocol P1446A-05/19/08 and Canada study Protocol 
P1446A-05/20/08). The MTD in these previous studies was identified as 600 mg when given 
daily for 14 days in a 21-day cycle, and 350 mg when given daily as a continuous administration. 
The initial dose level was 75 mg in both studies. 
The initial dose level in this current study was 50 mg voruciclib daily in Cohort 1, followed by 
additional dose cohorts increasing stepwise up to 250 mg (i.e., 50, 100, 150, 200, and 250 mg). 
Due to dose limiting toxicities at 100 mg QD, intermittent dosing regimens are being studied at 
100, 150, or 200 mg either on an IS2w,2w or an IS1w,3w. The previously planned maximum daily 
dose of 250 mg was based on data from previous clinical studies which indicate the dose is 
tolerated (less than the previously identified MTD of 350 mg daily). Additionally, data from the 
prior Phase 1 studies show that doses of 150-250 mg are associated with trough serum levels of 
voruciclib that exceed the level required for maximum in vitro activity against CLL and AML 
cells.  
4.2.1.1. 
Rationale for Dose and Schedule Changes in Amendment 7 – Voruciclib 
Monotherapy 
Prior to Amendment 7, a total of 16 subjects had been administered voruciclib; 8 in Cohort 1 and 
8 in Cohort 2, including 12 subjects with B-cell malignancies and 4 subjects with AML; with all 
4 AML subjects enrolled in Cohort 2 following the implementation of Amendment 5. During the 
continuous daily dosing cohorts, there were no DLTs in the 50 mg QD dose cohort. At the 
100 mg QD dose cohort, 2 subjects with AML had a DLT of pneumonitis, pre-empting further 
dose escalation on the continuous daily dosing schedule. In addition, one subject with DLBCL 

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enrolled at the 50 mg QD dose cohort experienced hypoxemic respiratory failure with pulmonary 
infiltrates in Cycle 4. There was no identified cause for this event, which was considered related 
to study drug and led to voruciclib discontinuation.  
The mechanism of this pulmonary toxicity is not understood. PK data from the Phase 1 studies in 
solid tumors indicated that voruciclib has a very high volume of distribution (>100 L), 
suggesting higher exposure in tissues than in plasma. Interstitial pneumonitis has been reported 
post-marketing with the CDK4/6 inhibitors, which are approved in the US for the treatment of 
patients with breast cancer (FDA Drug Safety Communications, September 2019).  
Because there were no objective responses reported at the dose of 50 mg QD, an IS was 
implemented to determine whether doses of 100 mg or greater could be administered safely. 
These doses were projected to achieve plasma concentrations needed for antitumor activity based 
on non-clinical models (data on file). The planned intermittent schedule allowed for complete 
clearance of the drug from the plasma and tissues during the 2-3 weeks off therapy and may 
mitigate the risk of toxicity. In the Phase 1 study P1446A-05/19/08 in various solid tumors, 
voruciclib was administered on a 2 weeks on/1 week off schedule with doses escalated up to 
850 mg and the MTD was established at 600 mg. The intermittent schedule to be evaluated in 
Amendment 7 will further expand the treatment-free interval to 2 weeks (Cohorts 6-8) or 
3 weeks (Cohorts 9-11) and evaluate voruciclib doses levels up to 200 mg. 
Beginning with Amendment 7, subjects with AML and B-cell malignancies were to be evaluated 
in up to 6 new potential IS dose regimens separately. 
4.2.2. 
Voruciclib + Venetoclax Combination Therapy in Subjects with AML 
Note: Amendments 8, 9 and 10 were not implemented. 
Upon determination of the safe and mBED of voruciclib monotherapy in AML subjects, the 
combination of voruciclib with venetoclax will be evaluated in subjects with relapsed or 
refractory AML. Based on preliminary safety and tolerability data with voruciclib monotherapy, 
the IS2w,2w dosing schedule was selected for use in the combination cohorts of voruciclib and 
venetoclax.  
4.2.2.1. 
Rationale for Voruciclib + Venetoclax Combination Therapy in Amendment 11 
For the treatment of AML subjects, the sponsor hypothesized that use of a CDK9 inhibitor (such 
as voruciclib) with its corollary effect on Mcl-1 inhibition when given in combination with a 
Bcl-2 inhibitor (such as venetoclax) could synergistically bring about disruption of the cell cycle 
and inhibition of pro-survival cell cycle pathways. Support for this hypothesis was provided by 
preclinical in vitro and murine xenograft studies. In vitro studies using selected AML cell lines, 
exposure to the combination of voruciclib + venetoclax produced significantly greater apoptosis 
compared to either agent alone; a finding that was observed in both venetoclax resistant and 
sensitive cell lines (Luedtke 2020). In a murine xenograft model using MV4-11 AML cells, the 
combination of voruciclib + venetoclax was associated with a significantly longer median overall 
survival time compared to either agent alone (Luedtke 2020). 

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4.2.2.2. 
Rationale for an Additional Voruciclib Schedule in Amendment 12 
The rationale for IS3w,1w is to decrease the number of days without voruciclib from 14 to 7 days 
in a treatment cycle, thereby reducing the potential risk of AML regrowth during the 2-week 
treatment break in the IS2w,2w schedule. 
4.3. 
Dose Escalation Scheme 
4.3.1. 
Voruciclib Monotherapy 
Dose cohorts are defined in Table 1 (prior to Amendment 7) and Table 2 (per Amendment 7), 
with the dose escalation scheme is detailed in Figure 1. The total number of cohorts will depend 
upon the incidence of DLTs.  
4.3.1.1. 
Dose Cohort Escalation Prior to Amendment 7 
Dose escalation will be allowed after 3 subjects have completed 1 cycle with no reported DLT, 
or 6 subjects have completed 1 cycle with no more than 1 DLT. Escalation to the next dose level 
will depend on demonstrated safety, tolerability, and DLT as defined in Section 4.4, and after 
approval by the Study Review Committee (SRC), which is composed of clinical investigators 
and sponsor representatives (including the Medical Monitor). The SRC will review ongoing 
safety data and any potential safety signals. Escalation to a new dose level may proceed only 
after the SRC conducts a review of safety data from all preceding subjects who are evaluable for 
DLTs.  
The SRC will evaluate the accumulated safety data and advise if enrollment needs to be held at 
any time in a dose cohort for further safety evaluation. 
The Investigator may increase the voruciclib dose level above the initial dose assigned at 
enrollment after the SRC has authorized opening enrollment at a new dose level, and after 
consultation with the Medical Monitor. Subjects whose voruciclib dose is increased to the next 
dose level will not count toward the assessment of DLTs at the higher dose level.  
Table 1: 
Voruciclib Dose Escalation (Prior to Amendment 7) 
Cohort/Dose Level 
Daily Dose 
1 
50 mg 
2 
100 mg 
3 
150 mg 
4 
200 mg 
5 
250 mg 
 

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Figure 1: 
Dose Escalation Scheme  
 
Abbreviations: DLT = dose-limiting toxicity; MTD = maximum tolerated dose. 
Note: a fourth subject may be enrolled in each dose cohort to mitigate the risk of one of the initial 3 subjects not 
being evaluable for DLT due to disease progression or other reason unrelated to voruciclib. 
4.3.1.2. 
Dose Cohort Escalation as of Amendment 7 
As of Amendment 7, dosing was modified to administer voruciclib monotherapy on an IS. The 
safety and tolerability, identification of a safe and mBED will be assessed independently for 
subjects with AML and B-cell malignancies, dose and regimen evaluations will be conducted in 
each of these disease groups separately by opening the next cohort in each disease group as 
determined by the SRC. In order to differentiate disease-specific cohorts, subjects with AML 
will be designated as Cohorts 6a-11a, and subjects with B-cell malignancies will be designated 
as Cohorts 6b-11b. 
Initially, IS of 2 weeks on therapy followed by 2 weeks off therapy (IS2w,2w) will be evaluated for 
up to 3 dose levels for AML and B-cell malignancies separately (Cohorts 6a - 8a and 6b - 8b, 
respectively). If the IS2w,2w in Cohort 6a or 6b (i.e., the lowest dose on IS2w,2w) for either disease 
group is not tolerated in that group then further evaluation of the IS2w,2w will be stopped in that 
disease group and the IS with 1 week on therapy followed by 3 weeks off (IS1w,3w), in a 28-day 
cycle will be evaluated in that disease group. The dose cohorts that will potentially be enrolled 
are defined in Table 2. 

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Table 2: 
Voruciclib Dose Levels in Amendment 7 
Cohort Dose Level 
Dose/Schedule 
6a, b 
100 mg IS2w,2w 
7a, b 
150 mg IS2w,2w 
8a, b 
200 mg IS2w,2w 
9a, b 
100 mg IS1w,3w 
10a, b 
150 mg IS1w,3w 
11a, b 
200 mg IS1w,3w 
Cohorts comprising subjects with AML are designated “a” and cohorts of subjects with B-cell malignancies are 
designated “b” 
Because enrollment will be conducted independently in subjects with AML and B-cell 
malignancies, it is possible the voruciclib dose and/or schedule under evaluation at any time 
point may be different in the 2 groups. 
Within each disease group, dose escalation will follow the 3+3 design described in Figure 2, and 
summarized below: 
• Cohort 6: 100 mg QD, administered IS2w,2w  
• If 0 of 3 subjects have a DLT, the study will continue to enroll in Cohort 7. 
• If >1 of 3 subjects have a DLT, this dose level will be declared as not safe, further 
dose escalation on the IS2w,2w regimen will not proceed, and Cohort 9 evaluating a 
less intensive dosing schedule (IS1w,3w) will be studied.  
• If 1 of 3 subjects have a DLT, 3 more subjects will be enrolled in Cohort 6. 
• If >1 of 6 subjects have a DLT, this dose level will be declared as not safe, further 
dose escalation on IS2w,2w will not proceed, and Cohort 9 will be studied.  
• If ≤1 of 6 subjects have a DLT, the study will continue to enroll in Cohort 7. 
• Cohort 7: 150 mg QD, administered IS2w,2w 
• If 0 of 3 subjects have a DLT, this dose and schedule will be declared safe for either 
dose escalation to Cohort 8 or evaluation of 3 additional subjects in Cohort 7; this 
will be determined by the SRC based on PK and clinical results. 
• If >1 of 3 subjects have a DLT, this dose will be considered as not safe, further dose 
escalation will not proceed, and 3 subjects will be enrolled in Cohort 6 (for up to 
6 evaluable subjects in Cohort 6) to confirm it is the MTD.  
• If 1 of 3 subjects have a DLT, 3 more subjects will be enrolled in Cohort 7. 
• If >1 of 6 subjects have a DLT, this dose level will be considered as not safe for 
further evaluation and 3 additional subjects will be enrolled in Cohort 6 to confirm it 
is the MTD. However, if Cohort 6 has previously enrolled 6 subjects with ≤1 DLTs, 
then the Cohort 6 dose level will be declared the MTD.  

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• If ≤1 of 6 subjects have a DLT, this dose and schedule will be declared safe for either 
dose escalation to Cohort 8 or evaluation of that dose in an expansion cohort; this will 
be determined by the SRC based on PK and clinical results. 
• Cohort 8: 200 mg QD, administered IS2w,2w 
• If 0 of 3 subjects have a DLT, this dose and schedule will be declared safe, and 
3 additional subjects will be enrolled in Cohort 8 to confirm it is the MTD. 
• If >1 of 3 subjects have a DLT, this dose will be considered as not safe, and 
3 subjects will be enrolled in Cohort 7 (for up to 6 evaluable subjects enrolled in 
Cohort 7) to confirm it is the MTD.  
• If 1 of 3 subjects have a DLT, 3 more subjects will be enrolled in Cohort 8. 
• If >1 of 6 subjects have a DLT, this dose level will be considered as not safe for 
further evaluation and 3 additional subjects will be enrolled in Cohort 7 to confirm it 
is the MTD. However, if Cohort 7 has previously enrolled 6 subjects with ≤1 DLTs 
then Cohort 7 dose level will be declared the MTD. 
• If ≤1 of 6 subjects have a DLT, this dose and schedule will be declared safe for cohort 
expansion. 
Cohorts 9 to 11, using IS1w,3w, will open to enrollment only if the IS2w,2w in Cohort 6 is deemed 
not tolerable. Enrollment in Cohorts 9 to 11 will follow the same dose escalation scheme 
described for Cohort 6 to 8. 
The potential cohorts and dose/schedule changes to evaluate the safety of dose levels with IS 
dosing is presented in Figure 2.  
Figure 2: 
Dose Level/Schedule Scheme for IS 
 

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If the next dose level in the AML or B-cell malignancies monotherapy cohorts has been declared 
safe by the SRC, subjects with the same disease type (AML or B-cell malignancies) enrolled in 
the monotherapy cohorts at a lower dose level may have their dose escalated to the next dose 
level after completing Cycle 1 without a DLT (intra-subject dose escalation). For example, a 
subject with B-cell malignancies enrolled in Cohort 6b (100 mg IS2w,2w) may have the dose 
increased to 150 mg IS2w,2w in Cycle 2 if the dose of 150 mg IS2w,2w was deemed safe in the 
B-cell malignancies cohort by the SRC. 
Once safe and mBED has been identified, the SRC may select a dose for an expansion cohort 
that may enroll up to 6 additional AML subjects in order to obtain additional safety and 
biomarker data. Formal stopping rules for excess toxicity in expansion cohorts are provided 
Section 4.5.  
Subjects may continue to receive voruciclib monotherapy while there is evidence of clinical 
benefit (partial remission [PR] or better) in subjects with B-cell malignancies or AML by the end 
of Cycle 6 and acceptable toxicity as judged by the Investigator.  
4.3.2. 
Dose Cohort Evaluation of Voruciclib + Venetoclax Combination Therapy 
in AML 
Combination therapy with voruciclib and venetoclax will be evaluated in AML subjects only, 
and only subsequent to the determination of the safety, tolerability, and minimum biologically 
effective dose of voruciclib monotherapy in AML subjects. Dose escalation of voruciclib in the 
combination cohorts will be informed by the safety, tolerability, and PK results and require the 
approval of the SRC. 
The voruciclib monotherapy results in AML subjects as of 21 September 2021 demonstrated the 
dose level voruciclib 200 mg IS2w,2w (Cohort 8a) as safe, had antitumor activity in some patients, 
and achieved steady state (Day 8) pre-dose plasma concentrations of 0.9 μM and Cmax of 1.5 μM 
(concentrations shown to be active in non-clinical models in AML and CLL). The Sponsor 
determined that 200 mg is a safe and minimum biologically effective dose, and in consultation 
with the SRC, the decision was made to stop voruciclib dose escalation because continued dose 
escalation solely to determine the MTD of single agent voruciclib in AML may expose subjects 
to potential toxicity, and single-agent CDK9 inhibitors are unlikely to induce durable responses 
in AML. A more clinically meaningful approach would be to evaluate voruciclib in combination 
with venetoclax, and to conduct the evaluation of additional dose levels with the combination 
therapy.  
Amendment 11 – IS2w,2w Dosing Schedule 
Voruciclib dosing in combination with venetoclax will utilize the IS2w,2w dosing schedule, 
starting with the dose level of voruciclib 50 mg QOD (Cohort 12) and escalating as per Table 3. 
The voruciclib starting dose of 50 mg QOD was selected because it is 4 dose levels lower than 
200 mg QD, the dose established to be safe as a monotherapy on IS2w,2w in AML. The dose of 
50 mg is 25% of the highest dose studied in AML, and for which no DLTs were reported, to take 
into account potential drug interaction with venetoclax and the first introduction in clinical 
studies of the voruciclib malonate salt tablets (see Section 4.3.2.2 for details). 
The dose levels of voruciclib to be evaluated range from 50 mg to 350 mg administered IS2w,2w. 
For reference, the MTD of voruciclib in Phase 1 studies in solid tumors was 600 mg when 

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administered daily for 14 days in a 21-day cycle and 350 mg daily when administered 
continuously.  
Only the tablet formulation containing the voruciclib malonate salt will be used in the voruciclib 
plus venetoclax combination group. 
Table 3: 
Dose Cohorts with Combination Voruciclib + Venetoclax (Amendment 11) 
Cohort Dose Level 
Doses and Schedule 
12 
voruciclib 50 mg QOD, administered IS2w,2w + venetoclax administered QD × 28 days 
13  
voruciclib 50 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
14 
voruciclib 100 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
15 
voruciclib 150 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
16 
voruciclib 200 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
17 
voruciclib 250 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
18 
voruciclib 300 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
19 
voruciclib 350 mg QD, administered IS2w,2w + venetoclax administered QD × 28 days 
Abbreviation: QOD = once every other day 
At the completion of the DLT period for each cohort, decisions to escalate in subsequent cohorts will be guided by 
SRC review of all available safety data, PK and PD data.  
For Cohort 12, the dosing of voruciclib will be Days 3, 5, 7, 9, 11, and 13 of Cycle 1, and Days 1, 3, 5, 7, 9, 11, 
and 13 of Cycle 2 and beyond. 
Dose escalation to the next cohort will be initiated after 3 subjects have completed 1 cycle with 
no reported DLTs, or after 6 subjects have completed 1 cycle with no more than 1 DLT (as 
defined in Section 4.4) and with the approval of the SRC after review of safety from the cohort 
under review. 
Intra-patient dose escalation to the next dose in Cycle 2 or later cycle is allowed at the discretion 
of the investigator and after consultation with the Sponsor if the next dose level has been 
declared safe by the SRC. More specifically, a subject enrolled at a dose level X may have their 
dose escalated to the next dose level X + 1 after completing Cycle 1 without a DLT. 
Dose escalation proceeds until assessment of clinical and PK parameters by the SRC establishes 
the safe BED for voruciclib in combination with venetoclax. More specifically, a voruciclib dose 
in combination with venetoclax that meets the following criteria:  
• DLT not to exceed 1 in 6 patients, overall response rate (ORR) ≥30%, as compared to 
historical ORR of 19% with 400-800 mg venetoclax alone in relapsed/refractory AML 
(Konopleva 2016), and  
• Trough plasma concentration of 1 to 1.5 µM, concentrations shown to be synergistic in 
combination with venetoclax in preclinical models.  
Once the safe and mBED of voruciclib in combination with venetoclax is identified by the SRC, 
which could be a dose less than 350 mg, dose escalation will stop and the SRC may recommend 
opening the dose expansion for the combination therapy (up to 12 subjects). At that time, 
subjects still actively dosing in the prior cohort may have their dose escalated to the next dose 
level after completing Cycle 1 (intra-subject dose escalation). Subjects may continue to receive 

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voruciclib plus venetoclax while there is evidence of clinical benefit (partial remission [PR] or 
better) by the end of Cycle 6 and acceptable toxicity as judged by the Investigator.  
Amendment 12 – IS3w,1w Dosing Schedule 
In Amendment 12, the combination of voruciclib with venetoclax will be evaluated in subjects 
with relapsed and/or refractory AML using a voruciclib intermittent schedule of daily dosing on 
Days 1–21 in a 28-day cycle, with no voruciclib dosing on Days 22–28 of the cycle, designated 
as IS3w,1w with the exception of Cycle 1 where voruciclib dosing begins on Day 3. In Cycle 1, 
venetoclax dose ramp-up will consist of venetoclax 100 mg on Day 1, then 200 mg on Days 2–
21, then 400 mg on Days 22–28, with voruciclib beginning on Day 3. 
The starting voruciclib dose level will be 150 mg in combination with venetoclax (i.e., 2 dose 
levels lower than the dose of 250 mg that has been shown to have no DLTs on IS2w,2w). Dose 
escalation will follow the same 3+3 design as in the IS2w,2w cohorts, and uses the same definition 
for DLT, MTD, and mBED. 
In the IS2w,2w dose escalation cohorts, no DLTs have been reported at doses ranging from 50 mg 
QOD to 250 mg QD, and enrollment was ongoing at the 300 mg dose level at the time of 
issuance of protocol Amendment 12. 
The combination cohorts on IS3w,1w will be numbered as listed below in Table 4. 
Table 4: 
Dose Cohorts with Combination Voruciclib + Venetoclax (Amendment 12) 
Cohort Dose Level 
Doses and Schedule 
21 
voruciclib 150 mg QD, administered IS3w,1w + venetoclax administered QD × 28 days 
22 
voruciclib 200 mg QD, administered IS3w,1w + venetoclax administered QD × 28 days 
23 
voruciclib 250 mg QD, administered IS3w,1w + venetoclax administered QD × 28 days 
24 
voruciclib 300 mg QD, administered IS3w,1w + venetoclax administered QD × 28 days 
25 
voruciclib 350 mg QD, administered IS3w,1w + venetoclax administered QD × 28 days 
Abbreviation: QD = once per day. 
4.3.2.1. 
Administration Schedules and Doses of Voruciclib + Venetoclax 
Amendment 11 – IS2w,2w Dosing Schedule 
For Cycle 1 in combination cohorts 12–19, the dosing will be as follows (Table 5): 
• Venetoclax will be ramped up starting with 100 mg on Day 1, 200 mg on Days 2–21, 
then 400 mg administered as a single agent on Days 22–28.  
• Voruciclib dosing will be administered on Days 3–14 at the appropriate Cohort 
Dose (Table 3). 
For Cycle 2 and beyond, the dosing will be as follows:  
• Venetoclax 200 mg will be administered on Days 1–21, and 400 mg administered as a 
single agent on Days 22–28.  
• Voruciclib at the cohort dose (Table 3) on Days 1–14. 

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Venetoclax should be taken with a meal and water. When both venetoclax and voruciclib are to 
be taken, venetoclax should be taken first with a meal followed by voruciclib at least 2 hours 
later (e.g., meal completed at 8 a.m. with venetoclax, dose of voruciclib taken after 10:00 a.m.). 
Voruciclib tablets must not be chewed, crushed, or broken.  
Table 5: 
Administration Schedules of Voruciclib given in Combination with 
Venetoclax (IS2w,2w) 
Administration Schedule of Voruciclib IS2w,2w and Venetoclax per 28-day Cycle 
Cycle 1 
Day 1 
Day 2 
Days 3 to 14 
Days 15 to 21 
Days 22 to 28 
Venetoclax 
100 mg 
200 mg 
200 mg 
200 mg 
400 mg 
Voruciclib QD 
- 
- 
Cohort dose 
None 
None 
Voruciclib QODa 
- 
- 
50 mga 
None 
None 
Cycle 2 and beyond  
Days 1 to 14 
Days 15 to 21 
Days 22 to 28 
Venetoclax 
200 mg 
200 mg 
400 mg 
Voruciclib QD 
Cohort dose 
None 
None 
Voruciclib QODa 
50 mga 
None 
None 
Abbreviation: QOD = once every other day 
a For cohort 12, the dose of voruciclib will be 50 mg once every other day (QOD) on Days 3, 5, 7, 9, 11, and 13 of 
Cycle 1, and on Days 1, 3, 5, 7, 9, 11, and 13 of Cycle 2 and beyond. 
 
Amendment 12 – IS3w,1w Dosing Schedule 
For Cycle 1 in combination cohorts 21–25, the dosing will be as follows (Table 6): 
• Venetoclax dose will be ramped up starting with 100 mg on Day 1, 200 mg on Days 2–21, 
then 400 mg administered as a single agent on Days 22–28.  
• Voruciclib dosing will be administered on Days 3–21 at the appropriate Cohort 
Dose (Table 4). 
For Cycle 2 and beyond, the dosing will be as follows:  
• Venetoclax 200 mg will be administered on Days 1–21, and 400 mg administered as a 
single agent on Days 22–28.  
• Voruciclib at the cohort dose (Table 4) will be administered on Days 1–21. 
Venetoclax should be taken with a meal and water. When both venetoclax and voruciclib are to 
be taken, venetoclax should be taken first with a meal followed by voruciclib at least 2 hours 
later (e.g., meal completed at 8 a.m. with venetoclax, dose of voruciclib taken after 10:00 a.m.). 
Voruciclib tablets must not be chewed, crushed, or broken.  

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Table 6: 
Administration Schedules of Voruciclib given in Combination with 
Venetoclax (IS3w,1w) 
Administration Schedule of Voruciclib IS3w,1w and Venetoclax per 28-day Cycle 
Cycle 1 
Day 1 
Day 2 
Days 3 to 21 
Days 22 to 28 
Venetoclax 
100 mg 
200 mg 
200 mg 
400 mg 
Voruciclib QD 
- 
- 
Cohort dose 
None 
Cycle 2 and beyond  
Days 1 to 21 
Days 22 to 28 
Venetoclax 
200 mg 
400 mg 
Voruciclib QD 
Cohort dose 
None 
Abbreviation: QD = once per day. 
In both IS2w,2w, and IS3w,1w, venetoclax dosing on Day 1 of Cycle 1 may proceed when any 
non-hematologic toxicity from prior antileukemic therapy has resolved to Grade ≤1 or is 
considered stable. 
4.3.2.2. 
Justification of Dose and Administration Sequence of Voruciclib + Venetoclax 
In vitro studies indicate that voruciclib has the potential to inhibit CYP3A4 and P-gp 
(Section 4.15). At the proposed starting dose of voruciclib of 50 mg, an increase of venetoclax 
exposure may be observed based on the following assessment of time dependent inhibition of 
CYP3A4 by voruciclib.  
CYP3A4 time-dependent inhibition potential of voruciclib  
The CYP3A4 time-dependent inhibition potential of voruciclib was evaluated according to FDA 
guidance (In Vitro Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-
Mediated Drug Interactions) using the following input parameters. 
Parameter 
Value (source) 
Voruciclib dose 
50 mg 
Voruciclib Cmax after 50 mg multiple dose 
225 ng/mL or 0.225 mg/L (extrapolated; IB Section 5.2.1.1) 
Fraction unbound in plasma 
0.05 (IB Section 4.3.2) 
Fraction absorbed after oral administration 
80% (preclinical data; IB Section 4.3.1) 
Fraction available after intestinal metabolism 
100% (unknown; assumed per FDA guidance) 
Ka 
0.67 h-1 (assumed based on slow absorption as evidenced by 
median Tmax 4 to 6 hours; IB Section 5.2.1.1) 
Blood: Plasma ratio of concentration 
1 (unknown; assumed) 
kinact 
0.021 min-1 (estimated from raw data; Study No. P1446APK16) 
KI 
5.0478 mg/L (estimated from raw data; Study No. P1446APK16) 
Kdeg,CYP3A4, liver 
0.00032 min-1 (literature) 
Kdeg,CYP3A4, interstine 
0.00048 min-1 (literature) 
Hepatic blood flow 
97 L/h (according to FDA guidance) 
Blood flow in enterocytes 
18 L/h (according to FDA guidance) 

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Based on the input parameter values listed in the table above, the effect of voruciclib on the PK 
of midazolam (a sensitive CYP3A4 substrate) was assessed. For these calculations, midazolam 
fmCYP3A4 and Fg values of 0.93 and 0.6, respectively were used and an AUCR value of 2.03 was 
determined indicating an approximately 2-fold increase in midazolam exposure when co-
administered with voruciclib 50 mg once daily. 
Therefore, during the period of coadministration with voruciclib, the dose of venetoclax was 
reduced by 50% to 200 mg once daily.  
Effective half-life of voruciclib 
In Study P1446A-05/19/08 and Study P1446A-05/20/08, voruciclib PK samples were collected 
for 24 hours post-dose after single and multiple administrations. Sample collection only during 
the 24-hour dosing interval precluded reliable estimation of terminal phase half-life. However, 
effective half-life may be calculated based on accumulation ratio (multiple dose AUC(0-24) 
divided by single dose AUC(0-24)) using the following formula:  
Accumulation Ratio = 1 / (1 - exp(-kel × tau)). 
Based on accumulation ratio, voruciclib effective half-life was estimated at the 600 mg and 
350 mg dose levels in Study P1446A-05/19/08 and Study P1446A-05/20/08, respectively. These 
dose levels were chosen because of the large sample size of 16 and 24, respectively, thus 
permitting a robust estimation. Based on average accumulation ratios of 2.06 and 2.77, 
voruciclib effective half-life value was estimated to be 24 to 36 hours. 
Preliminary PK results for voruciclib and venetoclax for Cohorts 12 (voruciclib 50 mg QOD) to 
15 (voruciclib 150 mg QD) indicate that administration of multiple doses of voruciclib does not 
have an effect on venetoclax PK. In these cohorts, on Cycle 1 Day 21 (i.e., 7 days after the last 
voruciclib dose on Cycle 1 Day 14), plasma voruciclib concentrations were either below the 
lower limit of quantitation or very low. At the highest voruciclib dose level evaluated for PK 
(150 mg QD, Cohort 15), average plasma voruciclib concentration on Cycle 1 Day 21 was 8 
ng/mL (less than 2% of maximum plasma concentration) indicating nearly complete elimination 
of voruciclib from the systemic circulation one week after the last dose. Lack of pharmacokinetic 
interaction at steady-state and very low voruciclib concentrations observed one week after the 
end of treatment justifies administration of the labeled dose of venetoclax on voruciclib 
treatment-free days. Therefore, in Cohorts 21–25 (voruciclib IS3w,1w) the labeled dose of 
venetoclax (400 mg QD) may be administered on Days 22 to 28 of each cycle when voruciclib is 
not administered. 
Sequence of administration 
Per the Venclexta [US Prescribing Information] Rev 2022, it is noted that P-gp substrates (such 
as voruciclib) should be administered at least 6 hours before venetoclax administration. 
However, this timing and sequence presents logistical considerations related to the collection of 
serial blood samples for PK analysis over the course of a treatment/PK sampling day. As 
venetoclax requires administration with food, it is administered first followed by voruciclib at 
least 2 hours after the meal, allowing for PK sampling through 8 hours post the venetoclax dose 
and pre-dose sampling on the subsequent day to be completed in the morning (see 
Section 9.14.2). 

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4.4. 
Dose-Limiting Toxicity (DLT) 
A DLT will be defined as any of the following treatment-emergent adverse events (TEAEs) 
occurring in Cycle 1 of voruciclib monotherapy or voruciclib + venetoclax combination therapy 
that are clearly unrelated to the underlying disease or extraneous causes: 
• Symptomatic nonhematological Grade ≥3 laboratory abnormalities or asymptomatic 
nonhematological Grade ≥3 laboratory abnormalities that fail to improve to Grade ≤2 
within 72 hours 
• Grade 3 vomiting lasting >48 hours despite recommended antiemetic support or any 
occurrence of Grade ≥4 vomiting 
• Grade 3 diarrhea lasting >48 hours despite recommended antidiarrheal support or any 
occurrence of Grade ≥4 diarrhea 
• All other Grade ≥3 nonhematological adverse event (AE) not listed above 
• Grade 3 or higher TLS regardless of prophylaxis 
• Hy’s law cases 
• Febrile neutropenia of any duration (not applicable to AML subjects) 
• Grade 4 neutropenia lasting ≥7 days; or lasting ≥42 days and not due to progressive disease 
in AML subjects 
• Grade ≥3 thrombocytopenia with Grade ≥2 bleeding or Grade 4 thrombocytopenia of any 
duration (not applicable to AML subjects) 
• Grade 4 thrombocytopenia lasting ≥42 days (AML subjects only) 
• Grade 4 anemia unexplained by underlying disease  
Hy’s law cases of drug-related hepatocellular injury are defined as elevated ALT or 
AST ≥3 × ULN, elevated total bilirubin >2 × ULN without findings of cholestasis, and no other 
reason can be found to explain the combination of increased aminotransferase and serum total 
bilirubin, such as viral hepatitis, alcohol abuse, ischemia, pre-existing liver disease, or another 
drug capable of causing the observed injury. 
Additionally, discontinuation of study drug in Cycle 1 due to an AE that is clearly unrelated to 
the underlying disease, or an extraneous cause will be considered a DLT.  
Safety will be assessed by AEs graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v5.0; laboratory safety tests including 
hematology (complete blood count [CBC]), serum chemistry; physical examination; vital signs; 
ECOG performance status; and 12-lead electrocardiogram (ECG).  
4.5. 
Expansion Cohort and Early Stopping Boundaries for Toxicity  
Once the safe and mBED of voruciclib in combination with venetoclax on IS2w,2w and IS3w,1w has 
been declared in subjects with AML, an expansion cohort of up to 12 additional subjects for each 
of the 2 voruciclib dose schedules will be enrolled to further characterize the safety, efficacy, 
PK, and pharmacodynamics of the mBED on IS2w,2w and IS3w,1w.  

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Sequential boundaries will be used to monitor the rate of unacceptable toxicities in AML 
subjects enrolled on expansion cohorts, using criteria consistent with those used to define DLTs 
in escalation cohort subjects, with focus on potential cumulative toxicities over time. If an 
excessive number of unacceptable toxicities are observed, the SRC will have the option of either 
halting study accrual or reducing the dose to reduce the level of toxicity. The boundaries at 
which enrollment into an expansion cohort will be halted or safe and mBED reduced are listed 
in Table 7. This is a Pocock-type boundary that yields 0.2 or greater probability of crossing the 
boundary when the rate of DLT/unacceptable toxicity is equal to the acceptable rate of 20% 
(Ivanova 2005).  
Since these boundaries are very conservative, to avoid a high false positive rate in the early stage 
of the enrollment period due to a small sample size, the Pocock boundary described below will 
be implemented after 4 subjects have been enrolled; for subjects 1-3 the decision to halt study 
accrual or reduce the dose will be based on clinical judgment, SRC, and Sponsor. 
Table 7: 
Early Stopping Boundaries for Toxicity – Expansion Cohort 
# Subjects 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Boundary 
- 
* 
* 
3 
3 
3 
4 
4 
4 
5 
5 
5 
*Subjects 1 – 3 will be based on clinical judgement.
4.6. 
Maximum Tolerated Dose (MTD) 
With respect to voruciclib monotherapy, for each disease group and schedule (continuous, 
IS2w,2w, IS1w,3w,), an MTD of voruciclib will be defined as the highest dose at which 
<2 of 6 subjects experience a DLT.  
With respect to voruciclib +venetoclax combination therapy, an MTD will be defined as the 
highest dose cohort level at which <2 of 6 subjects experience a DLT.  
4.7. 
Recommended Phase 2 Dose (RP2D) for Voruciclib Monotherapy 
The study may not be sufficient to determine the RP2D and schedule of voruciclib monotherapy 
in hematologic malignancies. It will evaluate the safety, efficacy, and the safe and mBED of 
voruciclib monotherapy. The safe and mBED and schedule will be determined based on safety 
and tolerability over two or more cycles, achievement of voruciclib blood levels that have 
demonstrable activity in non-clinical studies, and/or additional evidence of biologic or clinical 
activity. The safe and mBED may be different in AML and B-cell malignancies and may be the 
same or lower than the MTD.  
4.8. 
Dose Modifications 
4.8.1. 
Dose Modifications for Cohorts 1 to 5 - Voruciclib Monotherapy Continuous 
Dosing 
Details are provided in the Dose Modification Schedule (Table 8), which is intended as a 
guideline as the final decision of dose reduction or whether to restart study medication is to be 
made by the Investigator. Variations from these recommendations may be warranted based on an 
Investigator’s individual judgment in considering potential risks, benefits, and therapeutic 

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alternatives available to each subject, and after discussion with the Medical Monitor. In addition, 
Investigators should always consider and eliminate other potential causes for AEs (e.g., 
underlying malignancy, intercurrent illness, comorbid conditions, or concomitant medications).  
During the first cycle, subjects experiencing a DLT should be considered for permanent 
discontinuation.  
Such subjects may, however, continue to receive additional voruciclib: 
• If additional treatment with voruciclib is clinically appropriate, and 
• At the discretion of the Investigator, after consultation with and approval by the Medical 
Monitor 
Continued treatment with voruciclib will follow the Dose Modification Schedule (Table 8).  
Table 8 
Dose Modification Schedule Cohorts 1 to 5 
Cohort/Dose Level 
Voruciclib Dose 
Reduced Dose 
-1 
Intermittent Schedule (QOD) 
Discontinue 
1 
50 mg 
Intermittent Schedule (QOD) 
2 
100 mg 
50 mg 
3 
150 mg 
100 mg 
4 
200 mg 
150 mg 
5 
250 mg 
200 mg 
Abbreviation: QOD = every other day. 

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Table 9: 
Dose Modification Cohorts 1 to 5 
Toxicity1 
Requirement for Holding Dose 
or Discontinuing Study Drug 
Amount of Dose Reduction 
Grade 4 non-hematologic 
Discontinue study drug 
Not allowed 
Grade 3 non-hematologic 
Hold dose until recovery to 
Grade ≤1 
Dose may remain unchanged or 
be reduced by one dose level (see 
Table 8) based on overall 
assessment of the subject  
Grade 3 vomiting or diarrhea 
Dose interruption required if not 
controlled within 48 hours by 
supportive therapy 
Grade 4 thrombocytopenia, 
or neutropenia2 with associated 
symptoms (e.g., fever)* 
Hold dose until recovery to 
Grade ≤3 
Reduce by one dose level (see 
Table 8) if recovery within 
7 days; if longer than 7 days, 
discontinue study drug 
Grade 3 hematologic  
(ANC ≤500 to 1000/mm3 or 
platelets ≤25,000 to 
50,000/mm3)* 
May continue on treatment, but 
requires weekly CBC until 
toxicity resolves to Grade ≤2 
(unless myelosuppression is due to 
disease) 
Dose may remain unchanged 
or be reduced by one dose level 
(see Table 8) based on overall 
assessment of the subject 
Consider use of G-CSF in 
subsequent cycles 
Abbreviations: ANC = absolute neutrophil count; CBC = complete blood count; G-CSF = granulocyte colony-
stimulating factor. 
1 Toxicity graded per CTCAE v5.0. 
2 Hematopoietic growth factor (see Section 4.14 regarding acceptable and prohibited types) may be administered to 
subjects with neutropenia per the institutional standard of care. 
* Not applicable to AML subjects. 
For an AE that is attributed to voruciclib, and which requires a dose modification, the dose 
should be reduced by 1 dose level. Successive single level adjustments to progressively lower 
dose levels can be made. After a dose reduction, the dose may be maintained at that reduced dose 
level. However, if the subject tolerates the drug at a reduced dose for ≥4 weeks, the dose may be 
re-escalated to the next higher dose level at the discretion of the Investigator (particularly if the 
AE-associated TLS; or if further evaluation reveals that the AE that led to the dose reduction was 
primarily related to the underlying malignancy, an intercurrent illness, a comorbid condition, 
or a concomitant medication). Successive single-level dose adjustments to progressively higher 
dose levels may be made at intervals of ≥4 weeks and will not exceed dose levels the SRC has 
not yet determined to be safe.  
The dose level for a subject may be escalated above the assigned enrollment dose once the SRC 
has determined that the higher dose is safe and after consultation with the Medical Monitor.  
Voruciclib re-challenge is prohibited in subjects experiencing Grade 4 non-hematologic toxicity 
and must be permanently discontinued. 

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4.8.2. 
Re-treatment Following Adverse Events in Cohorts 6 to 11 with Intermittent 
Schedules of Voruciclib Monotherapy  
Subjects enrolled in Cohorts 6a and b to 11a and b, i.e., receiving voruciclib on an IS, who 
experience Grade 3-4 AEs will be managed as follows: 
During the first cycle, subjects experiencing a DLT should be considered for permanent 
discontinuation. Such subjects may, however, continue to receive voruciclib on the same dosing 
schedule upon resolution of the DLT to Grade ≤1: 
• If additional treatment with voruciclib is clinically appropriate, and 
• At the discretion of the Investigator, after consultation with and approval by the Medical 
Monitor 
In later cycles, subjects experiencing a Grade 3-4 AE in Cohorts 6 to 11, may continue to receive 
voruciclib at the same dose but using the IS1w,3w schedule upon resolution of the AE to Grade ≤1 
as outlined in Table 10. 
Table 10: 
Re-treatment Following a Grade 3-4 Adverse Event in Cycles ≥2 in the 
Intermittent Schedules 
Toxicity1 
Requirement for Holding Dose or 
Discontinuing Study Drug 
Retreatment with Voruciclib 
Grade 4 non-hematologic 
Discontinue study drug 
Not allowed 
Grade 3 non-hematologic 
Hold dose until recovery to Grade ≤1 
Allowed based on overall 
assessment of the subject 
Grade 3 vomiting or diarrhea 
Dose interruption required if not controlled 
within 48 hours by supportive therapy 
Grade 4 thrombocytopenia, 
or neutropenia2 with associated 
symptoms (e.g., fever)* 
Hold dose until recovery to Grade ≤3 
Allowed if recovery within 
7 days; if longer than 7 days, 
discontinue study drug 
Grade 3 hematologic  
(ANC ≤500 to 1000/mm3 or 
platelets ≤25,000 to 
50,000/mm3)* 
May continue on treatment, but requires 
weekly CBC until toxicity resolves to 
Grade ≤2 (unless myelosuppression is due 
to disease) 
Allowed based on overall 
assessment of the subject 
Consider use of G-CSF in 
subsequent cycles 
Abbreviations: ANC = absolute neutrophil count; CBC = complete blood count; G-CSF = granulocyte colony-
stimulating factor. 
1 Toxicity graded per CTCAE v5.0. 
2 Hematopoietic growth factor (see Section 4.14 regarding acceptable and prohibited types) may be administered to 
subjects with neutropenia per the institutional standard of care. 
* Not applicable to AML subjects. 
4.8.3. 
Dose Modifications for Cohorts 12–19 and 21–25 - Voruciclib + Venetoclax 
Combination Dosing in AML 
Dose reductions for toxicities attributed to venetoclax or for the combined effect of voruciclib 
and venetoclax will be managed according to the Venclexta [US Prescribing Information] 
Rev 2022. 
The safety profile of venetoclax in AML has been characterized in several studies, including 
Phase 3 trials in combination with azacitidine or low dose cytarabine. The safety profile of 

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voruciclib has not been well defined due to the small number of subjects (~100) studied to date. 
However, the emerging voruciclib safety profile suggests potential overlapping toxicities with 
venetoclax, including gastrointestinal (nausea, diarrhea, vomiting, abdominal pain), hematologic 
(myelosuppression and febrile neutropenia), fatigue, infections, and dyspnea. 
Venetoclax and voruciclib dose modifications for drug-related adverse reactions are shown in 
Table 11. For more details on voruciclib dose interruption and re-treatment during the DLT 
window and after the DLT window see Table 10.  
Study drug dose reduction will proceed stepwise upon recovery to Grade ≤2 in subjects in CR, 
CRh, or CRi who experience Grade 4 neutropenia, with or without fever or infection, or Grade 4 
thrombocytopenia. Upon recovery, voruciclib will be restarted at one dose level lower and 
venetoclax will resume at the same dose. If there is a recurrence of Grade 4 neutropenia or 
thrombocytopenia, then venetoclax will be resumed at the lower dose level upon recovery to 
Grade ≤2.  
Table 11: 
Venetoclax Schedule Modification and Voruciclib Dose Modification for 
Toxicity 
Adverse Reaction 
Venetoclax 
Voruciclib 
Hematologic Adverse Reactions 
Grade 3-4 neutropenia 
with or without fever or 
infection; or Grade 4 
thrombocytopenia 
Prior to achieving a remission: 
• Continue venetoclax unless 
treatment interruption is deemed 
necessary by the Investigator 
• A bone marrow evaluation is 
recommended 
For subjects who achieve CR, CRh, or 
CRi, at the end of Cycle 1 (or later 
cycle):  
• Hold venetoclax until recovery to 
Grade ≤2 
• Monitor blood counts 
• Upon resolution to Grade 1 or 2, 
resume at the same dose 
 
Prior to achieving a remission: 
• Continue voruciclib unless 
treatment interruption is deemed 
necessary by the Investigator 
• A bone marrow evaluation is 
recommended 
For subjects who achieve CR, CRh, or 
CRi, at the end of Cycle 1 (or later cycle) 
• Hold voruciclib until recovery to 
Grade ≤2 
• Monitor blood counts 
• Re-treatment at the same dose and 
schedule is allowed 
• If no recovery by Day 42 after start 
of Grade 4 neutropenia, retreat at 
one dose level lower and same 
schedule 
 
Cycle 2 and beyond: 
For subsequent occurrences in cycles 
after achieving remission and lasting 
≥7 days, the following stepwise schedule 
duration reductions are allowed for 
persistent cytopenia: 
• Hold venetoclax until recovery to 
Grade ≤2 
• Monitor blood counts. 
Retreat at same dose level and same 
schedule (no reduction)   
Cycle 2 and beyond: 
• Hold voruciclib until recovery to 
Grade ≤2 
• Monitor blood counts. 
• Retreat at one dose level lower and 
same schedule. 

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4.9. 
Tumor Lysis Syndrome (TLS) 
TLS includes electrolyte abnormalities (hyperkalemia, hypocalcemia, hyperuricemia, and 
hyperphosphatemia), cardiac dysrhythmias, and renal failure. TLS is a known risk in subjects 
treated with CDK9 inhibitors. The risk of TLS depends on tumor type, tumor burden, and subject 
factors such as pre-existing renal impairment and splenomegaly. Therefore, risk assessment for 
TLS, prophylaxis, and monitoring, including assessment of need for hospitalization, is required 
for all subjects. Investigators must institute appropriate prophylactic measures, including for 
low-risk subjects, during screening and prior to Cycle 1 Day 1. 
Risk assessment for subjects with B-cell tumors and AML are provided in Appendix 9 in 
Table 24 and Figure 3, respectively. All AML subjects should have white blood cell count less 
than 25 × 109/L prior to initiation of venetoclax; cytoreduction prior to treatment may be 
required. 
Recommended TLS prophylaxis and monitoring in Table 24 are per those indicated for 
CLL/SLL patients in the Venclexta [US Prescribing Information] Rev 2022. Additional guidance 
for subjects with AML is provided in Appendix 9. Guidance on the diagnosis of TLS is provided 
in Appendix 10. 
4.10. 
Differentiation Syndrome 
Differentiation syndrome (DS) is a relatively common and potentially severe complication seen 
in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and/or arsenic 
trioxide. The syndrome includes, but may not be limited to, unexplained fever, weight gain, 
dyspnea with pulmonary infiltrates, pleuro-pericardial effusion, hypotension, and/or renal failure. 
Cases of DS have been recently reported in patients with various types of AML administered 
FMS-like tyrosine kinase 3 (Flt3) inhibitors and isocitrate dehydrogenase (IDH) inhibitors.  
Although the pathogenesis of DS has not been entirely clarified, it has been speculated it is due 
to a cascade of pathophysiologic mechanisms, leading to a systemic inflammatory response 
syndrome, endothelium damage with capillary leak syndrome, occlusion of microcirculation, and 
tissue infiltration with leukocytes. In this study, a diagnosis of DS should be suspected in 
subjects with AML in the presence of any of the above-mentioned signs and symptoms, and 
preemptive treatment with dexamethasone should be started immediately, particularly in patients 
with leukocyte counts greater than 10,000/µL. Other supportive measures can also be crucial for 
Adverse Reaction 
Venetoclax 
Voruciclib 
 
Reduction level 1: venetoclax duration 
may be reduced to administration on 
Days 1 through 21 of the 28-day cycle  
Reduction level 2: venetoclax duration 
may be reduced to administration Days 1 
through 14 of the 28-day cycle 
 
Nonhematologic Adverse Reactions 
Grade 3 or 4 
nonhematologic 
toxicities 
Interrupt venetoclax if not resolved with 
supportive care. Upon resolution to 
Grade 1 or baseline level, resume 
venetoclax at the same dose. 
See Requirement for Holding Dose or 
Discontinuing Study Drug and 
Retreatment with Voruciclib rules for 
non-hematologic toxicities in Table 10 

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the correct management of DS, especially in patients with life-threatening complications 
(Sanz 2014). Temporary interruption of voruciclib is indicated for patients in poor clinical 
condition. Treatment with hydroxyurea (or an anthracycline if appropriate) to control rising 
leukocyte counts is also recommended. 
Two subjects with AML enrolled in Cohort 2 (monotherapy) of this study experienced symptoms 
consistent with DS in Cycle 1 of voruciclib administration, including fever, hypoxemia, 
pulmonary infiltrate, and pleural effusion. The mechanism by which voruciclib may induce DS is 
unclear. Investigators should be aware of DS as differential diagnosis in patients with AML 
experiencing fever, pulmonary or hemodynamic complications in the first weeks of voruciclib 
administration. After ruling out an infection or other causes, treatment with dexamethasone and 
supportive care measures is recommended. Hydroxyurea (1-2 g/day) or an anthracycline (if 
appropriate) can be used to control rising leukocyte counts. 
4.11. 
Interstitial Lung Disease/Pneumonitis 
Interstitial lung disease (ILD)/pneumonitis has been reported post-marketing with the CDK4/6 
inhibitors, which are approved in the US for the treatment of patients with breast cancer 
(FDA Drug Safety Communications, September 2019). With the continuous dosing schedule of 
voruciclib, 2 subjects with AML had DLTs of pneumonitis (n = 1) or ILD (n = 1) at the 100 mg 
QD dose level. Of note, the 2 subjects had confounding factors that may have contributed to this 
toxicity, including a history of secondary AML following a myelodysplastic syndrome, heavily 
pretreated disease, allogeneic stem cell transplantation in the preceding 12 months, and evidence 
of differentiation syndrome occurring 1 to 2 weeks after voruciclib initiation. These DLTs 
prompted the Sponsor decision to no longer pursue a QD dosing schedule in either disease group. 
In addition, one subject with DLBCL enrolled at the 50 mg QD dose cohort experienced 
hypoxemic respiratory failure with pulmonary infiltrates in Cycle 4. There was no identified 
cause for this event, which was considered related to study drug and led to voruciclib 
discontinuation. 
The mechanism of this pulmonary toxicity is not understood. PK data from the Phase 1 studies in 
solid tumors indicated that voruciclib has a very high volume of distribution (>100 L), 
suggesting higher exposure in tissues than in plasma.  
Subjects should be monitored for symptoms indicative of ILD/pneumonitis (e.g., hypoxia. cough, 
dyspnea), with management as indicated in Table 12. In subjects with new or worsening 
respiratory symptoms and in whom pneumonitis is suspected, voruciclib administration is to be 
suspended and permanently discontinued if pneumonitis is confirmed.  
Table 12: 
Monitoring and Management of Interstitial Lung Disease/Pneumonitis 
Grade 1 
Monitor patients weekly with history and physical examination, pulse oximetry and imaging 
Grade 2 
Hold voruciclib until at least ≤ Grade 1 
Consider prednisone 1-2 mg/kg/day with taper by 5-10 mg/week over 4-6 weeks 
Consider bronchoscopy with bronchoalveolar lavage (BAL) 
Consider empiric antibiotics 
Monitor Q3 days with history and physical examination, pulse oximetry and imaging 

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Grade 3 or 4 
Permanently discontinue voruciclib 
Consider empiric antibiotics 
Consider methylprednisolone IV 1-2 mg/kg/day 
Consider infliximab 5 mg/kg or mycophenolate mofetil IV 1 gm twice daily or IVIG X 5 days 
or cyclophosphamide if no improvement 
Consider pulmonary and infectious disease consults 
Patients should be hospitalized for further management 
Adapted from Brahmer 2018. 
4.12. 
Subject Replacement 
Subjects who discontinue study therapy prior to completing Cycle 1 (Day 28) for reasons other 
than the development of a DLT will be replaced. Subjects who miss one or more doses for 
reasons other than DLT, must receive at least 75% of the total planned voruciclib dose in Cycle 1 
to be assessed for DLT. Subjects with no DLT who fail to receive at least 75% of the planned 
Cycle 1 voruciclib dose will be replaced. 
For Cohort 12, subjects must receive 100% of Cycle 1 doses (i.e., all 6 doses) to be DLT 
evaluable; subjects with no DLT who fail to receive 100% of Cycle 1 voruciclib doses will be 
replaced.  
4.13. 
Discontinuation of Voruciclib Administration 
Subjects may continue to receive voruciclib monotherapy or voruciclib + venetoclax 
combination therapy provided there is evidence of clinical response (PR or better) by the end of 
Cycle 6. Subjects may discontinue voruciclib monotherapy or voruciclib + venetoclax 
combination therapy for reasons including the following: 
• 
Documented progression of disease while receiving therapy 
• 
Unacceptable AE(s) considered secondary to voruciclib despite appropriate therapy and/or 
dose modification 
• 
Intercurrent illness that precludes continued study therapy 
• 
Withdrawal of consent by the subject 
• 
Changes in the subject’s medical condition that render further administration of voruciclib 
unacceptable in the judgment of the Principal Investigator or sponsor 
• 
Treatment of the disease with another therapeutic regimen 
• 
Pregnancy or breastfeeding 
• 
Substantial noncompliance with study procedures 
• 
Termination of study by the sponsor 
4.14. 
Prohibited Treatments and Concomitant Medications – Cautions 
and Prohibitions 
4.14.1. 
Concomitant Medications with Voruciclib – Cautions and Prohibitions 
In vitro studies have shown that voruciclib has the potential to inhibit cytochrome (CYP) 
CYP2C9, CYP2C19, CYP2D6, and CYP3A4, therefore, drugs with a narrow therapeutic 

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window that are metabolized by these enzymes should be avoided or used with caution (see 
Appendix 7). 
Subjects receiving warfarin treatment are excluded, since voruciclib is highly protein bound and 
is a competitive inhibitor of CYP2C9 at higher concentrations and increased INR was a DLT in 
the previous Phase 1 studies. Subjects on study who initiate warfarin therapy must discontinue 
voruciclib.  
Consistent with subject safety and comfort, administration of any prescription or 
over-the-counter (OTC) drug products other than study medication will be minimized during the 
study period. Subjects should be discouraged from use of herbal remedies, self-prescribed drugs, 
tobacco products, or street drugs during their participation in the clinical study and should be 
counseled to minimize use of alcohol or nonmedical marijuana. 
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the Investigator. The Investigator’s 
decision to authorize the use of any drug other than study drug will take into account subject 
safety, the medical need, the potential for drug interactions, the possibility for masking 
symptoms of a more significant underlying event, and whether use of the drug will compromise 
the outcome or integrity of the study. 
Subjects will be instructed about the importance of the need to inform the clinic staff of the use 
of any drugs or remedies (whether prescribed, OTC, or illicit) before and during the course of the 
study.  
No other anti-cancer therapeutics or investigational agents are permitted during the study 
treatment period, except for hydroxyurea or anthracycline for the treatment of DS and to manage 
rapidly rising white blood cell counts in Cycles 1 and 2 only in patients with AML. Palliative 
radiotherapy is permitted after Cycle 1 but should be minimized and used for control of local 
tumor-related symptoms only.  
If a subject experiences an AE, appropriate supportive care (e.g., antiemetics, antidiarrheals, 
antibiotics, granulocyte colony-stimulating factor [G-CSF] hydration) should be instituted 
consistent with the nature of the event. If the AE requires a dosing modification, the treatment 
regimen should be interrupted, as necessary. A decision should be made as to whether the subject 
can reasonably continue with the study drug based upon the nature and severity of the AE.  
Recommendations regarding specific types of concomitant therapies, supportive care, diet, and 
other interventions are provided below. To minimize variations in supportive care, the 
recommended supportive care agents (e.g., loperamide, granisetron) should be used unless there 
is a medical rationale in a specific subject for use of an alternative product. 
Antibiotics, Antifungals, Antivirals 
Care should be taken to avoid or minimize concomitant administration of prophylactic 
or therapeutic antibacterial, antifungal, or antiviral agents that are moderate or strong CYP3A4 
inhibitors or inducers. For subjects with CLL/SLL and a history of recurrent infections, 
prophylaxis with intravenous immunoglobulin may be offered and consideration may be given to 
initiation of antibiotic prophylaxis against pneumocystis infection (e.g., with trimethoprim-
sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone) beginning prior to study 
drug administration. Such support also offers the benefit of reducing the risk for other bacterial 
infections. Local practices or guidelines regarding infection prophylaxis may be followed.  

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Subjects developing an intercurrent infection during study drug treatment may receive 
therapeutic antibacterial, antiviral, or antifungal drugs for intercurrent infections as needed. 
Continuation of study therapy during treatment for an intercurrent infection is at the discretion of 
the Investigator. Given that voruciclib is a CYP3A4 substrate and the critical role of azole 
antifungals (commonly strong CYP3A4 inhibitors) in the treatment of fungal infections in 
patients with AML, voruciclib must be held during treatment with an azole and restarted when 
the azole therapy is completed. Antifungals other than azoles may be used if considered by the 
investigator as a clinically appropriate alternative to azoles.  
In the voruciclib and venetoclax combination groups, antifungal prophylaxis (excluding azoles) 
may be provided according to institutional guidelines and in accordance with guidance for 
management of potential venetoclax interactions per the venetoclax PI (Venclexta 
[US Prescribing Information] Rev 2022) provided in Table 13. 
Of note, hepatitis B virus reactivation can occur in subjects previously treated with anti-CD20 
therapeutic antibodies. The median time to diagnosis of hepatitis among subjects with 
hematologic malignancies is 4 months after the initiation of therapy, but such events can occur 
months after completion of anti-CD20 antibody therapy. 
Anticoagulants 
Use of systemic anticoagulants should be avoided unless necessary for a serious intercurrent 
thrombotic or embolic condition. Because voruciclib appears to increase exposure to warfarin, 
subjects receiving warfarin are ineligible for enrollment and subjects on study who start warfarin 
must discontinue voruciclib. 
Antidiarrheals 
Subjects experiencing diarrhea (and/or abdominal cramping) may take loperamide at the earliest 
sign of a loose stool, an increase in bowel movements by 1 to 2 episodes compared to baseline, 
or an increase in stool volume or liquidity. The recommended regimen is 4 mg at the first onset 
of diarrhea, and then 2 mg with each succeeding diarrheal stool until the subject is diarrhea-free 
for at least 12 hours.  
Additional antidiarrheal measures may be implemented at the discretion of the Investigator. 
Subjects should also be instructed to maintain oral fluid intake to help sustain fluid 
and electrolyte balance during episodes of diarrhea. 
Antiemetics 
While prophylactic antiemetics can be considered, antiemetics should not be given 
prophylactically before initial study drug administration on Cycle 1 Day 1. Choice of antiemetic 
therapy should be based on standard practice and/or institutional guidelines. 
Antihistamine, Anti-inflammatory, and Antipyretic Drugs 
Antihistamines (e.g., cetirizine, diphenhydramine), and anti-inflammatory/antipyretic drugs 
(e.g., acetaminophen [paracetamol], nonsteroidal anti-inflammatory drugs [NSAIDs]), may be 
used during the study, as medically warranted. 
Corticosteroids 

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At study entry, subjects may not be using enteric corticosteroids but may be receiving systemic 
corticosteroids (at doses of ≤20 mg/day of prednisone or equivalent) or topical or inhaled 
corticosteroids. During study therapy, subjects may use systemic, enteric, topical, or inhaled 
corticosteroids as required for treatment-emergent conditions.  
Calcineurin inhibitors are prohibited during study treatment.  
CYP3A4 Inhibitors and Inducers 
Whenever possible moderate or strong inhibitors or inducers of CYP3A4 should be avoided 
and only administered if essential for patient care (Appendix 7). 
Drugs Affecting Gastric pH 
A potential effect of altering gastric pH on the absorption of voruciclib cannot be excluded. 
Proton pump inhibitors should be avoided if possible. Antacids and H2-receptor antagonists 
should be taken at least 4 hours before or after voruciclib. 
Drugs with a Narrow Therapeutic Range that are P-gp substrates 
Based on in vitro studies, voruciclib may be a P-gp inhibitor; however, the clinical relevance of 
this finding is not known. Drugs with a narrow therapeutic range that are P-gp substrates should 
be avoided or used with caution (e.g., digoxin, colchicine). 
Hematopoietic Support 
Granulocyte colony-stimulating factor (G-CSF) (e.g., filgrastim, filgrastim-snd, peg-filgrastim, 
lenograstim) may be administered in response to Grade ≥3 neutropenia or neutropenic 
complications. 
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered, given 
the potential for GM-CSF-related inflammatory symptoms.  
Erythropoietic agents (e.g., erythropoietin or darbepoetin) may be administered for 
Grade ≥ 3 anemia, at the discretion of the treating physician. 
Red blood cell or platelet transfusions may be administered as medically indicated. 
Drugs Known to Prolong QT Interval 
The effect of voruciclib on the QT interval has not been determined, therefore, drugs known to 
prolong QT interval should be avoided, if possible (ondansetron use is acceptable). See 
Appendix 8 for a list of medications known to prolong the QT/QTc interval. 
Immunization 
For subjects who are at risk of an infection (e.g., influenza, herpes zoster) that might be 
prevented by immunization, consideration should be given to providing the vaccine prior 
to initiation of study therapy.  
Immunization for the SARS-CoV-2 virus, responsible for COVID-19 infection, may be 
performed according to institutional guidelines. 
Whether voruciclib would increase the risk of live viral vaccines during study therapy is 
unknown. Pending the acquisition of additional information, live viral vaccination should be 
avoided 10 days prior to first dose and during study therapy. 

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Do not administer live attenuated vaccines prior to, during, or after treatment with venetoclax 
until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated 
vaccines during or following venetoclax therapy have not been studied. Advise patients that 
vaccinations may be less effective (Venclexta [US Prescribing Information] Rev 2022). 
Cytoreductive Therapy in AML patients 
Cytoreduction with hydroxyurea (or another cytoreductive therapy) must be implemented prior 
to initiating voruciclib, or venetoclax in Cohorts 12–25, if the subject has white blood cell counts 
≥25 × 109/L. 
In subjects with rapidly rising white blood cell counts in Cycles 1 and 2, a short course of 
hydroxyurea (or another cytoreductive therapy) may be administered at the discretion of the 
Investigator to control rising cell counts while continuing study drug(s) administration.  
4.14.2. 
Procedures and Surgery 
The extent to which voruciclib may affect wound healing, enhance the risk of infection, or 
increase the risk of bleeding is unknown. Considering parameters such as ANC, platelet count, 
and PT/aPTT, Investigators may use clinical discretion in deciding whether to interrupt study 
therapy before and after surgery or other invasive procedures. 
4.14.3. 
Concomitant Medications with Venetoclax – Cautions and Prohibitions 
Drugs prohibited according to the Venclexta [US Prescribing Information] Rev 2022 (PI) are not 
permitted in patients enrolled in venetoclax combination cohorts. Per the Venclexta US PI, 
concomitant use of venetoclax with strong CYP3A inhibitors (e.g., posaconazole) at initiation 
and during the ramp-up period is contraindicated but allowed for AML with dose reduction 
(Table 13). Subjects administered prohibited drugs (e.g., azoles) during the screening period 
must undergo a wash out period (at least 4 half-lives of the prohibited drug) prior to starting 
Day 1 dosing. For subjects who complete the ramp-up phase and are on a steady daily dose of 
venetoclax, the venetoclax dose should be reduced by at least 75% when used concomitantly 
with strong CYP3A inhibitors (e.g., posaconazole). Moderate CYP3A and P-gp inhibitors can be 
used with venetoclax dose reduction of 50%. 
Table 13: 
Management of Potential Venetoclax Interactions with CYP3A and P-gp 
Inhibitors 
Coadministered Drug 
Venetoclax Initiation and 
Ramp-Up Phase 
Steady Daily Dose 
(After Ramp-Up Phase) 
Posaconazole  
CLL/SLL 
Contraindicated 
Reduce venetoclax dose to 70mg 
AML 
Day 1 – 10 mg 
Day 2 – 20 mg 
Day 3 – 50 mg 
Day 4 – 70 mg 
Other strong CYP3A inhibitor 
CLL/SLL 
Contraindicated 
Reduce venetoclax dose to 100mg 
AML 
Day 1 – 10 mg 
Day 2 – 20 mg 
Day 3 – 50 mg 
Day 4 – 100 mg 

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Coadministered Drug 
Venetoclax Initiation and 
Ramp-Up Phase 
Steady Daily Dose 
(After Ramp-Up Phase) 
Moderate CYP3A inhibitor 
Reduce venetoclax dose by at least 50% 
P-gp inhibitor 
Avoid concomitant use of venetoclax with a P-gp substrate. If a concomitant use is unavoidable, 
separate dosing of the P-gp substrate by at least 6 hours before venetoclax. 
4.15. 
CYP3A4 and P-gp Inhibition Potential of Voruciclib 
In in vitro studies, voruciclib was found to inhibit CYP3A4 (testosterone 6β-hydroxylase activity 
but not midazolam 1’-hydroxylase activity). Nevertheless, an assessment of voruciclib CYP3A4 
inhibition potential was performed using preliminary estimates of enzyme inhibition parameters 
in a static mechanistic model, and it was estimated that concomitant administration of voruciclib 
(100 mg dose) and midazolam, a sensitive and specific CYP3A4 substrate widely used in clinical 
drug-drug interaction studies, may result in approximately 2.5-fold increase in midazolam 
exposure. 
Based on in vitro studies, voruciclib may be a P-gp inhibitor with an IC50 value of 50 μM; 
however, the clinical relevance of this finding is not known. The P-gp inhibition potential of 
voruciclib was assessed according to FDA guidance. At the 100 mg dose level, the ratio of gut 
concentration to IC50 (Igut/IC50) was estimated to be 17 (0.4 mg/mL divided by 0.024 mg/mL) 
which is only slightly greater than the threshold value of 10, indicating that the potential for 
intestinal P-gp inhibition after a voruciclib oral dose of 100 mg is low. Additionally, venetoclax 
and voruciclib administration will be separated by at least 2 hours (venetoclax will be 
administered before voruciclib) to further minimize the effect of intestinal P-gp inhibition by 
voruciclib on venetoclax exposure. 
Thus, for the combined therapy portion of the study, at the proposed starting dose of 50 mg of 
voruciclib, based on in vitro CYP3A4 and P-gp inhibition data presented above, an increase in 
venetoclax exposure may be observed. [Note that a daily dose of venetoclax above 800 mg has 
been used in AML without DLTs (Konopleva 2016).] Therefore, during the period of 
coadministration with voruciclib, the dose of venetoclax is limited to 200 mg. When 
administered as a single agent (i.e., on Day 22 through Day 28 with no voruciclib 
co-administered) the venetoclax dose is 400 mg, consistent with the Venclexta [US Prescribing 
Information] Rev 2022. The summary of the sensitive cytochrome P450 substrates can be found 
in Appendix 7.  
For the combination cohorts on IS2w,2w (Amendment 11), the starting dose of voruciclib in 
Cohort 12 is 50 mg QOD, which will further reduce voruciclib exposure to account for potential 
increases (if any) in bioavailability of the new malonate tablet formulation during the exposure 
cycles. Dosing in Cohort 13 (50 mg QD) will commence only after the safety of QOD dosing of 
voruciclib with venetoclax in Cohort 12 is established.  
For the first two dose levels (50 mg QOD and 50 mg QD), for which voruciclib dose reduction is 
not possible, voruciclib will be temporarily stopped if the subject requires treatment with an 
azole antifungal due to the potential of drug-drug interactions and increase exposure to 
voruciclib. Subjects who recover from the infection can restart voruciclib after the last dose of 
the azole antifungal (after at least 5 times the half-life of the agent). For subjects receiving 

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voruciclib at or above 100 mg, a dose reduction by 1 dose level will be required for concomitant 
treatment with an azole or other strong CYP3A4 inhibitor.  
4.16. 
Impact of COVID-19 on Study Procedures/Visits 
MEI Pharma requires the subject to attend the Cycle 1 Day 1 visit on-site; however, if 
subsequent on-site visits are not possible, study visits during the treatment period may be 
conducted remotely if a subject is unable to visit a study site due to COVID-19. In this situation, 
study drug may be shipped directly to a subject if this is deemed appropriate by the Investigator 
and is acceptable per institutional guidelines and local regulations. If any study visits during the 
treatment period are conducted via telephone or a tele-health platform, this will be documented 
in the source file and any missed visit procedures will be recorded as protocol deviations. 
4.17. 
Removal of Subjects from Study 
Subjects will be removed from the study for any of the following reasons: 
• 
Withdrawal of consent 
• 
Investigator deems removal to be in the subject’s best interest 
• 
Subject is lost to follow-up 
• 
Termination of study by sponsor 
5. 
VORUCICLIB ADMINISTRATION 
5.1. 
Preparation and Administration of Voruciclib 
Voruciclib is provided as 50 mg and 100 mg capsules or tablets (requiring no preparation prior to 
administration) and is dosed on a milligram (mg) basis with no adjustment in dosing based on 
subject weight. It is recommended that voruciclib be taken in the morning. Voruciclib is to be 
administered orally once a day on dosing days.  
• 
Monotherapy cohorts: voruciclib is to be taken on an empty stomach at least 1 hour prior to 
food or 2 hours after food at the same time each day. 
• 
Combination voruciclib + venetoclax cohorts: subjects should take venetoclax with a meal 
and water, and then take voruciclib (malonate salt tablets) at least 2 hours later (e.g., meal 
completed at 8 a.m. with venetoclax, dose of voruciclib taken after 10:00 a.m.).  
Note that voruciclib is only to be taken on dosing days in the monotherapy IS regimens (i.e., on 
Days 1 through 14 of the 28-day cycle on the IS2w,2w, and on Days 1 through 7 only in the 28-day 
cycle on the IS1w,3w). Dosing days for voruciclib when given in combination with venetoclax are 
defined in Table 5 for IS2w,2w, and in Table 6 for IS3w,1w. 
If a dose is missed it may be taken up to 12 hours after the specified time. After 12 hours the 
dose should be omitted. If a subject vomits after taking voruciclib, no replacement dose will be 
given. 

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5.2. 
Voruciclib Accountability and Compliance 
The Principal Investigator or their representative will maintain detailed drug accountability 
records for all voruciclib provided by the sponsor. All voruciclib will be stored in a temperature-
controlled (see Section 5.3), secure, locked location, and away from direct sunlight. The 
Principal Investigator shall maintain adequate records of the disposition of voruciclib, including 
dates, quantity, and use by subjects. Upon completion of the study, all remaining voruciclib will 
be accounted for and unused material will be returned to the Sponsor (or designee) using a 
traceable method (UPS, FedEx, etc.) or disposed of as otherwise instructed by the sponsor. 
5.3. 
Storage of Voruciclib 
The capsules and tablets should be protected from direct sunlight and stored in a cool place or at 
controlled room temperature, 15-25°C (59-77°F). Some US sites will store between 20-25°C 
(68-77°F) per investigational product label.  
5.4. 
Storage of Venetoclax 
Venetoclax will not be provided by the Sponsor. Venetoclax should be stored at or below 86°F 
(30°C) according to the US Prescribing Information (Venclexta [US Prescribing Information] 
Rev 2022). 
6. 
ADVERSE EVENTS 
6.1. 
Adverse Event (AE) Definition Using CTCAE V5.0 
An AE is any untoward medical event that occurs to a subject following the start of voruciclib 
administration in monotherapy cohorts or the start of venetoclax in combination cohorts, whether 
or not the event is considered drug related. Pre-existing conditions are not considered an AE 
unless the condition worsens by at least one grade following the start of voruciclib administration 
in monotherapy cohorts or the start of venetoclax in combination cohorts. 
Any drug-related AE of Grade 2 or higher should be followed for resolution until: 
• 
The start of subsequent anti-cancer therapy or  
• 
Subject discontinuation from the study or 
• 
A new stable baseline or 
• 
Death 
Disease-related out-of-range laboratory values will not be considered AEs/SAEs if there is no 
change from the screening laboratory values, or if they are not deemed clinically significant by 
the Investigator. 
6.2. 
Assessment of AEs 
The Investigator will assess AEs for severity and relationship to voruciclib and to venetoclax and 
determine if an AE meets the criteria for an SAE. Each AE will be graded in the source 
documents using CTCAE v5.0. 

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6.3. 
Serious Adverse Event (SAE) Definition 
An SAE is an AE that results in any of the following outcomes: 
• 
Death 
• 
A life-threatening condition 
• 
An inpatient hospitalization or prolongation of an existing hospitalization 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect 
• 
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of 
the other outcomes listed above  
Elective hospitalization not in response to an AE is not considered an SAE. Adverse events 
constituting an SAE will be reported beginning from the first dose of voruciclib, or venetoclax in 
the combination therapy group. 
Disease progression, including death due to disease progression, is not considered an SAE.   
6.4. 
Serious Adverse Event (SAE) Reporting 
Serious adverse events will be captured from the first dose of voruciclib monotherapy or 
venetoclax in the combination regimen and continue to be captured until 30 days after the last 
dose of study drug(s), or until a subsequent anti-cancer therapy is initiated. SAEs occurring after 
30 days will be captured if believed to be related to study drug. 
All SAEs, regardless of drug attribution, must be reported to the Sponsor or designee within 
24 hours of the Investigator becoming aware of the SAE. The SAEs must be reported in EDC; 
however, if EDC is not accessible, a paper SAE form must be submitted to the Medpace Safety 
email or fax number within 24 hours of being aware of the event. When the EDC system 
becomes available, all applicable SAE information must be entered in EDC. The designee, as 
listed below, will also be specified in the Study Manual. 
To report an SAE, contact Medpace Clinical Safety as listed below:  
Email: medpace-safetynotification@medpace.com 
Phone: (800) 730-5779, Option 3 OR (513) 579-9911, Option 3 
Fax: 866) 336-5320 OR (513) 570-5196 
Sites must follow-up to confirm receipt of the SAE Report. 
The Investigator must report new significant follow-up information for these events to the 
sponsor or designee immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 

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• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
SAEs must be reported by each site to the appropriate Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) in accordance with local reporting requirements. 
Reporting requirements will also be based on the Investigator's assessment of causality and 
seriousness, with allowance for upgrading by the sponsor as needed. 
Deaths within 30 days of the administration of voruciclib or the administration of combination 
therapy must be reported as an SAE unless the death is due to disease progression. Deaths 
occurring >30 days after the last dose of voruciclib or the last dose of combination therapy must 
be reported as an SAE if considered by the investigator as related to study drug(s).  
The Investigator should make every effort to obtain and send death certificates and autopsy 
reports for all deaths to the sponsor. 
In the event of a medical emergency (requiring immediate attention regarding operation of the 
clinical study and/or the use of study drug), study site staff will apply appropriate medical 
intervention according to current standards of care and contact the Medical Monitor or other 
designated sponsor representative. 
6.5. 
Pregnancies 
To ensure subject safety, each pregnancy in a subject on study treatment must be reported within 
24 hours of learning of its occurrence; refer to Section 6.4 and the study reference manual for 
reporting contact information. Study drug must be discontinued in a subject who becomes 
pregnant. The pregnancy must be followed for at least 3 months after term or spontaneous or 
voluntary termination to determine outcome including details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy is not an AE but should be recorded and reported by the Investigator to the Sponsor or 
Designee. Pregnancy follow-up should be recorded and should include an assessment of the 
possible relationship to the study drug of any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
Fertile male subjects, defined as all males physiologically capable of conceiving offspring, with 
female partners of childbearing potential must use condoms plus spermicidal agent during the 
study treatment period and for 90 days after the last dose of study drug, and should not father a 
child during this period. 
Male subjects must also refrain from donating sperm during their participation in the study. 
6.6. 
Relationship of Adverse Events to Study Treatment 
The Investigator is obligated to assess the relationship between voruciclib or venetoclax and the 
occurrence of each AE. The Investigator is to use his/her best medical judgment in determining 

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the likely relationship of the AE to voruciclib or venetoclax. The relationship of an AE or SAE to 
voruciclib or venetoclax is to be classified as either ‘Related’ or ‘Not Related.’ 
7. 
RESPONSE ASSESSMENT 
7.1. 
Response Assessment for Subjects with CLL/SLL 
For subjects with CLL/SLL, efficacy assessments will be based on International Workshop on 
Chronic Lymphocytic Leukemia (IWCLL) criteria (Halleck 2008). Lymphocytosis may feature 
prominently during early treatment and can persist over time and should not be confused with 
disease progression in subjects with otherwise persistent disease control. Absent other objective 
evidence of disease progression, the occurrence of lymphocytosis will not preclude subjects from 
meeting the criteria for PR (if other criteria for PR are met) and will not be considered evidence 
of CLL/SLL progression if occurring in isolation. Response criteria are summarized in 
Appendix 5. 
7.2. 
Response Assessment for Subjects with FL and Other B-Cell 
Lymphomas 
For subjects with FL, MCL, MZL, DLBCL, and high-grade B-cell lymphomas, efficacy 
assessments will be based on the Lugano Classification response criteria (Cheson 2014). 
Response criteria are summarized in Appendix 6. 
7.3. 
Response Assessment for Subjects with AML 
Response assessments will be based on the European LeukemiaNet (ELN) recommendations 
(Döhner 2017). Response criteria are summarized in Appendix 4. 
8. 
STUDY PROCEDURES 
See the Schedule of Assessments (Appendix 1) for a detailed list of study procedures and 
assessments for subjects with CLL/SLL, FL, MCL, MZL, DLBCL, and high-grade B-cell 
lymphomas. See the Schedule of Assessments (Appendix 2 and Appendix 3) for a detailed list of 
study procedures and assessments for subjects with AML receiving voruciclib monotherapy or 
voruciclib + venetoclax combination therapy, respectively. Instructional details (where 
applicable) for procedures are contained in Section 9. 
8.1. 
Informed Consent 
Each subject’s signature must be obtained on a written Inform Consent Form (ICF), which has 
been approved by an IRB or IEC, prior to any study-related procedures being performed. The 
ICF must incorporate a Release of Medical Information that authorizes release of medical 
records to the trial investigators, monitors, sponsor and its designees, the FDA or other 
regulatory authority. The ICF must be in a language fully comprehensible to the prospective 
subject. The consenting process must be documented in the medical chart, and a signed copy of 
the ICF provided to the subject. 

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8.2. 
Subject Enrollment 
Prior to Amendment 11, sites submitted a Subject Enrollment Form to the sponsor or designee 
(e.g., contract research organization [CRO]) for approval prior to enrolling each subject in the 
study. The Subject Enrollment Form is no longer implemented as of Amendment 11.  
8.3. 
Screening Period 
During the screening period, the Investigator should carefully review each subject’s past medical 
history to ensure eligibility. All inclusion and exclusion criteria should be supported by 
corresponding documentation in the medical records. 
Screening assessments are to be performed within 28 days of first dose of voruciclib or the first 
dose of venetoclax in combination cohorts. Laboratory assessments need not be repeated on 
Day 1 if performed within the prior 72 hours. Physical examinations need not be repeated on 
Day 1 if performed within the prior 7 days. Some tests performed as part of routine care prior to 
obtaining ICF (e.g., computed tomography [CT] scan, bone marrow biopsy) may not need to be 
repeated for the study as long as they were performed within the allowed screening window. This 
avoids unnecessary repeat tests and undue burden on subjects. 
The risk for TLS must be assessed and the Investigator must make sure appropriate prophylaxis 
has been provided (see guidelines in Table 24 and Figure 3, Appendix 9). 
8.4. 
Enrollment and Randomization 
There is no randomization in this study. Once the subject has been deemed eligible, approved, 
and registered, the subject may enroll on study. 
8.5. 
Cycle 1 Day 1 Tests and Administration of Voruciclib or Venetoclax 
The Investigator should assess any changes in the subject’s medical condition or history since the 
Screening visit. Any significant changes since screening should be discussed with the Medical 
Monitor to confirm that the subject can start study drug administration. All Cycle 1 Day 1 tests 
and procedures outlined in the Schedule of Assessments (Appendix 1, Appendix 2, and 
Appendix 3) must be performed prior to study drug administration. Cycle 1 Day 1 should be on 
Monday, if possible, so that specimens for correlative and biomarker assays can be shipped for 
receipt no later than a Friday. 
The risk for TLS must be assessed and the Investigator must make sure appropriate prophylaxis 
has been followed (see guidelines in Table 24, Appendix 9). 
A record of the administration of the first dose of voruciclib or venetoclax (AML only) will be 
documented in the source documents. 
Any safety laboratory tests at Cycle 1 Day 1 should be performed at the local institutional 
laboratory as specified on the Schedule of Assessments.  
PK samples will be shipped to a central laboratory for analysis. 

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8.6. 
Treatment 
The treatment phase begins on the day voruciclib or venetoclax is first administered and 
continues through the last day of administration. Treatment will be tracked by 28-day periods 
identified by a numerical cycle (e.g., Cycle 1, Cycle 2…). Response assessments for subjects 
with CLL/SLL, FL, MCL, MZL, DLBCL, and high-grade B-cell lymphomas, as defined in 
Section 7, will be performed according to the Schedule of Assessments (Appendix 1) and 
detailed in Appendix 5 and Appendix 6. Response assessments for subjects with AML will be 
performed according to the Schedule of Assessments (Appendix 2 and Appendix 3) and detailed 
in Appendix 4. 
8.7. 
End of Study Visit 
The End of Study (EOS) visit will occur 30 days (± 3 days) from the last day of treatment 
drug(s) administration (or prior to starting a new treatment if urgent treatment is required). The 
end of treatment date and reason for discontinuation study drugs will be entered in the End of 
Treatment form in the EDC. 
8.8. 
End of Study 
The study will be closed when all subjects who received study drug have competed their EOS 
visit and all study data have been collected for analysis. 
9. 
STUDY ASSESSMENTS 
The following sections describe the methods for assessments of clinical and functional outcomes 
included in the trial. Refer to the Schedule of Assessments (Appendix 1, Appendix 2, and 
Appendix 3) for frequency and specific timing of assessments. 
9.1. 
Medical History and Prior Anti-Cancer Treatment  
A complete medical history will be collected during screening. Data associated with any 
interventional procedure, surgical operation (for any reason), and all prior cancer therapies will 
be collected. 
9.2. 
Demographics 
Subject demographic data including date of birth (year of birth required at a minimum), sex, 
race, and ethnicity will be recorded in the electronic case report forms (eCRFs). 
9.3. 
Concomitant Medication 
Data on concomitant prescription and OTC medications will be collected. This data will be 
recorded from 28 days prior to Day 1 of any study drug administration through 30 days after the 
last dose of voruciclib or venetoclax (combination cohorts), or until a subsequent anti-cancer 
therapy is initiated. See Section 4.14 for further details regarding prohibited treatments and 
concomitant medications. 

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9.4. 
Physical Examination and Vital Signs 
The physical examination will include the examination of all organ systems (at the Investigator’s 
discretion, genitourinary system may be excluded). Vital sign measurements will include systolic 
and diastolic blood pressure, heart rate (HR), body temperature, height (Screening visit only), 
and weight. 
A symptom-directed exam will be performed as indicated in Schedule of Assessments, and 
additional exams may be performed as clinically indicated. 
9.5. 
Adverse Events 
Adverse events will be collected at each visit as described in Section 6.  
A treatment-emergent AE (TEAE) is defined as an adverse event starting or worsening in 
CTCAE grade after the first dose until 30 days after the last dose of study drug(s), or start of new 
anti-cancer therapy, whichever is earlier. An adverse event reported ≥30 days after the last dose 
of study drug(s) will be reported and counted as TEAE if considered related to study drug and 
resulted in study drug discontinuation or an SAE.  
9.6. 
Electrocardiograms 
12-lead ECGs will be performed in triplicate, approximately 2–5 minutes apart while the subject 
is resting (See Schedule of Assessments for timing of ECGs (Appendix 1, Appendix 2, and 
Appendix 3)  
9.7. 
Laboratory Tests 
Laboratory tests listed on the Schedule of Assessments (Appendix 1, Appendix 2, and 
Appendix 3) will be analyzed at a local laboratory and used in all safety analyses and or response 
assessments (see Appendix 4, Appendix 5, and Appendix 6). PK samples discussed in 
Section 9.14 will be shipped to a central laboratory for analysis. 
The following are descriptions of the tests to be performed. For timing and frequency of the 
below listed tests, refer to the Schedule of Assessments (Appendix 1, Appendix 2, and 
Appendix 3): 
• CBC with differential – WBCs, ANC, red blood cells (RBCs), hemoglobin (Hgb), 
hematocrit (Hct), platelets, mean corpuscular hemoglobin (MCH), and differential 
• Serum chemistry – glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
chloride, calcium, phosphate, uric acid, phosphorus, carbon dioxide, alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, 
total protein, albumin, and lactate dehydrogenase (LDH). (Additional chemistry will be 
performed as indicated in the TLS management plan and as clinically indicated.) 
• Coagulation – activated partial thromboplastin time (aPTT), PT, and INR 
• Urinalysis (Dipstick) 
• Pharmacokinetic sampling – see Section 9.14 

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• Pharmacodynamic and biomarker studies – see Section 9.12, Site Laboratory Manual and 
Schedule of Assessments 
• Pregnancy test – serum/urine pregnancy test in females of childbearing potential  
• HIV testing 
• Hepatitis B core antibody, surface antibody and surface antigen, and hepatitis C virus 
antibody (HCV Ab) tests are required. Hepatitis B polymerase chain reaction (PCR) is 
required if hepatitis B core antibody and/or surface antigen is positive. Hepatitis C PCR is 
required if HCV Ab test is positive. 
• Cytogenetics  
o Classical cytogenetics for subjects with AML only. At least 20 bone marrow 
metaphases are needed to define a normal karyotype and recommended to describe an 
abnormal karyotype. Abnormal karyotypes may be diagnosed from blood specimens. 
If abnormal cytogenetics at screening, repeat cytogenetics in a subject with CR/CRi 
to confirm a cytogenetic remission. 
o Fluorescence in situ hybridization [FISH] for subjects with SLL or CLL only – FISH 
for del(13q), del(11q), del(17), trisomy 12, del(6q) performed on blood or biopsy 
specimen. Result is not required prior to enrollment 
• IgHV mutational testing (subjects with SLL or CLL only) – IgHV mutational testing 
performed in the peripheral blood lymphocytes or biopsy specimen. Result is not required 
prior to enrollment 
• Quantitative serum immunoglobulin levels (IgA, IgG, IgM) will be performed for subjects 
with SLL and CLL  
• Screening for gene mutations and gene rearrangements for subjects with AML only. 
Screening is not required for enrollment in the study but will be collected if performed as 
part of the standard of care, including genes defined in the 2017 ELN response criteria. If 
obtained as screening, repeat the test for the genetic marker by RT-qPCR or flow cytometry 
in a subject with CR/CRi to confirm CR with minimal residual disease per the 2017 ELN 
response criteria. 
• Bone marrow aspiration/biopsy are required for assessment of response and as clinically 
indicated. For subjects with CLL/SLL, FL, MCL, MZL, DLBCL, and high-grade B-cell 
lymphomas refer to Appendix 5, Table 19 and Appendix 6, Table 21. For subjects with 
AML refer to Appendix 4, Table 18. Additionally, for monotherapy cohorts, optional 
biopsy/aspirates pre-first dose, at the end of Cycle 6 and at end of treatment may be 
conducted for correlative studies. See Laboratory Manual. For AML combination therapy 
cohorts, bone marrow aspirate/biopsy and laboratory evaluation should be completed at 
screening (up to 28 days prior to starting venetoclax), Cycle 2 Day 1, and Day 1 of every 
subsequent cycle until a CR or CRi is achieved. Thereafter, response assessments should be 
performed when bone marrow examinations are obtained as clinically indicated and at EOS. 
Both biopsy and aspirate are recommended for disease assessment, but biopsy may be 
omitted if aspirate is considered to be sufficient. Bone marrow aspirate sample collected at 
the time of disease assessment may be used for exploratory biomarker analysis in bone 

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marrow/bone marrow aspirate. If any remaining sample is available after evaluation for 
disease assessment, it should be submitted to the central laboratory for pharmacodynamic 
biomarker/correlative study (refer to the Lab Manual).  
• Tumor biopsy – Formalin fixed material is acceptable although fresh tissue is preferred. 
• Chest X-ray, unless recent CT scan shows no pulmonary abnormalities (for patients treated 
with voruciclib/venetoclax combination therapy). 
9.8. 
Disease Assessment 
Computed tomography (CT) scans, positron emission tomography (PET)-CT scans, bone 
marrow aspirate/biopsy, and laboratory evaluation will be completed as appropriate for 
individual subjects. For subjects with CLL/SLL, efficacy assessments will be based on criteria of 
the IWCLL guidelines per Appendix 5. For subjects with FL, MCL, MZL, DLBCL, and high 
grade- B-cell lymphomas, efficacy assessments will be based on the Lugano Classification 
response criteria per Appendix 6. For subjects with AML, efficacy assessments will be based on 
European LeukemiaNet (ELN) Response Criteria per Appendix 4. 
9.9. 
ECOG 
Eastern Cooperative Oncology Group (ECOG) performance status to be evaluated at Screening, 
Day 1 of each cycle, and EOS.  
9.10. 
Pregnancy Test 
Serum pregnancy test in females of childbearing potential at screening, urine pregnancy test 
Day 1 of each cycle and at EOS. 
9.11. 
Virology 
HIV antibody testing is required to determine eligibility. 
Hepatitis B core antibody, surface antibody and surface antigen, and hepatitis C virus antibody 
(HCV Ab) tests are required to determine eligibility. Hepatitis B polymerase chain reaction 
(PCR) is required if hepatitis B core antibody and/or surface antigen is positive. Hepatitis C PCR 
is required if HCV Ab test is positive. 
9.12. 
Compliance Diary 
A compliance diary will be provided to the subject at each study drug dispensing timepoint, 
according to the Schedule of Assessments (Appendix 1, Appendix 2, and Appendix 3).  
9.13. 
Dispensation, Administration, and Accountability of Voruciclib and 
Venetoclax 
Voruciclib is administered orally once daily on dosing days, on an empty stomach at least 1 hour 
prior to food, or 2 hours after food at approximately the same time each day. On days of PK 
sampling, subjects should be instructed not to take voruciclib until after the pre-dose PK sample 
is collected.  

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Venetoclax is commercially available as 10 mg, 50 mg, and 100 mg tablets. Venetoclax is to be 
taken once daily with a meal and water. 
In order to minimize intestinal P-gp interaction, venetoclax must be taken with a meal, followed 
by voruciclib administration 2 hours later.  
A compliance diary assessment and returned drug accountability will be performed at each visit 
which includes voruciclib dispensing. Refer to Section 5 for additional information on the 
storage and management of voruciclib and venetoclax. 
9.14. 
Pharmacokinetics 
Pharmacokinetic (PK) samples are to be obtained as noted below: 
9.14.1. 
Voruciclib Monotherapy 
In monotherapy IS Cohorts 1-5: 
Pre-dose specimens should be drawn within 2 hours prior to dosing and post-dose within 
±30 minutes of designated post-dose sampling times. 
Samples for voruciclib plasma concentration analysis will be collected as follows: 
• Cycle 1 Day 1: Pre-dose, 4-, and 6-hours post-dose 
• Cycle 1 Day 2: Pre-dose (24 hours after the preceding last dose) 
• Cycle 1 Day 8: Pre-dose (24 hours after the preceding last dose) 
• Cycle 1 Day 15: Pre-dose (24 hours after the preceding last dose), 4- and 6-hours post-dose 
In monotherapy IS Cohorts 6-11: 
• Cycle 1 Day 1: Pre-dose, 4-, and 6-hours post-dose 
• Cycle 1 Day 2: Pre-dose (24 hours after the preceding last dose) 
• Cycle 1 on Day 8 (24 hours after the preceding last dose) 
• Cycle 1 Day 15 (24 hours after the preceding last dose, if applicable [Day 15 samples only 
to be collected for IS2w2w schedule]) 
• Cycle 2 Day 1: Pre-dose 
9.14.2. 
Voruciclib + Venetoclax Combination Therapy  
Pre-dose specimens should be drawn within 2 hours prior to dosing and post-dose within 
+30 minutes of designated post-dose sampling times. 
Blood samples for characterization of voruciclib PK will be collected in Cohorts 12–19 and 
21–25 as shown in Table 14 and Table 15, relative to dosing of voruciclib.  

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Table 14: 
PK Sample Collection for Voruciclib, Cohort 12 (QOD Dosing)  
Cycle 
Day 
Time of Collection 
Pre-dose 
Post-dose 
1 
3 
X 
2, 4, 6 hours 
4* 
- 
approximately 24 hours after Day 3 dose 
8 
-  
approximately 24 hours after Day 7 dose 
13 
X 
2, 4, 6 hours 
14 
- 
approximately 24 hours after Day 13 dose 
21 
anytime during clinic visit 
2 
1 
X 
- 
4, 6 
1, 14 (±3 days) 
anytime during clinic visit 
Every 3 cycles 
thereafter  
1, 14 (±3 days) 
anytime during clinic visit 
* Day 4 sample to be collected only if the subject is able to visit the clinic. 
 
Table 15: 
PK Sample Collection for Voruciclib, Cohorts 13–19 and 21–25 (QD Dosing) 
Cycle 
Day 
Time of Collection 
Pre-dose 
Post-dose 
1 
3 
X 
2, 4, 6 hours 
4* 
X  
(approximately 24 hours 
after Day 3 dose) 
- 
8 
X  
(approximately 24 hours 
after Day 7 dose) 
- 
14 
X 
2, 4, 6 hours 
15 
- 
approximately 24 hours after Day 14 dose 
21 
anytime during clinic visit 
2 
1 
X 
- 
4, 6 
1, 14 (±3 days) 
anytime during clinic visit 
Every 3 cycles 
thereafter  
1, 14 (±3 days) 
anytime during clinic visit 
* Day 4 sample to be collected only if the subject is able to visit the clinic. 
 
Drug-Drug Interaction (DDI) Assessment: Voruciclib exposures (when co-administered with 
venetoclax) will be compared to historical single agent data to assess DDI and the effect of 
venetoclax on voruciclib PK. 
Blood samples for characterization of venetoclax PK will be collected in Cohorts 12–19 and 
21–25 as shown in Table 16 and Table 17, relative to dosing of venetoclax. 

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Table 16: 
PK Sample Collection for Venetoclax, Cohort 12 (QOD Dosing) 
Cycle 
Day 
Time of Collection 
Pre-dose 
Post-dose 
1 
13 
X 
2, 4, 6, 8 hours 
14 
X  
(approximately 
24 hours after 
Day 13 dose) 
- 
21 
anytime during clinic visit  
2 
1 
X 
2, 4, and 6-hours post-dose of venetoclax 
(voruciclib to be dosed 6 hours after venetoclax 
administration, after completion of the 6- hour 
sample collection) 
4, 6 
1, 14 (±3 days) 
anytime during clinic visit 
Every 3 cycles 
thereafter  
1, 14 (±3 days) 
anytime during clinic visit 
 
Table 17: 
PK Sample Collection for Venetoclax, Cohorts 13–19 and 21–25 (QD Dosing)  
Cycle 
Day 
Time of Collection 
Pre-dose 
Post-dose 
1 
14 
X 
2, 4, 6 and 8-hours 
15 
X  
(approximately 
24 hours after 
Day 14 dose) 
- 
21 
anytime during clinic visit  
2 
1 
X 
2, 4 and 6-hours post-dose of venetoclax 
(voruciclib to be dosed 6 hours after venetoclax 
administration, after completion of the 6- hour 
sample collection) 
4, 6 
1, 14 (±3 days) 
anytime during clinic visit 
Every 3 cycles 
thereafter  
1, 14 (±3 days) 
anytime during clinic visit 
DDI Assessment: Venetoclax exposure (when co-administered with voruciclib) will be 
compared to historical single agent data to assess DDI and the effect of voruciclib on venetoclax 
pharmacokinetics. Venetoclax concentrations on Cycle 2 Day 1 and Cycle 1 Day 14 will also be 
compared assuming limited effect, if any, on voruciclib on Cycle 2 Day 1.  
Voruciclib PK and other relevant data from all clinical trials (including late phase clinical trials) 
will be pooled and analyzed using population PK methods. Additionally, voruciclib exposure-
response and exposure-safety assessments will be performed and the results will be presented in 
a separate report. 

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PK of voruciclib in subjects receiving co-administered azole antifungals versus those without 
azole antifungals will be compared.  
Detailed instructions on collection of plasma for determination of voruciclib and venetoclax will 
be provided in the Site Laboratory Manual. 
9.15. 
Pharmacodynamics of Voruciclib and Voruciclib + Venetoclax  
Blood will be collected for determination of the effect of voruciclib monotherapy and the 
combination of voruciclib + venetoclax on biomarkers, e.g., apoptotic pathway proteins, and to 
correlate antitumor activity with baseline tumor characteristics, according to the following 
schedules, as follows: 
Monotherapy Cohorts 6a,b – 8a,b 
• Cycle 1 Day 1: Pre-dose, and approximately 6-hours post-dose 
• Cycle 1 Day 2: Pre-dose (approximately 24 hours after preceding dose) 
• Cycle 1 Day 15: Pre-dose (approximately 24 hours after preceding dose) 
Combination therapy Cohorts 12–19 and 21–25: 
• Cycle 1 Day 1: Pre-dose of venetoclax and approximately 6-hours post-dose of venetoclax 
for Cohorts 12–16 or 4–6 hours post-dose for Cohorts 17–25 
• Cycle 1 Day 3: Pre-dose of voruciclib and approximately 6-hours post-dose of voruciclib 
for Cohorts 12–16 or 4–6 hours post-dose for Cohorts 17–25 
• Cycle 1 Day 14*: Pre-dose of venetoclax and approximately 6-hours post-dose of 
voruciclib for Cohorts 12–16 or 4–6 hours post-dose for Cohorts 17–25 
* For Cohort 12, since there is no voruciclib dosing on Cycle 1 Day 14, blood will be collected on 
Cycle 1 Day 13 pre-dose of venetoclax and approximately 6-hours post-dose of voruciclib during 
clinic visit for PK sample collection.  
For PK and PD collection visits that fall on weekends or holidays, please contact the Sponsor to 
discuss sampling schedule. 
10. 
STATISTICS 
10.1. 
Number of Subjects 
At the start of Amendment 12, a total of 40 subjects have been enrolled in the now-completed 
monotherapy dose escalation/expansion cohorts. Assuming an average enrollment of 4 subjects 
per dose level for DLT evaluation, up to 12 subjects to be enrolled in the 2 combination AML 
expansion cohorts, and an additional 10% for early drop-outs due to non-evaluability after failure 
to complete Cycle 1 treatment for reasons other than AEs related to voruciclib, the total 
enrollment for the voruciclib plus venetoclax combination group is estimated to be 
approximately 68 subjects, for a total of approximately 108 subjects to be enrolled in the study.  

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10.2. 
Study Endpoints 
The primary study objectives are to determine the safety and tolerability and safe and mBED of 
voruciclib monotherapy in subjects with relapsed and/or refractory B-cell malignancies and 
AML and to determine the safety, tolerability and safe and mBED of voruciclib in combination 
with venetoclax in subjects with relapsed and/or refractory AML.  
Safety will be assessed by AEs graded according to NCI CTCAE v5.0; laboratory safety tests 
including hematology (CBC), serum chemistry; physical examination; vital signs; ECOG 
performance status; and triplicate 12-lead ECG. If 2 or more of 6 subjects experience a DLT in a 
dose cohort, then the next lower dose will be the MTD.  
The primary endpoint is: 
• The incidence of AEs, including DLTs. 
Secondary endpoints are: 
• Efficacy endpoints within each tumor type: 
a. Overall Response Rate (ORR), defined as the proportion of subjects who achieve a 
best overall response of 
o CR, CRi, or PR, with responses defined per 2008 International Workshop on CLL 
(IWCLL) guidelines,  
o CR or PR by 2014 Lugano criteria for non-Hodgkin lymphoma,  
o CR, CRi, CRMRD, MLFS by the 2017 ELN criteria for AML  
b. DOR defined as the time from first achieving a response to date of documented 
disease progression or death from any cause. Subjects who die due to any cause prior 
to progression will be censored 
c. PFS defined as time from first dose of study drug to date of documented disease 
progression or death from any cause 
d. Estimates of the exposure and association with efficacy and safety variables for 
voruciclib administered as monotherapy, and the PK of voruciclib and venetoclax 
when administered in combination 
The exploratory endpoints are: 
a. Effects on biomarkers and functional activities of proteins in the apoptotic pathway 
b. Correlations of anti-tumor activity and baseline tumor characteristics 
10.3. 
Analysis Methods 
Subjects completing the first cycle of treatment with at least 75% of study drug compliance or 
experiencing a DLT during the first cycle (28 days) of treatment, will be considered evaluable 
for the occurrence of DLTs. The 3 + 3 design targets a DLT rate for the MTD of approximately 
20–25%.  

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Summary statistics for continuous variables will include the mean, standard deviation, median 
and range (minimum/maximum). Categorical variables will be presented as frequency counts and 
percentages.  
See Section 10.6 for efficacy analysis methods. 
10.3.1. 
Handling of Missing Data 
For summary statistics, missing data will not be imputed; results will be reported based upon 
observed data. 
10.3.2. 
Analysis Populations 
The Safety population is defined as subjects who receive at least one dose of study drug(s). 
The DLT evaluable population includes subjects in dose escalation cohorts who complete the 
first cycle of treatment with at least 75% of study drug compliance or experience a DLT during 
the first cycle (28 days) of treatment. 
The Efficacy evaluable population is defined as subjects who complete the first scheduled post-
baseline efficacy evaluation (scheduled on C3D1 for B-cell lymphoma subjects and C2D1 for 
AML subjects) or develop progression of disease or death prior to the first scheduled post-
baseline efficacy.  
The PK population will include all subjects who receive at least 1 dose of voruciclib or 
venetoclax and have at least 1 non-missing post-dose concentration value. 
10.4. 
Safety Analyses 
10.4.1. 
Adverse Events 
The incidence of all TEAEs will be tabulated by cohort. These TEAEs will be classified by 
system organ class and preferred term or by preferred term in descending order of frequency 
using the Medical Dictionary for Regulatory Activities (MedDRA). For incidence reporting, if a 
subject reported more than one AE that was coded to the same system organ class or preferred 
term, the subject will be counted only once for that specific system organ class or preferred term. 
An overview of AEs, which includes subject incidence of TEAEs, TEAEs by severity, related 
TEAEs, related TEAEs by severity, SAEs, deaths, and AEs leading to discontinuation, will be 
presented. 
10.4.2. 
Clinical Safety Laboratory Results 
The observed data and change from baseline for each measurement day will be summarized with 
descriptive statistics. 
Where criteria are available, laboratory values will be assigned toxicity grades, using 
NCI CTCAE v5.0. Directional shifts in laboratory toxicity grades (comparing baseline grade 
with worst post-baseline grade) will be analyzed using standard shift tables, presenting number 
and proportion of subjects and their maximum grade shift. 

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10.4.3. 
Vital Signs 
The observed data and change from baseline for each measurement day will be summarized with 
descriptive statistics. 
10.4.4. 
Electrocardiogram 
The observed QTc data and change from baseline for each measurement day will be summarized 
with descriptive statistics. 
10.5. 
Pharmacokinetic Analyses 
For all monotherapy cohorts, the PK of voruciclib will be summarized by descriptive statistics. 
Pharmacokinetic parameters will be estimated, where appropriate, by non-compartmental 
analysis using statistical computer packages as specified in the statistical analysis plan. Graphic 
evaluation will be used for data analysis where appropriate. Pharmacokinetics and fit will be 
evaluated graphically; modeling will also be used if sufficient data are available. 
For the combination treatment cohorts, the PK of voruciclib and venetoclax will be summarized 
separately, as above and compared to historical data. 
10.6. 
Efficacy Analyses 
For the Efficacy population, response to treatment will be tabulated with 95% exact binominal 
CIs.  
The Kaplan-Meier method will be used to estimate PFS and DOR within subjects of the same 
tumor type. For PFS, subjects without documented progression will be censored at the date of 
last disease assessment.  
11. 
REGULATORY AND REPORTING REQUIREMENTS 
The study will be conducted according to the principles of the Declaration of Helsinki 
(World Medical Association 2013), the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH), Guideline E6(R2): Good Clinical 
Practice (ICH 2016), and the requirements of all local regulatory authorities regarding the 
conduct of clinical trials and the protection of human subjects. The study will be conducted by 
scientifically and medically qualified persons and the rights and welfare of the subjects will be 
respected. 
Each subject will provide written informed consent before any study-related tests or evaluations 
are performed. 
11.1. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) 
Approval of this study will be obtained from an IRB/IEC prior to enrolling subjects and will be 
reviewed and approved on an annual basis by the IRBs/IECs representing the participating 
institutions. Such IRBs/IECs must be appropriately constituted and meet all requirements as 
described in Title 21, Part 56 of the Code of Federal Regulations. The review must include the 

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protocol, subject recruitment materials, the Investigator’s Brochure, the ICF, any other 
study-related material that will be provided to subjects (including study drug compliance 
diaries). A copy of the Letter or Notice of Approval from the IRB/IEC must be received by the 
sponsor prior to shipment of drug supplies to the Investigator. The IRB/IEC membership list or 
Federal Wide Assurance (FWA) number must be submitted to the Sponsor with the written IRB 
approval, and lists must be updated, if applicable. 
11.2. 
Public Clinical Trial Registry 
This study will be listed on a public clinical trial registry such as www.clinicaltrials.gov, per 
applicable regulations. 
11.3. 
Confidentiality 
The Principal Investigator and designees, employees, and agents involved with this study will 
comply with relevant state and federal laws relating to the confidentiality, privacy, and security 
of subjects’ health information. Data generated during this study or disclosed by the sponsor 
to the Investigator will only be used as appropriate for the execution, analysis, review, 
and reporting of this study. Such information shall not be used for any other purposes and will 
remain confidential. 
In order to verify subject eligibility criteria and ensure ongoing subject safety during the study 
and preserve the integrity of study data, notwithstanding source data verification at the study site, 
the Sponsor/CRO may request to review subject source medical data. Should the Sponsor request 
copies of subject medical data, the rationale for such request will be ethically and scientifically 
justified. Such records will promptly be destroyed by the Sponsor/CRO when the purpose of the 
review has been met. 
In order to ensure subject safety and in adherence with regulatory guidelines, personal medical 
information may be reviewed by the IRB/IEC, or regulatory authorities. Every reasonable effort 
will be made to maintain strict confidentiality.  
Though the results of the study may be presented in reports, published in scientific journals, 
or presented at medical meetings; subject names or identifiers will never be used. 
11.4. 
Financial Disclosure 
Investigators must maintain compliance with the current FDA guidelines and regulations 
concerning financial disclosure. 
11.5. 
Data Quality Assurance 
Good Clinical Practice (GCP) guidelines regarding clinical data management practices 
and procedures are to be utilized to ensure accurate, consistent, and reliable data. The sponsor 
or designee will establish a Data Management Plan for this study. 

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12. 
DATA MANAGEMENT 
12.1. 
Use of Electronic Case Report Forms 
Study data will be stored and transmitted using eCRFs, with a system determined by the sponsor. 
The sponsor will provide secure access and eCRF completion guidelines, as well as 
study-specific training, as needed, to each site. 
Data recorded in the eCRFs must be supported by information captured in source documents, 
which must be available at all times for inspection by authorized representatives of the sponsor, 
the FDA, or other regulatory agencies. The eCRFs must be completed as soon as possible after 
each study visit or contact. 
12.2. 
Study Site Monitoring 
A sponsor-designated study monitor will conduct a site initiation visit prior to study enrollment, 
a visit shortly after enrollment of the first subject, and periodic interim monitoring visits during 
the study, as per the study-specific monitoring plan. 
The primary purposes of the site visits are to: 
• Ensure the accuracy and completeness of eCRF entries, as verified against the source 
documentation 
• Verify that the conduct of the study adheres to the written protocol approved by the 
IRB/IEC, as well as regulatory requirements 
• Verify that regulatory and other study-related documentation is maintained and current 
• Perform voruciclib study drug accountability (reconcile study drug receipt, storage, 
dispensing, and return records) 
12.3. 
Record Retention 
The Investigator will retain the records of the study for 2 years following the last date that 
a marketing application for voruciclib is approved in any ICH region, or if marketing approval 
is not obtained, for 2 years after the Investigational New Drug (IND) for voruciclib has been 
closed. The sponsor will notify the Investigators when study records retention is no longer 
required. 
For studies conducted outside the US under a US IND, the Principal Investigator must comply 
with the record-retention requirements set forth in the US FDA IND regulations and the relevant 
national and local health authorities, whichever is longer. 
The site will retain copies of all versions of the protocol, Investigator’s Brochure, 
correspondence with the IRB/IEC (including submission and approval letters, approved ICFs), 
curricula vitae and medical licenses of the Investigator and sub-Investigator(s), Forms 
FDA-1572, correspondence, laboratory documentation (including accreditation documents, 
reference ranges, and manuals), Delegation of Authority Log (documenting procedures delegated 
by the Investigator to be performed by study staff), voruciclib study drug records (including 
receipt, storage, dispensing, and return records), source documents (including clinic charts, 

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medical records, laboratory results, radiographic reports), training records, screening/enrollment 
logs, monitoring visit logs, and study procedure manuals. 
Should the Investigator leave the institution or otherwise withdraw from the investigation or 
should there be any changes in the archival arrangements for the study records, the sponsor will 
be notified. The sponsor will be notified of the identity of any individual assuming responsibility 
for maintaining the study records and the location of their storage. If no other individual at the 
investigational site is willing to assume this responsibility, the sponsor will assume responsibility 
for maintaining the study records. 
13. 
AMENDMENTS TO THE PROTOCOL 
Amendments will be originated and documented by the sponsor. Individual study sites should 
communicate requests for protocol amendments directly to the sponsor. The sponsor may be 
required to discuss potential protocol amendments with the appropriate regulatory agencies. 
Amendments shall only be implemented following the required regulatory and ethical review 
and approval. Protocol amendments also may require changes to the ICF. 
14. 
PUBLICATION POLICY 
The sponsor intends to publish the results of this trial as soon as possible following completion 
of data analysis. Data derived from the trial are the exclusive property of the sponsor. Authorship 
(both inclusion and sequence) will be determined by mutual agreement. In the event of a 
disagreement on authorship, the sponsor will serve as adjudicator. 

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15. 
REFERENCES 
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision of the World Health Organization 
classification of myeloid neoplasms and acute leukemia. Blood. 2016;2391-2405. 
Blum W, Phelps MA, Klisovic RB, et al. Phase I clinical and pharmacokinetic study of a novel 
schedule of flavopiridol in relapsed or refractory acute leukemias. Haematologica. 2010; 95(7): 
1098–1105. 
Bogenberger J, Whatcott C, Hansen N, et al. Combined venetoclax and alvocidib in acute 
myeloid leukemia, Oncotarget. 2017; 8(63): 107206–107222. 
Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management 
of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: 
American Society of Clinical Oncology Practical Guidance. J Clin Oncol. 2018, 4:1-55. 
Cairo MS, Coiffier B, Feiter A and Younes A. Recommendations for the evaluation of risk and 
prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an 
expert TLS panel consensus. BJH. 2010; 149:578-586. 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol. 2014; 32(27): 3059–3067.  
Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, et al. Phase I 
first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin 
lymphoma. J Clin Oncol. 2017; 35(8): 826–833. 
DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with 
decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a 
non-randomised, open-label, phase 1b study. Lancet Oncol. 2018; 19(2): 216–228. 
Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood. 2017; 129:424-447.  
FDA Drug Safety Communications, September 2019. Can be accessed at: 
https://www.fda.gov/drugs/fda-warns-about-rare-severe-lung-inflammation-ibrance-kisqali-and-
verzenio-breast-cancer  
Ghia P, Sarfò L, Perez S, Pathiraja K, Derosier M, Small K, et al. Efficacy and safety of 
dinalciclib vs ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia. 
Blood. 2017; 129(13): 1876–1878. 
Gojo I, Sadowska M, Walker A, et al. Clinical and laboratory studies of the novel cyclin-
dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias. Cancer Chemoth 
Pharm. 2013; 72(4): 897–908. 
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines 
for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International 
Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working 
Group 1996 guidelines. Blood. 2008; 111(12): 5446–5456. 
Howard SC, Jones DP, and Pui CH. The Tumor Lysis Syndrome. N Eng J Med:2011; 
364(19):1844-1854. 

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International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH), Guideline E6 (R2): Good Clinical Practice, adopted 15 December 2016 
[Internet]. Available from: http://www.ich.org/products/guidelines/efficacy/article/efficacy-
guidelines.html. 
Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in oncology. 
Biometrics. 2005;61(2):540-545. 
Jones JA, Rupert AS, Poi M, Phelps MA, Andritsos L, Baiocchi R, et al. Flavopiridol can be 
safely administered using a pharmacologically derived schedule and demonstrates activity in 
relapsed and refractory non-Hodgkin’s lymphoma. Am J Hematol. 2014: 89(1): 19–24. 
Konopleva M, Pollyea DA, Poluri J, et al. Efficay and biological correlates of response in a 
Phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. 
Cancer Discov. 2016;6(10): 1106-1117. 
Lanasa MC, Andritsos L, Brown JR, Gabrilove J, Califaris-Cappio F, Ghia P, et al. Final results 
of EFC6663: a multicenter, international, phase 2 study of alvocidib for patients with 
fludarabine-refractory chronic lymphocytic leukemia. Leuk Res. 2015; 39(5): 495–500. 
Luedtke DA, Niu X, Pan Y, et al. Inhibition of Mcl-1 enhances cell death induced by the 
Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Signal Transduct and Target 
Ther. 2017; 2: e17012. 
Luedtke DA, Su Y, Edwards H, et al. Voruciclib, an oral, selective CDK9 inhibitor, enhances 
cell death induced by the bcl-2 selective inhibitor venetoclax in acute myeloid leukemia. 
American Society of Hematology 2018 Annual Meeting:#1361. 
Luedtke DA, Su Y, Ma J, et al. Inhibition of CDK9 by voruciclib synergistically enhances cell 
death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid 
leukemia. Signal Transduct Target Ther. 2020; 5:17. 
Pan R, Ruvolo VR, Wei J, et al. Inhibition of Mcl-1 with the pan–Bcl-2 family inhibitor 
(–) BI97D6 overcomes ABT-737 resistance in acute myeloid leukemia. Blood. 2015; 126: 
363-372.
Paiva C, Godberson JC, Soderquist RS, Rowland T, Kilmarx S, Spurgeon SE, et al. 
Cyclin-dependent kinase inhibitor P1446A induces apoptosis in a JNK/p38 MAPK-dependent 
manner in chronic lymphocytic leukemia B-cells. PLoS One. 2015; 10(11): 1–16. 
Sanz MA, Montesinos P. How we prevent and treat differentiation syndrome in patients with 
acute promyelocytic leukemia. 2014 1;123(18):2777-82. 
Venclexta US Prescribing Information. North Chicago, IL: AbbVie Inc., and South 
San Francisco, CA: Genentech Inc.; 2022. 
World Medical Association. World Medical Association Declaration of Helsinki: ethical 
principles for medical research involving human subjects. JAMA. 2013; 310(20): 2191–2194. 
Yecies D, Carlson NE, Deng J, Letai A. Acquired resistance to ABT-737 in lymphoma cells that 
up-regulate MCL-1 and BFL-1. Blood. 2010: 115(16): 3304–3313. 

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APPENDIX 1. SCHEDULE OF ASSESSMENTS – CLL/SLL, FL, MCL, MZL, DLBCL, AND 
HIGH-GRADE B-CELL LYMPHOMAS 
 
Screening b 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7c 
End of Studyd 
Day(s) a 
-28 to -1 
1 a 
2 
8 
15 
1 
15 
1 
1 
1 
1 
1 
30 days (± 3 days) 
post last dose 
Informed consent 
X 
 
 
 
 
  
 
 
 
 
 
  
  
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
Symptom-directed exam e 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Vital signs f 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Height f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight f  
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy test g 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
HIV testing h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C testing i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for PD/biomarker assays 
 
X*** 
X 
 
 
X 
 
 
 
 
 
 
 
Bone marrow biopsy/aspiration* 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
Tumor biopsy** (optional) 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Cytogenetics (FISH) j 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
IgHV mutational testing k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events l 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG n 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
X 
CBC with differential o 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TLS risk assessment and monitoring p 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Immunoglobulin tests q  
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Coagulation r 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Urinalysis (Dipstick) s 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
X  
Issue and assess compliance diary t 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
  
Dispense voruciclib u 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
  
PK Sampling (all subjects) v 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Disease assessment w 
X 
 
 
 
 
  
 
X 
 
 
 
X 
 X 

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APPENDIX 1.  SCHEDULE OF ASSESSMENTS – CLL/SLL, FL, MCL, MZL, DLBCL, AND 
HIGH-GRADE B-CELL LYMPHOMAS (CONTINUED) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BP = blood pressure; BUN = blood urea nitrogen; CBC = complete blood count; CLL = chronic lymphocytic leukemia; CR = complete response; CT = Computed 
tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = End of Study; FISH = fluorescence in situ hybridization; FL = follicular lymphoma; 
Hct = hematocrit; HCV Ab = hepatitis C virus antibody; Hgb = hemoglobin; HIV  = human immunodeficiency virus; HR = heart rate; ICF = informed consent form; 
IgHV = immunoglobulin heavy-chain variable-region gene; INR = international normalized ratio; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; PCR = polymerase 
chain reaction; PD = pharmacodynamic; PK = pharmacokinetic; PT = prothrombin time; RBC = red blood cell; SLL = small lymphocytic lymphoma; TLS = tumor lysis syndrome; 
WBC = white blood cell. 
a. Cycle 1 Day 1 and Study Assessment Day(s) – C1D1 and visits when blood for pharmacodynamic/biomarker studies are collected should be conducted Monday through Wednesday if 
possible so that specimens can be shipped for receipt no later than a Friday. There is ± 3day window allowable for each clinic visit during Cycle 1. Following Cycle 1, the allowable 
window is up to 7 days prior and 2 days after the scheduled clinic visit and its associated assessments. 
b. Screening – Screening assessments are to be performed within 28 days of first dose of voruciclib. Laboratory assessments need not be repeated on Day 1 if performed within the prior 
72 hours. Physical examination need not be repeated on Day 1 if performed within the prior 7 days. Some tests performed prior to obtaining ICF (e.g., CT scan, bone marrow biopsy) 
may not need to be repeated for the study as long as they were performed within the allowed screening window.  
c. Cycle 7+ – Subjects who remain on study after 7 cycles should follow the following study visit procedures: 
• 
For Cycles 8-12, and Cycles 14-18, study visit procedures from Cycle 6 should be performed 
• 
For Cycles 13 and 19, study visit procedures from Cycle 7 should be performed  
• 
Cycles after 19 should follow the same schedule as Cycle 7 assessments every 6 cycles 
d. EOS – The EOS visit will occur 30 days ± 3 days from the last day of voruciclib administration (or prior to starting a new treatment if urgent treatment is required). 
e. Symptom-directed exam – Performed only as needed/indicated, based on interim history. 
f. Vital signs, Height, Weight – includes systolic and diastolic blood pressure (BP), heart rate (HR) and body temperature. Height collected at Screening only.   
g. Pregnancy test – Serum pregnancy test in females of childbearing potential at screening, urine pregnancy test Day 1 of each cycle and at EOS. 
h. HIV testing – HIV antibody testing is required. 
i. Hepatitis B and Hepatitis C testing – Hepatitis B core antibody, surface antibody and surface antigen, and hepatitis C virus antibody (HCV Ab) tests are required. Hepatitis B 
polymerase chain reaction (PCR) is required if hepatitis B core antibody and/or surface antigen is positive. Hepatitis C PCR is required if HCV Ab test is positive. 
j. Cytogenetics (FISH) – For subjects with SLL, CLL only; perform cytogenetics (FISH) for del(13q), del(11q), del(17), trisomy 12, del(6q) performed on blood or biopsy specimen of 
histologically-confirmed CLL/SLL. To be repeated when subject achieves a CR. The result does not need to be available for enrollment or initiation of study treatment. 
k. IgHV mutational testing – For subjects with SLL, CLL only; perform IgHV mutational testing in the peripheral blood lymphocytes or biopsy specimen at any time prior to initiation of 
therapy (may be collected prior to study screening). The result does not need to be available prior to enrollment or initiation of study treatment. 
l. Adverse events – Recorded from the first dose of voruciclib and continue until 30 days after the last dose, or until a subsequent anti-cancer therapy is initiated. 
m. Concomitant medications – Recorded from 28 days prior to Cycle 1 Day 1 through 30 days after the last dose of voruciclib, or until a subsequent anti-cancer therapy is initiated. 
n. ECG – 12 lead ECGs performed in triplicate (approximately 2–5 minutes apart while the subject is resting) at screening, Day 1 (Pre-dose and 4 hours post-dose), Day 8 (24 ± 3 hours 
after the preceding last dose in Cohorts 9-11), Day 15 (Pre-dose and 4 hours post-dose in Cohorts 1-5, and 24 ± 3 hours after the preceding last dose in Cohorts 6-8), and a single 
triplicate ECG at Day 1 of Cycle 2, pre-dose, if possible, and EOS. Additional ECG’s as clinically indicated. For Cycle 1, pre-dose ECG should be within the 2 hours prior to dosing and 
post-dose within a 30-minute window either side of the nominal time. When a PK blood draw is scheduled at the same time as ECG, the ECG should be performed first and as close as 
possible immediately followed by the PK draw. 
o. CBC with differential – WBC, ANC, RBC, Hgb, Hct, platelets, MCH, and differential. 

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APPENDIX 1.  SCHEDULE OF ASSESSMENTS – CLL/SLL, FL, MCL, MZL, DLBCL, AND 
HIGH-GRADE B-CELL LYMPHOMAS (CONTINUED) 
p. TLS monitoring/ Serum chemistry –Chemistry for monitoring of TLS risk (including potassium, uric acid, phosphorus, calcium and creatinine) will be performed as indicated in the 
TLS management plan (see Appendix 9 and as clinically indicated. Subjects must be assessed for TLS risk during screening and before first dose of voruciclib (monotherapy) on cycle 1 
Day 1. Standard chemistry panel to include glucose, BUN, creatinine, sodium, potassium, chloride, calcium, phosphate, uric acid, CO2, ALP, AST, ALT, total bilirubin, total protein, 
albumin, LDH.  
q. Immunoglobulin tests – Quantitative serum immunoglobulin levels (IgA, IgG, IgM) will be performed for subjects with SLL and CLL at screening, at Day 1 of Cycle 1, and then every 
6 months.  
r. Coagulation – aPTT, PT, and INR. 
s. Urinalysis – Dipstick. 
t. Issue and Assess Compliance Diary – Compliance diary to record voruciclib administration. Returned diaries assessed for study drug compliance. New compliance diary dispensed with 
each dispensing of voruciclib. 
u. Dispense study drug – Voruciclib is administered orally once a day on an empty stomach at least 1 hour prior to food or 2 hours after food at approximately the same time each day. On 
days of PK sampling, subjects should be instructed not to take voruciclib until after the PK sample is collected (note that in Amendment 7, there is no dosing on Day 8 for the IS1w3w and 
Day 15 for the IS2w,2w). A compliance diary assessment and returned voruciclib drug accountability should be performed at each visit which includes voruciclib dispensing.  
As of Amendment 7, voruciclib will be administered on an intermittent dosing schedule of 2 weeks on/2 week off (IS2w,2w) or 1 week on/3 weeks off (IS1w,3w), in the 28-day cycle. Note 
that voruciclib is taken daily on dosing days only, i.e., Days 1 through 14 for IS2w,2w, and on Days 1 through 7 only on the IS1w,3w regimen.  
v. PK sampling – Pre-dose specimens should be within 2 hours of dosing and for post-dose within ± 30 minutes) after dosing. 
Cohorts 1-5:  
• 
Cycle 1 Day 1: pre-dose (before voruciclib dose is taken); and at 4- and at 6- hours post-dose 
• 
Cycle 1 Day 2: pre-dose (i.e., 24 hours after the Cycle 1 Day 1 voruciclib dose) 
• 
Cycle 1 Day 8: pre-dose (24 hours after the preceding last dose, before voruciclib is taken)  
• 
Cycle 1 Day 15: pre-dose (before voruciclib dose is taken); at 4- and at 6- hours post dose 
Cohorts 6b-11b (IS dosing): 
• 
Cycle 1 Day 1: pre-dose and at 4- and at 6- hours post-dose 
• 
Cycle 1 Day 2: pre-dose (24 hours after the preceding last dose)  
• 
Cycle 1 Day 8: pre-dose (24 hours after the preceding last dose) 
• 
Cycle 1 Day 15: (24 hours after the preceding last dose), if applicable [Day 15 samples only collected for the IS2w,2w schedule] 
• 
Cycle 2 Day 1: pre-dose 
w. Disease assessment – Scans, bone marrow aspirate/biopsy and laboratory evaluation as appropriate for individual subjects. Scans to be performed at baseline within 3 months of Cycle 1 
Day 1 and after termination of prior therapy, Cycle 3 Day 1, Cycle 7 Day 1, every 6 cycles thereafter, and upon permanently stopping study treatment. Response assessments for 
CLL/SLL and FL and other B-cell lymphomas, refer to Appendix 5 and Appendix 6, respectively. 
* 
Bone marrow – Biopsy/aspirate are required for assessment of response (as described in Appendix 5, Table 19, and Appendix 6, Table 21) and as clinically indicated. Bone marrow 
biopsies may not need to be repeated for the study as long as they were performed within the allowed 28-day screening window. Additionally, optional biopsy/aspirates pre-first dose, at 
the end of cycle 6 and at end of treatment may be conducted for correlative studies. See Laboratory Manual. 
** Tumor biopsy – tissue can be collected after completion of prior therapy and within 3 months of Cycle 1 Day 1 per Site Laboratory Manual. Formalin fixed material acceptable although 
fresh tissue preferred. Both the initial and repeat biopsy at Cycle 1 Day 8 are optional. 
*** For Cohorts 6b-8b, the first blood specimen for Pharmacodynamic /Correlative studies must be taken prior to first dose on Cycle 1 Day 1, a second specimen approximately 6 hours post 
dose on Day 1, and a third specimen pre-dose on Day 2. The specimen obtained prior to starting study drug may be taken up to 7 days prior to Cycle 1 Day 1. On Cycle 1 Day 15, a 
specimen will be taken prior to administration of study drug. 

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APPENDIX 2. SCHEDULE OF ASSESSMENTS - AML SUBJECTS ONLY - MONOTHERAPY 
 
Screeningb 
Cycle 1 
Cycle 2 
Cycle 3 and 
Subsequent 
Cyclesc 
End of Studyd  
Day(s) a 
-28 to -1 
1a 
2 
8 
15 
1 
15 
1 
30 days (± 3 days) 
post last dose 
Informed consent 
X 
 
 
 
 
  
 
 
  
Medical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
X 
Symptom-directed exam e 
 
 
 
X 
X 
X 
 
X 
 
Vital signs f 
X 
X 
 
X 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
 
X 
X 
ECOG performance status 
X 
X 
 
 
 
X 
 
X 
X 
Pregnancy test g 
X 
X 
 
 
 
X 
 
X 
X 
HIV testing h 
X 
 
 
 
 
 
 
 
 
Hepatitis B and C testing i 
X 
 
 
 
 
 
 
 
 
Adverse events j 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG l 
X 
X 
 
X 
X 
X 
 
 
X 
CBC with differential m 
X 
X 
 
X 
X 
X 
X 
X 
X 
Serum chemistry n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TLS risk assessment and monitoring n 
X 
X 
X 
 
 
 
 
 
 
Coagulation o 
X 
 
X 
 
X 
X 
 
X 
X 
Urinalysis (dipstick) p 
X 
 
 
 
 
X 
 
 
X  
Issue and assess compliance diary q 
 
X 
 
 
 
X 
 
X 
  
Dispense study drug r 
 
X 
 
 
 
X 
 
X 
  
PK Sampling (all subjects) s 
 
X 
X 
X 
X 
X 
 
 
 
Disease assessment / Bone marrow t 
X 
 
 
 
 
 X 
 
X 
 X 
Cytogenetics u  
X 
 
 
 
 
 
 
 
 
Molecular mutations v 
optional 
 
 
 
 
 
 
 
 
Blood for PD/biomarker assays w 
 
X 
X 
X 
X 
 
 
 
X 

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Version Date 29 January 2024  
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APPENDIX 2. SCHEDULE OF ASSESSMENTS - AML SUBJECTS ONLY - MONOTHERAPY 
(CONTINUED) 
Abbreviations: AML = acute myeloid leukemia; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; BP = blood pressure; BUN = blood urea nitrogen; CBC = complete blood count; CR = complete response; 
CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = End of Study; Hct = hematocrit; HCV Ab = hepatitis C virus 
antibody; Hgb = hemoglobin; HIV = human immunodeficiency virus; HR = heart rate; ICF = informed consent form; INR = international normalized ratio; LDH = lactate 
dehydrogenase; MCH = mean corpuscular hemoglobin; PCR = polymerase chain reaction; PD = pharmacodynamic; PK = pharmacokinetic; PT = prothrombin time; 
RBC = red blood cell; TLS = tumor lysis syndrome; WBC = white blood cell. 
a. Study Assessment Day(s) – C1D1 and visits when blood for pharmacodynamic/biomarker studies are collected should be conducted Monday through Wednesday if possible so 
that specimens can be shipped for receipt no later than a Friday. There is ± 3-day window allowable for each clinic visit during Cycle 1. Following Cycle 1, the allowable 
window is up to 7 days prior and 2 days after the scheduled clinic visit and its associated assessments. 
b. Screening – Screening assessments are to be performed within 28 days of first dose of voruciclib. Laboratory assessments need not be repeated on Day 1 if performed within 
the prior 72 hours. Physical examination need not be repeated on Day 1 if performed within the prior 7 days. Some tests performed prior to obtaining ICF (e.g., CT scan, bone 
marrow biopsy) may not need to be repeated for the study as long as they were performed within the allowed screening window.  
c. Cycle 3 and subsequent cycles, and EOS – All cycles after Cycle 3 should follow the same schedule of activities as Cycle 3.  
d. EOS - The End of Study (EOS) visit will occur 30 days (±3 days) from the last day of voruciclib administration (or prior to starting a new treatment if urgent treatment 
is required). 
e. Symptom-directed exam – performed only as needed/indicated, based on interim history 
f. Vital signs, Height and Weight – includes systolic and diastolic blood pressure (BP), heart rate (HR), and body temperature. Height collected at Screening visit only.  
g. Pregnancy test – Serum pregnancy test in females of childbearing potential at screening, urine pregnancy test Day 1 of each cycle and at EOS. 
h. HIV testing – HIV antibody testing is required. 
i. Hepatitis B and Hepatitis C testing – Hepatitis B core antibody, surface antibody and surface antigen, and hepatitis C virus antibody (HCV Ab) tests are required. Hepatitis B 
polymerase chain reaction (PCR) is required if hepatitis B core antibody and/or surface antigen is positive. Hepatitis C PCR is required if HCV Ab test is positive. 
j. Adverse events – Recorded from the first dose of voruciclib and continue until 30 days after the last dose, or until a subsequent anti-cancer therapy is initiated. 
k. Concomitant medications – Recorded from 28 days prior to Cycle 1 Day 1 through 30 days after the last dose of voruciclib, or until a subsequent anti-cancer therapy 
is initiated. 
l. ECG – 12 lead ECGs performed in triplicate (approximately 2–5 minutes apart while the subject is resting) at screening, Cycle 1 Day 1, Day 8 (24 ± 3 hours after the preceding 
last dose in Cohorts 9-11), and Cycle 1 Day 15 (pre-dose and 4 hours post-dose voruciclib in Cohorts 1-5, and 24 ± 3 hours after the preceding last dose in Cohorts 6-8), and at 
Cycle 2 Day 1 (pre-dose voruciclib) and EOS (single triplicate post-dose). 
m. CBC with differential – WBC, ANC, RBC, Hgb, Hct, platelets, MCH, and differential. 
n. TLS monitoring/ Serum chemistry – Chemistry for monitoring of TLS risk (including potassium, uric acid, phosphorus, calcium and creatinine) will be performed as 
indicated in the TLS management plan (see Appendix 9) and as clinically indicated. Subjects must be assessed for TLS risk during screening and before first dose of voruciclib 
(monotherapy) on Cycle 1 Day 1. Standard chemistry panel to include glucose, BUN, creatinine, sodium, potassium, chloride, calcium, phosphate, uric acid, CO2, ALP, AST, 
ALT, total bilirubin, total protein, albumin, LDH.  
o. Coagulation – aPTT, PT, and INR. 

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Version Date 29 January 2024  
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Page 85 of 110 
APPENDIX 2. SCHEDULE OF ASSESSMENTS - AML SUBJECTS ONLY - MONOTHERAPY 
(CONTINUED) 
p. Urinalysis – Dipstick. 
q. Issue and Assess Compliance Diary – Compliance diary to record voruciclib administration. Returned diaries are to be assessed for study drug compliance. New compliance 
diary to be dispensed with each dispensing of voruciclib. 
r. Dispense study drug – Voruciclib is administered orally once a day on dosing days, on an empty stomach at least 1 hour prior to food or 2 hours after food at approximately the 
same time each day. On days of PK sampling, subjects should be instructed to not take voruciclib until after the pre-dose PK sample is collected. 
As of Amendment 7, voruciclib will be administered on an intermittent dosing schedule of 2 week on/2 week off (IS2w,2w) or 1 week on/3 weeks off (IS1w,3w), in the 28-day cycle. 
Note that voruciclib is taken daily on dosing days only, i.e., days 1 through 14 on IS2w,2w , and on days 1 through 7 only on the IS1w,3w regimen. Therefore, there is no dosing on Day 8 
on IS1w,3w and on Day 15 of the IS2w,2w cycle. 
s. PK sampling – Unless stated otherwise, pre-dose specimens should be within 2 hours prior to dosing, post-dose samples within ±30 minutes of the sampling time 
For monotherapy for Cohorts 1-5:  
• 
Cycle 1 Day 1: pre-dose (before voruciclib dose is taken); and at 4- and at 6- hours post-dose 
• 
Cycle 1 Day 2: pre-dose (i.e., 24 hours after the Cycle 1 Day 1 voruciclib dose) 
• 
Cycle 1 Day 8: pre-dose (24 hours after the preceding last dose, before voruciclib is taken)  
• 
Cycle 1 Day 15: pre-dose (before voruciclib dose is taken); at 4- and at 6- hours post dose 
For monotherapy Cohorts 6a-11a (IS dosing): 
• 
Cycle 1 Day 1: pre-dose and at 4- and at 6- hours post-dose 
• 
Cycle 1 Day 2: pre-dose (24 hours after the preceding last dose)  
• 
Cycle 1 Day 8: pre-dose (24 hours after the preceding last dose) 
• 
Cycle 1 Day 15: 24 hours after the preceding last dose), if applicable [Day 15 samples only collected for the IS2w,2w schedule] 
• 
Cycle 2 Day 1: pre-dose  
t. Disease assessment / Bone marrow – Bone marrow aspirate/biopsy and laboratory evaluation at screening, Cycle 2 Day 1, Cycle 3 Day 1, and Day 1 of every subsequent cycle 
until a CR or CRi is achieved after which bone marrow examinations are obtained if clinically indicated, and at EOS. Both biopsy and aspirate are recommended for disease 
assessment, but biopsy may be omitted if aspirate is considered to be sufficient. A fresh specimen of aspirate is to be obtained at each timepoint as described in the Study 
Manual and submitted to the central laboratory for pharmacodynamic/correlative study. The first blood specimen for pharmacodynamic/correlative studies must be taken prior 
to first dose on Cycle 1 Day 1 and a second specimen approximately 6 hours after the first dose on Day 1. Specimen may be taken up to 7 days prior to C1D1. 
u. Cytogenetics – If abnormal cytogenetics at screening, repeat cytogenetics in a subject with CR/CRi to confirm a cytogenetic remission. 
v. Molecular mutations/rearrangements analysis – Not required for the study. Collect if obtained as standard of care for a subject. If abnormalities identified at screening, 
repeat the test for the genetic marker by RT-qPCR or flowcytometry in a subject with CR/CRi to confirm CR with minimal residual disease. 
w. Pharmacodynamic biomarker – The first blood specimen for Pharmacodynamic/biomarker assay must be taken prior to first dose on Cycle 1 Day 1, a second specimen 
approximately 6 hours post-dose on Day 1, and a third specimen pre dose on Day 2. The specimen obtained prior to starting study drug may be taken up to 7 days prior to 
C1D1. On Days 8 and 15 specimen will be taken prior to administration of study drug (Cohorts 1-5). 

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Version Date 29 January 2024  
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APPENDIX 3. SCHEDULE OF ASSESSMENTS - AML SUBJECTS ONLY – COMBINATION 
THERAPY 
 
Screeningb 
Cycle 1- Inclusive of Venetoclax Ramp-upc 
Cycle 2 
Cycle 3 and 
Subsequent 
Cyclesd 
End of Studye 
 
-28 to -1 
1a 
2 
3 
8 
14 
1 
14 
1 
30 days (± 3 days) Post 
Last Dose 
Study Drug 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history/Prior 
Treatment/Demographics 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
X 
Symptom-directed exam f 
 
 
 
X 
X 
X 
X 
 
X 
 
Vital signs g 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
X 
 
X 
X 
ECOG performance status 
X 
X 
 
 
 
 
X 
 
X 
X 
Pregnancy test h 
X 
X 
 
 
 
 
X 
 
X 
X 
HIV testing i 
X 
 
 
 
 
 
 
 
 
 
Hepatitis B and C testing j 
X 
 
 
 
 
 
 
 
 
 
Adverse events k 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG m 
X 
X 
 
X 
X 
X 
X 
 
 
X 
CBC with differential n 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TLS risk assessment and monitoring o 
X 
X 
X 
X 
 
 
 
 
 
 
Coagulation p 
X 
 
X 
 
 
X 
X 
 
X 
X 
Urinalysis (dipstick) q 
X 
 
 
 
 
 
X 
 
 
X 
Baseline chest x-ray r 
X 
 
 
 
 
 
 
 
 
 
Issue and assess compliance diary s 
 
X 
 
 
 
 
X 
 
X 
 
Dispense study drug(s) t 
 
X 
 
 
 
 
X 
 
X 
 
Disease assessment, bone marrow 
aspirate u  
X 
 
 
 
 
 
X 
 
X 
X 
Cytogenetics v 
X 
 
 
 
 
 
 
 
 
 
Molecular mutations w 
optional 
 
 
 
 
 
 
 
 
 
Blood for PD/biomarker assays x  
 
X 
 
X 
 
X 
 
 
 
 
Blood for PK analysis 
See specific PK collection timepoints in table below  

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APPENDIX 3. SCHEDULE OF ASSESSMENTS - AML SUBJECTS ONLY – COMBINATION 
THERAPY (CONTINUED) 
Abbreviations: AML = acute myeloid leukemia; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; BP = blood pressure; BUN = blood urea nitrogen; CBC = complete blood count; CR = complete response; 
CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = End of Study; Hct = hematocrit; HCV Ab = hepatitis C virus 
antibody; Hgb = hemoglobin; HIV = human immunodeficiency virus; HR = heart rate; ICF = informed consent form; INR = international normalized ratio; LDH = lactate 
dehydrogenase; MCH = mean corpuscular hemoglobin; PCR = polymerase chain reaction; PD = pharmacodynamic; PK = pharmacokinetic; PT = prothrombin time; 
RBC = red blood cell; RU = ramp-up; TLS = tumor lysis syndrome; WBC = white blood cell. 
a. Study Assessment Day(s) – C1D1 and visits when blood for pharmacodynamic/biomarker studies are collected should be conducted Monday through Wednesday if possible 
so that specimens can be shipped for receipt no later than a Friday. There is ± 3-day window allowable for each clinic visit during Cycle 1. Following Cycle 1, the allowable 
window is up to 7 days prior and 2 days after the scheduled clinic visit and its associated assessments. 
b. Screening – Screening assessments are to be performed within 28 days before the first dose of venetoclax. Laboratory assessments need not be repeated on Day 1 if performed 
within the prior 72 hours. Physical examination need not be repeated on Day 1 if performed within the prior 7 days. Some tests performed prior to obtaining ICF (e.g., CT scan, 
bone marrow biopsy) may not need to be repeated for the study as long as they were performed within the allowed screening window. 
c. Venetoclax Ramp-up – applies to combination Cohorts 12–19 and 21–25. Venetoclax ramp-up dosing begins on Cycle 1 Day 1 at 100 mg and 200 mg on Day 2. Dosing 
continues at 200 mg on Days 3–21, then 400 mg on Days 22–28. Increasing venetoclax dose from 200 mg to 400 mg on Day 22 is not considered dose ramp-up. 
d. Cycle 3 and subsequent cycles – all cycles after Cycle 3 should follow the same schedule of activities as Cycle 3.  
e. EOS - The End of Study (EOS) visit will occur 30 days (±3 days) from the last day of study drug (voruciclib or venetoclax) administration or prior to starting a new treatment 
if urgent treatment is required. 
f. Symptom-directed exam – performed as indicated, and additional exams may be performed based on interim history 
g. Vital signs – includes systolic and diastolic blood pressure (BP), heart rate (HR), and body temperature. 
h. Pregnancy test – Serum pregnancy test in females of childbearing potential at screening, urine pregnancy test Day 1 of each cycle and at EOS. 
i. HIV testing – HIV antibody testing is required. 
j. Hepatitis B and Hepatitis C testing – Hepatitis B core antibody, surface antibody and surface antigen, and hepatitis C virus antibody (HCV Ab) tests are required. Hepatitis B 
polymerase chain reaction (PCR) is required if hepatitis B core antibody and/or surface antigen is positive. Hepatitis C PCR is required if HCV Ab test is positive. 
k. Adverse events – Recorded from the first dose of venetoclax and continues until 30 days after the last dose of any study drug, or until a subsequent anti-cancer therapy 
is initiated, whichever is earlier. 
l. Concomitant medications – Recorded from 28 days prior to Cycle 1 Day 1 through 30 days after the last dose of any study drug, or until a subsequent anti-cancer therapy 
is initiated. 
m. ECG – 12 lead ECGs performed in triplicate (approximately 2–5 minutes apart while the subject is resting). ECGs will be performed at screening and pre venetoclax dose on 
Cycle 1 Day 1. On Cycle 1 Day 3, pre voruciclib dose and 4 hours post voruciclib dose, on Cycle 1 Day 8 pre voruciclib dose, on Cycle 1 Day 14* pre voruciclib dose and 
4 hours post voruciclib dose, at Cycle 2 Day 1 pre-dose voruciclib, and EOS. Additional ECGs as clinically indicated. For Cycle 1, pre-dose ECG should be within the 2 hours 
prior to dosing and post-dose within a 30-minute window either side of the nominal time. When a PK blood draw is scheduled at the same time as ECG, the ECG should be 
performed first and as close as possible immediately followed by the PK draw. 
*For Cohort 12 (QOD dosing), since there is no dosing on Cycle 1 Day 14, ECGs will be performed on Cycle 1 Day 13 pre voruciclib dose and 4 hours post voruciclib dose. 
n. CBC with differential – WBC, ANC, RBC, Hgb, Hct, platelets, MCH, and differential. 
o. TLS monitoring/ Serum chemistry – Chemistry for monitoring of TLS risk (including potassium, uric acid, phosphorus, calcium and creatinine) will be performed as 
indicated in the TLS management plan (see Appendix 9) and as clinically indicated. Subjects must be assessed for TLS risk during screening and before first dose of 
venetoclax. Standard chemistry panel to include glucose, BUN, creatinine, sodium, potassium, chloride, calcium, phosphate, phosphorus, uric acid, CO2, ALP, AST, ALT, 
total bilirubin, total protein, albumin, LDH.  

MEI Pharma Inc. 
 
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Version Date 29 January 2024  
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APPENDIX 3. SCHEDULE OF ASSESSMENTS - AML SUBJECTS ONLY – COMBINATION 
THERAPY (CONTINUED) 
p. Coagulation – aPTT, PT, and INR. 
q. Urinalysis – Dipstick. 
r. Baseline chest x-ray – recommended if the subject has not had recent chest imaging. 
s. Issue and Assess Compliance Diary – Assess returned diaries for study drug dosing compliance. New compliance diary to be dispensed with each dispensing of study drug. 
t. Dispense study drug –Venetoclax is administered orally once daily to be taken with food and water. Voruciclib is administered orally once a day on dosing days, at least 
2 hours after venetoclax. On days of PK sampling (for PK sampling schedules refer to Section 9.14.2), subjects should be instructed to not to take venetoclax or voruciclib until 
after the pre-dose PK sample is collected.  
As of Amendment 11, voruciclib will be administered on an intermittent dosing schedule of 2 week on/2 week off (IS2w,2w) in the 28-day cycle. Note that voruciclib is taken 
once daily on dosing days only (i.e., Days 1 through 14 on IS2w,2w), with the exception of Cohort 12 which is taken every other day (i.e., Days 3, 5, 7, 9, 11, and 13 of Cycle 1 
and Days 1, 3, 5, 7, 9, 11, and 13 of Cycle 2 and beyond).  
As of Amendment 12, voruciclib will be administered on an intermittent dosing schedule of 3 weeks on/1 week off (IS3w,1w) in the 28-day cycle for Cohorts 21–25. Voruciclib 
is taken once daily on dosing days only (i.e., Days 1 through 21 on IS3w,1w). 
u. Disease assessment / Bone marrow – Bone marrow aspirate/biopsy and laboratory evaluation at screening (up to 28 days prior to starting venetoclax), Cycle 2 Day 1, and 
Day 1 of every subsequent cycle until a CR or CRi is achieved. Thereafter when bone marrow examinations are obtained as clinically indicated, and at EOS. Both biopsy and 
aspirate are recommended for disease assessment, but biopsy may be omitted if aspirate is considered to be sufficient. Bone marrow assessment may be omitted if the subject 
has clear evidence of disease progression based of peripheral blood count/blasts analysis. Bone marrow aspirate sample collected at the time of disease assessment may be used 
for exploratory biomarker analysis in bone marrow/bone marrow aspirate. If any remaining sample is available after evaluation for disease assessment. it should be submitted 
to the central laboratory for pharmacodynamic biomarker/correlative study (refer to the Lab Manual).  
v. Cytogenetics – If abnormal cytogenetics at screening, repeat cytogenetics in a subject with CR/CRi to confirm a cytogenetic remission 
w. Molecular mutations/rearrangements analysis – Not required for the study. Collect if obtained as standard of care for a subject. If abnormalities identified at screening, 
repeat the test for the genetic marker by RT-qPCR or flow cytometry in a subject with CR/CRi to confirm CR with minimal residual disease 
x. Blood Pharmacodynamic biomarker assays– Blood for pharmacodynamic/biomarker assays for Cohorts 12–19 and 21–25 will be collected as follows: 
• 
Cycle 1 Day 1*: Pre-dose of venetoclax and approximately 6 hours post-dose of venetoclax for Cohorts 12–16, or 4–6 hours post-dose for Cohorts 17–25. 
• 
Cycle 1 Day 3: Pre-dose of voruciclib and at approximately 6 hours post-dose of voruciclib for Cohorts 12–16, or 4–6 hours post-dose for Cohorts 17–25. 
• 
Cycle 1 Day 14**: Pre-dose of venetoclax and approximately 6 hours post-dose of voruciclib for Cohorts 12–16, or 4–6 hours post-dose for Cohorts 17–25. 
 
* 
The specimen obtained prior to starting study drug may be taken up to 7 days prior to C1D1.  
** For Cohort 12, since there is no dosing on Cycle 1 Day 14, blood will be collected at the Cycle 1 Day 13 pre-dose of venetoclax and approximately 6 hours post-dose of 
 
voruciclib during the clinic visit for PK sample collection.  
 

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APPENDIX 3. BLOOD SAMPLING SCHEDULE FOR PHARMACOKINETC ANALYSES, 
COMBINATION THERAPY  
Unless stated otherwise, pre-dose specimens should be obtained 2 hours prior to dosing and for post-dose within ±30 minutes after 
dosing) for Cohorts 12–19 and 21–25. 
Blood Sampling Schedule for Voruciclib, Cohort 12 (QOD Dosing),  
Cycle 
Day 
Time of Collection 
Pre-dose 
Post-dose 
1 
3 
X 
2, 4, 6 hours 
4* 
- 
approximately 24 hours after Day 3 dose 
8 
-  
approximately 24 hours after Day 7 dose 
13 
X 
2, 4, 6 hours 
14 
- 
approximately 24 hours after Day 13 dose 
21 
anytime during clinic visit 
2 
1 
X 
- 
4, 6 
1, 14 (±3 days) 
anytime during clinic visit 
Every 3 cycles thereafter  
1, 14 (±3 days) 
anytime during clinic visit 
*Day 4 sample to be collected only if the subject is able to visit the clinic. 
Blood Sampling Schedule for Voruciclib, Cohorts 13–19 and Cohorts 19–25 (QD Dosing) 
Cycle 
Day 
Time of Collection 
Pre-dose 
Post-dose 
1 
3 
X 
2, 4, 6 hours 
4* 
X 
(approximately 24 hours after 
Day 3 dose) 
- 
8 
X 
(approximately 24 hours after 
Day 7 dose) 
- 
14 
X 
2, 4, 6 hours 
15 
- 
approximately 24 hours after Day 14 dose 
21 
anytime during clinic visit 
2 
1 
X 
- 

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Blood Sampling Schedule for Voruciclib, Cohorts 13–19 (QD Dosing, Continued) 
Cycle 
Day 
Time of Collection 
Pre-dose 
Post-dose 
4, 6 
1, 14 (±3 days) 
anytime during clinic visit 
Every 3 cycles thereafter  
1, 14 (±3 days) 
anytime during clinic visit 
*Day 4 sample to be collected only if the subject is able to visit the clinic. 
Blood Sampling Schedule for Venetoclax, Cohort 12 (QOD Dosing) 
Cycle 
Day 
Time of Collection 
Pre-dose 
Post-dose 
1 
13 
X 
2, 4, 6, 8 hours 
14 
X 
(approximately 24 hours after 
Day 13 dose) 
- 
21 
anytime during clinic visit  
2 
1 
X 
2, 4, and 6-hours post-dose of venetoclax (voruciclib to be dosed 6 hours after 
venetoclax administration, after completion of the 6- hour sample collection) 
4, 6 
1, 14 (±3 days) 
anytime during clinic visit 
Every 3 cycles thereafter  
1, 14 (±3 days) 
anytime during clinic visit 
Blood Sampling Schedule for Venetoclax, Cohorts 13–19 and Cohorts 21–25 (QD Dosing) 
Cycle 
Day 
Time of Collection 
Pre-dose 
Post-dose 
1 
14 
X 
2, 4, 6, and 8-hours 
15 
X 
(approximately 24 hours after 
Day 14 dose) 
- 
21 
anytime during clinic visit  
2 
1 
X 
2, 4, and 6-hours post-dose of venetoclax (voruciclib to be dosed 6 hours after 
venetoclax administration, after completion of the 6- hour sample collection) 
4, 6 
1, 14 (±3 days) 
anytime during clinic visit 
Every 3 cycles thereafter  
1, 14 (±3 days) 
anytime during clinic visit 
 

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APPENDIX 4. AML RESPONSE CRITERIA 
Table 18: 
European LeukemiaNet (ELN) Response Criteria in AML 
Category 
Definition 
Comment 
Response 
 
 
CR without minimal 
residual disease 
(CRMRD-) 
If studied pretreatment, CR with negativity for a 
genetic marker by RT-qPCR, or CR with 
negativity by MFC 
Sensitivities vary by marker tested, and 
by method used; therefore, test used, 
and sensitivity of the assay should be 
reported; analyses should be done in 
experienced laboratories (centralized 
diagnostics) 
Complete remission 
(CR) 
Bone marrow blasts < 5%; absence of 
circulating blasts and blasts with Auer rods; 
absence of extramedullary disease; 
ANC ≥1.0 × 109/L (1000/µL); platelet count 
≥100 × 109/L (100,000/µL) 
MRD+ or unknown 
CR with incomplete 
hematologic recovery 
(CRi) 
All CR criteria except for residual neutropenia 
(<1.0 × 109/L [1000/µL]) or thrombocytopenia 
(<100 × 109/L [100,000/µL]) 
 
Morphologic 
leukemia-free state 
(MLFS) 
Bone marrow blasts <5%; absence of blasts with 
Auer rods; absence of extramedullary disease; 
no hematologic recovery required 
Marrow should not merely be 
“aplastic”; at least 200 cells should be 
enumerated, or cellularity should be at 
least 10% 
Partial remission (PR) 
All hematologic criteria of CR; decrease of bone 
marrow blast percentage to 5% to 25%; 
and decrease of pretreatment bone marrow blast 
percentage by at least 50% 
Especially important in the context of 
phase 1-2 clinical trials 
Treatment Failure 
 
 
Primary refractory 
disease 
No CR or CRi after 2 courses of intensive 
induction treatment; excluding subjects with 
death in aplasia or death due to indeterminate 
cause‡ 
Regimens containing higher doses of 
cytarabine are generally considered as 
the best option for subjects not 
responding to a first cycle of 7+3; the 
likelihood of responding to such 
regimens is lower after failure of a first 
Death in aplasia 
Deaths occurring ≥ 7 days following completion 
of initial treatment while cytopenic; with an 
aplastic or hypoplastic bone marrow obtained 
within 7 days of death, without evidence of 
persistent leukemia‡ 
 
Death from 
indeterminate cause 
Deaths occurring before completion of therapy, 
or <7 days following its completion; or deaths 
occurring ≥7 days following completion of 
initial therapy with no blasts in the blood, but no 
bone marrow examination available‡ 
 
Response criteria for clinical trials only 
 
Stable disease 
Absence of CRMRD−, CR, CRi, PR, MLFS; and 
criteria for PD not met 
Period of stable disease should last at 
least 3 months 

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Table 18: 
European LeukemiaNet (ELN) Response Criteria in AML (Continued) 
Category 
Definition 
Comment 
Progressive disease 
(PD)*,† 
Evidence for an increase in bone marrow blast 
percentage and/or increase of absolute blast 
counts in the blood: 
Category mainly applies for older 
subject given low-intensity or 
single-agent “targeted therapies” 
in clinical trials 
 
• 
>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/µL], and/or platelet 
count to >50 × 109/L [50,000/µL] 
non-transfused); or 
In general, at least 2 cycles of a novel 
agent should be administered 
 
• 
>50% increase in peripheral blasts 
(WBC × % blasts) to >25 × 109/L 
(>25,000/μL) (in the absence of 
differentiation syndrome)†; or 
Some protocols may require blast 
increase in 2 consecutive marrow 
assessments at least 4 weeks apart; the 
date of progression should then be 
defined as of the first observation date 
 
• 
New extramedullary disease 
Some protocols may allow transient 
addition of hydroxyurea to lower blast 
counts 
“Progressive disease” is usually 
accompanied by a decline in ANC and 
platelets and increased transfusion 
requirement and decline in performance 
status or increase in symptoms 
Relapse 
 
 
Hematologic relapse 
(after CRMRD−, CR, 
CRi) 
Bone marrow blasts ≥5%; or reappearance of 
blasts in the blood; or development of 
extramedullary disease 
 
Molecular relapse 
(after CRMRD−) 
If studied pretreatment, reoccurrence of MRD as 
assessed by RT-qPCR or by MFC 
Test applied, sensitivity of the assay, 
and cutoff values used must be 
reported; analyses should be done in 
experienced laboratories (centralized 
diagnostics) 
Abbreviations: ANC = absolute neutrophil count; IDH = isocitrate dehydrogenase; MFC = multiparameter flow cytometry; 
MLFS = morphologic leukemia-free state; MRD = minimal residual disease; RT-qPCR = quantitative reverse transcription 
polymerase chain reaction (assay); WBC = white blood cell. 
‡ For this study, “intensive induction treatment” and “completion of initial therapy” are not applicable, and “completion of 
therapy” is defined as the last day of voruciclib administration followed by treatment discontinuation. 
* The authors acknowledge that this new provisional category is arbitrarily defined; the category aims at harmonizing the various 
definitions used in different clinical trials. 
† Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation syndrome, that is, a 
transient increase in the percentage of bone marrow blasts and an absolute increase in blood blasts; in the setting of therapy 
with such compounds, an increase in blasts may not necessarily indicate PD. 
Reference: Döhner 2017. 

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APPENDIX 5. CLL/SLL RESPONSE CRITERIA: IWCLL 
Table 19: 
Schedule of Response Assessments for Subjects with CLL/SLL 
Day(s) 
-28 to -1 
1 
1 
History, physical examination 
X 
X 
X 
CBC and differential count 
X 
X 
X 
CT chest/abdomen/pelvis a 
X 
X 
Xa 
Bone marrow biopsy/aspirate b 
X 
X 
X 
Abbreviations: CBC = complete blood count; CLL = chronic lymphocytic leukemia; CR = complete response; 
CT = computed tomography; EOS = end of study; SLL = small lymphocytic lymphoma. 
NOTE: Subjects who meet diagnostic criteria for SLL (i.e., absolute lymphocyte count <5,000) will have formal 
response assessment per Lugano criteria (Cheson 2014). 
a CT of the chest, abdomen and pelvis must be obtained at screening; at Cycles 3 and 7; and every 6 months 
thereafter.  
b Bone marrow biopsy/aspirate is obtained at screening only as clinically indicated (at the discretion of the 
Investigator). Bone marrow biopsy/aspirate must be performed at least 2 months after other criteria for CR are 
met. Bone marrow biopsy is otherwise optional unless clinically indicated or to confirm CR. 
Response Assessment 
Screening 
Cycle 3, Cycle 7 
Every 6 Cycles 
Thereafter and EOS 

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Table 20: 
Response Criteria for CLL/SLL per IWCLL (Hallek et al) 
Parameter 
Complete Remission 
(CR) All Criteria Must 
be Meta 
Partial Remission (PR) 
At Least 2 Criteria 
from Group A AND At 
Least 1 Criterion from 
Group B Must be Met 
Progressive Disease (PD) at 
Least 1 Criterion from 
Group A OR 1 Criterion 
from Group B 
Must be Metb 
Stable 
Disease (SD) 
All Criteria 
Must be Met 
Group A 
Lymphadenopathyi 
None >1.5 cm 
Decrease ≥50%c 
Increase ≥50%d or any new 
LN >1.5 cm 
Changee of  
-49% to 
+49%  
Blood 
Lymphocytes 
<4000/µL 
Decrease ≥50% from 
baseline 
Increase ≥50% over nadir 
(≥5000/µL) 
Change of  
–49% to 
+49% 
Hepatomegalyf 
None 
Decrease ≥50% 
Increase ≥50%g 
Change of  
–49% to 
+49% 
Splenomegalyf 
None 
Decrease ≥50% 
Increase ≥50%g 
Change of  
–49% to 
+49% 
Marrow 
Normocellular, <30% 
lymphocytes, no 
B-lymphoid nodules; 
hypocellular marrow 
defines CRi 
N/A 
N/A 
N/A 
Group B 
Platelet Count 
>100,000/μLh 
>100,000/µL or increase 
≥50% over baselineh 
Decrease of ≥50% from 
baseline secondary to CLL 
Change of  
–49% to 
+49% 
Hemoglobin 
>11.0 g/dLh 
>11.0 g/dL or increase 
≥50% over baselineh 
Decrease of >2 g/dL from 
baseline secondary to CLL 
Increase to 
≤11.0 g/dL 
over 
baseline, or 
decrease 
<2 g/dL 
Neutrophils 
>1500/μLh 
>1500/µL or increase 
≥50% over baselineh 
Decrease ≥50% from 
baseline secondary to CLL 
N/A 
Other Considerations 
New Lesions 
None 
None 
Appearance of new palpable 
lymph nodes (>1.5 cm in 
longest diameter) or any new 
extranodal lesion (regardless 
of size) or transformation to 
a more aggressive histology, 
e.g., Richter syndromed 
None 
Non-Target 
Lesions 
Nodes must be normal 
size as visually estimated; 
extranodal and other 
assessable disease should 
be absent 
No change/decreased 
Unequivocal progression 
No change or 
decrease or 
non-
substantial 
increase 
Target Extranodal 
Disease 
Absence of any 
extranodal disease by 
physical examination 
(palpable, visualized 
extranodal) and CT scan 
≥50% decrease in SPD 
≥50% increase in the longest 
diameter of any extranodal 
lesion 
Not CR, CRi, 
PR, or PD 

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Table 18: 
Response Criteria for CLL/SLL per IWCLL (Hallek et al) (Continued) 
Abbreviations: CLL = chronic lymphocytic leukemia; CRi = complete remission with incomplete marrow recovery; 
CT = Computed tomography; LN = lymph nodes; N/A = Not applicable; PD = SPD = sum of the products of diameter. 
a CR also requires the lack of disease-related constitutional symptoms. 
b Transformation to a more aggressive histology (e.g., Richter syndrome) would also qualify as a PD. 
c Sum of the products of multiple LNs (as evaluated by CT scans). 
d Increase in SPD of multiple nodes, or in greatest diameter of any previous site, or appearance of any new lymphadenopathy or 
organomegaly. Degree of change in LN or lymphocyte counts should be measured from nadir (lowest post-treatment) values.  
e Sum products of up to 6 LNs or LN masses (target lesions), with no increase in an LN or new enlarged LN. Increase of <25% 
in small LNs (<2 cm) not significant. Decreases should be measured compared to baseline (pre-treatment) values. 
f If enlarged before therapy. 
g An increase in the previously noted enlargement of the liver or spleen by 50% or more or the de novo appearance of 
hepatomegaly or splenomegaly. 
h Without the need for exogenous growth factors or transfusions. 
i Lymphocytosis can be prominent early during treatment and can persist over time, and should not be confused with disease 
progression in subjects who otherwise have persistent disease control. In the absence of other objective evidence of disease 
progression, the occurrence of lymphocytosis will not preclude subjects from meeting the criteria for PR if other criteria for PR 
are met, and will not be considered evidence of CLL progression if occurring in isolation. 
The goal of confirmation of objective response is to avoid overestimating responses. In cases 
where confirmation of response is not feasible, it should be made clear when reporting the 
outcome that the response(s) is (are) not confirmed. 
For subjects experiencing disease progression due to Richter's Syndrome while on study, 
supplemental data may be collected. 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed at least 2 months after the criteria for response 
is first met. Bone marrow biopsy and aspirate to confirm CR must be obtained at least 2 months 
after other criteria for CR are first met. 

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APPENDIX 6. FOLLICULAR LYMPHOMA RESPONSE CRITERIA: 
LUGANO CLASSIFICATION 
Table 21: 
Schedule of Response Assessments for Subjects with Follicular Lymphoma 
and Other B-Cell Lymphomas 
Response Assessment 
Screening 
Cycle 3, Cycle 7 
Every 6 Cycles Thereafter and EOS 
Day(s) 
-28 to -1 
1 
1 
History, physical examination 
X 
X 
X 
CBC and differential count 
X 
X 
X 
CT chest/abdomen/pelvis a 
X 
X 
Xa 
FDG-PET scan a 
X 
Xa 
Xa 
Bone marrow biopsy/aspirate b 
X 
X 
X 
Abbreviations: CBC = complete blood count; CR = complete response; CT = computed tomography; EOS = End of Study visit; 
FDG-PET = fluorodeoxyglucose positron emission tomography. 
a CT of the chest, abdomen and pelvis must be obtained at screening; at Cycles 3, 5, 7, 13, 27; and every 6 months thereafter. 
FDG-PET scan must be obtained at screening (within 6 weeks prior to Cycle 1 Day 1) and subsequently for subjects who 
achieve a CR by CT criteria. 
b Bone marrow biopsy/aspirate is obtained at screening only as clinically indicated (at the discretion of the Investigator). Bone 
marrow biopsy/aspirate must be performed at least 2 months after other criteria for CR are met. Bone marrow biopsy is 
otherwise optional unless clinically indicated or to confirm CR. 
SELECTION OF TARGET LESIONS 
Up to 6 of the largest dominant nodes or tumor masses selected according to all of the following: 
1. Clearly measurable in 2 diameters (longest diameter [LDi] and shortest diameter [SDi]) at 
baseline 
a. All nodal lesions must measure >1.5 cm in longest diameter regardless of short axis 
measurement 
b. All measurable extranodal lesions should have a longest tumor diameter ≥1.0 cm 
2. All other lesions (including nodal, extranodal, and assessable disease) should be followed 
as non-target lesions 
3. If possible, the lesions should be from disparate regions of the body 
4. Should include mediastinal and retroperitoneal areas of disease whenever these sites are 
involved 
SELECTION OF NON-TARGET LESIONS 
Non-target lesions will be qualitatively assessed at each subsequent time point. All of the sites of 
disease present at baseline and not classified as target lesions will be classified as non-target 
lesions, including any measurable lesions that were not chosen as target lesions. 
Examples of non-target lesions include: 
1. All bone lesions, irrespective of the modality used to assess them 
2. Lymphangitis of the skin or lung 
3. Cystic lesions 

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4. Splenomegaly and hepatomegaly (all lymphomas) 
a. Cutoff for splenomegaly of more than 13 cm 
b. Diffusely increased or focal uptake, with or without focal or disseminated nodules, 
supports spleen or liver involvement 
5. Irradiated lesions 
6. Measurable lesions beyond the maximum number of 6 
7. Groups of lesions that are small and numerous 
8. Pleural/pericardial effusions and/or ascites 
a. Effusions, ascites, or other fluid collections will be followed as non-target lesions 
b. At each assessment point, radiologists will check for the presence or absence of 
effusions/ascites. If there is a significant volume increase in the absence of a benign 
etiology, progression can be assessed 
c. Significant new effusions, ascites or other fluid collections, which are 
radiographically suggestive of malignancy should be recorded as new lesions and 
should be assessed 
Response should be determined on the basis of radiographic and clinical evidence of disease. For 
subjects who achieve a CR by CT criteria, an FDG-PET will be performed. Assessment by PET 
should follow the criteria described by Cheson et al (Cheson 2014) which is summarized in the 
table below (Table 22). 
 

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Table 22: 
Revised Criteria for Response Assessment from Cheson et al 2014 
Response and 
Site 
PET-CT−Based Response 
CT-Based Response 
Complete 
Response 
Complete Metabolic Response 
Complete Radiologic Response 
(all of the following) 
Lymph nodes 
and 
extralymphatic 
sites 
• Score 1, 2, or 3 a with or without a residual mass on 5PS b 
• It is recognized that in Waldeyer’s ring or extranodal 
sites with high physiologic uptake or with activation 
within spleen or marrow (e.g., with chemotherapy or 
myeloid colony stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the tissue 
has high physiologic uptake 
• Target nodes/nodal masses 
must regress to ≤1.5 cm in LDi 
• No extralymphatic sites of 
disease 
Nonmeasured 
lesion 
• Not applicable 
• Absent 
Organ 
enlargement 
• Not applicable 
• Regress to normal 
New lesions 
• None 
• None 
Bone marrow 
• No evidence of FDG-avid disease in marrow 
• Normal by morphology; if 
indeterminate, IHCnegative 
Partial 
Response 
Partial Metabolic Response 
Partial Remission 
(all of the following): 
Lymph nodes 
and 
extralymphatic 
sites 
• Score 4 or 5b with reduced uptake compared with 
baseline and residual mass(es) of any size 
• At interim, these findings suggest responding disease 
• At end of treatment, these findings indicate residual 
disease 
• ≥50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites 
• When a lesion is too small to 
measure on CT, assign 
5 mm × 5 mm as the default 
value 
• When no longer visible, 0 × 0 
mm 
• For a node >5 mm × 5 mm, but 
smaller than normal; use actual 
measurement for calculation 
Nonmeasured 
lesions 
• Not applicable 
• Absent/normal, regressed, but 
no increase 
Organ 
enlargement 
• Not applicable 
• Spleen must have regressed by 
>50% in length beyond normal 
New lesions 
• None 
• None 
Bone marrow 
• Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, consideration 
should be given to further evaluation with MRI or biopsy 
or an interval scan. 
• Not applicable 

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No Response 
or Stable 
Disease 
No Metabolic Response 
Stable Disease 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
• Score 4 or 5 with no significant change in FDG uptake 
from baseline at interim or end of treatment 
• <50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
Nonmeasured 
lesions 
• Not applicable 
• No increase consistent with 
progression 
Organ 
enlargement 
• Not applicable 
• No increase consistent with 
progression 
New lesions 
• None 
• None 
Bone marrow 
• No change from baseline 
• Not applicable 
Progressive 
Disease 
Progressive Metabolic Disease 
Progressive Disease Requires at 
least one of the following 
Individual 
target 
nodes/nodal 
masses 
• Score 4 or 5 with an increase in intensity of uptake from 
baseline and/or 
• PPD progression: any new 
nodal mass or increase in an 
existing nodal mass 
Extranodal 
lesions 
• New FDG-avid foci consistent with lymphoma at interim 
or end-of-treatment assessment 
• An individual node/lesion must 
be abnormal with 
• LDi >1.5 cm and 
• Increase by ≥50% from PPD 
nadir and 
• An increase in LDi or SDi from 
nadir 
o 0.5 cm for lesions ≤2 cm 
o 1.0 cm for lesions >2 cm 
• In the setting of splenomegaly, 
the splenic length must increase 
by >50% of the extent of its 
prior increase beyond baseline 
(e.g., a 15 cm spleen must 
increase to >16 cm). If no prior 
splenomegaly, must increase by 
at least 2 cm from baseline. 
New or recurrent splenomegaly 
Nonmeasured 
lesions 
• None 
• New or clear progression of 
pre-existing nonmeasured 
lesions 

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New Lesions 
• New FDG-avid foci consistent with lymphoma rather 
than another etiology (e.g., infection, inflammation). If 
uncertain regarding etiology of new lesions, biopsy or 
interval scan may be considered 
• Regrowth of previously 
resolved lesions 
• A new node >1.5 cm in any 
axis 
• A new extranodal site >1.0 cm 
in any axis; if <1.0 cm in any 
axis, its presence must be 
unequivocal and must be 
attributable to lymphoma 
• Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone Marrow 
• New or recurrent FDG-avid foci 
• New or recurrent involvement 
Abbreviations: 5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; GI = gastrointestinal; 
IHC = immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI = magnetic resonance imaging; 
PET = positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; SDi = shortest axis 
perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for multiple lesions. 
a. Measured dominant lesions: up to 6 of the largest dominant nodes, nodal masses, and extranodal lesions selected to be 
clearly measurable in 2 diameters. Nodes should preferably be from disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (e.g., liver, spleen, 
kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: any disease not 
selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include 
any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements 
for measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease 
that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, 
leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In 
Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the 
mediastinum with complete metabolic response, but should be no higher than surrounding normal physiologic uptake 
(e.g., with marrow activation as a result of chemotherapy or myeloid growth factors). 
b. PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to 
lymphoma. 
 

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APPENDIX 7. LIST OF SENSITIVE CYTOCHROME P450 
SUBSTRATES: CYP2C9, CYP2C19, CYP2D6, AND 
CYP3A4  
Substrates can be classified by their sensitivity as: 
• sensitive substrates (≥5-fold increase in AUC with a strong inhibitor of the cytochrome 
P450 [CYP] specified)  
• moderately sensitive substrates (≥2 to <5-fold increase in AUC with a strong inhibitor of 
the CYP specified) 
Following is a table of sensitive substrates of CYP2C9, CYP2C19, CYP2D6, and CYP3A4.  
Table 23: 
Sensitive Substrates of CYP2C9, CYP2C19, CYP2D6, and CYP3A4 
 
Sensitive substrates 
Moderate sensitive substrates 
CYP2C9 
celecoxib(c) 
glimepiride, phenytoin, tolbutamide, warfarin 
CYP2C19 
S-mephenytoin, omeprazole 
diazepam, lansoprazole(d), rabeprazole, 
voriconazole 
CYP2D6 
atomoxetine, desipramine, 
dextromethorphan , eliglustat(e), 
nebivolol, nortriptyline, perphenazine, 
tolterodine, venlafaxine 
amitriptyline, encainide, imipramine, 
metoprolol, propafenone, propranolol, 
tramadol, trimipramine, 
CYP3A4 
alfentanil, avanafil, buspirone, 
conivaptan, darifenacin, darunavir(f), 
ebastine, everolimus, ibrutinib, 
lomitapide, lovastatin(g), midazolam, 
naloxegol, nisoldipine, saquinavir(f), 
simvastatin(g), sirolimus, tacrolimus, 
tipranavir(f), triazolam, vardenafil 
alprazolam, aprepitant, atorvastatin(c), 
colchicine, eliglustat(e), pimozide, rilpivirine, 
rivaroxaban, tadalafil 
budesonide, dasatinib, dronedarone, 
eletriptan, eplerenone, felodipine, 
indinavir(f), lurasidone, maraviroc, 
quetiapine, sildenafil, ticagrelor, 
tolvaptan 
 
Please note the following: Additional drug-drug interaction data can be obtained from the University of Washington 
Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61-72]. 

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APPENDIX 8. LIST OF DRUGS KNOWN TO PROLONG QT/QTC 
INTERVAL 
The table below includes a list of drugs known to prolong QT/QTc interval from 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
Note: Medicines on this list must be reviewed by Principal Investigators on an ongoing basis to 
assure updates.  
LIST OF DRUGS KNOWN TO PROLONG QT/QTc INTERVAL 
Generic Name 
Brand Names (Partial List) 
Alfuzosin 
Uroxatral® 
Amantadine 
Symmetrel®, Symadine® 
Amiodarone 
Cordarone®, Pacerone®, Nexterone® 
Amisulpride (Only on Non-US Market) 
Solian®, Supitac®, Soltus®, Amitrex®, Amazeo® 
Amitriptyline 
Elavil® (Discontinued 6/13), Tryptomer®, Tryptizol®, Laroxyl®, 
Saroten®, Sarotex® Lentizol®, Endep® 
Anagrelide 
Agrylin®, Xagrid® 
Apomorphine 
Apokyn®, Ixense®, Spontane®, Uprima® 
Aripiprazole 
Abilify®, Aripiprex® 
Arsenic trioxide 
Trisenox® 
Artenimol+piperaquine 
Eurartesim® 
Asenapine 
Saphris®, Sycrest® 
Astemizole (Removed from Market) 
Hismanal® 
Atazanavir 
Reyataz® 
Atomoxetine 
Strattera® 
Azithromycin 
Zithromax®, Zmax® 
Bedaquiline 
Sirturo® 
Bepridil (Removed from Market) 
Vascor® 
Bortezomib 
Velcade®, Bortecad® 
Bosutinib 
Bosulif® 
Ceritinib 
Zykadia® 
Chloral hydrate 
Aquachloral®, Novo-Chlorhydrate®, Somnos®, Noctec®, Somnote® 
Chloroquine 
Aralen® 
Chlorpromazine 
Thorazine®, Largactil®, Megaphen® 
Cilostazol 
Pletal® 
Ciprofloxacin 
Cipro®, Cipro-XR®, Neofloxin® 
Cisapride (Removed from Market) 
Propulsid® 
Citalopram 
Celexa®, Cipramil® 
Clarithromycin 
Biaxin®, Prevpac® 
Clomipramine 
Anafranil® 
Clozapine 
Clozaril®, Fazaclo®, Versacloz® 
Cocaine 
Cocaine 
Crizotinib 
Xalkori® 

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APPENDIX 8. LIST OF DRUGS KNOWN TO PROLONG QT/QTC 
INTERVAL (CONTINUED) 
LIST OF DRUGS KNOWN TO PROLONG QT/QTc INTERVAL 
Generic Name 
Brand Names (Partial List) 
Cyamemazine (cyamepromazine) (Only on 
Non-US Market) 
Tercian® 
Dabrafenib 
Tafinlar® 
Dasatinib 
Sprycel® 
Degarelix 
Firmagon® 
Delamanid (Only on Non-US Market) 
Deltyba® 
Desipramine 
Pertofrane®, Norpramine® 
Dexmedetomidine 
Precedex®, Dexdor®, Dexdomitor® 
Diphenhydramine 
Benadryl®, Nytol®, Unisom®, Sominex®, Dimedrol®, Daedalon® 
Disopyramide 
Norpace® 
Dofetilide 
Tikosyn® 
Dolasetron 
Anzemet® 
Domperidone (Only on Non-US Market) 
Motilium®, Motillium®, Motinorm Costi®, Nomit® 
Donepezil 
Aricept® 
Doxepin 
Sinequan®, Silenor®, Aponal®, Adapine®, Doxal®, Deptran®, 
Sinquan® 
Dronedarone 
Multaq® 
Droperidol 
Inapsine®, Droleptan®, Dridol®, Xomolix® 
Eribulin mesylate 
Halaven® 
Erythromycin 
E.E.S.®, Robimycin®, EMycin®, Erymax®, Ery-Tab®, Eryc Ranbaxy®, 
Erypar®, Eryped®, Erythrocin Stearate Filmtab®, Erythrocot®, E-
Base®, Erythroped®, Ilosone®, MY-E®, Pediamycin®, Zineryt®, 
Abboticin®, Abboticin-ES®, Erycin®, PCE Dispertab®, Stiemycine®, 
Acnasol®, Tiloryth® 
Escitalopram 
Cipralex®, Lexapro®, Nexito®, Anxiset-E® (India), Exodus® (Brazil), 
Esto® (Israel), Seroplex®, Elicea®, Lexamil®, Lexam®, Entact® 
(Greece), Losita® (Bangladesh), Reposil® (Chile), Animaxen® 
(Colombia), Esitalo® (Australia), Lexamil® (South Africa) 
Famotidine 
Pepcid®, Fluxid®, Quamatel® 
Felbamate 
Felbatol® 
Fingolimod 
Gilenya® 
Flecainide 
Tambocor®, Almarytm®, Apocard®, Ecrinal®, Flécaine® 
Fluconazole 
Diflucan®, Trican® 
Fluoxetine 
Prozac®, Sarafem®, Fontex® 
Foscarnet 
Foscavir® 
Furosemide (frusemide) 
Lasix®, Fusid®, Frumex® 
Galantamine 
Reminyl®, Nivalin®, Razadyne-ER®, 
Gatifloxacin (Removed from Market) 
Tequin® 
Gemifloxacin 
Factive® 
Granisetron 
Kytril®, Sancuso®, Granisol® 

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APPENDIX 8. LIST OF DRUGS KNOWN TO PROLONG QT/QTC 
INTERVAL (CONTINUED) 
LIST OF DRUGS KNOWN TO PROLONG QT/QTc INTERVAL 
Generic Name 
Brand Names (Partial List) 
Grepafloxacin 
Raxar® 
Halofantrine 
Halfan® 
Haloperidol 
Haldol® (US & UK), Aloperidin®, Bioperidolo®, Brotopon®, Dozic®, 
Duraperidol® (Germany), Einalon S®, Eukystol®, Halosten®, 
Keselan®, Linton®, Peluces®, Serenace®, Serenase®, Sigaperidol® 
Hydrochlorothiazide 
Apo-Hydro®, Aquazide H®, BP Zide®, Dichlotride®, Hydrodiuril®, 
HydroSaluric®, Hydrochlorot®, Microzide®, Esidrex®, Oretic® 
Hydrocodone - ER 
Hysingla™ ER, Zohydro ER 
Hydroxychloroquine 
Plaquenil®, Quineprox® 
Hydroxyzine 
Atarax®, Vistaril®, Aterax®, Alamon®, Durrax®, Equipose®, 
Masmoran®, Orgatrax®, Paxistil® Quiess®, Tran-Q®, Tranquizine® 
Ibutilide 
Corvert® 
Iloperidone 
Fanapt®, Fanapta®, Zomaril® 
Imipramine (melipramine) 
Tofranil® 
Indapamide 
Lozol®, Natrilix®, Insig® 
Isradipine 
Dynacirc® 
Itraconazole 
Sporanox®, Onmel® 
Ivabradine 
Procoralan®, Coralan®, Corlentor®, Coraxan®, Ivabid®, Bradia® 
Ketoconazole 
Nizoral®, Sebizole®, Ketomed®, Keton® 
Lapatinib 
Tykerb®, Tyverb® 
Lenvatinib 
Lenvima® 
Leuprolide 
Lupron®, Eligard®, Viadur®, Carcinil®, Enanton®, Leuplin®, Lucrin®, 
Procren®, Prostap® and others 
Levofloxacin 
Levaquin®, Tavanic® 
Levomepromazine (Only on Non-US 
Market) 
Nosinan®, Nozinan®, Levoprome® 
Levomethadyl (Removed from Market) 
Orlaam® 
Lithium 
Eskalith®, Lithobid® 
Mesoridazine (Removed from Market) 
Serentil® 
Methadone 
Dolophine®, Symoron®, Amidone®, Methadose®, Physeptone®, 
Heptadon® 
Metoclopramide 
Reglan®, Afipran®, Maxolon®, Cerucal®, Clopamon®, Clopra®, 
Maxeran®, Maxolon®, Metozolv®, Plasil®, Pramin®, Primperan®, 
Perinorm® 
Metronidazole 
Flagyl® and many others 
Mifepristone 
Korlym®, Mifeprex® 
Mirabegron 
Myrbetriq® 
Mirtazapine 
Remeron 
Moexipril/HCTZ 
Uniretic®, Univasc® 
Moxifloxacin 
Avelox®, Avalox®, Avelon® 

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APPENDIX 8. LIST OF DRUGS KNOWN TO PROLONG QT/QTC 
INTERVAL (CONTINUED) 
LIST OF DRUGS KNOWN TO PROLONG QT/QTc INTERVAL 
Generic Name 
Brand Names (Partial List) 
Nelfinavir 
Viracept® 
Nicardipine 
Cardene® 
Nilotinib 
Tasigna® 
Norfloxacin 
Noroxin®, Ambigram® 
Nortriptyline 
Pamelor®, Sensoval®, Aventyl®, Norpress®, Allegron®, Noritren®, 
Nortrilen® 
Ofloxacin 
Floxin® 
Olanzapine 
Zyprexa®, Zydis®, Relprevv® 
Ondansetron 
Zofran®, Anset®, Ondemet®, Zuplenz®, Emetron®, Ondavell®, 
Emeset®, Ondisolv®, Setronax® 
Osimertinib 
Tagrisso® 
Oxaliplatin 
Eloxatin® 
Oxytocin 
Pitocin®, Syntocinon® 
Paliperidone 
Invega®, Xepilon® 
Panobinostat 
Farydak® 
Pantoprazole 
Protonix® and others 
Papaverine HCl 
none 
Paroxetine 
Paxil®, Aropax®, Pexeva®, Seroxat®, Sereupin® 
Pasireotide 
Signifor® 
Pazopanib 
Votrient® 
Pentamidine 
Pentam® 
Perflutren lipid microspheres 
Definity® 
Pimozide 
Orap® 
Pipamperone (Only on Non-US Market) 
Dipiperon (E.U), Propitan (Japan) 
Posaconazole 
Noxafil®, Posamol® 
Probucol (Removed from Market) 
Lorelco® 
Procainamide 
Pronestyl®, Procan® 
Promethazine 
Phenergan® 
Propofol 
Diprivan®, Propoven® 
Quetiapine 
Seroquel® 
Quinidine 
Quinaglute®, Duraquin®, Quinact®, Quinidex®, Cin-Quin®, Quinora® 
Quinine sulfate 
Qualaquin® 
Ranolazine 
Ranexa®, Ranozex® 
Rilpivirine 
Edurant®, Complera®, Eviplera® 
Risperidone 
Risperdal® 
Ritonavir 
Norvir® 
Roxithromycin (Only on Non-US Market) Rulide®, Xthrocin®, Roxl-150®, Roxo®, Surlid®, Rulide®, Biaxsig®, 
Roxar®, Roximycinv®, Roxomycin®, Rulid®, Tirabicin®, Coroxin® 

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APPENDIX 8. LIST OF DRUGS KNOWN TO PROLONG QT/QTC 
INTERVAL (CONTINUED) 
LIST OF DRUGS KNOWN TO PROLONG QT/QTc INTERVAL 
Generic Name 
Brand Names (Partial List) 
Saquinavir 
Invirase®(combo) 
Sertindole (Only on Non-US Market) 
Serdolect®, Serlect® 
Sertraline 
Zoloft®, Lustral®, Daxid®, Altruline®, Besitran®, Deprax®, Elrval®, 
Emergen®, Gladem®, Implicane®, Sedoran®, Sealdin®, 
SerivoLowfin®, Stimuloton®, Tresleen®, Sertralin Bluefish® 
Sevoflurane 
Ulane®, Sojourn® 
Solifenacin 
VESIcare® 
Sorafenib 
Nexavar® 
Sotalol 
Betapace®, Sotalex®, Sotacor® 
Sparfloxacin (Removed from Market) 
Zagam® 
Sulpiride (Only on Non-US Market) 
Dogmatil®, Dolmatil®, Eglonyl®, Espiride®, Modal®, Sulpor® 
Sunitinib 
Sutent® 
Tacrolimus 
Prograf®, Prograf®, Advagraf®, Protopic® 
Tamoxifen 
Nolvadex®(discontinued 6/13), Istubal®, Valodex® 
Telaprevir 
Incivo® 
Telavancin 
Vibativ® 
Telithromycin 
Ketek® 
Terfenadine (Removed from Market) 
Seldane® 
Tetrabenazine 
Nitoman®, Xenazine® 
Thioridazine 
Mellaril®, Novoridazine®, Thioril® 
Tizanidine 
Zanaflex®, Sirdalud® 
Tolterodine 
Detrol®, Detrusitol® 
Toremifene 
Fareston® 
Torsemide 
Demadex®, Diuver®, Examide® 
Trazodone 
Desyrel® (discontinued 6/13), Oleptro®, Beneficat®, Deprax®, 
Desirel®, Molipaxin®, Thombran®, Trazorel®, Trialodine®, Trittico®, 
Mesyrel® 
Trimipramine 
Surmontil®, Rhotrimine®, Stangyl® 
Tropisetron (Only on Non-US Market) 
Navoban®, Setrovel® 
Vandetanib 
Caprelsa® 
Vardenafil 
Levitra® 
Vemurafenib 
Zelboraf® 
Venlafaxine 
Effexor®, Efexor® 
Voriconazole 
VFend® 
Vorinostat 
Zolinza® 
Ziprasidone 
Geodon®, Zeldox® 
 

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APPENDIX 9. MANAGEMENT OF TUMOR LYSIS SYNDROME 
Prior studies with the CDK inhibitors, flavopiridol and dinaciclib have shown that these drugs 
can cause severe and potentially life-threatening TLS in patients with CLL. The Investigator 
must assess the risk of TLS for each patient based on the tumor type, extent of disease and 
patient factors such as comorbidities, in particular renal function, and age. 
All subjects enrolled in this study, even those considered at low risk for TLS, must take 
prophylaxis. 
Guidance for TLS risk assessment, prophylaxis, and monitoring, based on the recommendations 
for CLL/SLL patients in the Venclexta [US Prescribing Information] Rev 2022, are provided in 
Table 24.  Patients with B-cell malignancies should be assessed for low, medium, or high risk for 
TLS, with prophylaxis and monitoring guidance as per Table 24.  
Patients with AML should be assessed for low, intermediate, or high risk of TLS, as defined in 
Figure 3. Additional considerations, prophylaxis, and monitoring of TLS in AML patients are as 
follows: 
• All AML subjects should have white blood cell count less than 25 × 109/L prior to initiation 
of venetoclax; cytoreduction (e.g., with hydroxyurea) prior to venetoclax treatment may be 
required if white blood cell counts greater than 25 × 109/L or lower than this cutoff but 
rapidly rising counts. 
• Prior to first dose of venetoclax, provide all patients with prophylactic measures including 
adequate hydration and anti-hyperuricemic agents (see Table 24) and continue during ramp-
up phase. 
• Blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) should be 
assessed prior to initiation of treatment with venetoclax, and pre-existing abnormalities 
corrected. 
• Monitor blood chemistries for TLS at pre-dose, 6 to 8 hours after each new venetoclax dose 
during ramp-up, and 24 hours after reaching final ramp-up dose (i.e., pre-dose on Day 3 in 
Cohorts 12–25). 
• For patients with risk factors for TLS (e.g., circulating blasts, high burden of leukemia 
involvement in bone marrow, elevated pretreatment lactate dehydrogenase [LDH] levels, or 
reduced renal function), consider additional measures, including increased laboratory 
monitoring. 
 

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Table 24: 
Guidelines for Prophylaxis and Monitoring for Patients with CLL/SLL and 
other B-cell Malignancies at Risk of TLS 
RISK 
Tumor/CLL 
Leukemic Burden 
Prophylaxis 
Hospital setting and 
biochemical monitoring 
 
 
Hydration 
Anti-
hyperuricemic 
therapy 
 
LOW 
All LN <5cm 
AND  
ALC <25 × 109/L 
Oral 1.5 – 2.0 L 
Allopurinol 
starting ≥2 days 
before treatment  
Outpatient 
• TLS blood panel 
monitoring* 
For each new dose: 
o pre-first dose; 6 to 
8 hr, and 24 hr  
After reaching final 
ramp up dose: 
o pre-dose only 
MEDIUM ANY LN 5 to <10 cm  
OR  
ALC ≥25 × 109/L 
Oral 1.5 – 2.0 L 
and consider 
intravenous  
(150 to 
200 mL/hr) 
Allopurinol 
starting ≥2 days 
before treatment  
Outpatient, but consider 
hospitalization based on 
age or renal function 
(creatinine clearance 
<80 ml/min) 
• TLS blood panel 
monitoring* 
o pre-first dose; 6 to 
8 hr, and 24 hr  
o for subsequent 
ramp-up doses: 
pre-dose 
HIGH 
ANY LN ≥10 cm 
OR  
ALC ≥25 × 109/L 
AND any LN ≥10 cm 
Oral 1.5 – 2.0 L 
and intravenous  
(150 to 
200 ml/hr) 
Allopurinol 
starting ≥2 days 
before treatment or 
consider 
rasburicase if 
baseline uric acid 
above ULN 
Inpatient for 24 hours post 
first dose  
• TLS blood panel 
monitoring* 
o pre-first dose; 6 to 
8 hr, and 24 hr  
Outpatient 
o for subsequent 
ramp-up doses: 
pre-dose; 6 to 8 hr, and 
24 hr  
Abbreviations: ALC = absolute lymphocyte count; LN = lymph node; TLS = tumor lysis syndrome; 
ULN = upper limit of normal. 
*Sampling timepoints ±30 minute window permitted. 
TLS blood chemistry panel must include potassium, uric acid, phosphorus, calcium, and 
creatinine. 

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Figure 3: 
TLS Risk Assessment for AML 
 
 
TLS risk assessment for acute leukemia. Classification of acute myeloid leukemia depends on 
white blood cell (WBC) counts and relative lactate dehydrogenase (LDH) levels to upper limit of 
normal (ULN) (adapted from Cairo 2010). 
 

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APPENDIX 10. CAIRO-BISHOP CRITERIA FOR DIAGNOSIS OF 
TUMOR LYSIS SYNDROME 
For a diagnosis of laboratory tumor lysis syndrome (TLS), 2 or more of the metabolic 
abnormalities shown in Table 25 must be present during the same 24-hour period within 3 days 
before the start of therapy, or up to 7 days after. Clinical TLS requires the presence of laboratory 
TLS plus an increased creatinine, seizures, cardiac dysrhythmia, or death. 
Table 25: 
Definitions of Laboratory and Clinical Tumor Lysis Syndrome 
Hyperuricemia 
Uric acid >8.0 mg/dL 
(475.8 μmol/L) in adults or above 
the ULN for age in children 
 
Hyperphosphatemia 
Adults: phosphorus >4.5 mg/dL 
(1.5 μmol/L)  
Children: phosphorus >6.5 mg/dL 
(2.1 μmol/L) 
 
Hyperkalemia 
Potassium >6.0 mmol/L 
Cardiac dysrhythmia or sudden 
death probably or definitely caused 
by hyperkalemia 
Hypocalcemia 
Corrected calcium <7.0 mg/dL 
(1.75 mmol/L) or ionized calcium 
<1.12 (0.3 mmol/L)a 
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(tetany, paresthesias, muscle 
twitching, carpopedal spasm, 
Trousseau’s sign, Chvostek’s sign, 
laryngospasm, or bronchospasm), 
hypotension, or heart failure 
probably or definitely caused by 
hypocalcemia 
Acute kidney injuryb 
Not applicable 
Increase in serum creatinine level 
of 0.3 mg/dL (26.5 μmol/L) (or 
single value >1.5 times the ULN of 
the age-appropriate range if no 
baseline creatinine measure is 
available) or the presence of 
oliguria, defined as an average 
urine output of <0.5 ml/kg/hr for 
6 hr 
Abbreviations: hr = hour; TLS = tumor lysis syndrome; ULN = upper limit of normal. 
a The corrected calcium level in mg/dL = measured calcium level in mg/dL + 0.8 × (4 – albumin g/dL). 
b Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg/dL (26.5 μmol/L) or a period of oliguria 
lasting 6 hr or more. By definition, if acute kidney injury is present, the patient has clinical TLS. See Levin et al for data about 
acute kidney injury. 
Reference: Howard 2011. 
 
Metabolic Abnormality 
Criteria for Classification of 
Laboratory TLS 
Criteria for Classification of 
Clinical TLS 

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